Note: Descriptions are shown in the official language in which they were submitted.
WO 2021/176434 PCT/IB2021/052858
CpG-Adjuvanted SARS-CoV-2 VIRUS VACCINE
FIELD OF THE INVENTION
The disclosure relates to CpG-adjuvanted SARS-CoV-2 vaccines and compositions
and methods for
producing said vaccines and administering the vaccines to subjects for the
generation of an anti-SARS-
CoV-2 immune response.
BACKGROUND OF 'THE INVENTION
SARS-CoV-2 (hereinafter the -virus") was detected for the first time in China
around November 2019.
Since then, the virus has caused a global pandemic. The natural reservoir are
bats and the virus belongs
to the Coronaviridae family, genus Betacoronavirus (betaCoV). The virus has a
ssRNA genome
composed of 29,903 bp (Wuhan-Hu-1: Genbank Reference sequence: NC_045512.2),
which encode a
9,860 amino acid polyprotein, comprising 25 non-structural proteins and 4
structural proteins: spike
(S), envelope (E), membrane (M) and nucleocapsid (N) proteins. The virus
particle has a variable
diameter of between 60 and 140 nm. It is enveloped and sensitive to UV, heat,
and lipid solvents. It has
89% nucleotide sequence identity with bat SARS-like-CoVZXC21 and 82%
nucleotide sequence
identity with human SARS-CoV (Chan et al. 2020). Evidence suggests that this
virus spreads when an
infected person coughs small droplets - packed with the virus - into the air.
These can be breathed in,
or cause an infection if one touches a surface they have landed on, then the
eyes, nose or mouth. In
addition, other vectors may exist, and the virus may be transmitted by blood
transfusion,
transplacentally, and through sexual transmission. Though infection with SARS-
CoV-2 may result in
only mild symptoms, such as, typically, a fever and a cough, or even be
asymptomatic; in the other
extreme, it can be fatal. The key symptoms are usually high temperature, cough
and breathing
difficulties. There is currently no specific treatment or vaccine for the
virus, and the only preventative
methods involve social distancing. SARS-CoV-2 presents a substantial public
health threat. The
Imperial College COVID-19 (disease caused by SARS-CoV-2) Response Team
published in March 16,
2020, a report evaluating all possible methods available to stop or delay the
spread of the virus, which
could ultimately lead to the break-down of the healthcare system and hundreds
of thousands of deaths
in the UK alone. The report stated that only population-wide social distancing
has a chance to reduce
effects to manageable levels and these measures need to be followed until a
vaccine is available. This
recommendation would mean for most of the population quarantine for at least
18 months. The report
concluded that a mass-producible vaccine is the only option to stop this
pandemic, other than a
willingness to sacrifice the elderly population. In view of the dramatic
situation, there is an absolute
urgent need for an effective vaccine against SARS-CoV-2 as fast as possible.
Furthermore, various
escape mutants have emerged (e.g. UK_B.1.1.7; South African_B.1.351;
Californian_B.1.427/B .1.429
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and Brazilian_P.1 variants, see also figure 2) which further worsen the
situation and thus addressing
this unfortunate development needs to be addressed as well.
SUMMARY OF TIIE INVENTION
Accordingly, the present invention provides an inactivated whole virus SARS-
CoV-2 vaccine. Multiple
SARS-CoV-2 vaccines are in development, including vectored vaccines, whole-
virion inactivated
vaccines, and recombinant protein vaccines. Although mRNA or DNA vaccines or
vectored vaccine
candidates elicit T cell responses without adjuvants, adjuvants may be
important for subunit and
inactivated vaccines to increase their immunogenicity. Furthermore, a major
challenge during rapid
development is to avoid safety issues both by thoughtful vaccine design and by
thorough evaluation in
a timely manner. With regard to a SARS-CoV-2 vaccine, safety concerns have
been raised in relation
to potential immune-mediated disease enhancement. There is evidence for
disease enhancement in
vaccinated animals after challenge with live virus in multiple studies with
SARS¨CoV-1 vaccine
candidates, including an alum-adjuvanted whole virus inactivated vaccine
candidate. In mice,
immunopathology induced by SARS-CoV-1 was considered a consequence of a
dominant Th2 type
response to the vaccine antigens (Tseng C-T et al. 2012 Immunization with SARS
Coronavirus
Vaccines Leads to Pulmonary Immunopathology on Challenge with the SARS Virus.
PlosOne
7(4):e35421). This was not observed after including other adjuvants (e.g. CpG)
in the vaccine or other
vaccine formulations known to drive immune responses towards ml. Insofar as an
inactivated vaccine
approach has been contemplated, the use of typical inactivating agents (e.g.
formaldehyde) under
standard conditions may have drawbacks, such as, particularly, destruction of
native epitopes, which
hinder development of an effective vaccine candidate. The present invention
aims to address these
problems and thus to produce a safe and effective whole-virus inactivated SARS-
CoV-2 vaccine that
overcomes the drawbacks of the prior art.
Thus in one aspect, the present invention provides a SARS-CoV-2 vaccine
comprising an inactivated
SARS-CoV-2 particle in combination with cytidine-phospho-guanosine (CpG) and
alum
adjuvantation. As mentioned above, the selection of an appropriate adjuvant or
adjuvants for the SARS-
CoV-2 vaccine may be of critical importance. Even though use of alum may not
necessarily lead to Th2
skewing in humans, the addition of CpG is believed to mitigate possible
vaccine-related disease
enhancement safety concerns. The addition of CpG may further allow for
significant reduction of the
antigen dose needed to achieve seroconversion in a subject (i.e. "dose
sparing"), another important
consideration in light of the urgent global need for a SARS-CoV-2 vaccine.
Lastly, addition of adjuvants
can help generating robust immune responses in subjects particularly
susceptible or vulnerable to
SARS-CoV-2 morbidity or mortality, i.e. immunocompromised, pregnant or elderly
subjects. Such
vaccine compositions are described in more detail below.
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In a preferred aspect, the surface of the inactivated SARS-CoV-2 particle in
the vaccine presents a
native conformation such that the vaccine is capable of generating
neutralizing antibodies against native
SARS-CoV-2 particles in a human subject. In particular, the present invention
aims to provide optimally
inactivated SARS-CoV-2 particles, which are incapable of replication and
infection of human cells, but
which retain immunogenic epitopes of viral surface proteins and are thus
suitable for generating
protective immunity in vaccinated subjects. By optimizing the inactivation
process (e.g. using beta-
propiolactone) and other steps in the production of the vaccine, including the
selection of an appropriate
adjuvant, a novel vaccine composition can be obtained that preserves a native
surface conformation of
SARS-CoV-2 particles and which reduces the risk of vaccine induced
immunopathology or
enhancement of disease. Thus in one aspect, the SARS-CoV-2 vaccine composition
comprises a beta-
propiolactone-inactivated SARS-CoV-2 particle, wherein the vaccine is capable
of generating
neutralizing antibodies against native SARS-CoV-2 particles in a human
subject, preferably wherein a
native surface conformation of the SARS-CoV-2 particle is preserved in the
vaccine.
In a further particular aspect, the inventions aims to provide an optimal
combination of optimally
inactivated (e.g. beta-propiolactone-inactivated) SARS-CoV-2 particles, which
are incapable of
replication and infection of human cells, but which retain immunogenic
epitopes of viral surface
proteins and are thus suitable for generating protective immunity in
vaccinated subjects. By an optimal
combination of inactivated SARS-CoV-2 particles also in combination with alum
and CpG
adjuvantation, an improved vaccine composition can be obtained that is capable
of generating
neutralizing antibodies against native SARS-CoV-2 particles and/or other
immunological responses in
a human subject that are able to protect partly or fully more than 50%,
preferably more than 60%, more
than 70%, more than 80%, more than 90% of said vaccinated human subjects.
Each of the limitations of the invention can encompass various embodiments of
the invention. It is
therefore anticipated that each of the limitations of the invention involving
any one element or
combinations of elements can be included in each aspect of the invention. This
invention is not limited
in its application to the details of construction and the arrangement of
components set forth in the
following description or illustrated in the drawings. The invention is capable
of other embodiments and
of being practiced or of being carried out in various ways.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings are not intended to be drawn to scale. The figures
are illustrative only and
are not required for enablement of the disclosure. For purposes of clarity,
not every component may be
labeled in every drawing. In the drawings:
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Figure 1. The process for production of the inactivated SARS-CoV-2 vaccine of
the current invention.
Steps include cell buildup of Vero host cells, infection of Vero cells with
SARS-CoV-2, virus harvest.
DNA reduction, primary inactivation, purification, optional secondary
inactivation and formulation
with adjuvant. The virus may be formulated with or without aluminium
hydroxide. The CpG adjuvant
may be included in the same vial with the virus (and optional alum) or mixed
with the virus before
administration.
Figure 2. During the course of the SARS-CoV-2 pandemic, SARS-CoV-2 genomic
sequences from
isolates from around the world have been reported including the recent new
variants or lineages such
as the UK B 1.1.7, Brazilian P1, Californian B.1.427/B .1.429 and South
African B.1.351 lineages. The
accession numbers and origins of complete SARS-CoV-2 genomic sequences are
provided in tabular
form, along with accession numbers for the corresponding orflab polyprotein
and S protein, when
available (- or no entry = not available).
Figure 3. A preferred set-up for the sucrose gradient centrifugation used as a
polishing step for the
SARS-CoV-2 vaccine of the invention.
Figure 4. Total IgG in response to SARS-CoV-2 vaccine. Coating antigens: Si
(A), receptor binding
domain of spike protein (B) and nucleoprotein (C). Endpoint titer: absorbance
of 3-fold the blank used
as cut-off (dashed line).
Figure 5. IgG1 and IgG2a titers in response to SARS-CoV-2 vaccine adjuvanted
with alum alone and
alum/CpG 1018. Antibody titers specific to SI protein were determined by
ELISA. The concentrations
were determined by comparison with a mAb subclass standard curve.
Figure 6. Neutralizing titers in response to SARS-CoV-2 vaccine. The tested
mouse sera were collected
at d35. Neutralizing response in the presence of alum/CpG 1018 observed to be
in the range of plasma
from convalescent donors positive for SARS-CoV-2 (NIBSC 20/162; pooled sera
from three donors).
Figure 7. Production process delivers high density and intact spike proteins.
Shown are electron
micrographs of the SARS-CoV-2 inactivated drug substance produced according to
Example 1. About
1-1.5 107viral particles per AU.
Figure 8. Comparison of Size-Exclusion-Chromatography and SDS-PAGE profiles of
SARS-CoV-2
and JEV drug substance. High purity (>95%) according to SDS-PAGE (silver
stain, reduced) and
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monomer virus (>95%) according to SE-HPLC. Difference in retention time due to
different virus
particle size (JEV (IXIARO) about 50nm, SARS-CoV2 about 100nm).
Figure 9. Study design for NIIP challenge study. Three groups of 8 animals
each; Two dose groups for
SARS-CoV-2 vaccine (10 AU & 40 AU, formulated with 0.5 mg/dose Ar+ and 1 mg
CpG 1018 per
dose added directly before administration) and a placebo group (DPBS). The
SARS-CoV-2 challenge
strain is BetaCoV/France/IDF/0372/2020 (Maisonmasse et al., Hydroxychloroquine
use against SARS-
CoV-2 infection in non-human primates, 2020, Nature 585:584-587). Methods and
timing of testing:
Hematology on d-28, dO, d7, d14, d21, d28, d35, d47, d49, d50, d51, d54, d62.
Ab response (ELISA,
IFA) on d-28, dO, d14, d21, d28, d35, d47, d54, d62. T cell response (ICS,
ELISPOT) on d-28, dO, d14,
d35, d54, d62. Cytokine response (LUMINEX) on d47, d49, d50, d51, d54, d62.
SWABS (viral load
(qRT-PCR-genomic + subgenomic): nasal & tracheal swabs on d35, d49, d50, d51,
d54, d57, d62; rectal
swabs at baseline and on d2, d7, d15. BAL viral load (qRT-PCR-genomic -h
subgenomic). d50.
Euthanasia: lung harvest, viral load (qRT-PCR - genomic + subgenomic): d54,
d62. CT scans: d35,
d50, d57.
Figure 10. Phase 1/2 clinical study: a blinded, randomized, dose-escalation
study. Study Population:
150 healthy volunteers (50 subjects per dose group) aged 18 to 55 years.
Dosage: two vaccinations (D1,
D22; also referred to as DO, D21), low (-3 AU), medium (-10 AU) and high (-40
AU) dose.
Immunization route: i.m.
Figure 11. Study design for a non-inferiority pivotal phase 3 immunogenicity
trial for initial licensure.
Vaccine efficacy determined by demonstrating non-inferior neutralizing
antibody titers between SARS-
CoV-2 vaccine of the invention and a licensed COVID-19 vaccine for which
efficacy has been
established.
Figure 12. Outline of the final SARS-CoV-2 manufacturing process-the fully
industrialized
production process.
Figure 13: Counts of residues within the footprints of 33 neutralizing mAbs,
or respectively clusters
13, 4, 10, 2, 1, 3. Listed are residues within the footprint of neutralizing
mAbs and/or which are lineage
defining mutation positions for B.1.1.7, B.1.351 or P.1 (marked "x"). E.g.
K417 and E484 mutations
which are amino acid positions in the S-protein are only to be found in the
South African and Brazilian
lineages.
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Figure 14: SDS-PAGE, silver stain, of two samples of SARS-CoV-2 candidates
according to example
1 (iCELLIS 500 bioreactor, protamine sulfate precipitated, BPL inactivated).
The bands could be
clearly attributed to the three main viral proteins (Spike-protein, Membrane-
protein, Nucleoprotein) as
well as to background proteins from the host system.
Figure 15: SARS-CoV-2 Mutations within the Spike Protein of strain UK MIG457
(B.1.1.7 lineage)
and strain SA P2 (B.1.351 lineage) from PHE.
Figure 16: Immunogenicity of the vaccine candidate in cynomolgus macaques. A)
Plates were coated
with ectodomain of spike protein with a T4 trimerization domain. B) Plates
were coated with receptor
binding domain (RBD) of spike glycoprotein. C) Plates were coated with
nucleoprotein.
Figure 17: Neutralizing titers determined by SNT. The dashed line represents
the limit of detection
(LOD, SNT50 = 5). Samples with a SNT50 titer below 5 were imputed to 2.5
Figure 18: Genomic copies of SARS-CoV-2 RNA determined by RT-qPCR. A)
Nasopharyngeal
swabs. B) Tracheal swabs. The dashed lines represent the limit of detection
(LOD = 476 RNA
copies/mL) and limit of quantification (LOQ = 4760 RNA copies/mL). Samples
with RNA copies/mL
below 476 were imputed to 238.
Figure 19: Subgenomic copies of SARS-CoV-2 RNA determined by RT-qPCR. A)
Nasopharyngeal
swabs. B) Tracheal swabs. The dashed lines represent the limit of detection
(LOD = 749 RNA
copies/mL) and limit of quantification (LOQ = 7490 RNA copies/mL). Samples
with RNA copies/mL
below 749 were imputed to 375.
Figure 20: Analyses of bronchoalveolar lavage by RT-qPCR. A) Genomic RNA,
samples with RNA
copies/mL below 476 (LOD) were imputed to 238. B) Subgenomic RNA, samples with
RNA copies/mL
below 749 (LOD) were imputed to 375. The dashed lines represent the limit of
detection (LOD) and
limit of quantification (LOQ) in the respective assays.
Figure 21: Graphical presentation of GMTs for male and female rats for each
treatment group.
Placebo is square symbols (male: filled symbols, female: unfilled symbols) and
inactivated SARS-
CoV-2 vaccine is circular symbols (male: filled symbols, female: unfilled
symbols) over the course of
the study. Error bars indicate 95% confidence intervals (CI). GMT <50 were
imputed to 25.
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Figure 22: Graphical presentation of GMTs for each treatment group, data for
male and female rats
combined. Placebo is square symbols and inactivated SARS-CoV-2 vaccine is
circular sym. Error
bars indicate 95% confidence intervals (CI). GMT <50 were imputed to 25.
Figure 23: Plot of SARS-CoV-2 neutralizing antibodies (MNA50) over time by
dose groups per-
protocol analysis set (N=150). Day 1: low (N=51), medium (N=49), and high
(N=50). Day 8: low
(N=51), medium (N=49), and high (N=50). Day 22: low (N=50), medium (N=48), and
high (N=48).
Day 36: low (N=51), medium (N=48), and high (N=50). Graph shows GMT and 95%
CI. Scatter dots
are the actual distribution of neutralizing antibody titres.
Figure 24: Reverse cumulative distribution function for SARS-CoV-2
neutralizing antibody titres
(ND50) for day 36 by dose groups per protocol analysis set (N=150). Low dose
(N=51), medium dose
(N-48) and high dose (N-50).
Figure 25: Neutralization titer correlates with S-protein specific IgG.
Scatter plot between neutralizing
antibody titres ND50 (MNA) and IgG antibody titres (ELISA) per-protocol
analysis set (N=150).
Scatter plot shows correlation between results of ELISA (ELU/mL) and MNA
(ND50). Pearson
correlation coefficient (r) between ELISA (ELU/mL) and MNA(ND50) and P-value
for testing the
significance of correlation coefficient is also presented in the plot. Red
dotted lines present the limit of
detection for ELISA (50.3 ELU/mL) and MNA (ND50=58).
Figure 26: Plot of S-protein specific IgG antibody titers (ELISA) over time by
dose groups per-protocol
analysis set (N=150). Day 1: low (N=51), medium (N=49), and high (N=50). Day
8: low (N=51),
medium (N=49), and high (N=50). Day 22: low (N=51), medium (N=49), and high
(N=50). Day 36:
low (N=51), medium (N=49), and high (N=50). Graph shows GMT and 95% CI.
Scatter dots are the
actual distribution of IgG antibody titres.
Figure 27: Plot of 1FN gamma spot forming units per 2x10^5 PBMC by dose groups
and assessment
days for panel 14 spike protein, full sequence (N=150). Dose groups comparison
(pvalue): day 1 (p =
0.321) and day 36 (p<0.001). Day 1: low (N=46), medium (N=43), and high
(N=44). Day 36: low
(N=44), medium (N=44), and high (N=45). The boxplots show the median, lower
quartile and upper
quartile. The horizontal line within each bar is the median and the plus sign
(+) represents the mean
value for each group. Scatter dots are the actual distribution of SFU per
2.5x10^5 PBMC within each
group.
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Figure 28: Plot of IFN gamma spot forming units per 2x10^5 PBMC by dose groups
and assessment
days for membrane protein (N=150). Dose groups comparison (pvalue): day 1
(p=0.704), day 36 (p-
0.014). Day 1: low (N=46), medium (N=43), and high (N=44). Day 36: low (N=44),
medium (N=44),
and high (N=45). The boxplots show the median, lower quartile and upper
quartile; the horizontal line
within each bar is the median and the plus (+) sign represents the mean value
for each group. Scatter
dots are the actual distribution of SFU per 2.5x10^5 PBMC within each group.
Figure 29: Plot of IFN gamma spot forming units per 2x10^5 PBMC by dose groups
and assessment
days for nucleocapsid (N=150). Dose groups comparison (pvalue): day 1
(p=0.378), day 36
(p=0.008). Day 1: low (N=46), medium (N=43), and high (N=44). Day 36: low
(N=44), medium
(N=44), and high (N=45). The boxplots show the median, lower quartile and
upper quartile. The
horizontal line within each bar is the median and the plus (+) sign represents
the mean value for each
group. Scatter dots arc the actual distribution of SFU per 2.5x10^5 PBMC
within each group.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention are directed to a SARS-CoV-2 vaccine or
immunogenic
composition comprising inactivated SARS-CoV-2 particles in combination with a
CpG adjuvant.
Typically, the inactivated SARS-CoV-2 particles are whole, inactivated
particles, i.e. the inactivated
virus particles are derived from whole native SARS-CoV-2 particles that have
been inactivated. As
used herein, "SARS-CoV-2" refers to the SARS-CoV-2 virus and "SARS-CoV-2
particles" typically
refers to whole SARS-CoV-2 viral particles, i.e. virions.
In one embodiment, the inactivated SARS-CoV-2 particles are combined with the
Thl response-
directing adjuvant CpG, preferably CpG 1018. As used herein, "CpG" refers to a
cytosine-phospho-
guanosine (CpG) motif-containing oligodeoxynucleotide (or CpG-ODN), e.g. which
is capable of
acting as a toll-like receptor 9 (TLR9) agonist. The CpG motif refers to an
unmethylated cytidine-
phospho-guanosine dinucleotide sequence, e.g. which is capable of binding to
TLR9. Thl response-
directing adjuvants such as CpG promote the induction of a predominantly T
helper type 1 (i.e. Thl)
immune response in an immunized subject (rather than a Th2 type response),
i.e. a -Thl-biased
response". The Thl- or Th2-directing properties of commonly used vaccines are
known in the art. It
has surprisingly been found that using an adjuvant that promotes a Thl
response, e.g., CpG 1018, can
improve immunogenicity of the vaccine and thus antiviral responses, as well as
reducing the risk of
disadvantageous effects such as immunopathology (which may result from a
predominantly Th2 type
response possibly due to hypersensitivity against viral components). In one
embodiment, the SARS-
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CoV-2 vaccine of the current invention also comprises the Th2-stimulating
adjuvant alum, which has a
known tendency for Th2 skewing in humans. Neutralizing antibodies, the
production of which is
critical for anti-viral immunity, are strongly stimulated by Th2-stimulating
adjuvants, such as e.g. alum.
Also important for anti-viral immunity are cellular immune responses, which
are only weakly
stimulated by alum. Delivered together, alum and 1111-inducing adjuvants, such
as CpG, can provide a
potent anti-viral response. In short, the use of CpG and alum together in a
vaccine formulation can
provide a more balanced immune response to antigens, including both humoral
and cellular
components, and may have less deleterious effects than alum alone with a
predominantly Th2 response.
In one embodiment, the CpG adjuvant comprised in the vaccine of the invention
is a class A, class B or
class C CpG (see Table A-1), preferably a class B CpG. Class B CpG molecules
include CpG 1018,
CpG 1826 and CpG 7909 (SEQ ID Nos: 4, 7 and 8, respectively; Table A-2). Most
preferred is CpG
1018.
Table A-1. Comparative features of CpG classes A, B and C (Campbell JD, 2017,
in Christopher B.
Fox (ed.), Vaccine Adjuvants: Methods and Protocols, Methods in Molecular
Biology, vol. 1494, DOI
10.1007/978-1-4939-6445-12).
Class Structural characteristics Immunological
characteristics
CpG-A Phosphodiester CpG motif(s) Strong pDC IFN-a
induction
Phosphorothioate poly-G at 5' and 3' Moderate pDC maturation
Forms aggregates Weak B cell activation
CpG-B Phosphorothioate backbone Strong B cell
activation
T-rich with CpG motifs Strong pDC maturation
Monomeric Weak pDC IFN-a
induction
CpG-C Phosphorothioate backbone Good pDC IFN-a
induction
5'-TCG, CpG motif in central palindrome Good pDC maturation
Forms duplexes Good B cell activation
IFN, intufcron; pDC. plasmacytoid dendritic ccll
Table A-2. Class B CpGs
Sequence SEQ ID NO:
CpG 1018 TGACTGTGAACGTTCGAGATGA 4
CpG 1826 TCCATGACGTTCCTGACGTT 7
CpG 7909 TCGTCGTTTTGTCGTTTTGTCGTT 8
CpG 1018 may be adsorbed onto alum and thus used as a combination adjuvant
that induces both Thl
and Th2 responses (as described in e.g. Tian et al. Oncotarget, 2017, Vol. 8,
(No. 28), pp: 45951-45964).
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Thus, in one embodiment, the CpG-adjuvanted vaccine composition of the
invention further comprises
aluminium (Al"), preferably in the form of an aluminium salt, e.g. aluminium
oxide, aluminium
hydroxide or aluminium phosphate, preferably aluminium hydroxide. A preferred
aluminium salt is the
aluminium hydroxide with reduced Cu content, e.g. lower than 1.25 ppb based on
the weight of the
vaccine composition, an adjuvant described in detail in W02013/083726 or
Schlegl et al., Vaccine 33
(2015) 5989-5996. In a preferred embodiment, the vaccine composition comprises
both CpG and Al",
i.e., the adjuvant is a combination or mixture of CpG and Al' I, preferably
CpG 1018 (SEQ ID NO: 4)
and Al" provided in the form of aluminium hydroxide (Al(OH)3). The presence of
Al' may reduce the
required dose of CpG, i.e., have a "dose-sparing" effect. In one embodiment,
the SARS-CoV-2 vaccine
is formulated with Al", and combined with a separate CpG-containing solution
directly before
vaccination of a subject; i.e. "bed-side mixing". In a preferred embodiment,
the two adjuvants are both
comprised in the formulation of the SARS-CoV-2 vaccine of the invention; i.e.
"single-vial
formulation".
In one embodiment, the Al":CpG weight/weight (w/w) ratio, preferably the Al"
provided in the form
of Al(OH)3:CpG 1018 (w/w) ratio, in the vaccine composition is about 1:10,
about 1:5, about 1:4, about
1:3, about 1:2, about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about
10:1, preferably between
about 1:3 and 3:1, more preferably between about 1:2 and 1:1, most preferably
about 1:2, even more
preferably 1:2 in humans. In this regard, the effects of CpG in mice and
humans are known to be very
different, in part due to different TLR9 receptors which respond differently
to CpG-DNA sequences as
well as unique cellular distribution patterns of TLR9 expression in mice and
humans (Chuang TS et al.
2002 Toll-like receptor 9 mediates CpG-DNA signaling. J Leukocyte Biol . (7
1)5 3 8 -544). Therefore,
the alum: CpG ratio giving an optimal response to any given antigen is likely
to differ, perhaps
substantially, in humans and mice. As referred to herein, the weight of the
alum component refers to
the weight of the Al' in the solution, regardless of what type of aluminium
salt is used. For example,
0.5 mg of Al" corresponds to 1.5 mg alum. In one embodiment, the amount alum
(Al") present in the
SARS-CoV-2 vaccine composition is between about 0.1 and 2 mg/mL, between about
0.2 and 1.5
mg/mL, between about 0.5 and 1.3 mg/mL, especially between about 0.8 to 1.2
mg/mL, most preferably
about 1 mg/mL, i.e., 0.5 mg/dose. In a preferred embodiment, the relatively
high amount of alum
(compared with currently licensed alum-adjuvanted vaccines) is used to ensure
complete binding of
antigen, as well as binding of at least a portion of the total CpG in the
formulation. In this regard, the
ratio of alum:CpG affects the amount of -free" &sorbed CpG, i.c., the CpG
which is not bound to alum
and/or antigen in the vaccine composition. In a preferred embodiment, the
amount of free (unbound)
CpG in the vaccine composition is greater than 10%, greater than 20%, greater
than 30%, greater than
40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%,
greater than 90%, greater
than 95%, preferably about 70% to 95%, most preferably about 80% to 90%, e.g.
by weight (based on
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the total weight of CpG in the vaccine composition). In particular, the alum:
CpG ratio should facilitate
a majority of the CpG content in -free" (desorbed) CpG: i.e., the CpG is not
bound to components of
the vaccine such that it remains in a depot. In a preferred embodiment, the
amount of free CpG versus
bound CpG is greater than 50%, greater than 60%, greater than 70%, greater
than 80%, greater than
85%, greater than 90%, preferably greater than between 70 to 90%, especially
between about 80 and
90%, e.g. by weight (i.e. the amount of free CpG by weight based on the total
weight of CpG in the
vaccine composition). In one embodiment, the amount of CpG in the SARS-CoV-2
vaccine
composition of the current invention is between about 0.25 and 6 mg/mL,
between about 0.5 and 3
mg/mL, between about 1 and 3 mg/mL, especially between about 1.5 to 2.5 mg/mL,
most preferably
about 2 mg/mL, i.e., 1 mg/dose. In an especially preferred embodiment, the the
SARS-CoV-2 vaccine
composition of the current invention is adjuvanted with 1 mg/mL Al3+ and 2
mg/mL CpG 1018; i.e., 0.5
mg Al' and 1 mg/mL CpG 1018 per dose.
In addition to the ratio of alum to CpG, different buffer systems may affect
the adsorption of CpG to
A13 and/or antigen in the vaccine composition. For example, the use of a Tris
buffer system in the
vaccine composition resulted in reduced free CpG (i.e. reduced desorption),
whereas a phosphate buffer
system allowed better desorption of CpG. In a particular example, a phosphate-
buffered formulation
containing 1 mg/mL Al3+ (aluminium hydroxide) and 2 mg/mL CpG 1018 (1:2 w/w
ratio) had only
about 10-20% bound CpG, i.e. about 80-90% free CpG. When formulated in
phosphate buffer, about
0.3 mg of CpG is adsorbed per mg of Al3+ (data not shown).
Typically, the adjuvant is combined with the inactivated SARS-CoV-2 particles
during manufacture of
the vaccine product, i.e. the manufactured vaccine product comprises the
adjuvant and is
sold/distributed in this form. In alternative embodiments the adjuvant may be
combined with the
inactivated SARS-CoV-2 particles at the point of use, e.g. immediately before
clinical administration
of the vaccine (sometimes referred to as "bedside mixing" of the components of
the vaccine). Thus the
present invention comprises both vaccine products comprising inactivated SARS-
CoV-2 particles and
an adjuvant as described herein, as well as kits comprising the individual
components thereof (e.g.
suitable for bedside mixing), and the combined use of the individual
components of the vaccine in
preventing or treating SARS-CoV-2 infection.
In some embodiments of the present invention, the SARS-CoV-2 particles are
inactivated without
substantially modifying their surface structure. In other words, a native
surface conformation of the
SARS-CoV-2 particles is retained in the inactivated virus particles. It has
surprisingly been found that
by optimizing an inactivation process, e.g. using beta-propiolactone,
infectivity of native SARS-CoV-
2 particles can be substantially abrogated, i.e., completely abolished,
without adversely affecting their
antigenicity and/or immunogenicity. Thus, the present invention provides in
one aspect an inactivated
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virus vaccine (e.g. a beta-propiolactone-inactivated virus vaccine) that
generates neutralizing antibodies
and/or protective immunity against SARS-CoV-2 infection.
In one embodiment, the SARS-CoV-2 particles are inactivated by a method that
preferentially targets
viral RNA. By this it is meant that e.g. the inactivation step modifies viral
RNA more than viral
proteins. Thus, the inactivated SARS-CoV-2 particles may comprise replication-
deficient viral RNA,
i.e. the viral RNA is modified in the inactivation step such that the
inactivated particles are incapable
of replicating. By utilizing an inactivation method that preferentially
targets viral RNA, the present
invention advantageously allows the preservation of immunogenic epitopes in
viral surface proteins.
Preferably, the inactivation method spares viral (surface) proteins relative
to viral RNA, e.g. the viral
surface proteins (e.g. the spike (S) protein) may comprise fewer or more
infrequent modifications
resulting from the inactivation step compared to viral RNA. For instance, a
lower proportion of amino
acid residues in the viral surface proteins (e.g. S protein) may be modified
by the inactivation step
compared to the proportion of modified nucleotide residues in the viral RNA.
In some embodiments,
the proportion of modified amino acid residues in the viral surface proteins
(e.g. S protein) may be at
least 5%, 10%, 20%, 30%, 50%, 70% or 90% lower than the proportion of modified
nucleotide residues
in the viral RNA. By "modifications" or "modified residues" it is meant to
refer to non-native residues
that are not present in the native SARS-CoV-2 particles, e.g. chemical
(covalent) modifications of such
residues resulting from the inactivation step.
In one embodiment, the viral RNA is inactivated by alkylation and/or
acylation, i.c. the modifications
in the SARS-CoV-2 inactivated particles comprise alkylated and/or acylated
nucleotide residues. In
some embodiments, the modifications are preferentially targeted to purine
(especially guanine)
residues, e.g. the SARS-CoV-2 inactivated particles comprise one or more
modified (e.g. alkylated or
acylated) guanine residues. In some cases, the inactivation step may lead to
cross-linking of viral RNA
with viral proteins, e.g. via guanine residues in the viral RNA. The
inactivation step may also introduce
nicks or strand breaks into viral RNA, e.g. resulting in fragmentation of the
viral genome.
Suitable alkylating and/or acylating agents arc known in the art. In one
cmbodimcnt, the inactivating
agent comprises beta-propiolactone, i.e. the vaccine comprises beta-
propiolactone-inactivated virus
particles. In any case, in a particular embodiment, beta-propiolactone (herein
referred to also as "BPL")
treatment is particularly preferred according to the present invention,
because it results in SARS-CoV-
2 particles, that are substantially inactive, but which retain high
antigenicity and immunogenicity-
against neutralizing epitopes present in native SARS-CoV-2. In particular, it
has been surprisingly
found that beta-propiolactone can be used to inactivate SARS-CoV-2 particles
with a minimum number
of protein modifications. For instance, as demonstrated in Examples 7 and 10
below, inactivation of
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SARS-CoV-2 particles using beta-propiolactone results in a much lower number
of modifications of
viral proteins compared to inactivation of influenza particles by beta-
propiolactone. Thus in beta-
propiolactone-inactivated SARS-CoV-2 particles, a native surface conformation
of the viral particles
can be preserved.
In a preferred embodiment of the invention, the viral RNA is inactivated in an
optimized manner, i.e.
such it is just sufficiently inactivated not to be infectious anymore but not -
over"-inactivated so that
numerous modification at different amino acids in particular at the S-protein
occur. In a further even
more preferred embodiment, the BPL inactivation not only sufficiently
inactivates (but not over-
inactivates) the SARS-CoV-2 virus but also just sufficiently inactivates
viruses that might be co-
enriched and co-cultured in the manufacturing process (see e.g. experimental
part). A particular hard
virus to inactivate that can co-culture and be co-enriched is PPV (porcine
parvovirus) - see experimental
part. The concentration of beta-propiolactone in the inactivation step may be
optimized to ensure
complete inhibition of viral replication whilst preserving the conformation of
surface proteins in the
virus. For instance, the concentration of beta-propiolactone in the
inactivation step may be e.g. 0.01 to
1% by weight, preferably 0.01 to 0.1% by weight, more preferably about 0.03%
by weight. A preferred
amount of BPL was found to be 500ppm where the SARS-CoV-2 virus but also other
concerning
viruses/impurities are inactivated whilst preserving (i.e. not modifying) most
of the amino acids of the
S-protein (i.e. only a few amino acids were shown to be modified at low
probability).
In some embodiments, the native SARS-CoV-2 particles may be contacted with
beta-propiolactone for
at least 5 hours, at least 10 hours, at least 24 hours or at least 4 days,
e.g. 5 to 24 hours or longer such
as 48 hours. The inactivation step may be performed at about 0 C to about 25
C, preferably about 4 C
or about 22 C, or e.g. 18 to 24 C. In one embodiment the inactivation step
(e.g. with beta-
propiolactone) is performed at 2 C to 8 C for 24 hours. The inactivation step
may optionally and
preferably be followed by a hydrolyzation step of the inactivating agent, as
is known in the art (which
may be performed e.g. at about 37 C+/- 2 C for a total time of 2.5 hours +/-
0.5 hours for beta-
propiolactone). Typically, longer incubation times and/or higher temperatures
in the inactivation step
may enhance viral inactivation, but may also lead to an increased risk of
undesirable surface
modifications of the viral particles, leading to reduced immunogenicity.
Therefore, the inactivation
step may be performed for e.g. the shortest time necessary in order to produce
a fully inactivated virus
particle. After completion of the hydrolysis, the inactivated viral solution
was in one embodiment
immediately cooled down to 5+3 C and stored there until inactivation was
confirmed by large volume
plaque assay and serial passaging assay.
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Beta-propiolactone inactivation of SARS-CoV-2 particles may preferentially
modify cysteine,
methionine and/or histidine residues. Thus in some embodiments, the
inactivated SARS-CoV-2 particle
comprises one or more beta-propiolactone-modified cysteine, methionine and/or
histidine residues.
IIovvever, in embodiments of the present invention, the beta-propiolactone-
inactivated SARS-CoV-2
particles show relatively few protein modifications. Thus, for example, an
inactivated SARS-CoV-2
particle in the vaccine may comprise fewer than 200, 100, 50, 30, 20, 15, 10,
9, 8, 7 or 6 beta-
propiolactone-modified amino acid residues. Preferably a spike (S) protein of
the inactivated SARS-
CoV-2 particle comprises fewer than 100, 50, 30, 20, 15, 10, 9, 8, 7 or 6 beta-
propiolactone-modified
amino acid residues. More preferably the inactivated SARS-CoV-2 particle or
spike protein thereof
comprises 20 or fewer, 15 or fewer, 10 or fewer, or 5 or fewer beta-
propiolactone-modified amino acid
residues. Most preferably the inactivated SARS-CoV-2 particle or spike protein
thereof comprises 1 to
100, 2 to 70, 3 to 50, 4 to 30, 5 to 25, 5 to 20, 10 to 20 or about 15 beta-
propiolactone-modified amino
acid residues.
In another embodiment, fewer than 20%, 15%, 10%, 5% or 4% of SARS-CoV-2
polypeptides are beta-
propiolactone-modified. For instance, 0.1 to 10%, 1 to 8%, 2 to 7% or about
3%, 4%, 5% or 6% of
SARS-CoV-2 polypeptides in the particle may be beta-propiolactone-modified.
Beta-propiolactone
modification of residues and/or polypeptides in the vaccine may be detected by
mass spectrometry, e.g.
using liquid chromatography with tandem mass spectrometry (LC-MS-MS), for
instance using a
method as described in Example 7 or Example 10. In such a method, the SARS-CoV-
2 particles may
be digested in order to fragment proteins into SARS-CoV-2 polypeptides for LC-
MS-MS analysis. The
digestion step may be performed by any suitable enzyme or combination of
enzymes, e.g. by trypsin,
chymotrypsin and/or PNGase F (peptide:N-glycosidase F), or by e.g. acid
hydrolysis. Preferably the
percentage of BPL-modified polypeptides detected by LC-MS-MS following
enzymatic digestion or
acid hydrolysis is: (a) trypsin digestion, 1 to 5%, 2 to 4% or about 3%; (b)
trypsin + PNGase F digestion,
1 to 5%, 2 to 4% or about 3%; (c) chymotrypsin, 1 to 10%, 3 to 8% or about 6%;
(d) acid hydrolysis,
1 to 6%, 2 to 5% or about 4%. In this context, a "beta-propiolactone-modified"
polypeptide means that
the polypeptide comprises at least one beta-propiolactone modification, e.g.
at least one beta-
propiolactone-modified residue.
In some embodiments, a spike (S) protein of the inactivated SARS-CoV-2
particle comprises a beta-
propiolactone modification at one or more of the following residues: 49, 146,
166, 177, 207, 245, 379,
432, 519, 625, 1029, 1032, 1058, 1083, 1088, 1101, 1159 and/or 1271, e.g. in
SEQ ID NO:3, or a
corresponding position in SEQ ID NO: 19, 21, 23, 25 or 27. Preferably the
inactivated SARS-CoV-2
particle comprises a beta-propiolactone modification at one or more of the
following residues: H49,
H146, C166, M177, H207, H245, C432, H519, H625, M1029, H1058, H1083, H1088,
H1101, H1159
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and/or H1271, e.g. in SEQ ID NO:3, or a corresponding position in SEQ ID NO:
19, 21, 23, 25 or 27.
In another embodiment, the inactivated SARS-CoV-2 particle comprises a beta-
propiolactone
modification at one or more of the following residues: H207, H245, C379, M1029
and/or C1032, e.g.
in SEQ ID NO:3, or a corresponding position in SEQ ID NO: 19, 21, 23, 25 or
27. By "a corresponding
position" it is meant a position in SEQ ID NO: 19, 21, 23, 25 or 27 that
aligns with position H207,
H245, C379, M1029 and/or C1032 in SEQ ID NO:3, e.g. when SEQ ID NO: 19, 21,
23, 25 or 27 is
aligned with SEQ ID NO:3 using a program such as NCBI Basic Local Alignment
Search Tool
(BLAST).
For instance, in some embodiments, the positions in SEQ ID NO: 19, 21, 23, 25
or 27 corresponding to
H207, H245, C379, M1029 and C1032 in SEQ ID NO:3 are shown below:
Seq ID
3 H207 H245 C379 M1029 C1032
19 H207 H244 C378 M1028 C1031
21 H207 H245 C379 M1029 C1032
23 H204 H242 C376 M1026 C1029
25 H207 H245 C379 M1029 C1032
27 H207 H245 C379 M1029 C1032
In some embodiments, a membrane (M) glycoprotein of the inactivated SARS-CoV-2
particle
comprises a beta-propiolactone modification at one or more of the following
residues: 125, 154, 155,
159 and/or 210, preferably H154, H155, C159 and/or H210, e.g. in SEQ ID NO:
29.
In some embodiments, a nucleocapsid (N) protein of the inactivated SARS-CoV-2
particle comprises a
beta-propiolactone modification at M234, es. in SEQ ID NO: 28.
In some embodiments, fewer than 30%, 20%, 10%, 5%, 3% or 1% of one or more of
the following
residues in the inactivated SARS-CoV-2 particles arc beta-propiolactone
modified: (i) in the spike (S)
protein, e.g. in SEQ ID NO:3, or a corresponding position in SEQ ID NO: 19,
21, 23, 25 or 27: residues
49, 146, 166, 177, 207, 245, 379, 432, 519, 625, 1029, 1032, 1058, 1083, 1088,
1101, 1159 and/or 1271;
preferably H49, H146, C166, M177, H207, H245, C432, H519, H625, M1029, H1058,
H1083, H1088,
H1101, H1159 and/or H1271; alternatively H207, H245, C379, M1029 and/or C1032;
(ii) in the
membrane (M) glycoprotein, e.g. in SEQ ID NO: 29: residues 125, 154, 155, 159
and/or 210; preferably
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H154, H155, C159 and/or H210; and/or (iii) M234 of the nucleocapsid (N)
protein, e.g. in SEQ ID NO:
28. In preferred embodiments, fewer than 30%, 20%, 10%, 5%, 3% or 1% of at
least 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or each of the above residues in
the inactivated SARS-CoV-
2 particles are beta-propiolactone modified. In this paragraph, the % of
modified residues is intended
to refer to the site occupancy, e.g. the ratio of modified to unmodified
peptide for the same modification
site normalized to the protein abundance as described in Example 7 or 10
below.
In another preferred embodiment, the proportion of beta-propiolactone-modified
residues (i.e. site
occupancy) at the following positions in the inactivated SARS-CoV-2 particles
is:
(i) in the spike (S) protein (e.g. of SEQ ID NO: 3, or a corresponding
position in SEQ ID NO: 19, 21,
23, 25 or 27):
(a) H207: less than 30%, preferably 0.01 to 25%; and/or
(b) H245: less than 10%, preferably 0.1 to 5%; and/or
(c) C379: less than 5%, less than 1% or less than 0.1%; and/or
(d) M1029: less than 5%, less than 1% or less than 0.1%; and/or
(e) C1032: less than 5%, less than 1% or less than 0.1%; and/or
(ii) in the membrane (M) glycoprotein (e.g. of SEQ ID NO: 29):
(f) H154: less than 5%, less than 1% or less than 0.1%; and/or
(g) H155: less than 10%, preferably 0.1 to 5%; and/or
(h) C159: less than 5%, less than 1% or less than 0.1%; and/or
(i) H210: less than 20%, preferably 0.1 to 10%; and/or
(iii) in the nucleocapsid (N) protein (e.g. of SEQ ID NO: 28):
(j) M234: less than 90%, less than 10% or less than 0.1%.
In another preferred embodiment, the proportion of beta-propiolactone-modified
residues (i.e. site
occupancy) at each of the following positions in the spike (S) protein (e.g.
of SEQ ID NO: 3, or a
corresponding position in SEQ ID NO: 19, 21, 23, 25 or 27) of the inactivated
SARS-CoV-2 particles
is:
(a) residues H49, H146, C166, H207, H519, M1029, H1083, H1088, H1101, H1159
and/or
H1271: less than 20%, preferably 0.01 to 10%, more preferably 0.1 to 5%;
and/or
(b) residues M177, C432, H625: less than 30%, preferably 0.1 to 20%, more
preferably 1 to
10%; and/or
(c) residues H245, H1058: less than 30%, preferably 0.1 to 20%, more
preferably 5 to 15%;
In some embodiments, the proportion of beta-propiolactone-modified amino acid
residues in the
inactivated SARS-CoV-2 particle (or spike (S) protein thereof) may be at least
5%, 10%, 20%, 30%,
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50%, 70% or 90% lower than the proportion of modified residues in a beta-
propiolactone-inactivated
influenza particle (or hemagglutinin (HA) or neuraminidase (NA) protein
thereof), e.g. in an influenza
particle that has been inactivated under similar conditions to the SARS-CoV-2
particle.
In an alternative embodiment, the viral RNA may be inactivated by treatment
with ultraviolet (UV)
light. UV treatment can be used to preferentially target RNA (compared to
polypeptides) in the viral
particles, resulting in e.g. modified nucleotides and/or fragmentation. In
some embodiments, UV
treatment can be combined with beta-propiolactone treatment to improve
inactivation of the virus, e.g.
a beta-propiolactone treatment step can be followed by a UV treatment step or
vice versa, or a UV
treatment step can be performed at the same time as the beta-propiolactone
treatment step.
In other embodiments, the native SARS-CoV-2 particles may be inactivated using
formaldehyde.
However, formaldehyde inactivation is typically less preferred in the present
invention, as it is less
suitable for preferentially targeting viral RNA while preserving immunogenic
epitopes in the viral
surface proteins.
Therefore, in preferred embodiments, the inactivation step(s) (especially when
using formaldehyde, but
also when using other inactivating agents such as e.g. beta-propiolactone) are
performed under mild
conditions in order to preserve surface antigen integrity, especially
integrity of the S protein.
In one embodiment, such a mild inactivation method comprises contacting a
liquid composition
comprising native SARS-CoV-2 particles with a chemical viral inactivating
agent (such as e.g. any of
the chemical inactivation agents as listed above or a combination thereof, for
instance formaldehyde or
preferably beta-propiolactone) in a container, mixing the chemical viral
inactivating agent and the liquid
composition comprising SARS-CoV-2 particles under conditions of laminar flow
but not turbulent
flow, and incubating the chemical viral inactivating agent and the liquid
composition comprising SARS-
CoV-2 particles for a time sufficient to inactivate the viral particles. The
mild inactivation step is
optionally performed in a flexible bioreactor bag. The mild inactivation step
preferably comprises five
or less container inversions during the period of inactivation. Preferably,
the mixing of the chemical
viral inactivating agent and the composition comprising native SARS-CoV-2
particles comprises
subjecting the container to rocking, rotation, orbital shaking, or oscillation
for not more than 10 minutes
at not more than 10 rpm during the period of incubation.
Suitable mild or gentle inactivation methods are described below in the
Examples. Further details of
such methods are also described in WO 2021/048221, the contents of which are
incorporated herein in
their entirety.
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Typically, the inactivation step substantially eliminates infectivity of
mammalian (e.g. human) cells by
the inactivated SARS-CoV-2 particle. For instance, infectivity of mammalian
cells may be reduced by
at least 99%, 99.99% or 99.9999% as compared to a native SARS-CoV-2 particle,
or infectivity of
human cells by the inactivated A SARS-CoV-2 particle may be undetectable.
Standard assays may be
used for determining residual infectivity and effective viral titer, e.g.
plaque assays, determination of
TCID50 (50% tissue culture infectious dose). For instance, the mammalian cells
may be MDCK, COS
or Vero cells.
In preferred embodiments of the present invention, a native surface
conformation of the SARS-CoV-2
particles is preserved in the inactivated virus particles. By this it is meant
that e.g. one or more, most
or all immunogenic (neutralizing) epitopes are retained in the inactivated
virus particles, such that the
inactivated particles are capable of generating neutralizing antibodies
against native SARS-CoV-2
particles when administered to a human subject. By "native surface
conformation", it is meant to refer
to the surface conformation found in native SARS-CoV-2 particles, i.e. SARS-
CoV-2 particles (virions)
that have not been inactivated. The property of the vaccine or inactivated
SARS-CoV-2 particles in
generating neutralizing antibodies in a subject may be determined using e.g. a
plaque reduction
neutralization test (PRNT assay), e.g. using a serum sample from the immunized
subject as known in
the art.
In preferred embodiments, the present invention comprises that a native
conformation of (i) spike (S)
protein; (ii) nucicocapsid (N) protein; (iii) membrane (M) glycoprotein,
and/or (iv) envelope (E) protein
is preserved in the inactivated viral particles. Preferably, the inactivated
SARS-CoV-2 particle
comprises a native conformation spike (S) protein. Thus, the S (and/or N
and/or M and/or E) protein
in the inactivated SARS-CoV-2 particle preferably comprises one or more or all
(intact) immunogenic
(neutralizing) epitopes present in native SARS-CoV-2 particles. Preferably,
the S (and/or N and/or M
and/or E) protein in the inactivated viral particles are not modified, or not
substantially modified by the
inactivation step.
Preservation of the surface conformation of the viral particles can be
assessed using standard techniques.
For instance, methods such as X-ray crystallography, MS analysis (shift of
amino acid mass by
modification) and cryo-electron microscopy may be used to visualize the virus
surface. The secondary
and tertiary structures of proteins present on the surface of viral particles
may also be analyzed by
methods such as by circular dichroism (CD) spectroscopy (e.g. in the far (190-
250 nm) UV or near
(250-300 nm) UV range). Moreover, preservation of a native surface
conformation can be confirmed
by using antibodies directed against epitopes present on the native viral
surface, e.g. in the S protein.
Reactivity of anti-SARS-CoV-2 antibodies with both the inactivated and native
virus particles can thus
be used to demonstrate retention of potentially neutralizing epitopes in the
vaccine.
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The surface conformation of SARS-CoV-2 virions and in particular the spike (S)
protein is known, and
has been published in several recent studies. See for instance Shang, J. et
al. (Structural basis of receptor
recognition by SARS-CoV-2. Nature https://doi.org/10.1038/s41586-020-2179-y
(2020)), which
describes the crystal structure of the SARS-CoV-2 receptor binding domain. In
addition, Walls et al.
(Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein,
Cell 180, 1-12 (2020),
https://doi.org/10.10167j.ce11.2020.02.058) provides a detailed description of
the S protein surface
conformation using cryo-EM, and describes cross-neutralizing antibodies that
target conserved S
protein epitopes.
Monoclonal antibodies against SARS-CoV-2 surface epitopes (including in the S
protein) are described
in the literature (e.g. as mentioned above), available from commercial sources
and/or can be generated
using standard techniques, such as immunization of experimental animals. For
example, as of
September 9, 2020, at least 169 different antibodies against SARS-CoV-2 were
available from
MyBioSource, Inc., San Diego, CA (e.g. cat. no. MBS8574747, see
www.MyBioSouree.com). On the
same date at least 28 different antibodies against SARS-CoV-2 were available
from Sino Biological US
Inc., Wayne, PA (e.g. cat. no. 40150-D006, see littpssiAkIvw sinobiological
corn!). Further suitable
antibodies are described in Ou et al. (Characterization of spike glycoprotein
of SARS-CoV-2 on virus
entry and its immune cross-reactivity with SARS-CoV, Nature Communications
(2020) 11:1620;
https://doi.org/10.1038/s41467-020-15562-9). In embodiments of the present
invention, a skilled
person can detect preservation of a native surface conformation of SARS-CoV-2
(or e.g. the S protein
thereof) via binding of such antibodies to the inactivated particles. In other
words, the inactivated
particles bind specifically to one or more anti-SARS-CoV-2 antibodies directed
against surface
epitopes, preferably anti-S-protein antibodies, e.g. to antibodies generated
against neutralizing epitopes
in native SARS-CoV-2 virions.
The SARS-CoV-2 particles in the vaccine composition may be derived from any
known strain of SARS-
CoV-2, or variants thereof For instance, the virus may be a strain as defined
in Figure 2, or may
comprise a nucleotide or amino acid sequence as defined therein, or a variant
sequence having at least
e.g. 95% sequence identity thereto. For instance, in one embodiment the SARS-
CoV-2 particle
comprises an RNA sequence corresponding to a DNA sequence as defined by SEQ ID
NOs: 1, 9, 12 or
15. In a preferred embodiment, the SARS-CoV-2 particle comprises an RNA
sequence corresponding
to the DNA sequence defined by SEQ ID NO: 9; i.e. the Italy-INMI1 SARS CoV-2
virus. This SARS-
CoV-2 isolate was the first to be identified and characterized at the National
Institute for Infectious
Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy (Capobianchi MR, et al.
Molecular
characterization of SARS-CoV-2 from the first case of COVID-19 in Italy. 2020
Clin Microbiol Infect.
2020 Jul; 26(7): 954-956; doi: 10.1016/j.cmi.2020.03.025). By "corresponding
to", it will be
understood that the defined DNA sequence is an equivalent of the viral RNA
sequence, i.e. is a DNA
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or cDNA sequence that encodes the viral RNA or a sequence complementary to the
viral RNA. As
described herein, the inactivation process may result in modification (e.g.
alkylation or acylation) and/or
fragmentation of viral RNA, and thus it will be understood that the
inactivated viral particles may not
comprise an intact RNA sequence as defined herein, but rather are derived from
native viral particles
which do comprise such a sequence.
The SARS-CoV-2 particles may also comprise variants of the known SARS-CoV-2
Wuhan-Hu-1
lineage or also referred to as the reference lineage, e.g. sequences having at
least 85%, at least 90%, at
least 95% or at least 99% sequence identity to SEQ ID NO: 1 and/or NCBI
Reference Sequence
NC 045512.2. Preferably, the variant sequence encodes an infectious SARS-CoV-2
particle, e.g. a
native (non-inactivated) SARS-CoV-2 particle comprising the RNA sequence that
is able to pack a
virulent SARS-CoV-2 virus.
Further known SARS-CoV-2 particles may also comprise variants of the known
SARS-CoV-2 South
African lineage B.1.351, e.g. sequences having at least 85%, at least 90%, at
least 95% or at least 99%
sequence identity to SEQ ID NO: 18 and/or NCBI Reference Sequence MW598408.
Preferably, the
variant sequence encodes an infectious SARS-CoV-2 particle, e.g. a native (non-
inactivated) SARS-
CoV-2 particle comprising the RNA sequence that is able to pack a virulent
SARS-CoV-2 virus. Further
examples of variants of the known SARS-CoV-2 South African lineage B.1.351 are
given in Figure 2.
Further known SARS-CoV-2 particles may also comprise variants of the known
SARS-CoV-2 Brazilian
lineage P.1, e.g. sequences having at least 85%, at least 90%, at least 95% or
at least 99% sequence
identity to SEQ ID NO: 20 and/or NCBI Reference Sequence MW520923. Preferably,
the variant
sequence encodes an infectious SARS-CoV-2 particle, e.g. a native (non-
inactivated) SARS-CoV-2
particle comprising the RNA sequence that is able to pack a virulent SARS-CoV-
2 virus. Further
examples of variants of the known SARS-CoV-2 Brazilian lineage P.1 are given
in Figure 2.
Further known SARS-CoV-2 particles may also comprise variants of the known
SARS-CoV-2 UK
lineage B.1.1.7, e.g. sequences having at least 85%, at least 90%, at least
95% or at least 99% sequence
identity to SEQ ID NO: 22 and/or NCBI Reference Sequence MVV422256.
Preferably, the variant
sequence encodes an infectious SARS-CoV-2 particle, e.g. a native (non-
inactivated) SARS-CoV-2
particle comprising the RNA sequence that is able to pack a virulent SARS-CoV-
2 virus. Further
examples of variants of the known SARS-CoV-2 UK lineage B.1.1.7 are given in
Figure 2.
Further known SARS-CoV-2 particles may also comprise variants of the known
SARS-CoV-2
Californian lineages B.1.427 and B.1.429, e.g. sequences having at least 85%,
at least 90%, at least 95%
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or at least 99% sequence identity to SEQ ID NO: 24 and/or SEQ ID NO: 26.
Preferably, the variant
sequence encodes an infectious SARS-CoV-2 particle, e.g. a native (non-
inactivated) SARS-CoV-2
particle comprising the RNA sequence that is able to pack a virulent SARS-CoV-
2 virus. Further
examples of variants of the known SARS-CoV-2 Californian lineages can be found
in Genebank.
Similarly, in preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the Wuhan
lineage comprising or consisting of (i) an amino acid sequence as defined in
SEQ ID NO: 3, or (ii) an
amino acid sequence having at least 95%, at least 97% or at least 99% identity
to SEQ ID NO: 3.
In further preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the South African
B1.351 lineage comprising or consisting of (i) an amino acid sequence as
defined in SEQ ID NO: 19,
or (ii) an amino acid sequence having at least 95%, at least 97% or at least
99% identity to SEQ ID NO:
19.
In further preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the Brazilian P.1
lineage comprising or consisting of (i) an amino acid sequence as defined in
SEQ ID NO: 21, or (ii) an
amino acid sequence having at least 95%, at least 97% or at least 99% identity
to SEQ ID NO: 21.
In further preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the UK B.1.1.7
lineage comprising or consisting of (i) an amino acid sequence as defined in
SEQ ID NO: 23, or (ii) an
amino acid sequence having at least 95%, at least 97% or at least 99% identity
to SEQ ID NO: 23.
In further preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the Californian
B.1.427 lineage comprising or consisting of (i) an amino acid sequence as
defined in SEQ ID NO: 25,
or (ii) a an amino acid sequence having at least 95%, at least 97% or at least
99% identity to SEQ ID
NO: 25.
In further preferred embodiments the SARS-CoV-2 particle comprises an S
protein of the Californian
B.1.429 lineage comprising or consisting of (i) an amino acid sequence as
defined in SEQ ID NO: 27,
or (ii) an amino acid sequence having at least 95%, at least 97% or at least
99% identity to SEQ ID NO:
27.
In some embodiments, the inactivated SARS-CoV-2 particles are combined with
other inactivated
SARS-CoV-2 particles in the vaccine (other = other sequence).
In some embodiments, a combination of SARS-CoV-2 particles in the vaccine
comprises or consists of
at least two SARS-CoV-2 particles selected from the group consisting of i) the
reference Wuhan_l
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lineage such as e.g. SEQ ID NOs 1, 9, 12, 15; ii) the South African B.1.531
lineage such as e.g. SEQ
ID NO: 18; the Brazilian P.1 lineage such as e.g. SEQ ID NO: 20; the UK
B.1.1.7 lineage such as e.g.
SEQ ID NO: 22 and the Californian B.1.427 such as e.g. SEQ ID NO: 24 or
B.1.429 lineages such as
e.g. SEQ ID NO: 26. A preferred embodiment is a combination comprising i) a
Wuhan_l lineage such
as e.g. SEQ ID NO: 9; and ii) a South African B.1.531 lineage such as e.g. SEQ
ID NO: 18.
In a further embodiment, a combination of SARS-CoV-2 particles in the vaccine
comprises or consists
of at least three, e.g. three SARS-CoV-2 particles selected from the group
consisting of i) the reference
Wuhan_l lineage such as e.g. SEQ ID NOs 1, 9, 12, 15; ii) the South African
B.1.531 lineage such as
e.g. SEQ ID NO: 18; the Brazilian P.1 lineage such as e.g. SEQ ID NO: 20; the
UK B.1.1.7 lineage
such as e.g. SEQ ID NO: 22 and the Californian B.1.427 such as e.g. SEQ ID NO:
24 or B.1.429 lineages
such as e.g. SEQ ID NO: 26. A preferred embodiment of such a trivalent vaccine
is a combination
comprising i) a Wuhan_l lineage such as e.g. SEQ ID NO: 9; and ii) a South
African B.1.531 lineage
such as e.g. SEQ ID NO: 18; and iii) an UK B.1.1.7 lineage such as e.g. SEQ ID
NO: 22. Another
preferred embodiment of such a trivalent vaccine is a combination comprising
i) a Wuhan 1 lineage
such as e.g. SEQ ID NO: 9; and ii) a South African B.1.531 lineage such as
e.g. SEQ ID NO: 18; and
iii) a Brazilian P.1 lineage such as e.g. SEQ ID NO: 20.
The similarity between amino acid sequences and/or nucleic acid sequences is
expressed in terms of the
percentage of identical matches between the sequences, otherwise referred to
as sequence identity.
Sequence identity is frequently measured in terms of percentage identity; the
higher the percentage, the
more similar the two sequences are. Homologs, orthologs, or variants of a
polynucleotide or polypeptide
will possess a relatively high degree of sequence identity when aligned using
standard methods.
Methods of alignment of sequences for comparison arc well known in the art.
Various programs and
alignment algorithms are described in: Smith & Waterman, Adv. Appl. Math.
2:482, 1981; Needleman
& Wunsch, Mol. Biol. 48:443, 1970; Pearson & Lipman, Proc. Natl. Acad. Sci.
USA 85:2444, 1988;
Higgins & Sharp, Gene, 73:237-44, 1988; Higgins & Sharp, CABIOS 5: 151-3,
1989; Corpet et al.,
Nuc. Acids Res. 16: 10881-90, 1988; Huang et al. Computer Appls. in the
Biosciences 8, 155-65, 1992;
and Pearson et al., Meth. Mol. Bio. 24:307-31, 1994. Altschul eta!, J. Mol.
Biol. 215:403-10, 1990,
presents a detailed consideration of sequence alignment methods and homology
calculations.
Once aligned, the number of matches is determined by counting the number of
positions where an
identical nucleotide or amino acid residue is present in both sequences. The
percent sequence identity
is determined by dividing the number of matches either by the length of the
sequence set forth in the
identified sequence, or by an articulated length (such as 100 consecutive
nucleotides or amino acid
residues from a sequence set forth in an identified sequence), followed by
multiplying the resulting
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value by 100. Preferably, the percentage sequence identity is determined over
the full length of the
sequence. For example, a peptide sequence that has 1166 matches when aligned
with a test sequence
having 1554 amino acids is 75.0 percent identical to the test sequence (1166
1554*100=75.0). The
percent sequence identity value is rounded to the nearest tenth. For example,
75.11, 75.12, 75.13, and
75.14 are rounded down to 75.1, while 75.15, 75.16, 75.17, 75.18, and 75.19
are rounded up to 75.2.
The length value will always be an integer.
The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., Mol.
Biol. 215:403, 1990) is
available from several sources, including the National Center for
Biotechnology Information (NCBI,
Bethesda, MD) and on the internet, for use in connection with the sequence
analysis programs BLASTP,
BLASTN, BLASTX, TBLASTN and TBLASTX. A description of how to determine
sequence identity
using this program is available on the NCBI website on the internet. The BLAST
and the BLAST 2.0
algorithms are also described in Altschul et al., Nucleic Acids Res. 25:3389-
3402, 1977. Software for
performing BLAST analyses is publicly available through the National Center
for Biotechnology
Information (ncbi.nlm.nih.gov). The BLASTN program (for nucleotide sequences)
uses as defaults a
word length (W) of 11, alignments (B) of 50, expectation (E) of 10, M=5, N=-4,
and a comparison of
both strands. The BLASTP program (for amino acid sequences) uses as defaults a
word length (W) of
3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff &
Henikoff, Proc. Natl.
Acad. Sci. USA 89: 10915, 1989).
Homologs and variants of a polynucleotidc or polypeptide arc typically
characterized by possession of
at least about 75%, for example at least about 80%, 85%, 90%, 91%, 92%, 93%,
94%, 95%, 96%, 97%,
98% or 99% sequence identity counted over at least 50, 100, 150, 250, 500,
1000, 2000, 5000 or 10,000
nucleotide or amino acid residues of the reference sequence, over the full
length of the reference
sequence or over the full length alignment with the reference amino acid
sequence of interest.
Polynucleotides or proteins with even greater similarity to the reference
sequences will show increasing
percentage identities when assessed by this method, such as at least 80%, at
least 85%, at least 90%, at
least 95%, at least 98%, or at least 99% sequence identity. For sequence
comparison of amino acid or
nucleic acid sequences, typically one sequence acts as a reference sequence,
to which test sequences
are compared. When using a sequence comparison algorithm, test and reference
sequences are entered
into a computer, subsequence coordinates are designated, if necessary, and
sequence algorithm program
parameters are designated. Default program parameters are used.
One example of a useful algorithm is PILEUP, which uses a simplification of
the progressive alignment
method of Feng & Doolittle, Mol. Evol. 35:351-360, 1987. The method used is
similar to the method
described by Higgins & Sharp, CABIOS 5:151-153, 1989. Using PILEUP, a
reference sequence is
compared to other test sequences to determine the percent sequence identity
relationship using the
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following parameters: default gap weight (3.00), default gap length weight
(0.10), and weighted end
gaps. PILEUP can be obtained from the GCG sequence analysis software package,
e.g., version 7.0
(Devereaux et al., Nuc. Acids Res. 12:387-395, 1984).
As used herein, reference to "at least 80% identity" refers to at least 80%,
at least 85%, at least 90%, at
least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least
96%, at least 97%, at least
98%, at least 99%, or even 100% identity to a specified reference sequence,
e.g. to at least 50, 100, 150,
250, 500, 1000, 5000 or 10,000 nucleotide or amino acid residues of the
reference sequence or to the
full length of the sequence. As used herein, reference to "at least 90%
identity" refers to at least 90%,
at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least
96%, at least 97%, at least
98%, at least 99%, or even 100% identity to a specified reference sequence,
e.g. to at least 50, 100, 150,
250, 500, 1000, 5000 or 10,000 nucleotide or amino acid residues of the
reference sequence or to the
full length of the sequence.
The SARS-CoV-2 vaccine may be produced by methods involving a step of
inactivation of native
SARS-CoV-2 particles, as described above. Generally, the native SARS-CoV-2
particles may be
obtained by standard culture methods, e.g.by in vitro production in mammalian
cells, preferably using
Vero cells. For instance, the native SARS-CoV-2 particles may be produced
using methods analogous
to those described in e.g. WO 2017/109225 and/or WO 2019/057793 (the contents
of which are
incorporated herein in their entirety), which describe methods for the
production of Zika and
Chikungunya viruses in Vero cells. The steps such as passaging, harvesting,
precipitation, dialysis,
filtering and purification described in those documents are equally applicable
to the present process for
producing SARS-CoV-2 particles.
For instance, in some embodiments, the method may comprise purifying the
inactivated SARS-CoV-2
particles by one or more size exclusion methods such as (i) a sucrose density
gradient centrifugation,
(ii) a solid-phase matrix packed in a column comprising a ligand-activated
core and an inactive shell
comprising pores, wherein the molecular weight cut-off of the pores excludes
the virus particles from
entering the ligand-activated core, and wherein a molecule smaller than the
molecular weight cut-off of
the pores can enter the ligand-activated core and collecting the virus
particles, and/or (iii) batch or size
exclusion chromatography; to obtain purified inactivated SARS-CoV-2 particles.
Preferably, in the
resulting purified preparation of viral particles, (i) the concentration of
residual host cell DNA is less
than 100 ng/mL; (ii) the concentration of residual host cell protein is less
than 1 ug/mL; and (iii) the
concentration of residual aggregates of infectious virus particles is less
than 1 iag/mL.
In some embodiments, the method may comprise a step of precipitating a
harvested culture medium
comprising SARS-CoV-2 particles, thereby producing native SARS-CoV-2 particles
in a supernatant.
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The precipitating step may comprise contacting the culture medium with
protamine sulfate or
benzonase. By using such a step, both contaminating DNA derived from host
cells as well as immature
and otherwise non-infectious virus particles can be separated from the
preparation. Moreover,
protamine sulfate can be very efficiently separated from the virus fraction,
e.g. using sucrose density
centrifugation or a solid-phase matrix packed in a column comprising a ligand-
activated core and an
inactive shell comprising pores, wherein the pores comprise a molecular weight
cut-off that excludes
the virus particles from entering the ligand-activated core, and wherein a
molecule smaller than the
molecular weight cut-off of the pores (e.g. the protamine sulfate) can enter
the ligand-activated coreõ
allowing for a safer vaccine produced at high yields.
Thus the residual host cell DNA of the obtained virus preparation or vaccine
may be less than 1 lag/mL,
especially less than 900, 800, 700, 600, 500, 400, 300 or 200 ng/mL,
preferably less than 150 or 100
ng/mL. In a preferred embodiment, the residual host cell DNA of the virus
preparation or vaccine is
less than 40 pg/mL. In some embodiments, the residual host cell protein of the
virus preparation or
vaccine is less than 10 p..g/mL, especially less than 9, 8, 7, 6, 5, 4, 3 or 2
lig/mL, preferably less than 1
mg/mL. In a preferred embodiment, the residual host cell protein of the virus
preparation or vaccine is
less than 150 ng/mL. In some embodiments, the residual non-infectious virus
particles of the virus
preparation or vaccine is less than 10 [tg/mL, especially less than 9, 8, 7,
6, 5, 4, 3 or 2 [tg/mL, preferably
less than 1 vig/mL. In a preferred embodiment, the content of residual non-
infectious virus particles of
the virus preparation or vaccine is less than 100 ng/mL.
In some embodiments, the vaccine and/or SARS-CoV-2 particles may comprise
residual protamine (e.g.
protamine sulfate), typically in trace amounts. In some embodiments, residual
protamine (e.g.
protamine sulfate) in the virus preparation or vaccine is less than 2 i_tg/mL
or 1 ps/mL, especially less
than 900, 800, 700, 600, 500, 400, 300 or 200 ng/mL, preferably less than 100
ng/mL, more preferably
is below the detection limit of HPLC, in particular below the detection limit
in the final drug substance.
In some embodiments, the PS content is tested by HPLC or size exclusion
chromatography (SEC). For
example, HPLC is validated for PS determination in JEV sucrose gradient pool
samples as a routine
release assay and is very sensitive (i.e., limit of quantification (LOQ) 3
i.tg/mL; limit of detection (LOD)
1 i_ig/mL). In the current invention, PS content in SARS-CoV-2 drug substance
was <LOD. In one
embodiment, the HPLC assessment of PS content can be performed on a Superdex
Peptide 10/300GL
column (GE: 17-5176-01) using 30% Acetonitrile, 0,1% Trifluoroacetic acid as
solvent with a flow rate
of 0.6 ml/min at 25 C and detection at 214 nm. A more sensitive method of
measurement for residual
protamine in a purified virus preparation is mass spectrometry (MS). In some
embodiments, the residual
PS levels in a Zika virus preparation are tested by MS or other such highly
sensitive method, e.g. nuclear
magnetic resonance (NMR). With this method, residual PS, as well as fragments
and/or break-down
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products of PS, can be detected at trace amounts, such as levels as low as,
for example, 106, 107 or 108
molecules per typical sample load. In some embodiments, the PS levels are
tested in the drug product.
In some embodiments, the PS levels are tested in the drug substance.
Preferably an amount of the inactivating agent (e.g. beta-propiolactone) in
the drug product or drug
substance (e.g. vaccine composition) is very low, e.g. less than 100 ppm, less
than 10 ppm, or less than
1 ppm (by weight).
The SARS-CoV-2 vaccine may be administered to a subject, preferably a
mammalian subject, more
preferably a human subject. Typically, the SARS-CoV-2 vaccine is administered
to a subject at risk of
SARS-CoV-2 infection, e.g. in order to prevent SARS-CoV-2 infection and/or to
prevent SARS-CoV-
2 associated disease (COVID-19). The subject is preferably (i) an elderly
subject (e.g. older than 65
years, 70 years or 80 years) (ii) a pregnant subject (iii) an
immunocompromised subject or (iv) a child
(e.g. a person younger than 18 years, 16 years, 14 years, 12 years, 10 years,
8 years, 6 years, 4 years, 2
years or younger). The SARS-CoV-2 vaccine described herein is advantageously
capable of generating
robust immune responses in subjects particularly susceptible or vulnerable to
SARS-CoV-2 morbidity
or mortality, i.e. immunocompromised, pregnant or elderly subjects. The SARS-
CoV-2 vaccine may
be administered to the subject in a single dose or two or more doses, e.g.
separated by intervals of about
7, 14,21 or 28 days.
In a preferred embodiment, on administration to a human subject the vaccine
does not induce vaccine
mediated disease enhancement (potentially through Antibody dependent
enhancement). Vaccine-
mediated disease enhancement is characterized by a vaccine that results in
increased disease severity if
the subject is later infected by the natural virus. It is an advantage of the
present invention that the
inactivated SARS-CoV-2 vaccine described herein does not promote vaccine
mediated disease
enhancement in human subjects, and can therefore be safely used for mass
vaccination purposes. In
particular, the vaccine described herein retains high quality immunogenic
epitopes, which therefore
results in high neutralizing antibody titers and diminishes the risk of
vaccine mediated disease
enhancement on administration to subjccts. The risk of vaccine mediated
disease enhancement
development may be assessed in non-human primates. Guidance in this regard is
given in the Consensus
summary report for CEP1/BC March 12-13, 2020 meeting: Assessment of risk of
disease enhancement
with COVID-19 vaccines (Lambert, P-H, etal. 2020, doi: 10.1016/j.vaccine
.2020.05.064).
In another preferred embodiment, on administration to a human subject the
vaccine does not result in
immunopathology. In mice, SARS-CoV-1 vaccine induced immunopathology was
considered a
consequence of a dominant Th2 type response to the vaccine antigens (Tseng et
al., 2012, supra). In
embodiments of the present invention, a Thl type response is enhanced or
favored, e.g. by use of the
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111-directing adjuvant CpG. The risk of immunopathology developing may be
assessed in animal
models, e.g. as described in Tseng C.T. et al. (2012) PLoS ONE 7(4):e35421.
Any of the SARS-CoV-2 vaccines or compositions described herein may be
administered to a subject
in a therapeutically effective amount or a dose of a therapeutically effective
amount. As used herein, a
"therapeutically effective amount" of vaccine is any amount that results in a
desired response or
outcome in a subject, such as those described herein, including but not
limited to prevention of infection,
an immune response or an enhanced immune response to SARS-CoV-2, or prevention
or reduction of
symptoms associated with SARS-CoV-2 disease.
In some embodiments, the therapeutically effective amount or prophylactically
effective amount
(dosage) of a SARS-Co V-2 vaccine or composition described herein is an amount
sufficient to generate
antigen-specific antibodies (e.g., anti-SARS-CoV-2 antibodies).
In some embodiments, the
therapeutically or prophylactically effective amount is sufficient to
seroconvert a subject with at least
70% probability. In some embodiments, the therapeutically or prophylactically
effective amount is
sufficient to seroconvert a subject with at least 75%, 80%, 85% 90%, 95%, 96%,
97%, 98%, or at least
99% probability. Whether a subject has seroconverted can be assessed by any
method known in the art,
such as obtaining a serum sample from the subject and performing an assay to
detect anti-SARS-CoV-
2 antibodies. In some embodiments, a subject is seroconverted if a serum
sample from the subject
contains an amount of anti-SARS-CoV-2 antibodies that surpasses a threshold or
predetermined
baseline. A subject is generally considered seroconverted if there is at least
a 4-fold increase in anti-
SARS-CoV-2 antibodies (i.e., anti-SARS-CoV-2 S protein IgG antibodies) present
in a serum sample
from the subject as compared to a serum sample previously taken from the same
subject.
In one embodiment, the dose of the inactivated SARS-CoV-2 virus in the vaccine
composition of the
current invention is between about 0.01 and 25 mAU (milli-absorption units x
minutes as assessed by
SEC-HPLC), preferably between about 0.05 and 10 mAU, more preferably between
about 0.1 and 5
mAU, most preferably between about 0.25 and 2.5 mAU. In one embodiment, the
dose is between about
0.05 and 50 ittg total protein as measured by (u)BCA assay, between about 0.1
and 25 jug, between about
0.25 and 12.5 lug, preferably between about 0.5 and 5 iug total protein. More
preferably the dose of the
inactivated SARS-CoV-2 virus in the vaccine composition is at least 2.5 lag
total protein, at least 3.5 lug
total protein or at least 2.5 lag total protein, e.g. the vaccine composition
comprises 2.5 lag to 25 lag, 3.5
lag to 10 lag or 4 lag to 6 lag total protein/dose, preferably about 5 lag
total protein/dose. In some
embodiments, the dosage is determined by the total amount of S protein in the
inactivated SARS-CoV-
2 formulation, as assessed by e.g. ELISA. The mass of antigen may also be
estimated by assessing the
SE-HPLC peak area per dose equivalent (recorded as milli-absorption units x
minutes, mAU), which is
estimated to be approximately 2 Kg/m1 total surface protein and approximately
1 Kg/mL S-protein. In
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one embodiment, the dose is between about 0.025 and 25 jig S-protein as
measured by ELISA, between
about 0.05 and 12.5 lag, between about 0.125 and 6.25 lag, preferably between
about 0.25 and 2.5 lag S-
protein.
In a preferred embodiment, the amount of antigen in the SARS-CoV-2 vaccine is
determined by ELISA.
In one embodiment, the ELISA measures a SARS-CoV-2 protein or portion of a
protein, e.g.,
nucleocapsid (N), membrane (M) or spike (S) protein; i.e., the ELISA utilizes
a coating antibody
specific to a SARS-CoV-2 protein or portion of a protein. In a preferred
embodiment, the coating
antibody is specific to the SARS-CoV-2 Spike protein Si subunit, e.g. residues
14-685 (or 14-683) of
the S-protein sequence of SEQ ID NO:3, 19, 21, 23, 25 or 27, or to the
Receptor Binding Domain
(RBD), e.g. residues 331 to 528 (or 319 to 541) of the S-protein sequence of
SEQ ID NO: 3, 19, 21, 23,
25 or 27 (see Figure 13). In one embodiment, the ELISA readout is a mass per
unit measure of the
detected protein, e.g. vig/mL S-protein. In a preferred embodiment, the
standard used is a spike protein
trimer and the results of the SARS-CoV-2 ELISA are reported as "antigen units"
(AU), corresponding
to the ACE-2 binding ability of the standard protein (determined by the
manufacturer).
In one embodiment, the amount of SARS-CoV-2 antigen administered to a subject
is between about 1
to 100 AU/dose, preferably between about 2 to 75 AU/dose, preferably between
about 3 and 60
AU/dose, more preferably between about 3 and 55 AU/dose, more preferably
between about 3 and 53
AU/dose. In an even more preferred embodiment, the amount of SARS-CoV-2
antigen administered to
a subject is 3 AU, 10 AU or 40 AU per dose, most preferred 40 AU per dose. In
further preferred
embodiments, the amount of SARS-CoV-2 antigen administered to a subject is at
least 10 AU/dose, at
least 20 AU/dose, at least 25 AU/dose or at least 30 AU/dose, e.g. about 10 to
60 AU/dose, 20 to 50
AU/dose, 25 to 45 AU/dose or 30 to 40 AU/dose, e.g. about 35 AU/dose. The
amount of SARS-CoV-
2 antigen (e.g. in AU/dose) may be assessed, for example, by a SARS-CoV-2
ELISA assay as described
in Example 1. It is estimated that there are about 1 to 1.5 x 107 viral
particles per AU, and the amounts
of SARS-CoV-2 antigen described above may be construed accordingly. Thus in
some embodiments,
the amount of SARS-CoV-2 antigen administered to a subject is between about
1.5 x 107 to 1.5 x 109
viral particles/dose, or between about 4.5 x 107 to 9.0 x 108 viral
particles/dose, e.g. at least 1.5 x 108
viral particles/dose or at least 3.0 x 108 viral particles/dose, about 1.5 x
108 to 7.5 x 108 viral
particles/dose or about 4.5 x 108 to 6.0 x 108 viral particles/dose.
In sonic embodiments, seroconversion of a subject is assessed by performing a
plaque reduction
neutralization test (PRINT). Briefly, PRINT is used to determine the serum
titer required to reduce the
number of SARS-CoV-2 plaques by 50% (PRNT50) as compared to a control
serum/antibody. The
PRNT50 may be carried out using monolayers of Vero cells or any other cell
type/line that can be
infected with SARS-CoV-2. Sera from subjects are diluted and incubated with
live, non-inactivated
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SARS-CoV-2. The senim/vinis mixture may be applied to Vero cells and incubated
for a period of time.
Plaques formed on the Vero cell monolayers are counted and compared to the
number of plaques formed
by the SARS-CoV-2 in the absence of serum or a control antibody. As a
guideline, a threshold of
neutralizing antibodies of 1:10 dilution of serum in a PRNT5o is generally
accepted as evidence of
protection in the case of JEV (Hombach et. at. Vaccine (2005) 23:5205-5211).
In some embodiments, the SARS-CoV-2 particles may be formulated for
administration in a
composition, such as a pharmaceutical composition. The term -pharmaceutical
composition" as used
herein means a product that results from the mixing or combining of at least
one active ingredient, such
as an inactivated SARS-CoV-2, and one or more inactive ingredients, which may
include one or more
pharmaceutically acceptable excipients. A preferred pharmaceutically
acceptable excipient is human
serum albumin (HSA), such as, especially recombinant HSA (rHSA). In one
embodiment, the SARS-
CoV-2 vaccine of the invention contains about 10 to 50 jug HSA/dose,
preferably about 20 to 40 lug
HSA/dose, more preferably about 25 to 35 ug HSA/dose.
Pharmaceutical compositions of the invention, including vaccines, can be
prepared in accordance with
methods well-known and routinely practiced in the art (see e.g., Remington:
The Science and Practice
of Pharmacy, Mack Publishing Co. 20th ed. 2000; and Ingredients of Vaccines -
Fact Sheet from the
Centers for Disease Control and Prevention, e.g., adjuvants and enhancers as
described above to help
the vaccine improve its work, preservatives and stabilizers to help the
vaccine remain unchanged (e.g.,
albumin, phenols, glycinc)). As used herein, the term -vaccine" refers to an
immunogenic composition,
e.g. a composition capable of inducing an immune response in a (human) subject
against an antigen
(e.g. against a SARS-CoV-2 antigen). For instance, the vaccine or composition
may be capable of
generating neutralizing antibodies against SARS-CoV-2, e.g. as determined in
an assay described herein
(e.g. a microncutralization assay). In some embodiments, the vaccine or
composition is capable of
generating antibodies (e.g. IgG) against SARS-CoV-2 S (spike) protein, e.g. as
detected by an S-protein
IgG ELISA assay as described herein. In some embodiments, the vaccine or
composition is capable of
generating a T cell response against SARS-CoV-2 proteins or peptides, for
instance a T cell response
against a SARS-CoV-2 S-protein, membrane (M) protein and/or nucleocapsid (N)
protein or peptides
derived therefrom, e.g. as detected by an ELISPOT assay as described herein
(e.g. based on IFN-y
production). Preferably the vaccine or immunogenic composition generates
neutralizing antibodies and
a T cell response against SARS-CoV-2. Typically the vaccine or immunogenic
composition is capable
of inducing a protective effect against a disease caused by the antigen, e.g.
a protective effect against
SARS-CoV-2 infection (e.g. symptomatic and/or asymptomatic infection) and/or
COVID-19 disease).
Pharmaceutical compositions are preferably manufactured under GMP conditions.
Typically, a
therapeutically or prophylactically effective dose of the inactivated SARS-CoV-
2 vaccine preparation
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is employed in the pharmaceutical composition of the invention. The
inactivated SARS-CoV-2
particles are formulated into pharmaceutically acceptable dosage forms by
conventional methods
known to those of skill in the art. Dosage regimens are adjusted to provide
the optimum desired
response (e.g., the prophylactic response).
Dosages of the active ingredients in the pharmaceutical compositions of the
present invention can be
varied so as to obtain an amount of the active ingredient which is effective
to achieve the desired
pharmaceutical response for a particular subject, composition, and mode of
administration, without
being toxic to the subject. The selected dosage level depends upon a variety
of pharmacokinetic factors,
including the activity of the particular compositions of the present invention
employed, the route of
administration, the time of administration, the rate of excretion of the
particular compound being
employed, the duration of the treatment, other drugs, compounds and/or
materials used in combination
with the particular compositions employed, the age, sex, weight, condition,
general health and prior
medical history of the subject being treated, and like factors.
A physician, veterinarian or other trained practitioner, can start dosing of
the inactivated SARS-CoV-2
vaccine employed in the pharmaceutical composition at levels lower than that
required to achieve the
desired therapeutic or prophylactic effect and gradually increase the dosage
until the desired effect (e.g.,
production of anti-SARS-CoV-2 virus antibodies) is achieved. In general,
effective doses of the
compositions of the present invention, for the prophylactic treatment of
groups of people as described
herein vary depending upon many different factors, including means of
administration, target site,
physiological state of the patient, whether the patient is human or an animal,
other medications
administered, and the titer of anti-SARS-CoV-2 antibodies desired. Dosages
need to be titrated to
optimize safety and efficacy. In some embodiments, the dosing regimen entails
subcutaneous or
intramuscular administration of a dose of inactivated SARS-CoV-2 vaccine
twice, once at day 0 and
once at about day 7. In some embodiments, the dosing regimen entails
subcutaneous administration of
a dose of inactivated SARS-CoV-2 vaccine twice, once at day 0 and once at
about day 14. In some
embodiments, the dosing regimen entails subcutaneous administration of a dose
of inactivated SARS-
CoV-2 vaccine twice, once at day 0 and once at about day 21. In some
embodiments, the dosing regimen
entails subcutaneous administration of a dose of inactivated SARS-CoV-2
vaccine twice, once at day 0
and once at about day 28. In some embodiments, the inactivated SARS-CoV-2
vaccine is administered
to the subject once. In a preferred embodiment, the SARS-CoV-2 vaccine is
administered to the subject
more than once, preferably two times. In a preferred embodiment, the vaccine
is administered on day 0
and day 21. In another preferred embodiment, the vaccine is administered on
day 0 and day 28.
In further embodiments, a first (prime) dose of the inactivated SARS-CoV-2
vaccine is administered
and a second (boost) dose of the inactivated SARS-CoV-2 vaccine is
administered at least 28 days, at
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least 60 days, at least 70 days, at least 80 days or 90 days after the first
dose. Thus in some embodiments,
the second dose of the inactivated SARS-CoV-2 vaccine is administered 30 to
120 days or 1 to 4 months
(preferably about 3 months) after the first dose.
In other embodiments, the inactivated SARS-CoV-2 vaccine is administered as a
booster dose only, e.g.
a first (prime) dose of a (different) SARS-CoV-2 vaccine is administered and
then a second (boost) dose
of the inactivated SARS-CoV-2 vaccine is administered, e.g. at least 7, 14,
28, 60 or 90 days after the
first dose. The first (prime) dose of the SARS-CoV-2 vaccine may comprise any
other vaccine or
immunogenic composition that stimulates an immune response and/or a protective
effect in subjects
against SARS-CoV-2 virus. For example, the first dose of SARS-CoV-2 vaccine
may comprise a
recombinant viral vector or an mRNA sequence encoding one or more SARS-CoV-2
proteins and/or
fragments thereof, e.g. a SARS-CoV-2 spike (S) protein. Alternatively the
first dose of SARS-CoV-2
vaccine may comprise a subunit vaccine, e.g. comprising one or more SARS-CoV-2
proteins and/or
fragments thereof, e.g. a SARS-CoV-2 spike (S) protein or fragment thereof
Also within the scope of the present disclosure are kits for use in
prophylactic administration to a
subject, for example to prevent or reduce the severity of SARS-CoV-2
infection. Such kits can include
one or more containers comprising a composition containing inactivated SARS-
CoV-2, such as an
inactivated SARS-CoV-2 vaccine. In some embodiments, the kit may further
include one or more
additional components comprising a second composition, such as a second
vaccine, e.g. a second kind
of SARS-CoV-2 vaccine that applies a different technology than in the first
dose. In some
embodiments, the second vaccine is a vaccine for an arbovirus. In some
embodiments, the second
vaccine is a Japanese encephalitis virus vaccine, a Zika virus vaccine, a
Dengue virus vaccine and/or a
Chikungunya virus vaccine.
In some embodiments, the kit comprises instructions for use in accordance with
any of the methods
described herein. The included instructions may comprise a description of
administration of the
composition containing inactivated SARS-CoV-2 vaccine to prevent, delay the
onset of, or reduce the
severity of SARS-CoV-2 infection. The kit may further comprise a description
of selecting a subject
suitable for administration based on identifying whether that subject is at
risk for exposure to SARS-
CoV-2 or contracting a SARS-CoV-2 infection. In still other embodiments, the
instructions comprise
a description of administering a composition containing inactivated SARS-CoV-2
vaccine to a subject
at risk of exposure to SARS-CoV-2 or contracting SARS-CoV-2 infection.
The instructions relating to the use of the composition containing inactivated
SARS-CoV-2 vaccine
generally include information as to the dosage, dosing schedule, and route of
administration for the
intended treatment. The containers may be unit doses, bulk packages (e.g.,
multi-dose packages) or
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sub-unit doses. Instructions supplied in the kits of the invention are
typically written instructions on a
label or package insert (e.g., a paper sheet included in the kit), but machine-
readable instructions are
also acceptable.
The kits of the present disclosure are in suitable packaging. Suitable
packaging includes, but is not
limited to, vials, bottles, jars, flexible packaging, and the like. Also
contemplated are packages for use
in combination with a specific device, such as a syringe or an infusion
device. The container may have
a sterile access port, for example the container may be a vial having a
stopper pierceable by a
hypodermic injection needle. At least one active agent in the composition is
an inactivated SARS-CoV-
2, as described herein.
This invention is not limited in its application to the details of
construction and the arrangement of
components set forth in the following description or illustrated in the
drawings. The invention is capable
of other embodiments and of being practiced or of being carried out in various
ways. Also, the
phraseology and terminology used herein is for the purpose of description and
should not be regarded
as limiting. The use of "including", "comprising", or "having", "containing",
"involving", and
variations thereof herein, is meant to encompass the items listed thereafter
and equivalents thereof as
well as additional items.
Unless otherwise defined herein, scientific and technical terms used in
connection with the present
disclosure shall have the meanings that are commonly understood by those of
ordinary skill in the art.
Further, unless otherwise required by context, singular terms shall include
pluralities and plural tcrms
shall include the singular. The methods and techniques of the present
disclosure are generally performed
according to conventional methods well-known in the art. Generally,
nomenclatures used in connection
with, and techniques of biochemistry, enzymology, molecular and cellular
biology, microbiology,
virology, cell or tissue culture, genetics and protein and nucleic chemistry
described herein are those
well-known and commonly used in the art. The methods and techniques of the
present disclosure are
generally performed according to conventional methods well-known in the art
and as described in
various general and more specific references that are cited and discussed
throughout the present
specification unless otherwise indicated.
The present invention is further illustrated by the following examples, which
in no way should be
construed as further limiting. The entire contents of all of the references
(including literature references,
issued patents, published patent applications, and co-pending patent
applications) cited throughout this
application are hereby expressly incorporated by reference, in particular for
the teaching that is
referenced hereinabove. However, the citation of any reference is not intended
to be an admission that
the reference is prior art.
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EXAMPLES
Example 1. Drug substance production
For the production of SARS-CoV-2, the JEV process platform (Srivastava et al.,
Vaccine 19 (2001)
4557-4565; US 6,309,650B1) was used as a basis, also taking into account
improvements in the process
as adapted to Zika virus purification as disclosed in W02017/109223A1 (which
is incorporated herein
in its entirety). Briefly, non-infectious SARS-CoV-2 particle aggregates, HCP
and other LMW
impurities are removed by protamine sulfate precipitation or benzonase
treatment and the resulting
preparation is optionally further purified by sucrose gradient centrifugation.
See Fig. 1 for an outline of
the production process.
"lhe first SARS-CoV-2 isolate from Italy, identified and characterized at the
National Institute for
Infectious Diseases "Lazzaro Spallanzani" IRCCS, Rome, Italy (Accession No:
MT066156), the RNA
sequence thereof corresponding to the DNA sequence provided by SEQ ID NO: 9,
was used in all
Examples disclosed herein. Other novel coronavirus SARS-CoV-2 isolates may
also be obtained from
the following sources:
1. -EVAg (European Virus Archive), e.g. one of the following strains:
BetaCoV/France/IDF0372/2020 (Re f-SKU : 014V-03890, lattps://www european-
virus-
archi ve .corn/vi rusihuman -2019-ric ov -0); 2019-nCoV/Italy-INMI1, (Ref-S KU
: 008V-03893, SEQ ID
NO: 9; Imps: /RV Vki european-virus-arclii ve corn/v ru in Ian -2019-neov -
strai n -20 I 9-ricovitalv-
himi1); BetaCoV/Netherlands/01, (Re f-SKU : 010V-03903, https://www .europeau -
virus-
archive ,cornivi rusisars-cov-2-strain-n12020)
2. -BET Resources (Biodefense and Emerging Infections Research Resources):
e.g. Isolate USA-
WA1/2020, NIAID, NIH: SARS-Related Coronavirus 2, NR-52281 (GenBank accession
MN985325).
3.
¨PHE (Public Health England): https://www.g_ov. v
ernment/colleetions/contacts-p ablic-
health-encdand-reg i on s-local -centre s-and-ern e rizen cy: e .g .
isolate of UK B .1.1.7
(UK_MIG457: EVAg Ref-SKU: 004V-04032; SEQ ID NO: 22) or South African B.1.531
(SA_P2: EVAg Ref-SKU: 004V-04071; SEQ ID NO: 18) lineage
Cell buildup and infection with SARS-CoV-2 The Vero cells used in the methods
described herein
were the VERO (WHO) cell line, obtained from the Health Protection Agency
general cell collection
under catalogue number 88020401, from which a master cell bank was generated.
A research viral seed
bank (rVSB) of SARS-CoV-2 (strain used 2019-nCoV/Italy-INMI1) was prepared
following two
rounds of plaque purification on Vero cells and the genomic sequence was
checked by sequencing. For
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production of SARS-CoV-2, Vero cells were grown in Eagle's minimal essential
medium (EMEM)
containing 10% fetal bovine serum (FBS) and monolayers were infected with SARS-
CoV-2 at a
multiplicity of infection (moi) of 0.01 plaque forming units (pfu) per cell.
Alternatively, the moi may
be 0.001 to 1, preferably 0.005 to 0.2, preferably 0.01 plaque forming units
(pfu) per cell. After allowing
virus adsorption, the cultures were washed 2-4 times with PBS, fed with serum-
free Opti-Pro and
incubated at 35 C with 5% CO2 until the virus titer reached a desired level.
SARS-CoV-2 harvest The culture medium was harvested at day 3 and harvests and
centrifuged in a
standard centrifuge. The crude harvest was treated with 0.2mg/mL Protamine
sulfate and filtered
(0.8/0.4vim) followed by incubation at RT C for 15-30 minutes. Host cell DNA
and protein reduction,
as well as reduction of non-infectious virus aggregates in the concentrated
material, was achieved by
precipitation with protamine sulfate. The clarified harvest was concentrated
by TFF ultrafiltration to
remove cell culture medium components and reduce batch volume. Alternatively,
the diafiltrated
SARS-CoV-2 material may be treated with benzonase.
Optional primary inactivation The SARS-CoV-2 virus was inactivated by
treatment with beta-
propiolactone directly after removal of virus-containing cell culture medium
from Vero cells, in order
to render the virus safe to handle at BSL2. Inactivation is possible at any
stage in the purification
process, however, such as e.g., after centrifugation, before, during or after
treatment with protamine
sulfate or benzonase or before or after sucrose gradient centrifugation.
Inactivation may be carried out
by the use of a chemical inactivation agent such as formaldehyde (formalin);
enzyme; beta-
propiolactone; ethanol; trifluroacetic acid; acetonitrile; bleach; urea;
guanidine hydrochloride; tri-n-
butyl phosphate; ethylene-imine or a derivative thereof; an organic solvent,
optionally Tween, Triton,
sodium deoxycholate, or sulfobetaine; or a combination thereof. It is
particularly preferred that
inactivation is carried out using beta-propiolactone, which preferentially
targets viral RNA whilst
relatively sparing viral surface proteins and their immunogenic epitopes.
Inactivation may also be
achieved by pH changes (very high or very low pH), by heat treatment or by
irradiation such as gamma
irradiation or UV irradiation, particularly UV-C irradiation. The SARS-CoV-2
virus may be optionally
inactivated by two separate inactivation steps, such as, e.g. beta-
propiolactone treatment and UV-C
irradiation.
EVALUATION OF BPL STARTING CONCEN
___________________________________________________ IRATION FOR INACTIVATION
OF A HIGHLY
RESISTANT MODEL VIRUS PPV
A preliminary study for evaluation of PPV virus inactivation kinetic was
conducted to initially support
our proposed SARS-CoV-2 BPL inactivation procedure. Porcine Parvovinis (PPV)
was selected as a
model virus to evaluate the inactivation capability of BPL in aqueous solution
because of its high
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resistance to physico-chemical inactivation. Three starting concentrations of
BPL were evaluated, 300
ppm (1/3333), 500 ppm (1/2000) and 700 ppm (1/1429). Virus solution was spiked
with BPL at these
concentrations and incubated at 5 2 C for 24 hours. Kinetic samples were taken
at 0.5, 2, 6, 24h and
after the BPL hydrolyzation step and analysed for remaining infectivity. The
results are shown in Table
A.
Table A: Summary of virus titers and reduction factors for PPV
inactivation by BPL concentration [ppm]
300 500 700
titer w/o BPL 9.97 10.04 9.98
[TCID50/mL]
titer 24h 6.66 4.98 4.1
incubation
[TCID50/mL]
titer after 5.1 2.6 ** <LOD.*
hydrolysis
[TCID50/mL1
reduction factor 4.84 0.39 7.43 0.92 >6.89 0.23
after hydrolysis
*below limit of detection
**Note limit of detection for 500ppm BPL is lower than for 700ppm BPL
A clear effect of initial BPL concentration on the inactivation effectivity
was observed with a reduction
between 3.3 and 5.9 log10 after 24h incubation at 5 2 C (before hydrolysis).
The following hydrolysis
step further reduced the titers by on average addition 1.7 log10 while the
hold control titers remained
constant throughout the whole procedure. This indicated that for highly
resistant virus contaminations
the hydrolysis step might serve as an additional inactivation step.
With overall reduction factors of 4.84 (300 ppm), 7.43 (500 ppm) and below the
limit of detection (700
ppm) the applied BPL treatment was considered effective for the inactivation
of Parvoviridae at
concentrations > 300ppm
Therefore, we decided to select 500ppm for SARS-CoV-2 virus inactivation in
all further studies.
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SARS-CoV-2 virus inactivation by BPL
Based on existing data on the inactivation of model viruses by BPL (see
section above on PPV
inactivation) a BPL concentration of 500 ppm (1/2000) was selected for the
inactivation of SARS-CoV-
2 virus harvest material. As the stability of BPL in solutions is highly
temperature dependent an
incubation temperature of 5 3 C and an incubation time of 24 hours were
selected to ensure enough
BPL present throughout the whole inactivation. After addition and mixing of
BPL to the concentrated
harvest, the inactivation solution is transferred to a fresh container where
the inactivation takes place
under controlled conditions. This transfer excludes the possibility of virus
particles in potential dead-
spots during initial mixing not being in contact with BPL.
To stabilize the pH of the inactivated viral solution during hydrolysis of the
BPL, protamine sulfate
(PS) treated concentrated harvest pre-cooled to 5 3 C is supplemented with 25
mM HEPES pH 7.4.
To reduce remaining BPL after the inactivation the solution is warmed to
temperatures above 32 C for
a total time of 2.5 hours 0.5 hours in a temperature-controlled incubator
set to 37 2 C. The total time
of the hydrolyzation step for the current process volume of about 1L was
between 5 hours 15 minutes
and 6 hours 15 minutes including the warming to and the incubation above 32 C.
After completion of the hydrolysis, the inactivated viral solution (IVS) was
immediately cooled down
to 5 3 C in a temperature-controlled fridge and stored there until
inactivation was confirmed by large
volume plaque assay and serial passaging assay which currently requires 18
days in total.
Recovery of virus particles throughout the inactivation process was monitored
by size-exclusion
chromatography.
Initial studies at lab-scale from 15 mL up to 1000mL indicated a very fast
inactivation kinetic for SARS-
CoV-2 where virus titers of up to 8 log10 pfu/mL were reduced below detectable
levels within 2 hours
after BPL addition. These results were confirmed for GMP production runs at a
final inactivation
volume of approximately IL.
Taken together with the inactivation data for model viruses the applied BPL
treatment can be considered
efficient and includes a significant safety margin for inactivation of SARS-
CoV-2 concentrated harvest
material.
In a further preferred embodiment, the inactivation step(s) are particularly
gentle, in order to preserve
surface antigen integrity, especially integrity of the S protein. In one
embodiment, the gentle
inactivation method comprises contacting a liquid composition comprising SARS-
CoV-2 particles with
a chemical viral inactivating agent (such as e.g. any of the chemical
inactivation agents as listed above
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or a combination thereof, preferably beta-propiolactone) in a container,
mixing the chemical viral
inactivating agent and the liquid composition comprising SARS-CoV-2 particles
under conditions of
laminar flow but not turbulent flow, and incubating the chemical viral
inactivating agent and the liquid
composition comprising SARS-CoV-2 particles for a time sufficient to
inactivate the viruses. The gentle
inactivation step is optionally performed in a flexible bioreactor bag. The
gentle inactivation step
preferably comprises five or less container inversions during the period of
inactivation. Preferably, the
mixing of the chemical viral inactivating agent and the composition comprising
SARS-CoV-2 particles
comprises subjecting the container to rocking, rotation, orbital shaking, or
oscillation for not more than
minutes at not more than 10 rpm during the period of incubation.
10 Purification of' SARS-CoV-2 Optionally, the material was immediately
further processed by batch
adsorption (also known herein as batch chromatography) with CaptoTM Core 700
(CC700) or CC400
chromatography media at a final concentration of ¨1% CC700 or CC400. The
material was incubated
at 4 C for 15 minutes under constant agitation using a magnetic stirrer. After
incubation, if used. the
CC700 or CC400 solid matter was allowed to settle by gravity for 10 minutes
and the SARS-CoV-2
material is removed from the top of the solution in order to avoid blockage of
the filter by CaptoCore
particles. Any remaining CaptoCore particles and DNA precipitate were then
removed from the solution
by filtration using a 0.2 JAM Mini Kleenpak EKV filter capsule (Pall). The
filtered harvest material was
adjusted to a final concentration of 25 mM Tris pH 7.5 and 10% sucrose (w/w)
using stock solutions of
both components. This allowed for freezing the concentrated harvest at <-65 C
if required.
The resulting filtrate was further processed by sucrose density gradient
centrifugation (also known
herein as batch centrifugation) for final concentration and polishing of the
SARS-CoV-2 material. The
concentrated protaminc sulfate (PS) or benzonase treated (preferred is PS
treated) harvest is loaded on
top of a solution consisting of three layers of sucrose with different
densities. The volumes of individual
layers for a centrifugation in 100 mL bottle scale are shown in Table 1.
Table 1: Volumes for sucrose density centrifugation.
Sucrose solution (w/w) Volume (mL)
PS-treated SARS-CoV-2 harvest (10% sucrose) 40
15% sucrose 15
35% sucrose 15
50% sucrose 20
Total volume 90
The sucrose gradient bottles are prepared by stratifying the individual
sucrose layers by pumping the
solutions into the bottom of the bottles, starting with the SARS-CoV-2
material with the lowest sucrose
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density (10% sucrose (w/w)), followed by the other sucrose solutions in
ascending order. The described
setup is shown in Figure 3. The prepared SG bottles are transferred into a
rotor pre-cooled to 4 C and
centrifuged at ¨11,000 RCF max at 4 C for at least 20 hours, without
brake/deceleration.
After centrifugation, harvest of serial 2 mL fractions of the sucrose gradient
was performed from the
bottom up with a peristaltic pump. The fractions were immediately tested by
SDS-PAGE / silver
staining to identify virus-containing fractions with sufficiently high purity.
Thus, identified fractions
were pooled and further processed. The purified SARS-CoV-2 was stored at <-65
C or immediately
formulated.
Formulation of SARS-CoV-2 with adjuvant CpG, and optionally alum, were added
to the SARS-CoV-
2 composition and/or prepared in a separate vial for bedside
SARS-CoV-2 ELISA Assay Inactivated SARS-CoV-2 antigen content (i.e. content of
Si as the major
antigenic protein) in preparations described herein was determined
(quantified) by ELISA. The SARS-
CoV-2 ELISA used herein is a four-layer immuno-enzymatic assay with a SARS-CoV-
2 spike antibody
(AM001414; coating antibody) immobilized on a microtiter plate to which the
SARS-CoV-2 sample
was added. On binding of the antigen to the coating antibody, the plate was
further treated with primary
antibody (i.e. AbElex SARS-COV-2 spike antibody (rAb) (AM002414)). This was
followed by
addition of the secondary antibody, which is an enzyme linked conjugate
antibody (i.e. Goat anti-Mouse
IgG HRP Conjugate). The plates were washed between various steps using a mild
detergent solution
(PBS-T) to remove any unbound proteins or antibodies. The plate was developed
by addition of a
tetramethyl benzidine (TMB) substrate. The hydrolyzed TMB forms a stable
colored conjugate that is
directly proportional to the concentration of antigen content in the sample.
The antigen quantification
was carried out by spectrophotometric detection at 2450nm (2630nm reference)
using the standard
curve generated in an automated plate reader as a reference. Standards were
prepared starting with a 20
antigen units (AU)/mL spike trimer working solution neat, which was further
serially diluted 1:2 for the
following standard concentrations: 20 AU/mL, 10 AU/mL, 5 AU/mL, 2.5 AU/mL,
1.25 AU/mL, 0.625
AU/mL, 0.3125 AU/mL and 0.1263 AU/mL. Each dilution was tested in duplicate
per plate. An
"antigen unit" of the spike trimer standard, according to the supplier (R&D
Systems), corresponds to
its binding ability in a functional ELISA with Recombinant Human ACE-2 His-
tag.
Reference Standards and Antibodies:
Coating Antibody: SARS-CoV-2 Spike Antibody (AM001414)
Spike Trimer (SI+S2), His-tag (SARS-CoV-2) (e.g. BPS Lot# 200826; Cat#100728)
SARS-CoV-2 QC (e.g. RSQC240920AGR)
Primary Detection Antibody AbFlex SARS-CoV-2 Spike Antibody (rAb) (AM002414)
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Secondary Detection Antibody Goat anti-Mouse IgG HRP Conjugate
Coating buffer: Carbonate buffer
ELISA wash buffer: PBS + 0.05% Tween-20 (PBS-T).
Sample dilution buffer: PBS-T + 1% BSA.
Production process delivered high density and intact spike proteins (see
Figure 7). Estimated were
about 1 to 1.5 x 10' viral particles per AU. Inactivation process by beta-
propiolactone provided for a
fast inactivation kinetic and no detectable chemical modification of the S-
protein. Key parameters and
relevant process related impurities were similar to the commercial IXIARO
production process (see
Table lb). SARS-CoV-2 drug substance according to the invention was highly
pure (>95%) according
to SDS-PAGE (silver stain, reduced) and free from aggregates (monomer virus
(>95%) according to
SE-HPLC (see Figure 8).
Further confirmatory studies aimed at characterizing modifications of S-
protein following beta-
propiolactone-inactivated SARS-CoV2 are carried out by mass spectrometric
analysis of tryptic digests
of the S-protein. The modification of amino acids in important epitopes is
minimal. Initial alignment of
receptor binding domains (RBD) within the S protein and hACE2 interfaces and
epitopes of several
known (cross)-neutralizing antibodies (SARS-CoV and SARS-CoV-2) have shown no
amino acids
within these epitopes with potential high conversion and only few with
potential lower conversion rates.
Table lb. Comparison of key parameters and relevant process related impurities
of the SARS-CoV-2
drug substance and 1XIAROV drug substance.
'SARS-CoV-Z:
IXIARO
Viral yield at harvest (logio PFU/mL) > 7.8 > 7.3
Residual host cell protein (HCP)
<150 <100
(ng/mL)
Residual host cell DNA (hcDNA)
(pg/mL) < LOQ < LOQ
(LOQ 40 pg/mL)
Virus Monomer by SEC-MALLS (%) >95 >95
=
Residual Protamine sulfate* ( g/mL)
< LOQ < LOQ
(LOQ 2 pg/mL)
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Endotoxins (EU/mL) <0.05 <0.05
LO < LOQ
<
Residual Inactivation reagent (LOQ
5 Oppm,
( LOQ 1ppm,13-Propiolactone)
Formalin)
Example 2. In vitro and in vivo assessment of immunogenicity and protective
capacity of
inactivated CoV-2 virus and adjuvanting/dose-sparing effects of CpG
Immunogenichy Prior to immunization, experimental groups of 10 BALB/c mice
were bled and pre-
immune sera are prepared. The mice are administered a dose titration of
inactivated SARS-CoV-2
formulated with alum or alum and CpG 1018 subcutaneously (see Table 2). At two
different intervals
after immunization (see below), blood was collected and immune sera prepared,
spleens were collected
at the final bleed. All animal experiments were carried out in accordance with
Austrian law (BGB1 Nr.
501/1989) and approved by "Magistratsabteilung 58". Sera were assessed for
total IgG and subclasses
(IgG1/IgG2a) by ELISA and neutralizing antibodies by PRNT. Th1/Th2 responses
were further
assessed by IFN-y ELISpot and intracellular cytokine staining (CD4L/CD8+).
-Schedule 1: Immunizations Day 0/Day 7, interim bleed Day 14, final bleed and
spleen harvest Day 28
-Schedule 2: Immunizations Day 0/Day 21, interim bleeds Day 14/Day 28 and
final bleed and spleen
harvest Day 35
Table 2. Design of dosing experiments, 10 mice/group: 3 dosage groups, first
set of experiments (A)
with higher dosages ranging from 0.1-1 mAU, second set of experiments (B) with
lower dosages
ranging from 0.05-0.5 mAU. (Total viral protein/mAU was estimated to be
approximately 2 ig/m1).
Adjuvants (mice/group)
Aluminium
Inactivated Aluminium
SARS-CoV-2 hydroxide hydroxide
dosages (A/B) (50 p,g) (5011g)/CpG
1018 (10 jug)
(1/0.5 mAU*) 10 10
(0.5/0.2 mAU) 10 10
(0.1 /0.05 m A U) 10 10
Placebo 10 10
* mAU - SE-HPLC peak area per dose equivalent (recorded as milli-absorption
units x minutes; mAU)
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Plaque reduction neutralization test (PR/VT) Each well of a twelve-well tissue
culture plate was seeded
with Vero cells and incubated 35 C with 5% CO2 for three days. Serial
dilutions from pools of heat-
inactivated sera from each treatment group are tested. Each serum preparation
was incubated with
approximately 50-80 pfu of SARS-CoV-2 at 35 C with 5% CO2 for 1 hour. The cell
culture medium
was aspirated from the Vero cells and the SARS-CoV-2 /serum mixtures are added
to each well. The
plates were gently rocked and then incubated for 2 hours at 35 C with 5% CO2.
To each well, 1 mL of
a 2% methylcellulose solution containing EMEM and nutrients were added, and
the plates were further
incubated for 4 days at 35 C with 5% CO2. The cells were then stained for 1
hour with crystal violet/5%
formaldehyde and washed 3 times with deionized water. The plates were air
dried and the numbers of
plaques in each well manually counted. Alternatively, other methods, such as
e.g. TCID50 may be
applied.
Table 3. Design of schedule and longevity experiments. Immunization schedule
as for Table 2, but in
addition; interim bleeds 2, 6, 10, 14, 18 and 22 weeks after second
immunization; end-bleed 26 weeks
after second immunization.
Adjuvants (mice/group)
Aluminium
Aluminium hydroxide
hydroxide (50 gimp/
(50 pg/m1) CpG 1018
(10 jig/m1)
Vaccine (high dose), s.c 20 20
Placebo, s.c. 10 10
Protective capacity The protective capacity of inactivated SARS-CoV-2 is
assessed using a SARS-
susceptible transgenic mouse expressing a humanized ACE2 protein (Jackson
Laboratory) (Tseng, C.-
T.K. et at., Severe Acute Respiratory Syndrome Coronavirus Infection of Mice
Transgenic for the
Human Angiotensin-Converting Enzyme 2 Virus Receptor (2007) J of Virol 81:1162-
1173) or a NHP
model developed for SARS-CoV-2 infection. Groups of animals are immunized
subcutaneously (s.c.)
with different dosages of inactivated SARS-CoV-2 with or without adjuvant or
PBS as a negative
control. Three weeks after the last dose, animals are challenged with SARS-CoV-
2 and monitored for
disease progression and survival. In addition, serum samples are taken in
order to determine the
neutralizing antibody titers induced by vaccination in a PRINT assay.
Table 3A. Design of dosing experiment 4743 using SARS-CoV-2 ELISA-determined
dosages.
Material SGP rVSB
Buffer PBS
AU/mouse 3.0
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1.2
0.3
A137mouse 17 jig
CpG 1018/mouse 10 jig
Immunization DO/D21
Bleeds D28/D35
Experiment 4743 Protocol Female BALB/c mice (10 mice/group) were immunized two
times s.c. (100
viL) on days 0 and 21 with doses and adjuvants as outlined in Table 3A. The
readouts from the
experiment were total IgG and subclasses (IgG1/IgG2a) and virus neutralization
(PRNT). Vaccine
formulation used in experiment 4743: purified inactivated SARS-CoV-2 produced
from a research virus
seed bank (rVSB) formulated in PBS with 17 lag Al3 (alum)/dose and 10 lag/dose
CpG 1018.
Antibody response to SARS-CoV-2 proteins The immune responses in mice for the
different doses
and adjuvant formulations were assessed with a total IgG ELISA (Figure 4).
Plates were coated with
either the Si part (Figure 4A) or receptor binding domain (RBD) (Figure 4B) of
the spike glycoprotein
or the nucleoprotein (Figure 4C). Sera taken on days 28 and 35 were analyzed.
Plates were coated with
2 1.1g/mL antigen (Si, RBD and N protein) and mouse sera were tested at a
starting dilution of 1:50 in
4-fold dilutions. For detection a secondary monoclonal antibody (HRP-
conjugated goat anti-mouse
IgG) was used and developed with ABTS and read at absorbance 405 nm. Wells
were washed with
PBS-T between each step. Endpoint titers were determined with a cut-offset to
3-fold the blank.
IgG subclass immune response Plates were coated with the Si part (Figure 4A)
of spike glycoprotein
and sera taken on day 35 were analyzed. Subclass specific secondary antibodies
(IgG1 and IgG2a)
conjugated with HRP were used for detection. As standard curves (4-paramater
regression) for
determination of the amount of the different IgG subclasses (IgG1 and IgG2a),
monoclonal antibodies
with different subclasses were used (IgG1 mAb clone 43 and IgG2a mAb clone
CR3022). Bound HRP-
conjugated secondary mAbs were developed with ABTS and read at absorbance 405
nm. Wells were
washed with PBS-T between each step. The relative IgG subclass concentration
is shown in Figure 5A
and the ratio of IgG2a/IgG1 in Figure 5B.
Observations from Experiment 4743 Inactivated SARS-CoV-2 formulated with alum
and CpG 1018
induced antibodies in mice against SARS-CoV-2 detected by ELISA measuring
antibodies to Si
protein, receptor binding domain (RBD) and nucleocapsid protein (N) (Fig. 4A-
C). An increase in
immunogenicity was observed between bleeds on day 28 and day 35. A significant
increase in
immunogenicity, i.e., a dose-sparing effect, was seen for Si and RBD in the
presence of CpG 1018. In
groups receiving the lowest doses (0.3 AU), a smaller increase not
significantly above the placebo was
seen for nucleoprotein, Si and RBD ELISA titers.
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The addition of CpG 1018 to alum-adjuvanted inactivated SARS-CoV-2 promoted a
substantial
immune response shift towards Thl (IgG2a) compared with Th2 (IgG1) as
demonstrated by
quantification of IgG subclasses by Si ELISA. The amounts of IgG2a and IgG1
measured and the ratio
of IgG2a:IgG1 in the treatment groups are shown in Figs. 5A and 5B,
respectively. A significant shift
in the immune response toward Thl (IgG2a) in the presence of CpG 1018 was
observed. In the presence
of CpG 1018 a stronger induction of IgG2a than IgGl was observed. In the alum
only groups a stronger
induction of IgG1 than IgG2a is observed.
Finally, the neutralizing response in the presence of alum/CpG in the group
immunized with the highest
SARS-CoV-2 dose was in the range of plasma from convalescent donors positive
for SARS-CoV-2
(NIBSC 20/162; three pooled donors)(see Fig. 6).
Further immunization experiments are carried out in mice using GMP material
with low doses (3, 1.2
and 0.3 AU) as a bridge between research and GMP material, as well as analyses
of GMP material in
mice with human doses (540, 10 and 3 AU).
Additionally, a challenge study is carried out in immunized non-human primates
(NHP) (see Figure 9)
and a passive transfer study is carried out in hamsters using sera from human
subjects vaccinated with
the SARS-CoV-2 vaccine candidate of the invention (see Table lc).
Table lc. Passive transfer study of the SARS-CoV-2 vaccine candidate of the
invention in hamsters.
Study objective: Proof of concept that the SARS-CoV-2 vaccine candidate of the
invention induces
neutralizing antibodies providing protection against SARS-CoV-2 challenge in
an animal model
Study design: Syrian hamsters receive sera from vaccinated subjects of the
SARS-CoV-2 vaccine
candidate of the invention Phase 1/2 study (see Example 4 below).
Hamsters arc then challenged intranasally with SARS-CoV-2, Victoria/1/2020
A 10 day follow up includes:
Clinical observations and body weights recorded daily
Viral shedding/viral loads determined via RT-qPCR
Circulating antibodies prior to challenge (neutralization)
Tissues (lung and upper respiratory tract) taken at necropsy for determination
of viral
load and for histology
Example 3. Testing of SARS-CoV-2 vaccine for antibody-dependent enhancement
(ADE) of
disease and immunopathology
Although the mechanism is poorly understood, antibodies produced in response
to a previous
coronavirus infection or vaccination can increase the risk for 1)
immunopathology and/or 2) antibody-
dependent enhancement of disease during subsequent coronavirus infection. As
such, any stimulation
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of antibodies to SARS-CoV-2 presents a hypothetical risk. In this regard,
several approaches are
undertaken to ensure safety of the current vaccine.
In vitro antibody-dependent enhancement assays Immune sera from inactivated
SARS-CoV-2-
vaccinated mice are assessed for hallmarks of enhanced disease in vitro. Such
assays are described by
e.g. Wang, S.-F., et at. 2014 (Antibody-dependent SARS coronavirus infection
is mediated by
antibodies against spike proteins (2014) BBRC 451:208-214). Briefly,
susceptible cell types or cell lines
are incubated with immune sera and subsequently infected with SARS-CoV-2.
Cells are assessed for
cytopathic effect and production of inflammatory markers.
Mouse model of immunopathology The risk of vaccine-enhanced immunopathology on
challenge is
assessed in a BALB/c mouse model as described by "fseng C.T. et at.
(Immunization with SARS
Coronavirus Vaccines Leads to Pulmonary Immunopathology on Challenge with the
SARS Virus
(2012) PLoS ONE 7(4):e35421). Briefly, the mice are immunized twice at two-
week intervals with
inactivated SARS-CoV-2 formulated as described herein followed by challenge
with SARS-CoV-2.
SARS-CoV-2 titers and immune cell infiltration of the lung are tested.
Non-human primate model of ADE The risk of ADE development in non-human
primates is assessed
as described by Luo F, etal. (Evaluation of Antibody-Dependent Enhancement of
SARS-CoV Infection
in Rhesus Macaques Immunized with an Inactivated SARS-CoV Vaccine (2018)
Virologica Sin/ca
33:201-204). Briefly, NHPs are immunized with inactivated SARS-CoV-2, followed
by SARS-CoV-2
challenge and evaluation of symptoms and disease pathology.
Example 4. Clinical Phase 1 study
Formulation of inactivated SARS-CoV-2 for Phase 1 trial The objective of the
Phase 1 trial is to assess
the safety of the vaccine, along with immunogenicity, and to determine an
optimal dose and adjuvant
in healthy human subjects. As such, three antigen doses were tested in
clinical phase 1: High, Medium
and Low, which are chosen to have a distance between each dose of
approximately 3-fold and a span
covering about a 10-fold difference between the high and low doses (e.g., 0.5,
2 and 5 ug/dose or 3, 10
and 40 AU/dose). About 150 healthy volunteers were enrolled (153), 50 subjects
per dose group aged
18 to 55 (see Figure 10). The dose range is selected in part to indicate any
potential dose-sparing effect
of CpG. As previously reported in the literature, a 2-3 fold reduction in
required antigen may be
expected in the presence of CpG. The three dosages are tested without antigen
and with 1 mg CpG plus
0.5 mg alum (A13). Currently 1st vaccination completed, 2nd vaccination
ongoing. Two DSMB meetings
have been performed with first meeting following availability of initial
safety data from sentinel
subjects (N=15), there no safety concerns identified, thus blinded randomized
study phase initiated. 2nd
DSMB for interim safety review upon completion of first vaccinations (N=153),
there no safety
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concerns identified. First data readout (day 36 safety and immunogenicity)
expected by April 2021 as
basis for dose decision for phase 3 (see Example 5).
The SARS-CoV-2 virus as purified herein has a high purity of >90% as assessed
by SDS-PAGE, SE-
HPLC and/or SARS-CoV-2 ELISA (Figure 8). Furthermore, preliminary studies have
indicated that
the incidence of genetic heterogeneities during passage of the virus is low
and no particular individual
mutations stand out (data not shown).
To arrive at a dose range, the SARS-CoV-2 virus was compared with JEV,
specifically assessing SE-
HPLC peak area per dose equivalent (recorded as milli-absorption units x
minutes; mAU), the total
amount of inactivated viral particles per dose and the total viral surface
equivalent per dose (see Table
4). "Ihis assessment was based on the assumption of a similar surface antigen
density between S (spike;
SARS-CoV-2) and E (envelope; JEV) proteins. Total protein was determined by
pECA assay (Table
4). Although the assay was variable, a correspondence of 1 mAU to ¨2 lig total
protein per mL was
observed. Another determination using an optimized SARS-CoV-2 S-protein ELISA,
as outlined in
Example 1, was also performed.
Table 4. Comparison of JEV and SARS-CoV-2 quantification parameters and an
approximation of the
total protein in Low. Medium and High SARS-CoV-2 dosage groups for Phase 1
clinical trials.
Ratio total Ratio surface
SE-HPLC peak particle antigen
Estimated total
area equivalent equivalent equivalent
protein/dose in
Dose CoV/JEV CoV/JEV CoV/JEV jug (
BCA assay)
Low 0.25 0.015 0.070
0.5
Medium 1 0.058 0.288 2
High 2.5 0.145 0.719 5
As SARS-CoV-2 virus particles (-92nm diameter) are much larger than Flavivirus
particles (-40nm),
corresponding to an approximately 5-fold greater virus surface area per
particle, an equivalently higher
antigen content is expected. Furthermore, other inactivated virus vaccine
preparations, including JEV
(IXIARO), TBE (Encepur) and HepA (VAQTA) reported antigen dose in the low pg
to ng protein
range. As these viruses are all formalin inactivated, the BPL-inactivated SARS-
CoV-2 virus of the
current invention has better preserved surface antigen proteins, i.e., a
better quality antigen, and requires
a lower total protein dose.
For entry into the clinic a further antigen determination assay (SARS-CoV-2
ELISA assay as described
in Example 1) was developed and the doses of the vaccine formulations for
entry into Phase 1 trials
were determined using this assay. The Phase 1 treatment groups are set forth
in Table 5.
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Formulation of SARS-CoV-2 vaccine for phase I trial (0.5 mL/dose,):
-Antigen (inactivated SARS-CoV-2) target doses (one dose = 0.5 mL):
Low: about 3 AU/0.5 mL *
Medium: about 10 AU/0.5 mL) *
High: about 40 AU/0.5 mL *
*doses determined by the SARS-CoV-2 ELISA assay as described in Example 1
-Aluminium hydroxide (A13 ): 0.5 mg/dose (1 mg/mL)
-CpG 1018: 1 mg/dose (2 mg/mL)
-Recombinant Human Serum Albumin (rHSA): ¨25 ug/dose (-50 ug/mL)
-Buffer: Phosphate buffered saline (PBS)
In some cases, vaccinated subjects are challenged with an infectious dose of
live SARS-CoV-2 virus
(Asian and/or European lineage).
Table 5. Treatment groups for Phase 1 testing of inactivated SARS-CoV-2
vaccine (low, medium and
high doses as set forth above). Two doses are administered (day 0 and day
21).
Group Antigen Aluminium CpG 1018
hydroxide
1 Low
2 Med
3 High
4 Low
5 Med
6 High
Example 5. Clinical Phase 3 study
Neutralizing antibodies are emerging as a robust clinical parameter:
= Emerging clinical evidence suggesting neutralizing antibodies are associated
with protection
against COVID-19
= Protection from moderate to severe COVID-19 disease has been shown to
coincide with
emergence of neutralizing antibody levels against SARS-CoV-2 (field efficacy
study with the
mRNA vaccine of Pfizer/Biontech)
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= Monoclonal antibody (Bamlanivimab) was shown to prevent subjects from
developing
symptomatic COVID-19 by 80% in a phase 3 trial conducted by the National
Institutes of
Health's National Institute of Allergy and Infectious Diseases (NIAID),
= Monoclonal antibody administration in hamsters or non-human primates have
been shown to
protect from disease induced by COVID-19 in these animal models.
= Adoptive transfer of purified IgG from convalescent rhesus macaques
(Macaca mulatta) has
been shown to protect naive recipient macaques against challenge with SARS-CoV-
2 in a
dose-dependent fashion
Plan for phase 3 Non-inferiority study (Figure 11)
= Randomized, observer-blind, controlled, non-inferiority study to compare
the immunogenicity
of inactivated SARS-CoV-2 vaccine of the invention*** to [Active Comparator,
e.g.
AZD1222 or BNT162b2, to be determined]
= Dosage: two i.m. vaccinations within 1 month; Dose level selected based
on Phase 1/2
= Study Population: 4000* healthy volunteers aged 18 years and above,
randomized 3:1 to
receive inactivated SARS-CoV-2 vaccine of the invention or [Active Comparator]
to establish
safety database for initial licensure
= Immunogenicity sub-set of approximately 600 participants** who have
tested sero-negative
for SARS-CoV-2 at screening; 1:1 distributed to inactivated SARS-CoV-2 vaccine
of the
invention or [Active Comparator]
= Primary Endpoint:
o Non-inferiority of immune response 4 weeks after
completion of a 2-dose
Immunization Schedule, as determined by the GMT of SARS-CoV-2-specific
neutralizing antibodies or seroconversion rate
* A sample size of 3000 subjects vaccinated with the inactivated SARS-CoV-2
vaccine of the
invention will allow for the detection of at least 1 rare event (incidence
rate 1/1000) with a probability
of 94% in this study.
** Sample size to be confirmed upon availability of phase 1/2 immunogenicity
results
***See Figure 12. Phase clinical trial material comparable to clinical study
material of phase I (see
Example 1)
Example 6. Testing of Sera of vaccinated organism with a neutralization assay
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Sera of vaccinated mice, hamsters, non-human primates or humans can be tested
in neutralization
assays such as e.g. described in -Szurgot, I., Hanke, L., Sheward, D.J. et al.
DNA-launched RNA
replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice. Sci
Rep 11, 3125
(2021). https://doi.org/10,1038/s41598-021-82498-5".
The read out of the test gives an indication how well sera of vaccinated
subjects can neutralize new
variants and thus guides in the design of the vaccine.
Example 7. Liquid chromatography with tandem mass spectrometry (LC-MSMS)
analysis of
inactivated SARS-CoV-2
Methodology:
Two samples of the BPL-inactivated SARS-CoV-2 particles were separated using
SDS-
polyacrylamide gel electrophoresis and the bands were visualized by silver
staining. The bands were
cut and subjected to in-gel digestion with trypsin and the resulting peptides
analysed with nano-liquid
chromatography coupled to a high-resolution accurate mass spectrometer.
Peptides were identified
from raw spectra using the MaxQuant software package and the UniProt reference
databases for
SARS-CoV-2 and Chlorocebus sabaeus. To account for modifications the data were
re-searched
specifically for B-propiolactone modifications, and the obtained results were
confirmed with a second
independent search algorithm (Sequest in Proteome Discoverer suite).
Additionally, data were
searched with the FragPipe package to account for further unknown MS-
detectable modifications.
Results:
Protein identification:
The bands could be clearly attributed to the three main viral proteins (Spike-
protein, Membrane-
protein, Nucleoprotein) as well as to background proteins from the host system
(see Figure 10).
Traces of SARS-CoV-2 ORF9b and the replicase polyprotein could also be
detected, but these
proteins were probably not well resolved on the gel due to their size. The
separation pattern on the gel
was very similar for both samples with the exception of a host protein band
(band 2.3), a slightly
different S-protein pattern (bands 2.10-2.13), and an expected strong band of
serum albumin in one of
the samples (sample 2). Additionally, a number of typical lab contaminants of
human origin (e.g.
keratins) were detected in the background of both samples. The processing of
the Spike-protein (from
full length to Si, S2, and S2') is difficult to resolve with the applied
methodology but is most likely
represented by the pattern in bands 9-13 in both samples.
Modification analysis:
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Based on a publication by Uittenbogaard et al. (Reactions of B-Propiolactone
with Nucleobase
Analogues, Nucleosides, and Peptides, Protein Structure and Folding l Volume
286, ISSUE 42,
P36198-36214, October 21, 2011), it was expected to find B-propiolactone (BPL)
modifications on
cysteine, methionine, and histidine. Uittenbogaard et at studied amino acids
which are subject to
modification by beta-propiolactone, along with the type of modification, e.g.,
acylation, alkylation.
They have shown that BPL can react with up to 9 different amino acids
(C,H,M,D,E,Y,K,E,S)
depending on actual pH. In their studies higher conversions within the
relevant pH range 7 to 9 were
observed for Cysteine (>95%), Histidine (15-25%) and Methionine (36%)
residues. The conversion
rates for Aspartic Acid, Glutamic acid and Tyrosine were much lower in the
range of approximately
3-15%. It was shown that disulfide groups in Cystine residues do not react.
In BPL-inactivated SARS-CoV-2 particles, BPL modifications could be detected
(mainly in the form
of +72 Da) but at a low abundance. Out of 2894 (sample 1) and 3086 (sample 2)
identified spectra for
SARS-CoV-2 proteins only 73 and 110, respectively, carried a BPL modification,
which translates to
2.5 to 3.65 % (see Table 6). This was also confirmed by the open modification
search using FragPipe,
which attributed a similarly low fraction of spectra to mass differences
matching the BPL-
modification.
Table 6. Number of identified SARS-CoV-2 peptide spectra
Sample Total spectra BPL spectra % modified
Sample 1 2894 73 2.5%
Sample 2 3086 110 3.6%
Spectra of all BPL-modified peptides reported for SARS-CoV-2 proteins were
inspected manually of
which 6 to 8 sites were confirmed for sample 1 and 2, respectively (see Table
6). For all of these
validated sites also the unmodified peptides were identified suggesting that
the modification with BPL
never reached 100%. We estimated the degree of modification on a particular
site (the so-called site
occupancy) as the ratio of modified to unmodified peptide for the same
modification site normalized
to the protein abundance for each band. We then selected the maximum occupancy
for each site as a
conservative measure of the degree of site modification. As shown in Table 7
the occupancy was in
general rather low for the sites identified, in agreement with the total
number of identified spectra.
The only exception, M234 of the nucleoprotein, has to be interpreted
carefully, as that particular
peptide sequence has problematic features which likely make the estimation for
this particular peptide
less accurate and reliable as compared to the other sites.
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Table 7. BPL-modified sites identified and their occupancy
Protein Site Position % occupancy sample %
occupancy sample
1 2
Spike-protein H207 <0.1% 16%
Spike-protein H245 1% 3%
Spike-protein C379 <0.1% n.d.
Spike-protein M1029 <0.1% <0.1%
Spike-Protein C1032 <0.1% n.d.
Membrane protein H154 <0.1% <0.1%
Membrane protein H155 1% 1%
Membrane protein C159 n.d. <0.1%
Membrane protein H210 5% 6%
Nucleoprotein M234 <0.1% 88%*
n.q. = not quantified; n.d. = not detected
*quantification uncertain, due to missed cleavages and oxidation
Apart from the expected modifications the FragPipe search revealed two other
modifications (most
likely acetaldehyde and acetylation) to occur in around 10% of the spectra.
These modifications
represent most likely artifacts introduced during gel staining and sample
preparation, as they also
occur on contaminant proteins.
Summary
Based on the results described above it is concluded that the main components
in these samples
corresponds to SARS-CoV2 proteins. The BPL modifications were detectable but
appeared to be low,
i.e. around 3% on whole SARS-CoV-2 proteome level (i.e. all SARS-CoV-2
proteins identified).
Only 5 amino acids of the S-protein were found to be modified and this was
also only detected for a
minority of the analysed S-protein (e.g. around 16% for the Spike-protein at
the H207 amino acids,
i.e. the probability to have a modification at H207 was around 16%). The two
samples differ only
slightly with respect to some background proteins and in their degree of
modification, with sample 1
showing slightly lower levels of BPL-modification. Please note that only about
30 to 40% of the
amino acids of the Spike protein could be tested.
Conclusion:
This data supports the view that the mild inactivation approach of the
invention minimizes the
modifications within the S-protein and thus the native surface of the S-
protein is largely preserved. In
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comparison, determination of modifications by BPL inactivation of flu samples
were more frequent,
i.e. 83 sites on HA and 43 sites on NA for one sample flu vaccine (NIBRG-
121xp) and 99 sites on HA
and 39 sites on NA for another sample (NYMC-X181A) were modified, wherein HA
and NA are the
two major membrane glycoproteins, i.e. the primary immunogens for flu (She Yi-
Min et at, Surface
modifications of influenza proteins upon virus inactivation by beta-
propiolactone; Proteomics 2013,
13, 3537-3547, DOT 10.1002/pmic.201300096). Thus BPL inactivation of influenza
virus can lead to
numerous protein modifications including some affecting membrane fusion.
Example 8. Immunogenicity, neutralizing antibody responses and protective
effect in non-
human primates
In this study, non-human primates (cynomolgus macaques) were immunized with
either a medium
dose or high dose of an inactivated SARS-CoV-2-vaccine as described above (see
e.g. Example 4).
Immunogenicity, neutralizing antibody responses and protective effect were
then determined (see e.g.
Examples 2 and 6).
Total IgG immune responses in cynomolgus macaques
The immune responses in cynomolgus macaques for the two doses (medium and
high) were assessed
with a total IgG ELISA. Plates were coated with either the soluble ectodomain
of spike protein with a
T4 trimerization domain (A) or receptor binding domain (RBD) (B) of the spike
glycoprotein or the
nucleoprotein (C). Sera taken at baseline (day -1) and on days 0, 14, 21 28,
35 and 47/49 were
analyzed. Antibody units (AU) were determined by fitting the relative
luminescence to the respective
standard curves with a known IgG concentration in AU/mL.
The results are shown in Figure 16. The inactivated SARS-CoV-2-vaccine was
highly immunogenic
in cynomolgus macaques, and a plateau in the immune response was already
reached one week after
the second immunization. There was no significant difference in the immune
responses between high
and medium dose.
Neutralizing antibody responses in cynomolgus macaques
Presence of functional antibodies in macaque immune sera after immunization
with the inactivated
SARS-CoV-2-vaccine was assessed in a serum neutralization test. Serial
dilutions of sera (days 0, 14,
21, 28, 35 and 47/49) were incubated with SARS-CoV-2 (SARS-CoV-2 strain
Slovakia/SK-
BMC5/2020), where spike glycoprotein specific antibodies bind to the virus,
thereby blocking virus
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attachment to the ACE2 receptor on the surface of the target cells, and
prevent entry into the cell. The
50% endpoint titers (SNT50) were determined with the Spearman-Karber method.
The results are shown in Figure 17. As for the total IgG titers, a plateau was
reached for both medium
and high doses one week (day 28) after the second immunization. There seems to
be a difference
between the high and the medium doses on days 28 and 35, however, this
difference is not statistically
significant.
Viral colonization in cynomolgus macaques
Four weeks after the second immunization, macaques were challenged
intranasally (0.25 mL per
nostril) and intratracheally (4.5 mL) with 1>< i05 PFU SARS-CoV-2 (SARS-CoV-2
strain
BetaCoV/France/IDF/ 0372/2020 SARS-CoV-2). Nasopharyngeal and tracheal swabs
were taken
before challenge (day 35) and on days 1, 2, 3, 4, 7 11 and 15 days post
infection. Bronchoalveolar
lavage (BAL) was collected on day 3 post infection. Swabs and BAL were
analyzed with RT-qPCR
(genomic and subgenomic) for presence of SARS-CoV-2.
The results are shown in Figures 18 to 20. Cynomolgus macaques immunized with
the inactivated
SARS-CoV-2-vaccine were protected from a combined intranasal and tracheal
challenge with SARS-
CoV-2. SARS-CoV-2 genomic RNA could transiently be detected in immunized
macaques on day 2
post infection at a very low level in nasopharyngeal and tracheal swabs, but
not at all in BAL. Sub-
genomic SARS-CoV-2 RNA was not detectable at all in nasopharyngeal and
tracheal swabs, nor in
BAL. Sub-genomic RNA is a measure of virus which has replicated in the host.
No difference
between the high and medium dose of the inactivated SARS-CoV-2-vaccine could
be detected in
regard to the level of protection observed.
Example 9. Immunogenicity of inactivated SARS-CoV-2 vaccine in rats
This study relates to a prophylactic, purified, inactivated SARS-CoV-2 vaccine
for the prevention of
COVID-19 caused by SARS-CoV-2. SARS-CoV-2 is propagated on Vero cells and
inactivated by 13-
propiolactone. In this example, a repeat dose and local tolerance toxicity
study was performed in
female and male rats to assess potential systemic toxicity and local
tolerability of the inactivated
SARS-CoV-2 vaccine.
A human dose of 53 antigen units (AU)/0.5 mL was formulated with an aluminium
salt (Alhydrogel)
and CpG 1018. Rats were given intramuscular injections (2 sites x0.2 mL, 42
AU) on three occasions
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with 2 weeks interval over a period of 29 days. Blood was collected by
yenipuncture from the jugular
(or other suitable) vein on day 8, day 15 and day 22 as well as on day 51.
Serum samples from the animals assigned to the recovery phase of the study
were analyzed to assess
the immunogenicity of the vaccine and monitor the immune response over time.
MATERIAL AND METHODS
EQUIPMENT
Multiplate washer BioTek ELx405 Select CW with Bio-Stack.
Multiplate reader BioTek Synergy 2 using Microplate software Gen5 (version
3.10.06) for data
acquisition and evaluation.
GraphPad Prism (version 8.4.3) was used for plotting and visualization of
data.
MATERIAL AND REAGENTS
Nunc MaxiSorpt flat-bottom 96 well microtiter plates (Thermo Scientific,
#439454) Microplate, 96
well, PS, F-bottom, clear (Greiner Bio-One International, #655161) Dulbecco's
Phosphate Buffered
Saline (DPBS) lx (Gibco, #14190-094) Dulbecco's Phosphate Buffered Saline
(DPBS) 10x (Gibco,
#14200-067)
Bovine Serum Albumin (BSA) Fraction V (biomol, #01400.100)
Tween 20 (Sigma-Aldrich, #P7949-500m1)
Goat Anti-Rat IgG-HRP (Southern Biotech, #3030-05)
ABTS [2,2' Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] (Sigma-Aldrich,
#A3219-100m1)
Sodium dodecyl sulfate (SDS) (Sigma-Aldrich, #71729)
Spike Si protein, 78 kDa (Aviva, #0PAN06665-100UG)
Biological material
Rat scrum samples were collected on study days 8, 15, 22 and 51 from the two
groups in the recovery
study (Table 8), frozen at the test facility, shipped on dry-ice and stored at
-80 C until analysis.
Table 8: Experimental design, recovery groups.
Dosage Dose Number of Animals
Treatment Level Volume Males Females
(AU/dose) (mL)*
0.9% sodium chloride 0 0.4 5 5
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Vaccine 42 0.4 5 5
* One injection to each hind limb (2x0.2 mL) on each dosing occasion
METHODS
ELISA
Vaccine-specific serum antibody responses were determined using the ELISA
protocol as described
below.
ELISA plates (Maxisorp, Nunc) were coated with 100 ng spike Si protein in PBS
and incubated at
4 C overnight. The plates were blocked with 5% BSA, 0.05% Tween-20, PBS for 1-
2 hours at RT.
Plates were washed with PBS/0.1T (PBS with 0.1% Tween-20). Individual rat sera
(five per plate)
were diluted in blocking buffer (five-fold dilution), added to 96-well plates
and tested in duplicates by
incubating for 1 hour at RT. Plates were then washed with PBS/0.1T. The
secondary antibody (Goat
Anti-Rat IgG-HRP, Southern Biotech) was diluted 1:4,000 in blocking buffer,
added to the 96-well
plates and incubated for 1 hour at RT. Plates were washed with PBS/0.1T and
ABTS (Sigma-Aldrich)
was added as substrate. After incubation for 30 min, the reaction was stopped
by the addition of 1%
SDS and the absorbance was read at 405 nm. The half-max titer (the reciprocal
of the dilution that
corresponds to the mean absorbance between highest and lowest dilution) was
determined.
Sample fate
After completion of the analysis and acceptance of the results, the remaining
samples were discarded.
RESULTS
Serum samples obtained from two study groups at different time points were
analyzed by ELISA. The
geometric mean titers for male and female rats from each group, time point are
shown in the Table 9
below.
Table 9: Geometric mean half-max titers for each group split into male and
female rats
Group Sex Study Day
8 15 22 51
0.9% sodium Male <50 <50 <50 <50
chloride Female <50 <50 <50 <50
Vaccine Male <50 253 6983 11431
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Female <50 127 19680 12279
Sera from rats in the placebo group (0.9% sodium chloride) showed no
reactivity (half-max titer <50)
at any of the time points when analyzed by ELISA (see Table 9 above).
Rats in the group vaccinated with inactivated SARS-CoV-2 vaccine showed after
the first
immunization a weak response, however, below a measurable half-max titer (data
not shown). One
week after the second immunization (day 22) a plateau in the immune response
was reached (see
Table 9 above, Figure 21 and Figure 22). A slightly higher immune response was
observed in female
rats on study days 15 and 22 (see Table 9 above, Figure 21). However, this
difference was not
statistically significant.
DISCUSSION
In this study, the inactivated SARS-CoV-2 vaccine was shown to be highly
immunogenic in all rats.
However, a low immune response was observed following a single immunization.
Subsequent
immunization resulted in continued increases in anti-spike Si protein antibody
titers. A plateau was
reached after the second immunization, suggesting that a two-dose regime could
be sufficient to reach
high antibody titers at least in rats. The third immunization did not further
increase the antibody titers.
A normal dose kinetics was seen in the animals.
CONCLUSION
The analysis described in this report indicated that the inactivated SARS-CoV-
2 vaccine was highly
immunogenic in rats and induced robust antibody titers in rats.
Example 10. Further liquid chromatography with tandem mass spectrometry (LC-
MSMS)
analysis of inactivated SARS-CoV-2
Methodology:
A further LC-MSMS analysis of BPL-inactivated SARS-CoV-2 particles, as
described in Example 7,
was performed in order to obtain greater coverage of the proteins. Five
aliquots of the BPL-
inactivated SARS-CoV-2 sample were separated on SDS-PAGE and the bands
visualized by either
silver staining for visualization or Coomassie staining for processing. The
Coomassie-stained bands
corresponding to spike protein (based on previous analysis) were subjected to
in-gel digestion with
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trypsin or chymotrypsin or to acid hydrolysis. Trypsin digests were performed
twice, once with and
once without previous PNGase F (peptide :N-glycosidase F) digestion, to
identify peptides masked by
glycosylation.
Digested peptides were analysed by LC-MSMS essentially as described in Example
7. In particular.
the resulting peptides were analyzed with nano-liquid chromatography coupled
to a high-resolution
accurate mass spectrometer. Peptides were identified from raw spectra using
the MaxQuant software
package and the UniProt reference databases for SARS-CoV-2 and Chlorocebus
sabaeus in
combination with a database of common lab contaminants. To account for
modifications the data were
also searched specifically for B-propiolactone (BPL) modifications, and
spectra of all BPL-modified
peptides of the SARS-CoV-2 spike protein were manually validated. The degree
of modification was
globally estimated as the percentage of BPL-modified spectra identified, and
on site-level by
calculating site occupancies from the ratio of modified to unmodified peptides
for each peptide/site
separately.
Results:
The total coverage of particular SARS-CoV-2 proteins, using the combination of
four digestion
methods (i.e. (i) trypsin (ii) trypsin + PNGase F (iii) chymotrypsin and (iv)
acid hydrolysis) was as
follows:
Spike (S) protein ¨ 91.5%
Membrane (M) protein ¨ 60.36%
Nucleoprotein (N) ¨ 74.70%
The number of BPL-modified peptides in the inactivated SARS-CoV-2 particles,
based on each
digestion method, is shown in Table 10 below:
Table 10: Number of identified SARS-CoV-2 peptide spectra across all bands
analyzed
Sample Total BPL % BPL
modified modified
Trypsin 3148 97 3.1%
Trypsin + PNGase 2354 61 2.6%
Chymotrypsin 2753 174 6.3%
Acid hydrolysis 939 33 3.5%
Total 9194 365 4.0%
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As shown in Example 7, this confirms that the percentage of BPL-modified
peptides is low regardless
of the digestion method, e.g. less than 7%, 2 to 7% or around 2-5% on average.
Using a combination of the four digestion methods described above, a greater
coverage of amino acid
residues in SARS-CoV-2 proteins could be achieved. Accordingly, BPL-
modifications were detected
at the positions in the spike (S) and membrane (M) proteins shown in Table 11
below. The mean %
occupancy at each site, as described in Example 7 above, is also shown in
Table 11.
Table 11. BPL-modified sites identified in S protein and their occupancy
Protein Site Position % occupancy
Spike-protein H49 1%
Spike-protein H146 2%
Spike-protein C166 1%
Spike-protein M177 6%
Spike-Protein H207 1%
Spike-protein H245 13%
Spike-protein C432 8%
Spike-protein H519 2%
Spike-protein H625 7%
Spike-Protein M1029 2%
Spike-Protein H1058 11%
Spike-protein H1083 3%
Spike-protein H1088 4%
Spike-protein H1101 1%
Spike-protein H1159 4%
Spike-Protein H1271 1%
Membrane protein H125 <10%
Membrane protein H154 <10%
Membrane protein H155 <10%
Membrane protein H210 <10%
From the data in Table 11, it can be seen that up to around 16 residues in the
spike (S) protein may be
modified, and up to 4 residues in the membrane (M) protein. The occupancy at
each site is low, e.g.
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less than 20%, typically less than 10%. Therefore the inactivated SARS-CoV-2
particles show a low
degree of BPL-modifications.
Example 11. A Phase I/II Randomized, Dose- Finding Study To Evaluate The
Safety,
Tolerability And Immunogenicity Of an Inactivated, Adjuvanted SARS-CoV-2 Virus
Vaccine
Candidate Against COVID-19 In Healthy Subjects
A Phase I/II clinical study based on the methodology set out in Example 4
above was carried out.
Thus the product composition is essentially as described in Examples 1 and 4
above. Three dose
levels (low, medium and high) were studied, as described in Table 12 below.
The dose levels (in
AU/dose) may be determined by the SARS-CoV-2 ELISA assay as described in
Example 1. For all
dose levels, the adjuvant comprised 0.5mg/dose aluminium hydroxide and 1
mg/dose CpG 1018.
Table 12. Product composition ¨ 0.5 mL/dose
Active substance Measured Antigen
Units per
dose in final product by ELISA
SARS-CoV-2 inactivated virus Low dose 3 AU
Medium dose 7 AU
High dose 35 AU
Excipients and buffer components
Aluminum hydroxide All dose levels 0.5 mg/dose
CpG 1018 All dose levels 1 mg/dosc
Dulbecco's Phosphate Buffered Saline (DPBS)/Tris Buffered Saline')
rHA All dose levels <25 ps/dose
1DPBS composition: 200 mg/mL KCl (2.68 mM), 200 mg/mL KH2PO4 (1.47 mM), 8000
mg/mL
NaCl (136.9 mM), 2160 mg/mL Na2HPO4*7H20 (8.06 mM); Tris buffered saline: 20
mM Tris, 100
mM NaC1, pH 7.5.
Study design
The study is a randomized, dose-escalation, multicenter study with three dose
groups. Two doses
were administered to each subject, 21 days apart (Day 1 and 22). The study
population was
approximately 150 healthy volunteers aged 18 to 55 years. The study is
conducted in two Parts. Part
A (covering the follow-up from Day 1 to Day 36) and Part B (covering the
follow-up from Day 37 to
Day 208). The study was carried out at 4 sites in the UK, Birmingham, Bristol,
Newcastle,
Southampton. The immunization route was intramuscular (i.m.).
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Objectives
Primary Objective:
The primary objective of this study is to evaluate the safety, tolerability
and immunogenicity of the
inactivated, adjuvanted SARS-CoV-2 vaccine candidate up to 14 days after
completion of a two-dose
(Day 1 and 22) schedule in healthy adults aged 18 to 55 years.
Secondary Objectives:
To determine the optimal dose level of inactivated, adjuvanted SARS-CoV-2
vaccine candidate in
healthy adults aged 18 to 55 years.
To evaluate tolerability, safety and immunogenicity of the inactivated,
adjuvanted SARSCoV-2
vaccine candidate up to 6 months after the last vaccination in healthy adults
aged 18 to 55 years.
Table 13. Study endpoints
Primary Endpoints Secondary Endpoints
SAFETY SAFETY
+ Frequency and severity of solicited + Frequency and severity of any
unsolicited AE until
adverse events (AEs) (local and systemic Day 36.
reactions) within 7 days after any + Frequency and severity of any
vaccine-related AE
vaccination. until Day 36.
+ Frequency and severity of any AE until Day 208.
+ Frequency and severity of any vaccine-related AE
until Day 208.
+ Frequency and severity of any SAE until Day 36.
+ Frequency and severity of any AESI until Day 36.
+ Frequency and severity of any SAE until Day 208_
+ Frequency and severity of an AESI until Day 208.
IMMUNOGENICITY IMMUNOGENICITY
+ Geometric mean titre (GMT) for + Immune response as measured by
neutralizing
neutralizing antibodies against SARS-CoV- antibody titers against SARS-CoV-2
on Day 8, Day
2 determined by wild-type virus 22, Day 106 and Day 208.
microneutralizing assay at Day 36. + Proportion of subjects with
seroconversion in
terms of neutralizing antibodies on Day 8, Day 22,
Day 36, Day 106 and Day 208.
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+ Fold increase of SARS-CoV-2 neutralizing
antibody titers on Day 8, Day 22, Day 36, Day 106
and Day 208 compared with baseline.
+ GMTs for TgG antibodies against SARS-CoV-2,
determined by IgG S-ELISA, at Day 1, 8, 22, 36,106
and 208.
+ Proportion of subjects with seroconversion in
terms of IgG antibodies against SARS-CoV-2 as
determined by ELISA on Day 8, Day 22, Day 36,
Day 106 and Day 208.
Results ¨ Safety and Tolerability
Primary Endpoint:
Frequency and severity of solicited adverse events (AEs) (local and systemic
reactions) within 7 days
after each vaccination. Solicited injection site reactions include injection
site pain, itching,
tenderness, redness and swelling/induration. Solicited systemic reactions
include include fever/body
temperature, fatigue, headache, nausea/vomiting, muscle pain.
Overall, 81.7% of participants reported at least one solicited reaction within
7 days after any
vaccination.
> 47.7% (after first vaccination) and 51.3% (after second vaccination) of
participants experienced a
solicited injection site reaction.
> 52.3% (after first vaccination) and 52.0% (after second vaccination) of
participants experienced a
solicited systemic reaction.
+ All solicited AEs across the dose groups were assessed as mild or moderate
with the exception of 3
events reported by 2 participants who experienced severe (Grade 3) solicited
adverse events (one
subject: severe headache and fatigue; one subject: severe fatigue). Both
participants were in the high
dose group.
+ Majority of solicited AEs resolved within 7 days post vaccination.
Solicited Local AEs:
+ Across all dose levels 66.7% of yaccinees reported at least one solicited
injection site reaction (no
statistical significant difference; p-value overall 0.631) with 68.6% in the
low dose, 60.8% in the
medium dose and 70.6% in the high dose group
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+ The most common injection site reaction after either vaccination was
tenderness affecting 58.2%
across dose groups and injection site pain 41.8% across dose groups.
Solicited Systemic AEs:
+ Across all dose levels 69.3% of vaccinees reported at least one solicited
systemic reaction (no
statistically significant difference between groups; p-value overall 0.507);
the rate of vaccinees with
solicited symptoms was 72.5% in both low and high dose and 62.7% in the medium
dose group.
+ Overall, most frequently reported solicited systemic adverse events
following vaccination included
headache (46.4%), fatigue (39.2%) and muscle pain (32.7%).
Unsolicited AEs:
+ Overall, 39.2% of participants reported at least one unsolicited adverse
event. No statistically
significant differences between dose groups were observed.
+ All unsolicited adverse events were mild and moderate.
+ 2 Cases of COVID-19 were confirmed by PCR up to Day 36. One mild case
occurred in a
participant of the medium dose group 16 days after the first vaccination. A
moderate COVID-19 case
was confirmed by PCR in a participant of the low dose group 4 days after the
second vaccination.
+ Rates of unsolicited adverse events considered treatment-related up to Day
36 were 17.6% (27/153)
with 23.5% in the low dose group, 13.7% in the medium dose group and 15.7% in
the high dose
group.
+ One adverse event of special interest has been reported (event term:
chilblains); the event was
assessed as mild and not-related to the study vaccination by the investigator.
+ AESI has been reported as serious adverse event as per protocol (medically
important condition); no
other serious adverse event has been reported.
Conclusions ¨ Safety and Tolerability
+ The vaccine candidate was generally safe and well tolerated across all dose
groups tested, with no
safety concerns identified by an independent Data Safety Monitoring Board.
+ There were no statistically significant differences between dose groups and
no differences between
first and second vaccinations in terms of reactogenicity.
+ The majority of Adverse Events (AEs) were mild or moderate and only two
subjects reported severe
solicited AEs (headache and fatigue).
+ All solicited AEs resolved quickly.
+ Only 17.6% of unsolicited adverse events up to day 36 were considered
related to the vaccine and
no severe unsolicited AEs were reported.
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+ There were no serious related AEs.
Results ¨ Immunogenicity
Neutralizing antibodies as measured by MNA50
Neutralizing antibodies were measured by a microneutralization assay (MNA50).
Vero/E6 cells are
seeded at 2.5 x 105 cells/mL in 100W/well in a microtiter plate and incubated
at 37 C overnight.
Serum samples from subjects were heat inactivated at 56 C for 30 minutes. The
neutralization plate
comprising virus and serum samples is prepared at 37 C for 1-1.5 hours. The
neutralized virus is then
transferred to the Vero/E6 cells in the microtiter plate and incubated at 37 C
for 1-1.5 hours. Cells are
overlayed in 2% CMC in 2xMEM and incubated at 37 C for 22-26 hours. Cells are
fixed with 10%
formalin at room temperature for >8 hours. Plaques are then visualized with a
SARS-CoV-2 RBD
spike antibody, detected by a secondary antibody and HRP-polymer. Pfu/well are
counted and used to
calculate the ND50.
+ A clear dose dependent response was observed with the highest Geometric Mean
Titre (GMT) for
neutralizing antibodies in the high dose group at both Day 22 (GMT 46.5;
95%CI: 38.79, 55.66)) and
Day 36 (GMT 530.4; 95%CI: 421.49, 667.52) ¨ see Figure 23.
+ On Day 36, the GMT of the high dose group was statistically significantly
higher than each of the
other dose groups. GMT in the low dose was 161.1 (95%CI: 121.35, 213.82) and
in medium dose
group, 222.3 (95%CI: 171.84, 287.67)
+ GMT- fold increases for neutralizing antibodies at Day 36 were 5.55 (95%CI:
4.18, 7.37) in the low
dose, 7.22 (95%CI: 5.64, 9.25) in the medium dose and 17.68 (95%CI: 14.04,
22.26) in the high dose
group.
+ On Day 22, prior to the second study vaccination, the number of participants
with seroconversion
for neutralizing antibodies (defined as >4-fold increase from baseline) was
10.0% (5/50 participants)
+ At Day 36, 90.0% (95%CI: 0.78,0.97) of participants in the high dose group,
were seroconverted
which was statistically significantly higher compared to the low dose (51.0%;
95%CI: 0.37, 0.65) and
medium dose group (73.5%; 95%CI: 0.59, 0.85) ¨ see Figure 24.
S-protein binding antibodies as measured by IgG ELISA
S-protein-binding antibodies were detected by a SARS-CoV-2 spike IgG ELISA.
The ELISA plate is
coated with a Spike protein (Wuhan). Anti-S protein antibodies in the serum
sample bind to the
immobilized Spike protein antigen, and are detected by a secondary (peroxidase-
conjugated) anti-
human IgG antibody. Results are presented as ELISA laboratory units per mL
(ELU/mL). A
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commercially available human serum screened for high pre-existing S antibody
titers is used as a
control.
+ The S-protein IgG antibody titers correlated with neutralization titers
(r=0.79, p<0.001) -see Figure
25.
+ Similar to the neutralization titer, a clear dose dependent response was
observed with the highest
GMT for neutralizing antibodies in the high dose group at both Day 22 (GMT
30.0 (95%CI: 26.92,
33.48)) and Day 36 (GMT 2147.9 (95%CI: 1705.98, 2704.22)) ¨ see Figure 26.
+ On Day 36, the GMT of the high dose group was statistically significantly
higher than each of the
other dose groups. GMT in the low dose was 325.1 (95%CI: 245.45, 430.46) and
in the medium dose
group 691.6 (95%CI: 494.91, 966,52)
+ GMFR for S-protein binding antibodies at Day 36 were 12.69 (95%CI: 9.54,
16.88) in the low dose,
26.16 (95%CI: 18.73, 36.53) in the medium dose and 85.91 (95%CI: 68.24,
108.17) in the high dose
group.
+ At Day 36, 100% (95%CI: 0.93,1.00) of participants in the high dose group
were seroconverted and
89.3% (95%CI: 0.78,0.97) in the medium dose group as well as 84.3% (95%CI:
0.71Ø93) (p=0.053
compared to high dose) in the low dose group (p=0.017 compared to high dose).
Cellular response:
Exploratory endpoints evaluated T-cell responses by IFNgamma ELISpot analysis
against S-protein,
Membrane-protein and Nucleocapsid-protein. Isolated PBMCs (fresh) are
stimulated with SARS-
CoV-2 peptides from the S, M and N proteins. Interferon-gamma production by T
cells is detected by
an anti-IFN7 antibody and visualized with a labelled secondary antibody. Spots
are thus produced
where interferon-gamma was released by activated T cells. A nil control and
phytohemagglutinin
(PHA) control are used. A 6 spot reactivity cut off was used, i.e. a sample is
considered reactive
against an individual stimulation panel (peptide pools) if normalized spot
counts (Nil control counts
substracted) per 2.10 x 105 PBMCs > 6.
At Day 36 in the high dose group, 76% of study participants (34/45) were
reactive against peptide
pools spanning the full-length S-protein (see Figure 27), 36% (16/45) against
the M-protein (see
Figure 28) and 49% (22/45) against the N-protein (see Figure 29).
Conclusions - Immunogenicity
+ The vaccine candidate was highly immunogenic with more than 90% of all study
participants
developing significant levels of antibodies to the SARS-CoV-2 virus spike
protein across all dose
groups tested.
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+ Seroconversion Rates (SCR) for S-protein binding IgG antibodies were 89.8%
in the medium dose
and 100% in the high dose group.
+ Two weeks after completion of the two dose schedule, Geometric Mean Fold
Rises (GMFRs) from
baseline were 26 in the medium dose and 86 in the high dose group.
+ Of note, the IgG antibody response was highly correlated with neutralization
titres (MNA50)
(r=0.79, p<0.001).
+ The vaccine candidate induced a dose dependent response with statistically
significant higher
Geometric Mean Titres (GMTs) for both IgG and neutralizing antibodies in the
high dose group
compared to the low and medium dose groups.
+ In the high dose group, the GMT of neutralizing antibodies antibody titres
measured 2 weeks after
completion of the 2-dose schedule was at or above levels for a panel of
convalescent sera (GMT 530.4
(95% CI: 421.49, 667.52)).
+ With a GMT ratio of vaccine vs. convalescent sera > 1 vaccine efficacy has
been reported above
80% for other vaccines *).
*)Earle et al. MedRxiv, March 2021,
https://doi.org/10.1101/2021.03.17.20200246); Khoury et al.
MedRxiv, March 2021, https://doi.org/10.1101/2021.03.09.21252641
+ The vaccine candidate induced broad T-cell responses across participants
with antigen-specific IFN-
gamma producing T-cells against the S-protein, M and N protein detected in
75.6 %, 35.6% and
48.9% of study participants, respectively.
ADDITIONAL ASPECTS OF THE INVENTION
In further aspects, the present invention provides:
Al. A SARS-CoV-2 vaccine comprising an optimally (e.g. wherein the
native surface of the S-protein
is preserved) inactivated SARS-CoV-2 particle, wherein the SARS-CoV-2 particle
is able to
seroconvert a subject that is administered the SARS-CoV-2 vaccine with at
least a 70%
probability.
A2. The SARS-CoV-2 vaccine of aspect Al, wherein the SARS-CoV-2 particle is
able to seroconvert
the subject that is administered the SARS-CoV-2 vaccine with at least 80%,
85%, 90%, or 95%
probability.
A3. The vaccine of aspect Al or A2, wherein the SARS-CoV-2 particle has a
RNA genome
corresponding to the DNA sequence provided by any one of the nucleic acid
sequences of
= SEQ ID NO: 1 (see Genbank NC 045512.2), or a variant nucleic acid
sequence that is at least
85% identical to SEQ ID NO: 1 and able to pack a virulent SARS-CoV-2; or
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= SEQ ID NO: 9 (see NCBI MT066156), or a variant nucleic acid sequence that
is at least 85%
identical to SEQ ID NO: 1 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 18 (see NCBI MW598408). or a variant nucleic acid sequence
that is at least
85% identical to SEQ ID NO: 18 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 20 (see NCBI MW520923). or a variant nucleic acid sequence
that is at least
85% identical to SEQ ID NO: 20 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 22 (see NCBI MW422256). or a variant nucleic acid sequence
that is at least
85% identical to SEQ ID NO: 22 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 22 (see NCBI MW422256). or a variant nucleic acid sequence
that is at least
85% identical to SEQ ID NO: 24 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 22 (see NCBI MW422256). or a variant nucleic acid sequence
that is at least
85% identical to SEQ ID NO: 26 and able to pack a virulent SARS-CoV-2.
A4. The vaccine of any one of aspects A1-A3, wherein the SARS-CoV-
2 particle has an S protein
as defined by the amino acid sequence
= SEQ ID NO: 3, or a variant amino acid sequence that is at least 95%
identical to SEQ ID NO:
3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 11, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 19, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 21, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 23, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 25, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2; or
= SEQ ID NO: 27, or a variant amino acid sequence that is at least 95%
identical to SEQ ID
NO: 3 and able to pack a virulent SARS-CoV-2.
AS. The SARS-CoV-2 vaccine of any one of aspects A1-A4, wherein the
SARS-CoV-2 particle has
a polyprotein selected from the amino acid sequences provided by any one of
SEQ ID NOs: 2,
10, 13 or 16, preferably SEQ ID NO: 10, or a variant amino acid sequence that
is at least 95%
identical to any one of SEQ ID NOs: 2, 10, 13 or 16, preferably SEQ ID NO: 10,
and able to pack
a virulent SARS-CoV-2.
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A6. The SARS-CoV-2 vaccine of any one of aspects Al-A5, wherein the SARS-
CoV-2 is inactivated
by chemical inactivation, thermal inactivation, pH inactivation, UV
inactivation or radiation
inactivation.
A7. The SARS-CoV-2 vaccine of aspect A6, wherein the chemical inactivation
comprises contacting
the SARS-CoV-2 particles with a chemical inactivation agent for longer than is
required to
completely inactivate the SARS-CoV-2 as measured by plaque assay or as
measured by plaque
assay plus one day.
A8. The SARS-CoV-2 vaccine of aspect A7, wherein the chemical inactivation
comprises contacting
the SARS-CoV-2 particle with formaldehyde and/or beta-propiolactone,
preferably beta-
propiolactone.
A9. The SARS-CoV-2 vaccine of aspect A8, wherein the formaldehyde and/or
beta-propiolactone
inactivation comprises contacting the SARS-CoV-2 particle with formaldehyde
and/or beta-
propiolactone for between 2-10 days.
A10. The SARS-CoV-2 vaccine of any one of aspects A6-A9, wherein the chemical
activation is
performed at about 4 C or about 22 C.
All. The SARS-CoV-2 vaccine of any one of aspects Al-A10, further comprising
an adjuvant.
Al2. The SARS-CoV-2 vaccine of aspect All, wherein the adjuvant is a CpG,
preferably CpG 1018,
optionally also comprising an aluminium salt adjuvant.
A13. The SARS-CoV-2 vaccine of aspect Al2, wherein the aluminium salt adjuvant
is aluminium
hydroxide or aluminium phosphate salt.
A14. The SARS-CoV-2 vaccine of aspect A13, wherein the aluminium hydroxide
comprises less than
1.25 ppb Cu.
A15. The SARS-CoV-2 vaccine of any one of aspects Al2 to A14, wherein the
alum:CpG (w/w) ratio
is about 1:10, about 1:5, about 1:4, about 1:3, about 1:2, about 1:1, about
2:1, about 3:1, about
4:1, about 5:1, about 10:1, preferably between about 1:3 and 3:1, more
preferably between about
1:2 and 1:1, most preferably about 1:2.
A16. The SARS-CoV-2 vaccine according to any one of aspects Al2 to A14,
wherein the amount of
free (unbound) CpG in the vaccine composition is greater than 10%, greater
than 20%, greater
than 30%, greater than 40%, greater than 50%, greater than 60%, greater than
70%, greater than
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80%, greater than 90%, greater than 95%, preferably about 70% to 95%, most
preferably about
80% to 90%.
A17. The SARS-CoV-2 vaccine according to any one of aspects Al to A16, wherein
the vaccine
composition comprises at least one buffer, preferably a phosphate buffer.
A18. The SARS-CoV-2 vaccine of any one of A 11-A13, wherein the vaccine
comprises or further
comprises an adjuvant comprising a peptide and a deoxyinosine-containing
immunostimulatory
oligodeoxynucleic acid molecule (1-0DN).
A19. The SARS-CoV-2 vaccine of aspect A18, wherein the peptide comprises the
sequence
KI,KI,5KI,K (SR) ID NO: 5) and the I-ODN comprises oligo-d(IC)13 (SEQ ID NO:
6).
A20. The SARS-CoV-2 vaccine of any one of aspects Al-A19, farther comprising
one or more
pharmaceutically acceptable excipients.
Bl. A kit comprising a SARS-CoV-2 vaccine of any one of aspects Al-
A15.
B2. The kit of aspect Bl, further comprising a second vaccine.
B3. The kit of aspect B2, wherein the second vaccine is another SARS-CoV-2
virus vaccine (e.g. of
another technology such as mRNA or adenovirus vectored), an influenza virus
vaccine or a
Chikungunya virus vaccine.
Cl. A method, comprising administering a first dose of a
prophylactically or therapeutically effective
amount of the SARS-CoV-2 vaccine of any one of aspects Al-A15 to a subject in
need thereof.
C2. The method of aspect Cl, further comprising administering a second dose
of a prophylactically
or therapeutically effective amount of the SARS-CoV-2 vaccine.
C3. The method of aspect Cl or C2, wherein the second dose of the SARS-CoV-2
vaccine is
administered about 7 days after the first dose of the SARS-CoV-2 vaccine.
C4. The method of aspect Cl or C2, wherein the second dose of the SARS-CoV-2
vaccine is
administered about 14 days after the first dose of the SARS-CoV-2 vaccine.
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C5. The method of aspect Cl or C2, wherein the second dose of the SARS-CoV-2
vaccine is
administered about 21 days after the first dose of the SARS-CoV-2 vaccine.
C6. The method of aspect Cl or C2, wherein the second dose of the SARS-CoV-2
vaccine is
administered about 28 days after the first dose of the SARS-CoV-2 vaccine.
C7. The method of any one of aspects C1-C6, wherein the administering results
in production of
SARS-CoV-2 neutralizing antibodies.
C8. The method of any one of aspects CI-C7, wherein the prophylactically or
therapeutically
effective amount of the SARS-CoV-2 vaccine is defined as about 0.01 to 25 mAU
(milli-
absorption units x minutes), preferably about 0.05 to 10 mAU, more preferably
about 0.1 to 5
mAU, most preferably about 0.25 to 2.5 mAU, as assessed by SE-HPLC.
C9. The method of any one of aspects C1-C7, wherein the prophylactically or
therapeutically
effective amount of the SARS-CoV-2 vaccine is defined as about 0.05 to 50 pg
total protein,
about 0.1 to 25 pg, about 0.25 to 12.5 pg, preferably about 0.5 to 5 pg total
protein, as measured
by ( )BCA.
C10. The method of any one of aspects C 1 -C7, wherein the prophylactically or
therapeutically
effective amount of the SARS-CoV-2 vaccine is defined as about 0.025 to 25 pig
S-protein, about
0.05 to 12.5 [is, about 0.125 to 6.25 g, preferably about 0.25 to 2.5 pg S-
protein, as measured
by ELISA.
Dl. A method of producing a SARS-CoV-2 vaccine, comprising
(i) passaging a SARS-CoV-2 on Vero cells, thereby producing a culture medium
comprising the
SARS-CoV-2;
(ii) harvesting the culture medium of (i);
(iii) precipitating the harvested culture medium of (ii), thereby producing a
SARS-CoV-2
supernatant; and
(iv) optimally inactivating the SARS-CoV-2 in the SARS-CoV-2 supernatant of
(iii) thereby
producing an inactivated SARS-CoV-2.
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D2. The method of aspect D1, further comprising concentrating the culture
medium of (ii) prior to
step (iii).
D3. The method of aspect D1 or D2, wherein the precipitation of (iii)
comprises contacting the culture
medium of (ii) with protamine sulfate or benzonase.
D4. The method of any one of aspects Dl-D3, further comprising (v) dialyzing
the inactivated SARS-
CoV-2 of (iv), thereby producing a dialyzed SARS-CoV-2.
D5. The method of aspect D4, further comprising (vi) filtering the dialyzed
SARS-CoV-2 of (v).
D6. The method of any one of aspects Dl-D5, wherein the inactivating is by
chemical inactivation,
thermal inactivation, pH inactivation, or UV inactivation.
D7. The method of aspect D6, wherein the chemical inactivation comprises
contacting the SARS-
CoV-2 particle with a chemical inactivation agent for at least 4 days.
D8. The method of aspect D6 or D7, wherein the chemical inactivation agent
comprises
formaldehyde.
D9. The method of any one of aspects D6-D8, wherein the chemical activation
is performed at about
4 C or about 22 C.
D10. The method of aspect D8 or D9, further comprising neutralizing the
formaldehyde.
D11. The method of aspect D10, wherein the neutralizing is performed with
sodium metabisulfite.
D12. The method of any one of aspects D 1-D 11, wherein the chemical
inactivation is performed with
BPL, preferably at a concentration of 300 to 700ppm, more preferably 500ppm
and inactivated
for about 1 to 48h, preferably 20 to 28h, most preferred 24 hours 2 hours
(such as also 1
hour or 0.5 hour) at 2 C to 8 C.
D13. The method of aspect D12, wherein the chemical inactivation is followed
by a hyd rol yzati on
step for 2.5 hours + 0.5 hours at 35 C to 39 C, preferably around 37 C.
El. The use of the optimally inactivated SARS-CoV-2 vaccine of any
one of aspects A 1-A 15 for the
treatment and prevention of a SARS-CoV-2 infection.
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E2. The use of aspect El, wherein the inactivated SARS-CoV-2 vaccine is
administered in a first
dose of a therapeutically effective amount to a subject in need thereof.
E3. The use of aspect E2, wherein the inactivated SARS-CoV-2 vaccine is
administered in a second
dose of a therapeutically effective amount to the subject.
E4. The use of aspect E3, wherein the second dose of the inactivated SARS-CoV-
2 vaccine is
administered about 7 days after the first dose of the SARS-CoV-2 vaccine.
E5. The use of aspect E3, wherein the second dose of the SARS-CoV-2 vaccine
is administered about
14 days after the first dose of the SARS-CoV-2 vaccine.
E6. The use of aspect E3, wherein the second dose of the SARS-CoV-2 vaccine
is administered about
21 days after the first dose of the SARS-CoV-2 vaccine.
E7. The use of aspect E3, wherein the second dose of the SARS-CoV-2 vaccine
is administered about
2g days after the first dose of the SARS-CoV-2 vaccine.
E8. The use of any one of aspects El-E6, wherein the administering results
in production of SARS-
CoV-2 neutralizing antibodies.
Fl. A pharmaceutical composition for use in the treatment and prevention of a
SARS-CoV-2
infection, wherein said pharmaceutical composition comprises the optimally
inactivated SARS-
CoV-2 vaccine of any one of aspects A 1 -A15.
F2. The pharmaceutical composition of aspect Fl, wherein the inactivated
SARS-CoV-2 vaccine is
administered in a first dose of a therapeutically effective amount to a
subject in need thereof.
F3. The use of aspect F2, wherein the inactivated SARS-CoV-2 vaccine is
administered in a second
dose of a therapeutically effective amount to the subject.
F4. The use of aspect F3, wherein the second dose of the inactivated SARS-
CoV-2 vaccine is
administered about 7 days after the first dose of the SARS-CoV-2 vaccine.
F5. The use of aspect F3, wherein the second dose ofthe SARS-CoV-2 vaccine is
administered about
14 days after the first dose of the SARS-CoV-2 vaccine.
F6. The use of aspect F3, wherein the second dose of the SARS-CoV-2
vaccine is administered about
21 days after the first dose of the SARS-CoV-2 vaccine.
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F7. The use of aspect F3, wherein the second dose ofthe SARS-CoV-2 vaccine
is administered about
28 days after the first dose of the SARS-CoV-2 vaccine.
F8. The use of any one of aspects F1-F6, wherein the administering results
in production of SARS-
CoV-2 neutralizing antibodies.
G1 . A SARS-CoV-2 vaccine comprising an effective amount of antigen, wherein
said effective
amount is able to seroconvert a subject that is administered the SARS-CoV-2
vaccine with at
least a 70% probability.
G2. The SARS-CoV-2 vaccine according to aspect G1 , wherein said effective
amount is able to
seroconvert a subject that is administered the SARS-CoV-2 vaccine with at
least 80%, 85%, 90%,
or 95% probability.
G3. The SARS-CoV-2 vaccine according to aspect G1 or G2, wherein said
effective amount is
between about 1 to 100 AU/dose, preferably between about 2 to 75 AU/dose,
preferably between
about 3 and 60 AU/dose, more preferably between about 3 and 55 AU/dose, more
preferably
between about 3 and 53 AU/dose.
G4. The SARS-CoV-2 vaccine according to aspect G3, where said effective
amount is determined by
ELISA wherein the antigen units (AU) correspond to ACE-2 binding capacity of
the spike protein
used as a standard.
Hi. An immunogenic composition for stimulating an immune response against a
severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a SARS-CoV-2
antigen and a
toll-like receptor 9 (TLR9) agonist, wherein the SARS-CoV-2 antigen is an
inactivated whole
SARS-CoV-2, the TLR9 agonist is an oligonucleotide of from 10 to 35
nucleotides in length
comprising an unmethylated cytidinc-phospho-guanosinc (CpG) motif, and the
SARS-CoV-2
antigen and the oligonucleotide are present in the immunogenic composition in
amounts effective
to stimulate an immune response against the SARS-CoV-2 antigen in a mammalian
subject.
H2. The composition of aspect HI, wherein the oligonucleotide comprises the
sequence 5'-
AACGTTCGAG-3' (SEQ ID NO:30).
H3. The composition of aspect HI, wherein the oligonucleotide comprises the
sequence of 5'-
TGACTGTGAA CGTTCGAGAT GA-3' (SEQ ID NO: 4).
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H4.
The composition of any one of aspects H1-3, wherein the oligonucleotide
comprises a modified
nucleoside, optionally wherein the modified nucleoside is selected from the
group consisting of
2'-deoxy-7-deazaguanosine, 2'-deoxy-6-thioguanosine, arabinoguanosine, 2'-
deoxy-
2'substituted-arabinoguanosine, and 2'-0-substituted- arabinoguanosine.
H5. The composition of aspect H4, wherein the oligonucleotide comprises the
sequence 5'-
TCGIAACGITTCG1-3' (SEQ ID NO: 31) in which Gi is 2'-deoxy-7-deazaguanosine,
optionally
wherein the oligonucleotide comprises the sequence 5'-TCGIAACGITTCGI-X-
GICTTGICAAGICT-5' (SEQ ID NO: 32), and in which G1 is 2'-deoxy-7-
deazaguanosine and X
is glycerol (5'-SEQ ID NO: 31-3'-X-3'-SEQ ID NO: 31-5').
H6. "lhe composition of any one of aspects H1-5, wherein the oligonucleotide
comprises at least one
phosphorothioate linkage, or wherein all nucleotide linkages are
phosphorothioate linkages.
H7. The composition of any one of aspects H1-6, wherein the oligonucleotide
is a single-stranded
oligodeoxynucleotide.
H8. The composition of any one of aspects H1-7, wherein a 0.5 ml dose of the
immunogenic
composition comprises from about 750 to about 3000 jig of the oligonucleotide,
or wherein the
immunogenic composition comprises about 750 mg, about 1000 lag, about 1500
lig, or about
3000 lig of the oligonucleotide.
H9. The composition of any one of aspects HI -8, wherein the SARS-CoV-2
antigen is propagated in
vitro in mammalian cells.
H10. The composition of any onc of aspects H1-9, wherein the SARS-CoV-2 is
inactivated by
treatment with one or both of formalin and ultraviolet light.
H11. The composition of any one of aspects H1-9, wherein the SARS-CoV-2 is
inactivated by
treatment with beta-propiolactone.
H12. The composition of any one of aspects H1-11, wherein the SARS-CoV-2
comprises a
combination of at least two different viral strains, or from two different
viral clades or lineages.
H13. The composition of ally one of aspects H1-12, wherein a 0.5 ml dose of
the immunogenic
composition comprises from about 0.025 to about 25 lig of the of the SARS-CoV-
2 spike (S)
protein, or from about 0.25 to about 25 lig of the of the S protein.
HI4. The composition of any one of aspects HI -13, further comprising all
aluminum salt adjuvant.
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H15. The composition of aspect H14, wherein the aluminum salt adjuvant
comprises one or more of
the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum
hydroxide,
aluminum phosphate, and potassium aluminum sulfate
H16. The composition of aspect H14, wherein the aluminum salt adjuvant
comprises aluminum
hydroxide.
H17. The composition of any one of aspects H14-16, wherein a 0.5 ml dose of
the immunogenic
composition comprises from about 0.05 to about 0.50 mg A13+, or about 0.075 to
about 0.175
mg A13+, or from about 0.25 to about 0.50 mg A13+, or about 0.375 mg A13+.
Hlg. The composition of any one of aspects H1-17, wherein the mammalian
subject is a human
subject.
H19. A kit comprising:
i) the immunogenic composition of any one of aspects H1-18, and
ii) instructions for administration of the composition to stimulate an
immune response against the
SARS-CoV-2 antigen in the mammalian subject.
H20. The kit of aspect H19, further comprising iii) a syringe and needle for
intramuscular injection of
the immunogenic composition.
H21. A method for stimulating an immune response against a severe acute
respiratory syndrome
coronavirus 2 (SARS-CoV-2) in a mammalian subject, comprising administering
the
immunogenic composition of any one of aspects H1-18 to a mammalian subject so
as to stimulate
an immune response against the SARS-CoV-2 antigen in the mammalian subject.
H22. The method of aspect H21, wherein the mammalian subject is a human
subject and/or the
immunogenic composition is administered by intramuscular injection.
H23. Use of the immunogenic composition of any one of aspects HI -18 for
stimulating an immune
response against a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) in a
mammalian subject, the method comprising administering to the subject an
effective amount of
the immunogenic composition.
H24. Use of the immunogenic composition of any one of aspects H1-18 for
protecting a mammalian
subject from infection with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), the
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method comprising administering to the subject an effective amount of the
immunogenic
composition.
H25. Use of the immunogenic composition of any one of aspects H1-18 for
preventing a mammalian
subject from contracting COVID-19 disease, the method comprising administering
to the subject
an effective amount of the immunogenic composition.
H26. The use of any one of aspects H23-25, wherein the mammalian subject is a
human subject and/or
the immunogenic composition is administered by intramuscular injection.
In some specific embodiments, there is provided an aspect of the invention as
described herein (e.g. as
in one or more of aspects A to H above, or as in the appended claims), wherein
one or more of the
following aspects (labelled X) is excluded:
X1 . An immunogenic composition for stimulating an immune response against a
severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a SARS-CoV-2
antigen and a
toll-like receptor 9 (TLR9) agonist, wherein the TLR9 agonist is an
oligonucleotide of from 10
to 35 nucleotides in length comprising an unmethylated cytidine- phospho-
guanosine (CpG)
motif, and the SARS-CoV-2 antigen and the oligonucleotide are present in the
immunogenic
composition in amounts effective to stimulate an immune response against the
SARS-CoV-2
antigen in a mammalian subject.
X2. The composition of aspect X 1, wherein the oligonucleotide comprises
the sequence 5'-
AACGTTCGAG-3' (SEQ ID NO: 30).
X3. The composition of aspect XI, wherein the oligonucleotide comprises the
sequence of 5'-
TGACTGTGAACGTTCGAGATGA-3' (SEQ ID NO: 4).
X4. The composition of aspect X 1, wherein the oligonucleotide comprises a
modified nucleoside,
optionally wherein the modified nucleoside is selected from the group
consisting of 2'-deoxy-7-
deazaguanosine, 2'-deoxy-6-thioguanosine, arabinoguanosine, 2'-deoxy-
2'substituted-
arabinoguanosine, and 2'-0-substituted-arabinoguanosine.
X5. The composition of aspect X4, wherein the oligonucleotide comprises the
sequence 5'-
TCGIAACGITTCG1-3' (SEQ ID NO: 31) in which G1 is 2'-deoxy-7-deazaguanosine,
optionally
wherein the oligonucleotide comprises the sequence 5'-TCGAACGITTCGI-X-
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GICTTGICAAGICT-5' (SEQ ID NO: 32), and in which G1 is 2'-deoxy-7-
deazaguanosine and X
is glycerol (5'-SEQ ID NO: 31-3'-X-3'-SEQ ID NO: 31-5').
X6. The composition of any one of aspects X1-5, wherein the oligonucleotide
comprises at least one
phosphorothioate linkage, optionally wherein all nucleotide linkages are
phosphorothioate
linkages.
X7. The composition of any one of aspects X1-6, wherein the oligonucleotide
is a single-stranded
oligodeoxynucleotide.
X8. The composition of any one of aspects X1-7, wherein a 0.5 ml dose of the
immunogenic
composition comprises from about 750 to about 3000 pg of the oligonucleotide,
optionally
wherein the immunogenic composition comprises about 750 lig, about 1500 lig,
or about 3000
lig of the oligonucleotide.
X9. The composition of any one of aspects X1-8, wherein the SARS-CoV-2
antigen is an inactivated
whole SARS-CoV-2.
X10. The composition of aspect X9, wherein the SARS-CoV-2 is inactivated by
treatment with one or
both of fonualin and ultraviolet light.
X11. The composition of any one of aspects X1-8, wherein the SARS-CoV-2
antigen comprises the
receptor-binding domain (RED) of the SARS-CoV-2 spike (S) protein.
X12. The composition of aspect X11, wherein the SARS-CoV-2 antigen comprises a
truncated,
recombinant S protein devoid of signal peptide, transmembrane and cytoplasmic
domains of a
full length S protein.
X13. The composition of aspect X11 or X12, wherein the SARS-CoV-2 antigen
further comprises one
or more of the SARS-CoV-2 membrane (M) protein, nucleocapsid (N) protein, and
envelope (E)
protein.
X14. "lhe composition of any one of aspects X1-13, further comprising an
aluminum salt adjuvant.
X15. The composition of aspect X14, wherein the aluminum salt adjuvant
comprises one or more of
the group consisting of amorphous aluminum hydroxyphosphate sulfate, aluminum
hydroxide,
aluminum phosphate, and potassium aluminum sulfate
X16. The composition of aspect X14, wherein the aluminum salt adjuvant
comprises aluminum
hydroxide.
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X17. The composition of any one of aspects X14-16, wherein a 0.5 ml dose of
the immunogenic
composition comprises from about 0.25 to about 0.50 mg A13+.
X18. The composition of any one of aspects X1-17, wherein the mammalian
subject is a human
subject.
X19. A kit comprising:
i) the immunogenic composition of any one of aspects X1-18, and
ii) instructions for administration of the composition to stimulate an
immune response against the
SARS-CoV-2 antigen in the mammalian subject.
X20. The kit of aspect X19, further comprising iii) a syringe and needle for
intramuscular injection of
the immunogenic composition.
X21. A method for stimulating an immune response against a severe acute
respiratory syndrome
coronavirus 2 (SARS-CoV-2) in a mammalian subject, comprising administering
the
immunogenic composition of any one of aspects X1-18 to a mammalian subject so
as to stimulate
an immune response against the SARS-CoV-2 antigen in the mammalian subject.
X22. The method of aspect X21, wherein the immunogenic composition is
administered by
intramuscular injection.
The present application claims priority from US 62/983,737 (1-Mar-2020),
EP20168324.0 (06 Apr
2020), EP20202124.2 (15 Oct 2020), EP20211936.8 (04 Dec 2020) EP21154645.2 (01
Feb 2021),
PCT/US21/20313 (1-Mar-2021) and EP21160933.4 (05 Mar 2021), the contents of
which are
incorporated herein by reference. All publications mentioned in the above
specification are herein
incorporated by reference. Various modifications and variations of the
described embodiments of the
present invention will be apparent to those skilled in the art without
departing from the scope and spirit
of the present invention. Although the present invention has been described in
connection with specific
preferred embodiments, it should be understood that the invention as claimed
should not be unduly
limited to such specific embodiments. Indeed, various modifications ofthe
described modes for carrying
out the invention which are obvious to those skilled in the art are intended
to be within the scope of the
following claims.
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SEQUENCES
SEQ ID NO: 1
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolate Wuhan-Hu-
1, complete genome
(GenBank: MN908947; Wu, F., et al. A new coronavirus associated with human
respiratory disease in China
(2020) Nature 579:265-269)
ATTAAAGGTTTATACCTTCCCAGGTAACAAACCAACCAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACGAACTTTA
AAATCTGTGTGG
CTGTCACTCGGCTGCATGCTTAGTGCACTCACGCAGTATAATTAATAACTAATTACTGTCGTTGACAGGACACGAGTAA
CTCGTCTATCTT
CTG CAG G CTG CTTACG GTTTCGTCCGTGTTG CAGCCGATCATCAG CACATCTAG GTTTCGTCCGG
GTGTGACCGAAAGGTAAGATG GAG
AGCCTTGTCCCTGGTTTCAACGAGAAAACACACGTCCAACTCAGTTTGCCTGTTTTACAGGTTCGCGACGTGCTCGTAC
GTGGCTTTGGA
GACTCCGTG GAG GAGGTCTTATCAGAGG CACGTCAACATCTTAAAGATG G CACTTGTGG
CTTAGTAGAAGTTG AAAAAG G CGTTTTG CC
TCAACTTGAACAGCCCTATGTGTTCATCAAACGTTCGGATGCTCGAACTGCACCTCATG
GTCATGTTATGGTTGAGCTGGTAGCAGAACT
CGAAGGCATTCAGTACGGTCGTAGTGGTGAGACACTTGGTGTCCTTGTCCCTCATGTGGGCGAAATACCAGTGGCTTAC
CGCAAGGTTC
TTCTTCGTAAG AACG GTAATAAAG G AG CTG GTG G CCATAGTTACG G CG CCG
ATCTAAAGTCATTTGACTTAG GCG A CGAG CTTG G CACT
G ATCCTTATG AAG ATTTTCAAGAAAACTGGAACACTAAACATAG CAGTG GTGTTACCCGT
GAACTCATGCGTGAGCTTAACG GAG GGG C
ATACACTCGCTATGTCGATAACAACTTCTGTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGT
GCTGGTAAAGC
TTCATG CACTTTGTCCGAACAACTGGACTTTATTGACACTAAGAGG G GTGTATACTGCTG CCGTG AACATG
AG CATG AAATTG CTTG GTA
CACGGAACGTTCTGAAAAGAGCTATGAATTGCAGACACCTTTTGAAATTAAATTGGCAAAGAAATTTGACACCTTCAAT
GGGGAATGTC
CAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAGGGTTGAAAAGAAAAAGCTTGATGGCTTTAT
GGGTAGAATTC
GATCTGTCTATCCAGTTGCGTCACCAAATGAATGCAACCAAATGTGCCTTTCAACTCTCATGAAGTGTGATCATTGTGG
TGAAACTTCATG
G CAGACGG G CG ATTTTGTTAAAGCCACTTG CGAATTTTGTG G CACTGAGAATTTG ACTAAAGAAG
GTGCCACTACTTGTG GTTACTTA CC
CCAAAATG CTGTTGTTAAAATTTATTGTCCAGCATG TCACAATTCAGAAGTAGGACCTGAG CATAGTCTTG
CCGAATACCATAATGAATC
TGGCTTGAAAACCATTCTTCGTAAGGGTGGTCGCACTATTGCCTTTGGAGGCTGTGTGTTCTCTTATGTTGGTTGCCAT
AACAAGTGTGC
CTATTG G GTTCCACGTG CTAG CGCTAACATAGGTTGTAACCATACAG GTGTTGTTG GAG AAG GTTCCG
AAG GTCTTAATG ACAACCTTCT
TGAAATACTCCAAAAAGAGAAAGTCAACATCAATATTGTTGGTGACTTTAAACTTAATGAAGAGATCGCCATTATTTTG
GCATCTTTTTCT
GCUCCACAAGTGC I I I I
GTGGAAACTGTGAAAGGTTTGGATTATAAAGCATTCAAACAAATTGTTGAATCCTGTGGTAATTTTAAAGTT
ACAAAAGGAAAAGCTAAAAAAGGTGCCTGGAATATTGGTGAACAGAAATCAATACTGAGTCCTCTTTATGCATTTG
CATCAG AG GCTGC
TCGTGTTGTACGATCAATTTTCTCCCGCACTCTTGAAACTGCTCAAAATTCTGTG CGTGTTTTACAGAAGG CCG
CTATAACAATACTAG AT
G GAATTTCACAGTATTCACTG AG ACTCATTG ATGCTATG ATGTTCACATCTG ATTTG G
CTACTAACAATCTAGTTGTAATGG CCTACATTA
CAGGTG GTGTTGTTCAGTTG ACTTCGCAGTG GCTAACTAACATCTTTG
GCACTGTTTATGAAAAACTCAAACCCGTCCTTG ATTG G CTTG A
AGAGAAGTTTAAG GAAGGTGTAGAGTTTCTTAGAGACG GTTG G GAAATTGTTAAATTTATCTCAACCTGTG
CTTGTG AAATTGTCG GTG
G ACAAATTGTCACCTGTG CAAA G GAAATTAAG G AG AGTGTTCAG
ACATTCTTTAAGCTTGTAAATAAATTTTTG GCTTTGTG TG CTG ACT
CTATCATTATTG GTG GAG CTAAACTTAAA GCCTTG AATTTAG GTG AAACATTTG TCACG CACTCAAAGG
G ATTGTACAG AAAGTGTGTTA
AATCCAGAGAAGAAACTGGCCTACTCATGCCTCTAAAAGCCCCAAAAGAAATTATCTTCTTAGAGGGAGAAACACTTCC
CACAGAAGTG
TTAACAG AG G AAGTTGTCTTGAAAACTG GTG ATTTACAACCATTAG AACAACCTACTAGTG AAG CTGTTG
AAG CTCCATTGGTTGGTACA
CCAGTTTGTATTAACGG GCTTATGTTG CTCGAAATCAAA G ACACAGAAAAGTACTGTG CC CTTG
CACCTAATATG ATGGTAACAAACAAT
ACCTTCACACTCAAAGGCGGTGCACCAACAAAGGTTACTTTTGGTGATGACACTGTGATAGAAGTGCAAGGTTACAAGA
GTGTGAATAT
CACTTTTG AACTTG AT GAAAG G ATTG ATAAAGTACTTAATG AG AAGTG CTCTG CCTATACAGTTG
AACTCGGTACAGAAGTAAATG AGTT
CGCCTGTGTTGTGGCAGATGCTGTCATAAAAACTTTGCAACCAGTATCTGAATTACTTACACCACTGGGCATTGATTTA
GATGAGTGGAG
TATGGCTACATACTACTTATTTGATGAGTCTGGTGAGTTTAAATTGGCTTCACATATGTATTGTTCTTTCTACCCTCCA
GATGAGGATGAA
G AAG AAG GTGATTGTG AA GAAGAAG AGTTTGAG CCATCAACTCAATATGAGTATG GTACTG AAGATG
ATTAC CAAG GTAAACCTTTGG
AATTTG GTGCCACTTCTGCTG CTCTTCAACCTG AAG AAG AG CAAG AAG AAG ATTG GTTAGATG ATG
ATAGTCAACAAACTGTTG GTCAA
CAAGACGG CAGTG AG GACAATCAGACAACTA CTATTCAAACAATTGTTGAG
GTTCAACCTCAATTAGAGATGGAACTTACACCAGTTGT
TCAGACTATTGAAGTGAATAGTTTTAGTG GTTATTTAAAACTTACTG ACAATGTATACATTAAAAATGCAG
ACATTGTG G AAG AAG CTAA
AAAG GTAAAACCAACAGTG GTTGTTAATG CAGCCAATGTTTACCTTAAACATG GAGGAGGTGTTG CAGG AG
CCTTAAATAAGG CTACTA
ACAATGCCATGCAAGTTGAATCTGATGATTACATAGCTACTAATGGACCACTTAAAGTGG
GTGGTAGTTGTGTTTTAAGCGGACACAATC
TTGCTAAACACTGTCTTCATGTTGTCGGCCCAAATGTTAACAAAGGTGAAGACATTCAACTTCTTAAGAGTGCTTATGA
AAATTTTAATCA
G CACG AAGTTCTACTTG CACCATTATTATCAG CTG GTATTTTTG GTG CTG A CCCTATACATTCTTTAAG
AGTTTG TGTAGATACTGTTCG CA
CAAATGTCTACTTAGCTGTCTTTGATAAAAATCTCTATGACAAACTTGTTTCAAGCTTTTTGGAAATGAAGAGTGAAAA
GCAAGTTGAAC
AAAAGATCG CTG AGATTCCTAAAG AG G AAGTTAAGCCATTTATAACTG AAAGTAAACCTTCAGTTG AACAG
AGAAAACAAGATGATAAG
AAAATCAAAGCTTGTGTTGAAGAAGTTACAACAACTCTGGAAGAAACTAAGTTCCTCACAGAAAACTTGTTACTTTATA
TTGACATTAAT
GGCAATCTTCATCCAGATTCTGCCACTCTTGTTAGTGACATTGACATCACTITCTTAAAGAAAGATGCTCCATATATAG
TGGGTGATGTTG
TTCAAGAGGGTGTTTTAACTGCTGTGGTTATACCTACTAAAAAGGCTGGTGGCACTACTGAAATGCTAGCGAAAGCTTT
GAGAAAAGTG
CCAACAGACAATTATATAACCACTTACCCGGGTCAGGGTTTAAATGGTTACACTGTAGAGGAGGCAAAGACAGTGCTTA
AAAAGTGTAA
AAGTGCCTTTTACATTCTACCATCTATTATCTCTAATGAG AAG CAAGAAATTCTTG GAACTGTTTCTTG
GAATTTG CGAGAAATG CTTG CA
CATG CAG AAG AAACACG CAAATTAATG CCTGTCTGTGTG G AAA CTAAAG CCATAGTTTCAACTATACAG
CGTAAATATAAG G GTATTAA
AATACAAGAGGGTGTGGTTGATTATGGTGCTAGATTTTACTTTTACACCAGTAAAACAACTGTAG
CGTCACTTATCAACACACTTAACGA
TCTAAATGAAACTCTTGTTACAATG CCACTTG G CTATGTAACACATG G CTTAAATTTGG AAG AAG CTG
CTCG GTATATGAG ATCTCTCA A
AGTGCCAGCTACAGTTTCTGTTTCTTCACCTGATGCTGTTACAGCGTATAATGGTTATCTTACTTCTTCTTCTAAAACA
CCTGAAGAACATT
TTATTGAAACCATCTCACTTGCTGGTTCCTATAAAGATTGGTCCTATTCTGGACAATCTACACAACTAGGTATAGAATT
TCTTAAGAG AG G
TGATAAAAGTGTATATTACACTAGTAATCCTACCACATTCCACCTAGATGGTGAAGTTATCACCTTTGACAATCTTAAG
ACACTTCTTTCTT
TG AG AG AAGTG AG G ACTATTAAG GTGTTTACAA CAGTAG ACAACATTAACCTC CACAC G
CAAGTTGTG G ACATGTCAATGACATATG GA
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CAACAGTTTG GTCCAACTTATTTG G ATG G AG CTGATGTTACTAAAATAAAACCTCATAATTCACATGAAG
GTAAAACATTTTAT GTTTTAC
CTAATG ATG ACA CT CTACGT GTTGAG G CTTTTG AGTA CTAC CA CA CAACTG ATC CTAGTTTT
CTG G GTAG GTACATGTCAGCATTAAATCA
CA CTAAAAAG TG GAAATACCCACAAGTTAATGGTTTAACTTCTATTAAATG G G CA G ATAA CAA
CTGTTATCTTG C CA CTG CATT GTTAA CA
CTC CAA CAAATA G A G TTG AA GTTTAAT C CA C CT G CTCTACAA G ATG CTTATTA CA GA G
C AA G GG CTG G TG AA G CTG CTAA CTTTT GTG CA
CTTATCTTAG C CTA CTG TAATAAG ACA G TA G G TG A GTTAG G TG AT GTTAG A G
AAACAATG A GTTACTTGTTTCAACATG C CAATTTA G AT
TCTTG CAAAA G AG TCTT G AA C GT G G TG TG TAAAA CTT G TG GACAACAG CA G A CAA
CC CTTAAG G GT GTAGAAG CTG TTATG TA CATG G G
CA CA CTTT CTTATG AA CAATTTAAG AAA G GT GTTCA G ATA C CTTG TA C G TGTG G TAAA
CAA G CTACAAAATATCTAGTACAACAG G AG TC
A C CTTTTG TTATG ATG TCA G CA C CA C CTG CTCAGTATGAACTTAAG CATG
GTACATTTACTTGTGCTA G TG AG TA CA CTG G TAATTA C CA G
TGTG GT CACTATAA A CATATAA CTTCTAAA G AAA CTTTG TATTG CATAGACG GTG
CTTTACTTACAAAGTCCTCAG AATACAAAG GTCCTA
TTACGGATGTTTTCTACAAAGAAAACAGTTACACAACAACCATAAAACCAGTTACTTATAAATTGGATGGTGTTGTTTG
TACAGAAATTG
ACCCTAAGTTG G ACAATTATTATAAG AAAG AC AATTCTT ATTTCACAGAG CAA CCAATTG AT
CTTGTACCAAACCAAC CATATC CAAACG C
AAG CTTCGATAATTTTAAGTTTGTATGTGATAATATCAAATTTG CTG ATG ATTTAAAC CA G TTAA CTG G
TTATAA G AAAC CT G CTTCA AG A
GAG CTTAAA GTTA CATTTTTC C CT G A CTTAAATG GTGATGTG GTGG CTATT G ATTATAAA
CACTACA CA C CCTCHTTAA G AAA G GAG CTA
AATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG CAA CTAATAAAG C CA C GTATAAA C
CAAATA CCTG GTGTATACGTTGTCTTTG
GAG CACAAAACCAGTTGAAACATCAAATTCGTTTGATGTACTGAAGTCAGAG GACG CGCAGGGAATG
GATAATCTTGCCTGCGAAGAT
CTAAAACCAGTCTCTGAAGAAGTAGTGGAAAATCCTACCATACAGAAAGACGTTCTTGAGTGTAATGTGAAAACTACCG
AAGTTGTAGG
AGACATTATACTTAAACCAGCAAATAATAGTTTAAAAATTACAGAAG AG GTTGG CCACACAGATCTAATGG CTG
CTTATGTAGACAATTC
TA GT CTTA CTATTAA G AAAC CTAATG AATTAT CTA G A G TATTA G G TTTG AAAA C C CTTG
CTACTCATG GTTTAG CTG CT GTTA ATA G T G TC
CCTTG G GATACTATAGCTAATTATG CTAAG CCTTTTCTTAA CA AAG
TTGTTAGTACAACTACTAACATAGTTACACG GTGTTTAAACCGTG
TTTGTACTAATTATATG CCTTATTTCTTTACTTTATTG CTA CAATTG TG TA CTTTTA CTAG AAG TA
CAAATT CTA G AATTAAAG CATCTATG C
C G ACTA CTATA G CAAAG AATA CTG TTAA G AG TG TC G GTAAATTTTGT CTA G AG G
CTTCATTTAATTATTT GAA G T CAC CTAATTTTTCTAA
ACTGATAAATATTATAATTTG G
____________________________________________________________ 1 1 1 1 1
ACTATTAAGTGTTTGCCTAGGTTCTTTAATCTACTCAACCGCTGCTTTAGGTGTTTTAATGTCTAA
TTTAG G CAT G C CTT CTTA CTG TA CTG GTTA CA G A G AA G G CTATTTG AA CTCTA
CTAATG TCA CTATTG CAA C CTA CTG TA CTG GTTCTATAC
CTT GTA GT GTTTG TCTTA GTG G TTTAG ATTCTTTAG A CA C CTAT C CTTCTTTAG AAACTATA
CAAATTAC CATTTCATCTTTTAAATG GGATT
TAACTGCTTTTG G CTTAGTTG CAGAGTGGTTTTTG G CATATATT CTTTT CA CTAG G _____ 1 1 1
1 1 CTATGTACTTG GATTG G CTG CAATCATG CAA
TTGTTTTTCAG CTATTTTG CAGTACATTTTATTAGTAATTCTTG G CTTATGTG
GTTAATAATTAATCTTGTACAAATGG CCCCGATTTCAG CT
ATG GTTAGAATGTACATCTTCTTTG CATCATTTTATTATG TAT G G AAAA G TTATG TG C AT GTTG
TAG AC G G TTGTAATT CAT CAA CTTG TAT
G ATG TG TTA CAAAC G TAATA G AG CAA CAAG A GT C G AATG TA CAA CTATTG TTAATG GT
GTTA G AA G G TC CTTTTATG TCTATG CTAATG G
A G G TAAAG G CTTTT G CA AACTACA CAATTG GAATTGTGTTAATTGTG ATACATTCTGTGCTG G TA
GTACATTTATTA GTG ATG AA G TTG C
G AG AGACTT GTCA CTA CA GTTTAAAAG AC CAATAAATC CTACTG ACCAGTCTTCTTA CATCG TTG
ATAG TG TTACAG TG AAGAATG GTTC
CATC CAT CTTTA CTTT G ATAAAG CTG G TCAAAA G A CTTATG AAAG A CATTCTCTCTCT
CATTTTG TTAA CTTA G ACA A C CTG AG A GCTAAT
AACACTAAAG GTTCATTGCCTATTAATGTTATAGTTTTTGATG GTAAATCAAAATG TG AA G AAT CATCTG
CAAA ATCA G C G TCTG TTTA CT
A CAG TCA G CTTATG TGT CAA C CTATA CTG TTA CTA G AT CA G G CATTAGTGTCTGATGTTG
G TG ATA G TG C G G AA GTTG CA GTTAAAATGT
TTGATG CTTACGTTAATACGTTTTCATCAACTTTTAACGTACCAATG G AAAAACTCAA AACA CTA G TT G
CAA CTG CA G AA G CTG AA CTTG C
AAAGAATGTGTCCTTAGACAATGTCTTATCTACTTTTATTTCAGCAGCTCGGCAAGGGTTTGTTGATTCAG
ATGTAGAAACTAAAGATGTT
GTTGAATGTCTTAAATTGTCACATCAATCTGACATAGAAGTTACTGG CGATAGTTGTAATAACTATATG
CTCACCTATAACAAAGTTG AAA
ACATGACACCCCGTGACCTTG GTG CTTGTATTGACTGTAGTG CG CGTCATATTAATG CG CAG
GTAGCAAAAAGTCACAACATTG CTTTG A
TATGGAACGTTAAAGATTTCATGTCATTGTCTGAACAACTACGAAAACAAATACGTAGTGCTGCTAAAAAGAATAACTT
ACCTTTTAAGT
TGACATGTGCAACTACTAGACAAGTTGTTAATGTTGTAACAACAAAGATAGCACTTAAGGGTGGTAAAATTGTTAATAA
TTGGTTGAAG
CA GTTAATTAAA GTTA CACTTG TGTT C CTTTTTG TTG CTG
CTATTTTCTATTTAATAACACCTGTTCATGTCATGTCTAAACATACTG A CTTT
TCAAGTGAAATCATAG GATACAAG G CTATTGATGGTG G TG TCA CTC GT G A CATA G CAT CTA CA
G ATA CTTG TTTTG CTAACAAACATG CT
GATTTTGACACATG GTTTAG CCAG CGTG GTGGTAGTTATACTAATGACAAAG CTTG CCCATTGATTG
CTGCAGTCATAACAAGAGAAGT
G G GTTTTGTCGTGCCTGGTTTGCCTG G CACGATATTACGCACAACTAATGGTGACTTTTTG
CATTTCTTACCTAGAGTTTTTAGTG CA GTT
GGTAACATCTGTTACACACCATCAAAACTTATAGAGTACACTGACTTTGCAACATCAGCTTGTGTTTTGGCTGCTGAAT
GTACAATTTTTA
AAGATG CTTCTG GTAAG CCAGTACCAT ATT GTTATG ATAC CAATG TA CTAGAAG GTT CTGTTG
CTTATG AAAGTTTACGCCCTGACACAC
GTTATGTG CTCATGGATG G CTCTATTATTCA ATTT CCTAA CAC CTACCTTG AAG GTTCTGTTAGAGTG
GTAACAA CTTTTG ATT CTGAG TA
CTG TA G G CA C G G CA CTTG TG AAA G ATCA G AA G CTG GT GTTTG TGTAT CTACTAG TG
G TA G ATG G GTA CTTAA CAAT G ATTATTA CA G AT
CTTTACCAG GAGTTTTCTGTG GT GTAG ATG
CTGTAAATTTACTTACTAATATGTTTACACCACTAATTCAACCTATTG GTG CTTTG GA CATA
TCAG CATCTATAG TA G CTG GT G G TATT GTA G CTATCGTAGTAACATG CCTTG C CTA
CTATTTTATG AG G TTTA G AAG AG CTTTTGGTGAAT
A CAG TCATG TA GTTG C CTTTAATA CTTTA CTATTC CTTATG TCATTCA CTG TACT CTG TTTAA
CAC CA G TTTA CTCATT CTTA C CTG GT GTTT
ATTCTG TTATTTA CTTG TA CTTG A CATTTTATCTTACTAATG AT G TTTCTTTTTT AG CA CATATT
CA GT G G ATG GTTATG TTCA CAC CTTTAG
TA C CTTT CTG GATAACAATTG CTTATATCATTTGTATTTCCACAAAG CATTT CTATTG GTT CTTTA G
TAATTAC CTAAA G AG A C GTG TA G TC
TTTAATG G TGTTTC CTTTAG TA CTTTTG AA G AA G CTG CG CT GT G CA C CTTTTTG
TTAAATAAA G AAAT GTAT CTAAA G TTG C G TAG TG ATG
TG CTATTACCTCTTACG CAATATAATAGATACTTAG CT CTTTATAATAA G TACAAGTATTTTA G TG GAG
CAATG GATACAACTAGCTACAG
A G AAG CT G CTTG TTG TCATCTC G CAAAG G CT CT CAATG A CTTCA G TAACT CA G
GTTCTGATGTTCTTTACCAACCACCACAAACCTCTATC
ACCTCAG CTGTTTTG CAGAGTGGTTTTAGAAAAATG GCATTCCCATCTGGTAAAGTTGAG GGTTGTATG
GTACAAGTAACTTGTGGTACA
ACTACACTTAACGGTCTTTGGCTTGATGACGTAGTTTACTGTCCAAGACATGTG
ATCTGCACCTCTGAAGACATGCTTAACCCTAATTATG
AAGATTTACTCATTCGTAAGTCTAATCATAATTTCTTGGTACAGGCTGGTAATGTTCAACTCAGGGTTATTGGACATTC
TATGCAAAATTG
TGTACTTAAGCTTAAG GTTGATACAG CCAATCCTAAGACACCTAAGTATAAGTTTGTTCGCATTCAACCAGGACAG
ACTTTTTCAGTGTTA
G CTTGTTACAATG GTTCACCATCTG GT GTTTACCAATG TG CTATG AG G CCCAATTTCACTATTAAG
GGTTCATTCCTTAATG GTTCATGTG
G TA GTG TT G G TTTTAACATA G ATTATG ACTG TG TCTCTTTTT GTTA CATG CA C CATATG G
AATTA C CAA CTG G AG TT C AT G CTG G CA CAG A
CTTA G AA G GTAACTTTTATG G A C CTTTTGTTG ACA G G CA AACA G CACAAG CA G CTG
GTACG GACACAACTATTACAGTTAATGTTTTAG C
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TTG GTTGTACG CT G CTGTTATAAATG GAG ACA G GT G GTTTCTCAATCG
ATTTACCACAACTCTTAATG ACTTTAACCTT GT G G CTATGAAG
TACAATTATGAACCTCTAACACAAGACCATGTTGACATACTAG GACCTCTTTCTG CTCAAACTG
GAATTGCCGTTTTAGATATGTGTG CU
CATTAAAAGAATTACTG CAAAATG GTATGAATG GACGTACCATATTGG GTAGTG
CTTTATTAGAAGATGAATTTACACCTTTTGATGTTG
TTAGACAATG CTCAG GTGTTACTTTCCAAAGTG CAGTGAAAAGAACAATCAAG GGTACACACCACTG
GTTGTTACTCACAATTTTGACTT
CACTTTTAGTTTTAGTCCAGAGTACTCAATG GTCTTTGTTCTTT 11111 GTATGAAAATG
CCTTTTTACCTITTGCTATG GGTATTATTGCTA
TGTCTG CTTTTG CAATGATGTTTGTCAAACATAAGCATG CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG
CCACTGTAG CTTATTTTAATA
TG GTCTATATGCCTGCTAGTTG G GT GATG CGTATTATGACATG GTTG GATATG
GTTGATACTAGTTTGTCTG GTTTTAAG CTAAAAG ACT
GTGTTATGTATGCATCAG CTGTAGTGTTACTAATCCTTATGACAG CAAG AACTGTGTATGATGATGGTG CTAG
GA G AG TGTG GACACTT
ATGAATGTCTTGACACTCGTTTATAAAGTTTATTATG GTAATG CTTTAGATCAAG CCATTTCCATGTG G
GCTCTTATAATCTCTGTTACTTC
TAACTACTCAG GTGTAGTTACAACTGTCATGTTTTTGG CCAGAG GTATTGTTTTTATGT GT GTTGAGTATTG
CCCTATTTTCTTCATAACTG
GTAATACACTTCAGTGTATAATG CTAGTTTATTGTTTCTTAG GCTATTTTTGTACTTGTTACTTTGG CCTC
_________ I I I I GTTTACTCAACCG CTACT
TTAGACTGACTCTTG GTGTTTATGATTACTTAGTTTCTACACAGGAGTTTAGATATATGAATTCACAG
GGACTACTCCCACCCAAG AATAG
CATAGATG CCTTCAAACTCAACATTAAATTGTTG GGTGTTG GTG GCAAACCTTGTATCAAAGTAG
CCACTGTACAGTCTAAA AT GTCAG A
TGTAAAGTG CACATCAGTAGTCTTACTCTCAGTTTTGCAACAACTCAG AGTAG AATCATCATCTAAATTGTG G
GCTCAATGTGTCCAGTTA
CACAATGACATTCTCTTAG CTAAAGATACTACTGAAG CCTTTGAAAAAATG GTTTCACTAC ______ I I I
CTGTTTTG CTTTCCATG CAGG GTG CTG
TAGACATAAACAAGCTTTGTGAAGAAATG CTG GACAACAG G GCAACCTTACAAG CTATAG CCTCAG
AGTTTAGTTCCCTTCCATCATATG
CAGCTTTTG CTACTG CTCAAGAAG CTTATG AG CAG G CT GTTG CTAATG GTG ATTCTG
AAGTTGTTCTTAAAAAGTT GAAGAAGTCTTTG A
ATGTG GCTAAATCTGAATTTGACCGTGATG CAG CCATG CAACGTAAGTTG GAAAAGATG GCTGATCAAG
CTATGACCCAAATGTATAAA
CAGG CTAGATCTGAG GACAAGAG G GCAAAAGTTACTAGTG CTATG CAGACAATGCTTTTCACTATG
CTTAGAAAGTTG GATAATGATGC
ACTCAACAACATTATCAACAATGCAAGAGATGGTTGTGTTCCCTTGAACATAATACCTCTTACAACAGCAG
CCAAACTAATGGTTGTCAT
ACCAGACTATAACACATATAAAAATACGTGTG AT G GTACAACATTTACTTATG CATCAGCATTGTG
GGAAATCCAACAG GTTGTAGATG C
AGATAGTAAAATTGTTCAACTTAGTGAAATTAGTATGG ACAATTCACCTAATTTAG CATGG
CCTCTTATTGTAACAG CITTAAGG G CCAAT
TCTG CTGTCAAATTACAG AATAATG AG CTTAGTCCTGTTG CACTACGACAGATGTCTTGTGCTG CCG
GTACTACACAAACTG CTTG CACT
GATGACAATG CGTTAGCTTACTACAACACAACAAAG GGAGGTAG GTTTGTACTTG
CACTGTTATCCGATTTACAG GATTTGAAATG GGC
TAGATTCCCTAAGAGTGATG GAACTG GTACTATCTATACAGAACTG GAACCACCTTGTAG
GTTTGTTACAGACACACCTAAAGGTCCTAA
AGTGAAGTATTTATACTTTATTAAAGGATTAAACAACCTAAATAGAGGTATG GTACTTG GTAGTTTAG CTG
CCACAGTACGTCTACA AG C
TG GTAATG CAACAGAAGTG CCTG CCAATTCAACTGTATTATCTTTCTGTG CTTTTG CT GTAG ATG CTG
CTAAAG CTTACAAAGATTATCTA
G CTAGTG G GG GACAACCAATCACTAATTGTGTTAAGATGTTGTGTACACACACTG GTACTG GTCAG
GCAATAACAGTTACACCGGAAGC
CAATATG GATCAAGAATCCTTTG GTGGTG CATCGTGTTGTCTGTACTG
CCGTTGCCACATAGATCATCCAAATCCTAAAG G ATTTTGTG A
CTTAAAAG GTAAGTATGTACAAATACCTACAACTTGTGCTAATGACCCTGTG
GGTTTTACACTTAAAAACACAGTCTGTACCGTCTGCG G
TATGTG GAAAGGTTATG G CTGTAGTTGTGATCAACTCCG CGAACCCATG CTTCAGTCAGCTGATG
CACAATCGTTTTTAAACG G GTTTG C
G GTGTAAGTGCAG CCCGTCTTACACCGTG CG G CACAG GCACTAGTACTGATGTCGTATACAG GG
CTTTTGACATCTACAATGATAAAGT
AG CTG GTTTTGCTAAATTCCTAAAAACTAATTGTTGTCG CTTCCAAGAAAAG GACG AAG AT
GACAATTTAATTG ATTCTTACTTTGTAGTT
AAGAGACACACTTTCTCTAACTACCAACATGAAGAAACAATTTATAATTTACTTAAGGATTGTCCAG CT GTTG
CTAAACATGACTTCTTTA
AGTTTAG AATAG ACGGTG ACATGGTACCACATATATCACGTCAACGTCTTACTAAATACACA ATG
GCAGACCTCGTCTATGCTTTAAGG C
ATTTTGATGAAG GTAATT GT GACACATTAAAAGAAATACTTGTCACATACAATT GTTGT G AT GATG
ATTATTTCAATAAAAAG GACTG GT
ATGATTTTGTAGAAAACCCAGATATATTACG CGTATACG CCAACTTAG GTGAACGTGTACG CCAAG
CTTTGTTAAAAACAGTACAATTCT
GTGATG CCATGCGAAATG CTG GTATTGTTGGTGTACTGACATTAGATAATCAAGATCTCAATGGTAACTG
GTATGATTTCG GTGATTTCA
TACAAACCACGCCAG GT AGTG GAGTTCCTGTTGTAGATTCTTATTATTCATTGTTAATG
CCTATATTAACCTTGACCAG GG CTTTAACTG C
AGAGTCACATGTTGACACTGACTTAACAAAG CCTTACATTAAGTGG GATTTGTTAAAATATG ACTTCACGG AAG
AG AG GTTAAAACTCTT
TGACCGTTATTTTAAATATTG G GATCAG ACATACCACCCAAATTGTGTTAACTGTTTG G AT G ACAGATG
CATTCTGCATTGTG CAAACTTT
AATGTTTTATTCTCTACAGTGTTCCCACCTACAAGTTTTG GACCACTAGTGAGAAAAATATTTGTTGATG
GTGTTCCATTTGTAGTTTCAAC
TG GATACCACTTCAG AG AG CTAG GTGTTGTACATAATCAG GATGTAAACTTACATAG
CTCTAGACTTAGTTTTAAGGAATTACTTGTGTA
TG CTG CTGACCCTG CTATG CACG CTG CTTCTGGTAATCTATTACTAGATAAACG
CACTACGTGCTTTTCAGTAG CTG CACTTACTAACAAT
GTTG CTTTTCAAACTGTCAAACCCG GTAATTTTAACAAAGACTTCTATGACTTTGCTGTGTCTAAG
GGTTTCTTTAAG GAAG GAAGTTCTG
TTGAATTAAAACACTTCTTCTTTG CTCAGGATG GTAATG CTG CTATCAG
CGATTATGACTACTATCGTTATAATCTACCAACAATGTGTGA
TATCAGACAACTACTATTTGTAGTTGAAGTTGTTGATAAGTACTTTGATTGTTACGATG GTG G CT GTATTAAT
G CTAACCAAGTCATCGTC
AACAACCTAGACAAATCAG CTG GTTTTCCATTTAATAAATGG G GTAAG G CTAG ACTTTATTAT GATTCA
ATG AGTTAT GAG GATCAAGAT
G CACTTTTCG CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATG CCATTAGTG
CAAAG AATAG AG CTCG CA
CCGTAG CTG GTGTCTCTATCTGTAGTACTATGACCAATAGACAGTTTCATCAAAAATTATTGAAATCAATAGCCG
CCACTAGAGGAGCTA
CTGTAGTAATTG GAACAAGCAAATTCTATG GT G GTTG G
CACAACATGTTAAAAACTGTTTATAGTGATGTAGAAAACCCTCACCTTATG G
GTTG GGATTATCCTAAATGTGATAGAGCCATG CCTAACATGCTTAGAATTATG G
CCTCACTTGTTCTTGCTCGCAAACATACAACGTGTTG
TAGCTTGTCACACCGTTTCTATAGATTAG CTAATGAGTGTGCTCAAGTATTGAGTGAAATGGTCATGTGTG GCG G
TTCACTATATGTTAA
ACCAG GTG GAACCTCATCAG G AG ATG CCACAACTG CTTATG CTAATAGTGTTTTTAACATTTGTCAAG
CTGTCACGG CCAATGTTAATG C
ACTTTTATCTACTG AT G GTAA CAAAATTG CCG ATAAGTATGTCCG CAATTTACAAC ACAGACTTTAT
GAGTGTCTCTATAGAAATAG AG AT
GTTGACACAGACTTTGTGAATGAGTTTTACG CATATTTG CGTAAACATTTCTCAATGATGATACTCTCTGACGATG
CT GTTGT GT GTTTCA
ATAGCACTTATG CATCTCAAG GTCTAGTG GCTAG
CATAAAGAACTTTAAGTCAGTTCTTTATTATCAAAACAATGTTTTTATGTCTGAAG C
AAAATGTTG GACTGAGACTGACCTTACTAAAGGACCTCATGAATTTTG CTCTCAACATACAATG
CTAGTTAAACAGG GTGATGATTATGT
GTACCTTCCTTACCCAGATCCATCAAGAATCCTAGG G GCCG G CTGTTTTGTAGATGATATCGTAAAAACAGATG
GTACACTT ATGATTG A
ACGGTTCGTGTCTTTAGCTATAGATGCTTACCCACTTACTAAACATCCTAATCAG GAGTATG
CTGATGTCTTTCATTTGTACTTACAATACA
TAAGAAAG CTACATG AT GAGTTAACAG
GACACATGTTAGACATGTATTCTGTTATGCTTACTAATGATAACACTTCAAG GTATTGG GAAC
CTG AGTTTTATG AG G CTATGTACACACCG CATACAGTCTTACAG GCTGTTGG G
GCTTGTGTTCTTTGCAATTCACAGACTTCATTAAGATG
79
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TG GTGCTTG CATAC G TA G ACCATT CTTATG TTG TAAAT G CTG TTAC G A CCATGT CATAT
CAA CATCA CATAAATTAG TCTTG T CTG TTAATC
CGTATGTTTG CAATGCTCCAG GTTGTG AT GT CAC A G AT GT GA CTCAA CTTTA CTTA G GAG
GTATG AG CTATTATT GTAAATCA CATAAA C
CA CCCATTAGTTTTCCATTGTGT G CTAATG GACAAGTTTTTGGTTTATATAAAAATACATGTGTTG GTAG CG
ATAATGTTA CT G A CTTTAA
TG CAATT G CAA CAT GTG A CTG G A CAAATG CTGGTGATTACATTTTAG CTAA CA CCTGTACT
GAAA GA CTCAAG CTTTTT G CA G CAG AAA C
G CTCAAAG CTACTGAG GAG ACATTTAAACT GT CTTATG GTATTG CTACT GTACGTG A AGTG
CTGTCTG A CA GA G AATTAC ATCTTTCATG
G GAAGTTG GTAAACCTAG ACCACCACTTAACCG AA ATTATGTCTTTA CTGGTTATCGTGTAA CTAAAAA
CAG TAAAGTA CAAATAG GAG
A GTACA CCTTTGAA AAA G GT GA CTATG GTG AT G CT GTTGTTTACCG AG GTA CAA CAA
CTTACAAATTAAATGTTG GT GATTATTTTGTG C
TG A CATCA CATA CA GTAATG CCATTAAGTG CA CCTA CACTAGTG CCA CAA G AG CA CTATGTTA
G AATTA CTG G CTTATACCCAACACTCA
ATATCTCAGATGAGTTTTCTAG CAATGTTGCAAATTATCAAAAGGTTG GTATG CAAAAGTATTCTACACTCCAG
GG A CCACCTGGTA CTG
GTAAG A GTCATTTT G CTATTG G CCTAGCTCTCTACTACCCTTCTG CTCGCATAGTGTATACAG CTTG
CTCTCATG CCG CT GTTGATG CA CTA
TGTG AG AAGG CATTAAAATATTTGCCTATAGATAAATGTAGTAGAATTATACCTG CACGTG CTCGTGTAG
AGTGTTTTG ATAAATTC AAA
GTGAATTCAACATTAGAACAGTATGTCTTTTGTACTGTAAATG CATTG
CCTGAGACGACAGCAGATATAGTTGTCTTTGATGAAATTTCA
ATG G CCA CAAATTATG ATTTG AGTGTTGTCAATG CCAG ATTACGTG CTAAG CACTATGTGTACATTG
GCGACCCTG CTCAATTACCTG CA
CCACG CA CATTG CTAACTAAG GG CA CACTAG AA CCA G AATATTTCAATTCAG TGTGTA G
ACTTATGAAAA CTATA G GTCCAG A CATGTTC
CTCG G AA CTTG TC G G CGTTGTCCTG CTG AAATTGTTG A CA CTGT G A G TG CTTTG G
TTTAT G ATAATAAG CTTAAA G CA CATAAAG A CAAA
TCAG CT CAATG CTTTAAAATGTTTTATAAGG GTGTTATCACGCATGATGTTTCATCTG CAATTAACAG
GCCACAAATAG GCGTG GTAAG A
GAATTCCTTACACGTAACCCTG CTTG GAG AAAAG CTGTCTTTATTT CAC CTTATAATT CACAG AATG
CTG TAG CCTCAAAG ATTTTG G GAC
TA CCAACTCAAA CTGTTG ATTCATCA CAG G G CT CAG AATATGA CTATGTCATATT CACTCAAA
CCACTG AAACA G CT CACT CTTGTAATGT
AAA CAGATTTAATGTTG CTATTACCAG AG CAAAAGTAGG CATACTTTG CATA AT GT CTGATA G
AGACCTTTATG ACAAGTTG CAATTTA C
AAGTCTTGAAATTCCACGTAG GAATGTG G CAA CTTTA CAA G CT GAAAATG TAA CAG G ACT
CTTTAAAG ATTGTA GTAA G GTAATCACTG
G GTTACATCCTACA CA G G CA CCTA CACA CCTCA GTGTTG ACA CTAAATTCAAAACTG AAG
GTTTATGTGTTGACATACCTG GCATACCTA
AGGACATGACCTATAGAAGACTCATCTCTATGATG GGI
____________________________________________ I I I AAAATGAATTATCAAGTTAATG
GTTACCCTAACATGTTTATCACCCG CG
AAGAAG CTATAAGACATGTACGTG CATG GATTGG CTTCG ATGTCG AG G GGTGTCATG CTACTAGAGAAG
CTGTTG GTACCAATTTACCT
TTA CA G CTA G GTTTTT CTA CA G GT GTTAACCTAGTT G CT GTACCTACAG GTTATGTTGATACA
CCTAATAATA CA G ATTTTTC CA G A G TTA
G TG CTAAA C CAC C G CCTG G AG ATCAATTTAAA CA C CTCATAC CACTTATG TA CAAA G G
ACTT C CTTG GAATGTAGTG CGTATAAAGATTG
TA CAAATG TTAA GT G A CA CACTTAAAAATCT CTCTG ACA G AG TC G TATTT GT CTTATG GG
CA CAT G G CTTTG A G TTG AC ATCTATG AA G T
ATTTTGTGAAAATAG GACCTGAG CG CACCTGTTGTCTATGTGATAGACGTG CCACATG
CTTTTCCACTGCTTCAGACACTTATG CCTGTTG
G CATCATTCTATTG GATTTGATTACGTCTATAATCCGTTTATGATTGATGTTCAACAATG GG GTTTTACAG
GTAACCTACAAAG CAACCAT
G ATCT GTATT GT CAA GTCCATG GTAATG CACATGTAG CTAGTTGTGATG CAATCATG A CTA G
GTGTCTA G CT GTCCA CG A GT G CTTT G TT
AAG C G TG TT G A CTG GACTATTGAATATCCTATAATTG GTG ATG AA CT G AAG ATTAATG CGG
CTTG TA G AAA G G TTCAACA CAT G GTTGTT
AAA G CTG CATTATTA G CA G ACA AATTCCCA GTTCTTCA C G ACATTG G TA A CCCTAAA G
CTATTAAG TG T G TA CCTCAAG CTG AT G TA G AA
TG G AA G TTCTATG ATG CA CA G CCTTG TA GTG A CAAA G CTTATAAAATA G AA G AATTATT
CTATTCTTATG CCA C ACATT CT GA CAAATTCA
CA GATG GTGTATGCCTATTTTG GAATTG CAATGTCGATA G ATAT CCTG CTAATT CCATT GTTTGTA
GATTTGA CA CTAG AGTG CTATCTAA
CCTTAACTTG CCTG GTTGTGATG GTG G CAGTTTGTATGTAAATA AA CATG CATTCCA CA CACCA G
CTTTTGATAAAAGTG CTTTTGTTAAT
TTAAAACAATTACCA _______________________________________________________ 1111
TCTATTACTCTGACAGTCCATGTGAGTCTCATG GAAAACAAGTAGTGTCAGATATAGATTATGTACCACTAA
A GTCT G CTAC G TG TATAA CA C G TTG CAATTTAG GTG GTG CTG TCTG TA G A CATCATG
CTAAT G A G TACAG ATTG TATCTC G ATG CTTATA
A CATG ATG ATCTCA G CTG G CTTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG G
AA CA CTTTTACAAG ACTT CAG A GTTT
A G AAAAT G TG G CTTTTAATG TT GTAAATAAG G G A CA CTTT G ATG G ACAA CA G G GTG
AA G TA C CAG TTT CTAT C ATTAATAA CACTGTTTA
CA CAAAAG TTG ATG G TGTTG ATG TA G AATT GTTTG AAAATAAAA C AA CATTA C CTG
TTAATG TA G CATTT G A G CTTTG G GCTAAG C G CAA
CATTAAACCA GTAC CAG AG GTG AAA ATACT CAATAATTTG G GT GTG G ACATTG CTG CTAATA
CTG TG AT CTG G G ACTACAAAAG AG ATG
CTCCA G CA CATATATCTA CTATTG G TG TTTG TTCTAT G A CT G A CATA G CCAA G AAACCAA
CTG AAAC G ATTTG TG CA CCA CTCA CTG TCTT
TTTTGATG GTAGAGTTGATG GT CAAGTAGACTTATTTA GAAATG CCC GTAATG GTG TT CTTATTA
CAGAAG GTAGTG TTAAAG GTTTA CA
ACCATCTGTAG GTCCCAAACAAG CTAGTCTTAATG GA GTCACATTAATTG G AGAAG CCGTAAAAA CA
CAG TTCAATTATTATAAG AAA GT
TGATG GT GTTG TC CAA CAATTA C CTG AAA CTTA CTTTA CTCA G AG TA G AAATTTAC AA G
AATTTAAA C C CAG G AG TCAAAT G G AAATT G A
TTTCTTAGAATTAG CTATGGATGAATTCATTGAACGGTATAAATTAGAAGG CTATG
CCITCGAACATATCGTTTATG G AG ATTTTAGTCAT
A GTCA GTTA G GT G GTTTACATCTA CTG ATTG GACTAG CTAAACGTTTTAAG G AATCA C CTTTTG
AATTA G AA G ATTTTATT C CTATG G A CA
G TA CA GTTAAAAACTATTTCATAA CA G ATG CG CAAACAG G TTCATCTAA GT G T GTG T G
TTCT GTTATTG ATTTATTACTTGATGATTTTGTT
G AAATAATAAAATC C CAA G ATTTATCTG TA G TTT CTAAG G TTG TCAAA G TG A CTATTG
ACTATACA G AAATTT CATTTATG CTTTG G TG TA
AAGATG GCCATGTAGAAACATTTTACCCAAAATTACAATCTAGTCAAGCGTG G CAACCG GGTGTTG CTATG
CCTAATCTTTACAAAATG C
AAA G AAT G CTATTAGAAAAGTGTGACCTTCAAAATTATG GTGATAGTG CAACATTACCTAAAG G
CATAATG AT G AATGTC G CAAAATAT
A CTCAA CTG TG TCAATATTTAAA CACATTAA CATTAG CT GTACCCTATAATATG AG
AGTTATACATTTTG GTG CTG GTT CTG ATAAAG G AG
TTG CACCAG GTACAG CTGTTTTAAGACAGTG GTTG CCTACG GGTACG CTG
CTTGTCGATTCAGATCTTAATG ACTTTG TCT CTG ATG CA G
ATTCAACTTTG ATTG GTGATTGTG CAA CTGTACATA CAG CTAATAAATG G G ATCTCATTATTAGTG
ATAT GTACG ACCCTAAG ACTAAA A
ATGTTA CAAAAG AAAATG ACTCTAAAGAG G GTTTTTT CA CTTA CATTTG TG
GGTTTATACAACAAAAGCTAG CTCTTG GAG GTT CCGTG G
CTATAAAG ATAACAG AA CATTCTTGG AATG CTGATCTTTATAAG CTCATG G GACACTTCG CATGGTG
GACAG CCTTTGTTA CTAATGTG A
ATGCGTCATCATCTGAAG CATTTTTAATTG GATGTAATTATCTTG G CAAACCACG CG AA CAAATAG ATG
GTTATGT CAT G CATGCAAATT
A CATATTTTG GAG GAATA CAAAT CCAATTCA GTT GTCTT CCTATTCTTTATTTG A CAT GA
GTAAATTTCCCCTTAAATTAAG G G G TA CTG CT
GTTATGTCTTTAAAAGAAGGTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAG GTAG ACTTATAATTA
GAG AAAACAACAG AGTT
GTTATTTCTAGTGATGTTCTTGTTAACAACTAAACGAACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTAGTCAGTGTGTTAATCT
TACAACCAGAACTCAATTACCCCCTGCATACACTAATTCTTTCACACGTG
GTGTTTATTACCCTGACAAAGTTTTCAGATCCTCAGTTTTAC
ATTCAACTCAG GACTTGTTCTTACCTTTCTTTTCCAATGTTACTTGGTTCCATG CTATACATGTCTCTG G
GACCAATGGTACTAAGAG GTTT
G ATAA CCCTGTCCTA CCATTTAATG AT G GTGTTTATTTTG CTTCCA CTG A GAA GT
CTAACATAATAAG A G G CTG GATTTTTGGTACTACTT
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TAGATTCGAAGACCCAGTCCCTACTTATTGTTAATAACG
CTACTAATGTTGTTATTAAAGTCTGTGAATTTCAATTTTGTAATGATCCATTT
TTG G GT GTTTATTA CCACAAAAA CAACAAAAGTTG G AT G G AAAGTG A GTT CAG A
GTTTATTCTA GTG CGAATAATTG CACTTTTGAATAT
GTCTCTCAGCCTTTTCTTATGGACCTTGAAG GAAAACAG GGTAATTTCAAAAATCTTAG G
GAATTTGTGTTTAAGAATATTGATG GTTATT
TTAAAATATATTCTAAG CA CACG CCTATTAATTTAGTG CGTGATCTCCCTCAG GGTTTTTCG G CTTTA G
AA CCATT G GTA G ATTTG CCAAT
AGGTATTAACATCACTAG GTTTCAAACTTTACTTG
CTTTACATAGAAGTTATTTGACTCCTGGTGATTCTTCTTCAG GTTGGACAG CTG GT
G CTG CA G CTTATTATGTG G GTTATCTTCAA CCTA G G A CTTTTCTATTAAAATATAATG AAAATG
GAACCATTACAGATG CTGTA GA CTGTG
CACTTGACCCTCTCTCAGAAACAAAGTGTACGTTGAAATCCTTCACTGTAGAAAAAG
GAATCTATCAAACTTCTAACTTTAGAGTCCAACC
AACAGAATCTATTGTTAGATTTCCTAATATTACAAACTTGTG CCCTTTTGGTG
AAGTTTTTAACGCCACCAGATTTG CAT CTGTTTATG CTT
G GAACAG G AA G A GAATCA G CA A CTGT GTTG
CTGATTATTCTGTCCTATATAATTCCGCATCATTTTCCACTTTTAAGTGTTATG GA GTGTC
TCCTACTAAATTAAATGATCTCTG CTTTA CTAATGTCTAT G CA G ATTCATTT GTAATTA G AG GTG AT
GAA GT CAG A CAAATCG CTCCAGG G
CAAACTG G AAA GATT G CT GATTATAATTATAAATTA CCAG ATG ATTTTA CA G G CTG CGTTATAG
CTTG GAATTCTAACAATCTTGATTCTA
AGGTTG GTG
GTAATTATAATTACCTGTATAGATTGTTTAGGAAGTCTAATCTCAAACCTTTTGAGAGAGATATTTCAACTGAAATCTA
TCA
G G CCG GTAGCA CACCTTGTAATGGTGTTG AAGGTTTTAATTGTTA CTTTCCTTTA CAAT CATATG
GTTTCCAACCCACTAATG GTGTTG GT
TACCAACCATACAGAGTAGTAGTACTTTCTTTTGAACTTCTACATG CACCAG CAACTGTTTGTG GA
CCTAAAAAGTCTA CTAATTTG GTTA
AAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CA CAG GT GTTCTTA CT GA GTCTAA
CAAAAA GTTTCT G CCTTTCCAA CAATT
TG G CA GAG A CATT G CT GA CA CTA CTGATG CTGTCCGTG AT CCACA G ACA CTTG A GATT
CTTGACATT ACA CC ATGTTCTTTTG GTG GTGTC
A GT GTTATAA CA CC AG G AACAAATACTTCTAACCAG GTTG CTGTTCTTTATCAG G ATGTTAACT G
CA CA GAA GT CCCTGTTG CTATTCATG
CA GATCAA CTTA CTCCTA CTTG G CGTGTTTATTCTACAG GTTCTAATGTTTTT CAAA CA CGTG CA G
GCTGTTTAATAG GG GCTGAACATGT
CAACAACTCATATGAGTGTGACATACCCATTG GTG CA G GTATATG CG
CTAGTTATCAGACTCAGACTAATTCTCCTCG GCGGG CACGTAG
TGTAGCTAGTCAATCCATCATTG CCTA CA CTATGTCA CTTG GTG CAGAAAATTCAGTTG
CTTACTCTAATAACTCTATTG CCATACCCA CAA
ATTTTACTATTAGTGTTACCACAGAAATTCTAC CAGTGTCTATG ACCAAG A CATCAGTAG ATTGTA CAATG
TACATTTGTG GTGATTCAAC
TGAATG CA G CAATCTTTTGTTG CAATATG G CA GTTTTTGTA CA CAATTAAA CCGT G CTTTAACT G
G AATAG CTGTTG AA CAA G ACAAAAA
CA CCCAA G AA GTTTTTG CACAA GT CAAA CAAATTTACAAAA CA CCACCAATTAAAG ATTTTG GTG
GTTTTAATTTTTC A CAAATATTA CCA
GATCCATCAAAACCAAG CAAGAG GTCATTTATTG AAG ATCTA CTTTT CAA CAAAGTG ACACTTGCAGATG
CTGG CTTCATCAAACAATAT
G GTGATTG CCTTG GTGATATTG CTGCTAGAGACCTCATTTGTGCACAAAAGTTTAACGG CCTTACTGTTTTG
CCACCTTTG CTCACAGATG
AAATGATTG CTCAATACACTTCTGCACTGTTAG CGG GTACAATCACTTCTGGTTG GACCTTTG GTGCAG
GTGCTGCATTACAAATACCATT
TG CTATG CAAATG G CTTATAG GTTTAATG GTATTG GA GTTA CA CAG AATGTT CTCTAT GA G AA
CCAAAAATT G ATTG CCAACCAATTTAA
TA GT G CTATT G G CAAAATTCAA GA CTCA CTTT CTTCCA CAG CAAGTG CA CTTG GAAAACTT
CAA G AT GT G GTCAA CCAAAAT G CA CAAG C
TTTAAACACG CTTGTTAAACAACTTAG CTCCAATTTTG GTG CAATTTCAAGTGTTTTAAATG
ATATCCTTTCACGTCTTGACAAAGTTG AG
G CTGAAGTGCAAATTGATAG GTTGATCA CA G G CA GA CTTCAAA GTTT G CA G ACATATGTG
ACTCAA CAATTAATTA G AG CTG CA GA AAT
CA GA G CTTCTG CTAATCTTG CTG CTA CTAAAATGTCA GA GTGTGTA CTTG GA CAATCAAAAA G A
GTTG ATTTTT GTG G AAA G GG CTATCA
TCTTATGTCCTTCCCTCA GT CAG CA CCTCATG GT GTAGTCTT CTTG CAT GT GA CTTATGTCCCT G
CA CAAG AAAAG AA CTT CACAA CTG CTC
CTG CCATTTGTCATGATG G AAAAGCA CA CTTTCCTCGTG AAG GTGTCTTTGTTTCAAATG G CACA CA
CTGGTTTGTAA CA CAAA G GAATT
TTTATG AACCACAAATCATTACTACAG ACAACACATTTGTGTCTG G TAACTGTGATGTTGTAATAG G
AATTGTCAACAA CACAGTTTATG A
TCCTTTGCAACCTGAATTAGACTCATTCAAG GAG G AGTTAGATAAATATTTTAA GAATC ATA CAT CACCAG
AT GTTG ATTTAGG TG ACATC
TCTG G CATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCG CCTCAAT G AG GTTG
CCAAGAATTTAAATGAATCTCTCATCGATC
TCCAAG AA CTTG GAAAGTATG A G CA GTATATAAAATG G CCATG GTACATTTGG CTAG GTTTTATAG
CTGG CTTGATTG CCATAGTAATG
GTGACAATTATG CTTTG CTGTATG A CCA G TTG CTGTAGTTGTCTCAAGG G CTGTTGTTCTTGTG
GATCCTGCTG CAAATTT GATG AA GAC
GACTCTGAG CCAGTG CTCAAAGG AGT CAAATTA CATTA CACATAAA CG AA CTTATG
GATTTGTTTATGAGAATCTTCACAATTG GAACTG
TAACTTTGAAG CAAG GTGAAATCAAG GATGCTACTCCTTCAGATTTTGTTCGCGCTACTG CAA CG ATACCG
ATA CAAG CCTCACTCCCTTT
CG GATG GCTTATTGTTG G CGTTG CACTTCTTG CTGTTTTTCA GA G CG CTTCCAAAATCATAACCCTCA
AAAA GA G AT G G CAACTAG CACT
CTCCAAGG GTGTTCACTTTGTTTG CAA CTTG CTGTTGTTGTTTGTAACAGTTTACTCACACCTTTTG
CTCGTTGCTG CTG GC CTTG AAG CCC
CTTTTCTCTATCTTTATGCTTTAGTCTACTTCTTGCAGAGTATAAACTTTGTAAGAATAATAATGAGG CTTTGG
CTTTGCTGGAAATG CCGT
TCCAAAAACCCATTACTTTATGATG CCAACTATTTTCTTTGCTG G CATACTAATT GTTACG A CTATTGTATA
CCTTA CAATA GT GTAACTTCT
TCAATTGTCATTACTTCAGGTGATG G CA CAACAA GT CCTATTTCTG AACATG A CTA CCA G ATTG
GTG GTTATA CTG AAA AATG GGAATCT
G GAGTAAAAGACTGTGTTGTATTA CA CAGTTACTT CACTTCAG ACTATTACCAG
CTGTACTCAACTCAATTGAGTACAG ACACTGGTGTT
G AA CATGTTACCTTCTTCATCTACAATAAAATTGTTG ATGAG CCTG AAG AA
CATGTCCAAATTCACACAATCG ACG GTTCATCCG GAGTT
GTTAATCCAGTAATG GAACCAATTTATGATGAACCGACGACGACTACTAG CGTG CCTTTGTAAG CA CAAG
CTG ATGAGTACGAA CTTAT
GTA CT CATTCGTTTCG GAAGAGACAGGTACGTTAATAGTTAATAG CGTACTTCTTTTTCTTGCTTTCGTG
GTATTCTTG CTAGTTA CA CTA G
CCATCCTTACTG CG CTTCGATTGTGTGCGTACTG CTG CAATATTGTTAACGTG A GT CTTGTAAAA C
CTTCTTTTTACGTTTACTCTCGT GTT
AAAAATCTGAATTCTTCTAGAGTTCCTGATCTTCTG GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTG
GAACTTTAATTTTAG CC
ATG G CA G ATTCCAACG GTA CTATTA CCGTTG AA G AG CTTAAAAAG CTCCTTGAACAATG
GAACCTAGTAATAG GTTTCCTATT CCTTA CA
TG GATTTGTCTTCTACAATTTG CCTATG CCAACAG
GAATAGGTTTTTGTATATAATTAAGTTAATTTTCCTCTGG CT GTTATG G CCAGTAAC
TTTAG CTTGTTTTGTG CTTG CTG CTGTTTACAGAATAAATTGGATCACCGGTG GAATTG CTATCG
CAATGGCTTGTCTTGTAG G CTTGATG
TG GCTCAG CTACTTCATTGCTTCTTTCAGACTGTTTG CG CGTACG CGTTCCATGTG
GTCATTCAATCCAGAAACTAACATTCTTCTCAACGT
G CCACTCCATG G CACTATTCTGACCAGACCGCTTCTAGAAAGTGAACTCGTAATCG GAGCTGTGATCCTTCGTG
GACATCTTCGTATTG C
TG GACACCATCTAGGACG CTGTGACATCAAG GACCTGCCTAAAGAAATCACTGTTG CTA CAT CACG AACG
CTTTCTTATTACAAATTGG G
AGCTTCGCAG CGTGTAG CAGGTGACTCAG GTTTTGCTG CATACAGTCG CTACAG GATTG G CAA CTATA
AATTAAA CACAG ACCATTCCA
GTAG CAGTGACAATATTG CTTTG CTTGTA CA GTAAGTG ACAACAG ATGTTTCATCTCGTTGACTTTCAG
GTTACTATAGCAGAGATATTAC
TAATTATTATG AGG ACTTTTAAAGTTTCCATTTGG AATCTTG ATTA CAT
CATAAACCTCATAATTAAAAATTTATCTAAGTCA CTAA CTG AG
AATAAATATTCT CAATTAGATG AAG AG CAACCAATGG AGATTG ATTAAAC G AA CATG AAAATTATT
CTTTTCTTG GCA CTG ATAA CA CTC
G CTACTTGTG AG CTTTAT CA CTACCAAGAGTGTGTTAGAG GTACAACAGTACTTTTAAAAGAACCTTG
CTCTTCTGGAACATAC G AG G G C
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AATTCACCATTTCATCCTCTAGCTGATAACAAATTTGCACTGACTTGCTTTAGCACTCAATTTGCTTTTGCTTGTCCTG
ACGGCGTAAAACA
CGTCTATCAGTTACGTGCCAGATCAGTTTCACCTAAACTGTTCATCAGACAAGAGGAAGTTCAAGAACTTTACTCTCCA
ATTTTTCTTATT
GTTGCGGCAATAGTGTTTATAACACTTTG
CTTCACACTCAAAAGAAAGACAGAATGATTGAACTTTCATTAATTGACTTCTATTTGTGCTT
TTTAG CCTTTCTG CTATTCCTTGTTTTAATTATG CTTATTATCTTTTG GTTCTCACTTG AACTGCAAG
ATCATAATG AAACTTGTCACG CCTA
AACGAACATGAAATTTCTTGTTTTCTTAGGAATCATCACAACTGTAGCTGCATTTCACCAAGAATGTAGTTTACAGTCA
TGTACTCAACAT
CAACCATATGTAGTTG ATGACCCGTGTCCTATTCACTTCTATTCTAAATGGTATATTAGAGTA G GAG
CTAGAAAATCAG CACCTTTAATTG
AATTGTG CGTG G ATG AG G CTG GTTCTAAAT CACCCATTCAGTACATC G ATATCG
GTAATTATACAGTTTCCTGTTTACCTTTTACAATTAA
TTGCCAGGAACCTAAATTGGGTAGTCTTGTAGTGCGTTGTTCGTTCTATGAAGACTTTTTAGAGTATCATGACGTTCGT
GTTGTTTTAGAT
TTCATCTAAAC G AACAAACTAAAATGTCTGATAATG GACCCCAAAATCAGCG AAATG CACCCCG
CATTACGTTTG GTGG ACCCTCAG ATT
CAACTG G CAGTAACCAGAATG GAGAACGCAGTG G G GCG CGATCAAAACAACGTCG
GCCCCAAGGTTTACCCAATAATACTGCGTCTTG
GTTCACCGCTCTCACT CAACATG GCAAGGAAGACCTTAAATTCCCTCG AGG ACAAG
GCGTTCCAATTAACACCAATAG CAGTCCAG ATG A
CCAAATTGGCTACTACCGAAGAGCTACCAGACGAATTCGTGGTGGTGACGGTAAAATGAAAGATCTCAGTCCAAGATGG
TATTTCTACT
ACCTAGGAACTG GG CCAGAAG CTG GACTTCCCTATGGTG CTAACAAAGACG GCATCATATG
GGTTGCAACTGAGG GAG CCTTGAATAC
ACCAAAAGATCACATTGGCACCCGCAATCCTGCTAACAATGCTGCAATCGTGCTACAACTTCCTCAAGGAACAACATTG
CCAAAAGGCTT
CTACGCAG AAG G GAG CAG AG G CG G CAGTCAAG
CCTCTTCTCGTTCCTCATCACGTAGTCGCAACAGTTCAAGAAATTCAACTCCAG G CA
G CAGTAG G G GAACTTCTCCTG CTAG AATG GCTG G CAATG G CG GTG ATG CTG CTCTTG CTTTG
CTG CTG CTTG A CAG ATTG AACCAG CU
G AG AG CAAAATGTCTG GTAAAG G CCAACAACAACAAG G C CAAACTGTCA CTAAGAAATCTG CTG
CTG AG G CTTCTAAG AAG CCTCG G C
AAAAACGTACTGCCACTAAAGCATACAATGTAACACAAGCTTTCGGCAGACGTGGTCCAGAACAAACCCAAGGAAATTT
TGGGGACCA
G G AACTAATCAG ACAAG G AACTG ATTACAAACATTG G C CG CAAATTG CACAATTTG CC CCCAG
CG CTTCAG CGTTCTTCG G AATGTCG C
G CATTGG CATG GAAGTCACACCTTCG G GAACGTGGTTG ACCTACACAG GTGCCATCAAATTGG ATG
ACAAAGATCCAAATTTCAAAG AT
CAAGTCATTTTGCTGAATAAG CATATTG A CGCATACAAAACATTCCCACCAACAG AG CCTAAAAAG G
ACAAAAAG AAG AAG G CTGATG A
AACTCAAG CCTTACCG CAGAGACAGAAG AAACAG CAAACTGTGACTCTTCTTCCTG CTG CAGATTTG G
ATG ATTTCTCCAAACAATTG CA
ACAATCCATGAGCAGTGCTGACTCAACTCAGGCCTAAACTCATGCAGACCACACAAGGCAGATGGGCTATATAAACGTT
TTCGCTTTTCC
GTTTACGATATATAGTCTACTCTTGTGCAGAATGAATTCTCGTAACTACATAGCACAAGTAGATGTAGTTAACTTTAAT
CTCACATAGCAA
TCTTTAATCAGTGTGTAACATTAG G G AG G ACTTG AAAG AG CCACCACATTTTCACCG AG G CCACG
CG G AGTACG ATCGAGTGTACAGTG
AACAATG CTAG G G AG AG CTG CCTATATG G AAG AG CC CTAATGTGTAAAATTAATTTTAGTAGTG
CTATCCCCATGTGATTTTAATAG CU
CTTAGGAGAATGACAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
SEQ ID NO: 2
Severe acute respiratory syndrome coronavirus 2 orf1ab polyprotein of isolate
Wuhan-Hu-1 (GenBank:
QHD43415)
MESLVPGFNEKTHVQLSLPVLQVRDVLVRGFGDSVEEVLSEARQHLKDGTCGLVEVEKG VLPQLEQPYVF I
KRSDARTAPH G HVMVE LVAE LE
G I QYG RSG ETLGVLVP HVG El PVAYRKVLLRKNGN KGAGGHSYGADLKSFDLG DELGTDPYE
DFC1ENWNTKHSSGVTR ELM RELN GGAYTRY
VDN NFCGPDGYPLECIKDLLARAGKASCTLSEQLDFIDTKRGVYCCREHEHEIAWYTERSEKSYELQTP
FEIKLAKKFDTFNGECPNFVFPLNSIIK
TIQPRVEKKKLDG FM G RI RSVYPVASP N ECN QM CLSTLM KCDH CG ETSWQTG DFVKATCEFCGTEN
LTKEGATTCGYLPQNAVVKIYCPACH
NSEVG PEHSLAEYHN ESG LKTI LRKGG RTIAFGGCVFSYVGCHNKCAYWVPRASANIGCN HTGVVG EGSEG
LNDN LLEI LQKEKVN I N IVG DFK
LN EEI AI I LASFSASTSAFVETVKG LDYKAFKQIVESCG N F KVTKG KAKKGAWN I
GEQKSILSPLYAFASEAARVVRSIFSRTLETAQNSVRVLQKA
AITILDG ISQYSLRLI DAM M FTSDLATNN LVVMAYITGGVVQLTSQWLTN I
FGTVYEKLKPVLDWLEEKFKEGVEFLRDGWEIVKFISTCACEIV
GGQIVTCAKEIKESVQTFFKLVNKFLALCADSI I IG GAKLKALN LG ET FVTHSKG LYR KCVKSRE ETG
LLM PLKAPKEI I FLEG ETLPTEVLTEEVVLK
TGDLQPLEQPTSEAVEAPLVGTPVCI NG LM
LLEIKDTEKYCALAPNMMVTNNTFTLKGGAPTKVTFGDDTVIEVQGYKSVNITFELDERI DKVL
NEKCSAYTVELGTEVNEFACVVADAVIKTLQPVSELLTPLG1DLDEWSMATYYLFDESGEFKLASHMYCSFYPPDEDEE
EG DCEEEEFEPSTQYE
YGTEDDYQGKPLEFGATSAALQPEEEQEEDWLDDDSQQTVGQQDGSEDN QTTTIQTIVEVQPQLEM ELTPVVQTI
EVNSFSGYLKLTDNVYI
KNADIVEEAKKVKPTVVVNAANVYLKHGGGVAGALNKATN NAM QVESDDYI ATN GP LKVG GSCVLSG
HNLAKHCLHVVG PNVN KG ED I QL
LKSAYENFNQHEVLLAPLLSAG I FGADPI HSLRVCVDTVRTNVYLAVFDKN LYDKLVSSFLEM KSEKQVEQKI
AEI P KEEVKP F ITESKPSVEQRKQ
DDKKIKACVEEVTTTLEETKFLTENLLLYI DING N LH PDSATLVSDI DITFLKKDA PYI VG
DVVQEGVLTAVVIPTKKAGGTTEM LAKALRKVPTDN
YITTYPGQG LN GYTVEEAKTVLKKCKSAFYI LPSI ISN EKQE I LGTVSWN LREM LAHAEETRKLM
PVCVETKAIVSTI QRKYKG I KIQEGVVDYGAR
FYFYTSKTTVASLI NTLN DLN ETLVTM PLGYVTHG LN LEEAARYM
RSLKVPATVSVSSPDAVTAYNGYLTSSSKTPEEHFI ETISLAGSYKDWSYS
GQSTQLGIEFLKRGDKSVYYTSNPTTFHLDGEVITEDNLKTLLSLREVRTIKVFTTVDNINLHTQVVDMSMTYGQQFGP
TYLDGADVTKIKPHNS
HEGKTFYVLPNDDTLRVEAFEYYHTTDPSFLG RYMSALN HTKKWKYPQVN G LTSI
KWADNNCYLATALLTLQQI ELKFN PPALQDAYYRARAG
EAANFCALI LAYCN
KTVGELGDVRETMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQFKKGVQ1PCTCGKQATKYL
VQQESPFVMMSAPPAQYELKHGTFTCASEYTGNYQCGHYKHITSKETLYCI
DGALLTKSSEYKGPITDVFYKENSY1111KPVTYKLDGVVCTE1D
PKLDNYYKKDNSYFTEQPIDLVPNQPYPNASFDNFKFVCDNIKFADDLNQLTGYKKPASRELKVTFFPDLNGDVVAIDY
KHYTPSFKKGAKLLHK
PIVWHVNNATNKATYKPNTWCI
RCLWSTKPVETSNSFDVLKSEDAQGMDNLACEDLKPVSEEVVENPTIQKDVLECNVKTTEVVGDIILKPAN
NSLKITEEVGHTDLMAAYVDNSSLTIKKPNELSRVLGLKTLATHGLAAVNSVPWDTIANYAKPFLNKVVSTTTN1VTRC
LNRVCTNYMPYFFTLL
LQLCTFTRSTNSR I KASM PTTIAKNTVKSVGKFCLEASFNYLKSPN FSKLIN I I
IWFLLLSVCLGSLIYSTAALG VLM SN LG M PSYCTGYREGYLNST
NVTIATYCTGSI PCSVCLSG LDSLDTYPSLETIQITISSFKWDLTAFG LVAEWFLAYILFTRFFYVLG LAAIM
QLFFSYFAVHFISNSWLM WLI I NLV
QMAPISAMVRMYIFFASFYYVWKSYVHVVDGCNSSTCM MCYKRNRATRVECTTIVN GVR RSFYVYAN G G KG
FCKLH NWN CVNCDTFCAG
STFISDEVARDLSLQFKRPI N PTDQSSYIVDSVTVKN GS! H LYFDKAG QKTYE RHSLS HFVN LDN
LRAN NTKGSLPI N VIVFDG KSKCEESSAKSAS
VYYSQLM CQP I LLLDQALVSDVG DSAEVAVKM FDAYVNTFSSTFNVPM
EKLKTLVATAEAELAKNVSLDNVLSTFISAARQG FVDSDVETKDV
VECLKLSHQSDI EVTGDSCN NYM LTYNKVEN MTPRDLGACI DCSARH I NAQVA KSH N I ALI
WNVIKDFM SLSEQLRKQI RSAAKKNNLPFKLTC
ATTRQVVNVVTTKIALKGGKIVNNWLKQLI KVTLVFLFVAAI FYLITPVHVMSKHTDFSSEI I
GYKAIDGGVTRDIASTDTCFAN KHADFDTWFS
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QRGGSYTNDKACPLIAAVITREVGFVVPGLPGTI LRTTN GDF LH FLPRVFSAVG N ICYTPSKLI EYT
DFATSACVLAAECT I FKDASGKPVPYCYDT
NVLEGSVAYESLRPDTRYVLM DGSIIQFPNTYLEGSVRVVTTFDSEYCRHGTCERSEAGVCVSTSGRWVLN
NDYYRSLPGVFCGVDAVNLLTN
M FTPLIQP IGALDISASIVAGGI VAIVVTCLAYYFM
RFRRAFGEYSHVVAFNTLLFLMSFTVLCLTPVYSFLPGVYSVIYLYLTFYLTN DVSF LAN! Q
WM VM FTP LVPFWITIAYI ICISTKH FYWFFSN YLKRRVVFN GVSFSTFEEAALCTF LLN
KEMYLKLRSDVLLP LTQYN RYLA LYN KYKYFSGAMD
TTSYREAACCHLAKALN DFSNSGSDVLYQPPQTSITSAVLQSG FRKMAF PSG KVEGCMVQVTCGTTTLNG
LWLDDVVYCP RHVICTSEDM LN
PNYEDLLIRKSNHNFLVOAGNVQLRVIGHSM QNCVLKLKVDTAN PKTPKYKFVRIQPG07
FSVLACYNGSPSGVYQCAM RP N FT! KGSFLN GS
CGSVGFNIDYDCVSFCYMHHMELPTGVHAGTDLEGNFYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVI NG
DRWFLN RFTTTLN DFN LVA
MKYNYEPLTQDHVDILGPLSAQTGIAVLDMCASLKELLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQSAVKRTI
KGTHHWLLLTI LTSL
LVLVQSTQWSLFFFLYENAFLPFAMGIIAMSAFAMM FVKHKHAFLCLFLLPSLATVAYFN MVYM PASWVM RI
MTWLDMVDTSLSG FKLKD
CVMYASAVVLLILMTARTVYDDGARRVWTLM NVLTLVYKVYYGNALDQAISM WALI ISVTSNYSG VVTTVM
FLARG IVFM CVEYCP 1 FF ITG N
TLQCIM LVYCFLGYFCTCYFGLFCLLN RYFRLTLGVYDYLVSTQEFRYMNSQGLLPPKNSI
DAFKLNIKLLGVGGKPCIKVATVQSKMSDVKCTSV
VLLSVLQQLRVESSSKLWAQCVQLH N DI LLAKDTTEAFEKMVSLLSVLLSMQGAVDI
NKLCEEMLDNRATLQAIASEFSSLPSYAAFATAQEAY
EQAVANG DSEVVLKKLKKSLNVAKSEFDRDAAM QRKLEKMADQAMTQM YKQARSEDKRAKVTSAM QTMLFTM
LRKLDN DALN Nil N NA
RDGCVPLN I I P LTTAAK LM VVI P DYNTYKNTCDGTTFTYASALWEIQQVVDADSKIVQLSEISM
DNSPNLAWPLIVTALRANSAVKLQNN ELSP
VALRQMSCAAGTTQTACTDDNALAYYNTTKGGRFVLALLSDLQDLKWARFP KSDGTGT1YTELEPPCRFVTDTP
KGP KVKYLYF1 KG LN NLNR
GMVLGSLAATVRLQAGNATEVPANSTVLSFCAFAVDAAKAYKDYLASGGQPITNCVKMLCTHTGTGQAITVTPEANMDQ
ESFGGASCCLYC
RCHIDHPNPKGFCDLKGKYVQIPTTCANDPVGFTLKNTVCTVCGMWKGYGCSCDQLREPMLQSADAQSFLN
RVCGVSAARLTPCGTGTSTD
VVYRAFDIYN DKVAG FAKFLKTNCCRFQEKDEDDN LI DSYFVVKRHTFSNYQHEETIYN
LLKDCPAVAKHDFFKFRI DGDMVPHISRQRLTKYT
MADLVYALR HFDEGN CDTLKEI LVTYNCCDDDYF N KKDWYDFVEN PDI LRVYAN
LGERVRQALLKTVQFCDAM RN AG IVGVLTLDN QDLNG
NWYDFG DFI QTTPGSGVPVVDSYYSLLM PI
LTLTRALTAESHVDTDLTKPYIKWDLLKYDFTEERLKLFDRYFKYWDQTYHPNCVNCLDDRCIL
HCANFNVLFSTVFPPTSFGPLVRKIFVDGVPFVVSTGYHFRELGVVHNQDVNLHSSRLSFKELLVYAADPAMHAASGNL
LLDKRTTCFSVAALT
NNVAFQTVKPGNFN KDFY DFAVSKG FFKEGSSVELKHFF FAQDG NAA1SDYDYY
RYNLPTMCDIRQLLFVVEVVDKY FDCY DGGC1 NANQV1V
NNLDKSAGFPFNKWGKARLYYDSMSYEDQDALFAYTKRNVI PTITQMN LKYAISAKN
RARTVAGVSICSTMTNRQFHQKLLKSIAATRGATVV
IGTSKFYGGWHNMLKTVYSDVENPHLMGWDYPKCDRAMPNMLRIMASLVLARKHTTCCSLSHRFYRLANECAQVLSEMV
MCGGSLYVKP
GGTSSGDATTAYANSVFNICQAVTANVNALLSTDGNKIADKYVRNLQHRLYECLYRN
RDVDTDFVNEFYAYLRKHFSMMILSDDAVVCFNST
YASQGLVASIKNFKSVLYYQN
NVFMSEAKCWTETDLTKGPHEFCSQHTMLVKQGDDYVYLPYPDPSRILGAGCFVDDIVKTDGTLMIERFVSL
Al DAYP LTKH PN QEYADVFHLYLQYIRKLHDELTGHM LDMYSVMLTN
DNTSRYWEPEFYEAMYTPHTVLQAVGACVLCNSQTSLRCGACI RR
PFLCCKCCYDHVISTSHKLVLSVN
PYVCNAPGCDVTDVTQLYLGGMSYYCKSHKPPISFPLCANGQVFGLYKNTCVGSDNVTDFNAIATCDWT
NAG DY1LANTCTERLKLFAAETLKATEETFKLSYG IATVREVLSDRELHLSWEVG KPRP PLN RN
YVFTGYRVTKNSKVQ1GEYTFEKG DYG DAVV
YRGTTTYKLNVGDYFVLTSHTVMP LSAPTLVPQEHYVRITGLYPTLN ISDEFSSN VAN YQKVG M QKYSTLQG
PPGTGKSHFAI GLALYYPSARI V
YTACSHAAVDALCEKALKYLPIDKCSRIIPARARVECFDKFKVNSTLEQYVFCTVNALPETTADIVVFDEISMATNYDL
SVVNARLRAKHYVYIGD
PAQLPAPRTLLTKGTLEPEYFNSVCRLM KTIG PDM FLGTCRRCPAEIVDTVSALVYDN KLKAH KDKSAQCFKM
FYKGVITHDVSSAI N RPQIGV
VREFLTRNPAWRKAVFISPYNSQNAVASKILGLPTQTVDSSQGSEYDYVIFTQTTETAHSCNVNRFNVAITRAKVGILC
I MSDRDLYDKLQFTSL
El P RRNVATLQAENVTG LFKDCSKVITG LHPTQAPTH LSVDTKFKTEG LCVDI PG 1 P KDMTYRRLISM
MG FK M NYQVNGYP NMFITREEA1 RH
VRAW1GFDVEGCHATREAVGTN LP LQLG FSTGVN LVAVPTGYVDTPN NTDFSRVSA KPPPG DQFKH LI
PLMYKGLPWNVVRIKIVQMLSDTL
KN LSDRVVFVLWAHG FELTSM KYFVKIG PERTCCLCDRRATCFSTASDTYACWH HSI GF DYVYN PFM I
DVQQWGFTGNLQSNHDLYCQVHG
NA HVASCDAI MTRCLAVHECFVKRVDWTI EYPI IGDELKI N AACRKVQH M VVKAALLADKFPVLHDIG N
P KAI KCVPQADVEWKFYDAQPCS
DKAYKI EELFYSYATHSDKFTDGVCLFWNCNVDRYPANSI VCRF DTRVLSN
LNLPGCDGGSLYVNKHAFHTPAFDKSAFVNLKQLPF FYYSDSP
CESHGKQVVSDIDYVPLKSATCITRCNLGGAVCRHHANEYRLYLDAYNMMISAGFSLWVYKQFDTYNLWNTFTRLQSLE
NVAFNVVNKGHF
DG QQG EVPVSI IN NTVYTKVDGVDVELFEN KTTLPVN VAFELWAKRNI KPVPEVKI LN N
LGVDIAANTVIWDYKRDAPAHISTIGVCSMTDIAK
KPTETI CAP LTVFFDG RVDG QVDLFRN ARNGVLITEGSVKG LQPSVGP KQASLNGVTLIG EAVKTQF N
YYKKVDGVVQQLP ETYFTQSRN LQE
FKPRSQM El DFLELAM DEF1 ERYKLEGYAFEHI VYGDFSHSQLGGLHLLIGLAKRFKESPFELEDFI PM
DSTVKNYFITDAQTGSSKCVCSV1 DLLL
DDFVEI I KSQDLSVVSKVVKVTIDYTEISFMLWCKDGHVETFYPKLCISSQAWQPGVAMPN LYKM QRM
LLEKCDLQNYGDSATLPKGI M M NV
AKYTQLCQYLNTLTLAVPYNM RVIHFGAGSDKGVAPGTAVLRQWLPTGTLLVDSDLN
DFVSDADSTLIGDCATVHTANKWDLIISDM YDPKT
KN VTKEN DSKEG FFTYICG FIQQKLALGGSVAIKITEHSWNADLYKLMG HFAWVVTAFVTNVN
ASSSEAFLIGCNYLG KPREQI DGYVM HAN YI
FWRNTN P1QLSSYSLFDMSKFP LKLRGTAVMSLKEG Q1 N DM 1 LSLLSKG RLI1R EN N
RVV1SSDVLVN N
SEQ ID NO: 3
Severe acute respiratory syndrome coronavirus 2 surface glycoprotein (GenBank:
QHD43416)
MFVFLVLLPLVSSQCVN LTTRTQLP PAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAI
HVSGTNGTKRFDNPVLPFNDGVYFAS
TEKSNI1RGWIFGTTLDSKTQSLLIVN NATNVV1KVCEFQFCNDPFLGVYYHKN NKSWMESEFRVYSSAN
NCTFEYVSQPFLMDLEG KQGNFK
N LREFVFKN I DGYF KlYSKHTPI N LVRDLPQG FSALEPLVDLPI GI N ITRFQTLLALHRSYLTPG
DSSSGWTAGAAAYYVGYLQP RTFLLKYN ENGT
ITDAVDCALDP LSETKCTLKSFTVEKG IYQTSN FRVQPTESI VRF P N ITN LCPFG
EVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYG
VSPTKLNDLCFTNVYADSFVIRGDEVRQ1APGQTGKIADYNYKLPDDFTGCVIAWNSNN
LDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAG
STPCNGVEG FNCYFPLQSYGFQPTN GVGYQPYRVVVLSF ELLHAPATVCG PKKSTN
LVKNKCVNFNFNGLTGTGVLTESN KKFLPFQQFGRDI
ADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAG
CLIGAEHVN NSYEC
DI P IGAGICASYQTQTNSP RRARSVASQSI IAYTMSLGAENSVAYSN NSIAI
PTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSF
CTQLN RALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFN FSQ1 LPDPSK PSKRSF1 EDLLFN
KVTLADAG Fl KQYGDCLGDIAARDLICAQKF
NG LTVLPPLLTDEM IAQYTSALLAGTITSGVVTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYEN
QKLIANQFNSAIGKIQDSLSSTASALGKLQ
DVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQI DRLITG RLQSLQTYVTQQLI RAAEI
RASA N LAATKMSECVLG QSKRVDFC
GKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRN
FYEPQIITTDNTFVSGNCDVVIGIVNN
83
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TVYDPLQPELDSFKEELDKYFKN HTSP DVDLG DISG I NASVVN I QKE I DRLN EVAKN
LNESLIDLQELGKYEQYI KWPWYIWLG Fl AG LIAIVM VT
I M LCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO: 4
CpG 1018
TGACTGTGAACGTTCGAGATGA
SEQ ID NO: 5
KLK peptide
KLKLLLLLKLK
SEQ ID NO: 6
Oligo-d(IC)13 (ODN1a)
icicicicicicicicicicicicic
SEQ ID NO: 7
CpG 1826
TCCATGACGTTCCTGACGTT
SEQ ID NO: 8
CpG 7909
TCGTCGTTTTGTCGTTTTGTCGTT
SEQ ID NO: 9
>hCoV-19/Ita ly/IN Ml 1-is1/20201 E PLISL41054512020-01-29 (Accession No:
MT066156)
ATTAAAGGTTTATACCTTCCCAGGTAACAAACCAACCAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACGAACTTTA
AAATCTGTGTGG
CTGTCACTCGGCTGCATGCTTAGTGCACTCACGCAGTATAATTAATAACTAATTACTGTCGTTGACAGGACACGAGTAA
CTCGTCTATCTT
CTG CAG G CTG CTTACGGTTTCGTCCGTGTTGCAGCCGATCATCAG CACATCTAGGTTTCGTCCG
GGTGTGACCGAAAG GTAAG ATG GAG
AGCCTTGTCCCTGGTTTCAACG AGAAAACACA CGTCCAACTCAGTTTG CCTGTTTTACAG GTTCG CGAC GTG
CTCGTACGTG G CTTTGG A
G ACTCCGTG G AG G AGGTCTTATCAG AGG CACGTCAACATCTTAAAG ATG GCACTTGTGG
CTTAGTAGAAGTTGAAAAAG G CGTTTTG CC
TCAACTTG AACAGCCCTATGTGTTCATCAAACGTTCGGATG CTCGAACTG CACCTCATG GTCATGTTATG
GTTG AG CTG GTAGCAGAACT
CGAAG GCATTCAGTACGGTCGTAGTG GTGAGACACTTG GTGTCCTTGTCCCTCATGTG G
GCGAAATACCAGTGG CTTACCG CAAG GTTC
TTCTTCGTAAGAACGGTAATAAAGGAGCTG
GTGGCCATAGTTACGGCGCCGATCTAAAGTCATTTGACTTAGGCGACGAGCTTGGCACT
G ATCCTTATG AAGATTTTCAAGAAAACTG GAACACTAAACATAG CAGTG GTGTTACCCGTGAACTCATG
CGTGAG CTTAACG GAGGG GC
ATACACTCGCTATGTCGATAACAACTTCTGTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGT
GCTGGTAAAGC
TTCATGCACTTTGTCCGAACAACTGGACTTTATTGACACTAAGAGGGGTGTATACTGCTGCCGTGAACATGAGCATGAA
ATTGCTTGGTA
CACGGAACGTTCTGAAAAGAGCTATGAATTGCAGACACCTTTTGAAATTAAATTGGCAAAGAAATTTGACACCTICAAT
GGGGAATGTC
CAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAGGGTTGAAAAGAAAAAGCTTGATGGCTTTAT
GGGTAGAATTC
GATCTGTCTATCCAGTTGCGTCACCAAATGAATGCAACCAAATGTGCCTTTCAACTCTCATGAAGTGTGATCATTGTGG
TGAAACTTCATG
GCAGACGGGCGATTTTGTTAAAGCCACTTGCGAATTTTGTGGCACTGAGAATTTGACTAAAGAAGGTGCCACTACTTGT
GGTTACTTACC
CCAAAATGCTGTTGTTAAAATTTATTGTCCAGCATGTCACAATTCAGAAGTAGGACCTGAGCATAGTCTTGCCGAATAC
CATAATGAATC
TG G CTTG AAAACCATTCTTCGTAAG G GTGGTCG CACTATTG CCTTTG G AG G
CTGTGTGTTCTCTTATGTTG GTTG CCATAACAAGTGTGC
CTATTG G GTTCCACGTG CTAG CGCTAACATAGGTTGTAACCATACAG GTGTTGTTG GAG AAG GTTCCG
AAG GTCTTAATG ACAACCTTCT
TGAAATACTCCAAAAAGAGAAAGTCAACATCAATATTGTTGGTGACTTTAAACTTAATGAAGAGATCGCCATTATTTTG
GCATCTTTTTCT
GCTTCCACAAGTGCTTTTGTGGAAACTGTGAAAGGTTTGGATTATAAAGCATTCAAACAAATTGTTGAATCCTGTGGTA
ATTTTAAAGTT
ACAAAAGGAAAAGCTAAAAAAGGTGCCTGGAATATTGGTGAACAGAAATCAATACTGAGTCCTCTTTATGCATTTG
CATCAG AG GCTGC
TCGTGTTGTACGATCAATTTTCTCCCG CACTCTTGAAACTG CTCAAAATTCTGTGCGTGTTTTACAG AAG G
CCG CTATAACAATACTAG AT
G GAATTTCACAGTATTCACTG AG ACTCATTG ATGCTATG ATGTTCACATCTG ATTTG G
CTACTAACAATCTAGTTGTAATGG CCTACATTA
CAGGTG GTGTTGTTCAGTTG ACTTCGCAGTG GCTAACTAACATCTTTG
GCACTGTTTATGAAAAACTCAAACCCGTCCTTG ATTG G CTTG A
AGAG AAGTTTAAGG AAG GTGTAGAGTTTCTTAG AGACG GTTGG G AAATTGTTAAATTTATCTCAACCT
GTG CTTGTG AAATTG TCG GTG
GACAAATTGTCACCTGTGCTAAGGAAATTAAGGAGAGTGTTCAGACATTCTTTAAGCTTGTAAATAAATTTTTGGCTTT
GTGTGCTGACT
CTATCATTATTG GTG GAG CTAAACTTAAA GCCTTG AATTTAG GTG AAACATTTG TCACG CACTCAAAGG
G ATTGTACAG AAAGTGTGTTA
AATCCAGAGAAGAAACTGGCCTACTCATGCCTCTAAAAGCCCCAAAAGAAATTATCTTCTTAGAG
GGAGAAACACTTCCCACAGAAGTG
TTAACAG AG GAAGTTGTCTTG AAAACTG GTG ATTTACAACCATTAG AACAACCTACTAGTGAAGCTGTTG
AAG CTCCATTGGTTGGTACA
CCAGTTTGTATTAACGG GCTTATGTTG CTCGAAATCAAA G ACACAGAAAAGTACTGTG CC CTTG
CACCTAATATG ATGGTAACAAACAAT
ACCTTCACACTCAAAGGCGGTGCACCAACAAAGGTTACTTTTGGTGATGACACTGTGATAGAAGTGCAAGGTTACAAGA
GTGTGAATAT
CACTTTTGAACTTGATGAAAGGATTGATAAAGTACTTAATGAGAAGTGCTCTGCCTATACAGTTGAACTCGGTACAGAA
GTAAATGAGTT
CGCCTGTGTTGTGGCAGATGCTGTCATAAAAACTTTGCAACCAGTATCTGAATTACTTACACCACTGGGCATTGATTTA
GATGAGTGGAG
TATGGCTACATACTACTTATTTGATGAGTCTGGTGAGTTTAAATTGGCTTCACATATGTATTGTTCHTCTACCCTCCAG
ATGAGGATGAA
G AAG AAG GTGATTGTG AA GAAGAAG AGTTTGAG CCATCAACTCAATATGAGTATG GTACTG AAGATG
ATTAC CAAG GTAAACCTTTGG
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AATTTG GT G CCA CTTCT G CTG CTCTT CAA CCTG AAG AAG A G CAA G AAG AA G ATTG
GTTA GATG ATG AT AGTCAA CAAA CTGTT G GT CAA
CAAGACG GCAGTG AG G ACAATCAG ACAA CTA CTATTCA AA CAATTGTTG AG GTTCAACCT
CAATTAG AG ATG GAA CTTA CA CCAGTTGT
TCA GA CTATT GAA GT GAATA GTTTTA GTG GTTATTTAAAA CTTA CTG A CAATGTATA
CATTAAAAATG CA G A CATTGT G GAAGAAG CTAA
AAAG GTAAAACCAA CA GTG GTTGTTAATG CAGCCAATGTTTACCTTAAACATG GAGGAGGTGTTG CAGG
AG CCTTAAATAAGG CTACTA
ACAATGCCATG CAAGTTGAATCTGATGATTACATAG CTACTAATG GACCACTTAAAGTG G
GTGGTAGTTGTGTTTTAAG CGGACACAATC
TTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAGGTGAAGACATTCAACTTCTTAAGAGTG
CTTATGAAAATTTTAATCA
G CACGAAGTTCTACTTG CACCATTATTATCAGCTG GTATTTTTG
GTGCTGACCCTATACATTCTTTAAGAGTTTGTGTAGATACTGTTCG CA
CAAATGTCTACTTAG CTGTCTTT GATAAAAATCTCTATG A CAAA CTTG TTTCAA G CTTTTTG
GAAATGAA G AGTG A AAA G CAA GTTG AA C
AAAA GAT CG CTG A GATTCCTAA A G AG G AA GTTAA G CCATTTATAA CTG AAA GTAAACCTT
CAGTTG AA CAG A GAAAACAA GATGATAAG
AAAATCAAAG
CTTGTGTTGAAGAAGTTACAACAACTCTGGAAGAAACTAAGTTCCTCACAGAAAACTTGTTACTTTATATTGACATTAA
T
G G CAATCTTCATCCAGATTCTG CCACTCTTGTTAGTGACATTGACATCACTTTCTTAAAGAAAGATG
CTCCATATATA GT G G GTG AT GTTG
TTCAAGAG GGTGTTTTAACTGCTGTG GTTATACCTACTAAAAAGG CTG GTGG CACTACTGAAATG
CTAGCGAAAG CTTTGAGAAAAGTG
CCAACAGACAATTATATAACCACTTACCCG GGTCAG GGTTTAAATG GTTACA CTGTAG AG GAG G
CAAAGACAGTG CTTAAAAAGTGTAA
AAGTG CCTTTTA CATT CTA CCAT CTATTAT CTCTAAT G AG AA G CAA GAAATTCTTG
GAACTGTTTCTTG GAATTTG CG A G AAATG CTTG CA
CATG CA G AAG AAA CA C G CAAATTAAT G C CTG TCT GT GTG G AAA CTAAAG C CATA
GTTTCAACTATA CA G CGTAAATATAAG G GTATTAA
AATACAAGAG G GTGTG GTTGATTATG GTGCTAG ATTTTA CTTTTA CAC CAGTAAAACAACTG TAG CGT
CACTTAT CAA CA CA CTTAACG A
TCTAAAT G AAA CT CTTG TTA CAAT G C CA CTTG G CTATG TAA CA CATG GCTTAAATTTGG
AAG AA G CTG CTCG G TATATG AG ATCTCTCA A
A GTG CCAG CTACA GTTT CT GTTTCTT CACCTG ATG CTGTTACAG CGTATAAT G GTTATCTTA
CTTCTTCTTCTAAAA CACCTG AA G AA CATT
TTATTG AAA CCATCTCA CTTG CTG GTTCCTATAAAGATTG GTCCTATTCTG GA CAATCTA CACAA CTA
G G TATA G AATTTCTTAA G A G AG G
TGATAAAAGTGTATATTACACTAGTAATCCTACCACATTCCACCTAGATG
GTGAAGTTATCACCTTTGACAATCTTAAGACACTTCTTTCTT
TG AG A G AA GTG AG GACTATTAAG GT GTTTA CAA CA GTAG A CAACATTAA CCTC CA CAC G
CAAGTTGTG GACATGTCAATGACATATG GA
CAA CA GTTTG G TC C AA CTTATTTG G ATGG AG CTG AT GTTACTAAAATAAAA C
CTCATAATTCACATG AAGGTAAAACATTTTAT GTTTTAC
CTAATGATG ACA CT CTACGT GTTGAG G CTTTTG AGTA CTACCA CA CAACTG ATC CTAGTTTT CTG
G GTAG GTACATGTCAGCATTAAATCA
CA CTAAAAAGTG GAAATACCCACAAGTTAATGGTTTAACTTCTATTAAATG G G
CAGATAACAACTGTTATCTTGCCACTG CATT GTTAA CA
CTCCAACAAATAG A GTTG AA G TTTAATC C A C CTG CT CTA CAA G AT G CTTATTA CAG A G
C AA G G G CTG GT G AA G CTG CTAA CTTTT GTG CA
CTTATCTTAG CCTACTGTAATAAG ACA G TA G G TG A GTTAG GTG AT GTTAG A G AAACAATG A
GTTACTTGTTTCAACATG C CAATTTA G AT
TCTTG CAAAAGAGTCTTGAACGTGGTGTGTAAAACTTGTG GA CAACA G CA GA CAACCCTTAA G G
GTGTA G AA G CTGTTATGTACATGG G
CA CACTTTCTTATG AACAATTTAA G AAA G GT GTT CAG ATA CCTTGTA CGT GT G G TAAAC AA
G CTACAAAATATCTAGTACAACAG GAGTC
A CCTTTTGTTATG ATGTCA G CA CCA C CTG CTCAGTATGAACTTAAG CATG GTA CATTTACTT GT G
CTA GTG AGTA CA CTG GTAATTACCAG
TGTG GT CACTATAA A CATATAA CTT CTAAA G AAA CTTTGTATT G CATA G ACG GT G
CTTTACTTACAAAGTCCTCAG AATA C AAA G GTCCTA
TTACG GATGTTTTCTA CAAA GAAAACA GTTA CA CAA CAACCATAAAA CCA GTTACTTATAAATTG G
AT GGTGTTGTTTGTACA G AAATTG
ACCCTAAGTTG G ACAATTATTATAAG AAAG AC AATTCTT ATTTCACAGAG CAA CCAATTG AT
CTTGTACCAAACCAACCATATCCAAACG C
AAG CTTCG ATAATTTTAA GTTTGTATGTG ATAATATCAAATTT G CTG ATG ATTTAAACCA GTTAACT G
GTTATAA G AAA CCTG CTTCA AG A
GAG CTTAAA GTTA CATTTTTCCCT GA CTTAAATG GTGATGTG GTGG CTATT GATTATAAA CACTACA
CA CCCTCTTTTAA G AAA G GAG CTA
AATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG CAA CTAATAAAG C CA C GTATAAA C
CAAATA CCTG GTGTATACGTTGTCTTTG
G AG CA CAAAA C CA GTTG AAA CATCA AATTCGTTTGATGTA CT G AAGTCA G AG GACG CG
CAGG GAATG GATAATCTTG CCTG CGAA GAT
CTAAAACCAGTCTCTGAAGAAGTAGTGGAAAATCCTACCATACAGAAAGACGTTCTTGAGTGTAATGTGAAAACTACCG
AAGTTGTAGG
AGACATTATACTTAAACCAG CAAATAATAGTTTAAAAATTACAGAAG AG GTTGG CCACACAGATCTAATGG
CTG CTTATGTAGACAATTC
TAGTCTTACTATTAAGAAACCTAATGAATTATCTAGAGTATTAGGTTTGAAAACCCTTG CTACTCATG GTTTAG
CTG CTGTTAATAGTGTC
CCTTG G GATACTATAGCTAATTATG CTAAG CCTTTTCTTAA CA AAGTT GTTAGTA CAACTA CTAA
CATAGTTACA CG GT GTTTAAA CCGTG
TTTGTACTAATTATATG CCTTATTTCTTTACTTTATTG CTA CAATT GT GTA CTTTTA CTAG AA GTA
CAAATTCTAG AATTAAAG CATCTATG C
CG ACTA CTATA G CAAAG AATACTGTTAAG AG TG TC G GTAAATTTTGT CTA G AG G
CTTCATTTAATTATTT GAA G T CAC CTAATTTTTCTAA
A CTG ATAAATATTATAATTTG GTTTTTACTATTAAGTGTTTGCCTAG GTTCTTTAATCTACTCAACCG
CTGCTTTAG GTGTTTTAATGTCTAA
TTTAG G CAT G C CTT CTTA CTG TA CTG G TTACA G AG AAG G CTATTTG AA CTCTA CTAAT
GT CA CTATTG CAACCTACTG TA CTG GTTCTATAC
CTTG TA G TG TTTG TCTTAG TG GTTTAG ATTCTTTAG A CAC CTATC CTTCTTTAG AAA CTATA
CAAATTAC CATTT CATCTTTTAAATG G GATT
TAA CT G CTTTTG G CTTAGTTG CAG A GT G G TTTTTG G CATATATT CTTTT CA CTA G
GTTTTTCTATGTACTTG GATTG G CTG CAATCATG CAA
TTGTTTTTCAG CTATTTTG CA G TACATTTTATTA G TA ATT CTTG G CTTATG TG G
TTAATAATTAATCTTG TA CAAATG G C CC C G ATTTCAG CT
ATG GTTAGAATGTACATCTTCTTTG CATCATTTTATTATGTATGGAAAAGTTATGTG CATGTTGTAGACG
GTTGTAATTCATCAACTTGTAT
G ATG TG TTA CAAAC G TAATA G AG CAA CAAG A GT C G AATG TA CAA CTATTG TTAATG GT
GTTAG AA G G TC CTTTTATG TCTATG CTAATG G
AGGTAAAG G CTTTTG CAAACTACACAATTG GAATTGTGTTAATTGTG ATACATTCTGTGCTG
GTAGTACATTTATTAGTGATGAAGTTG C
G AG AGACTT GTCA CTA CA GTTTAAAAG ACCAATAAATCCTACTG ACCAGTCTTCTTA CATCGTTG
ATAGTGTTACAGTG AAGAATG GTTC
CATCCATCTTTACTTTGATAAAG CTG GTCAAAA GA CTTATG AAAG A CATTCTCTCTCT CATTTTGTTAA
CTTA G ACA A CCTG AG A G CTAAT
AA CA CTAAA G GTTCATTG CCTATTAATGTTATAGTTTTTGATG GTAAATCAAAATGTG AAG AAT CAT
CTG CAAA AT CAG CGTCTGTTTA CT
A CAGTCA G CTTATGTGT CAA CCTATA CTGTTA CTA G AT CA G G CATTAGTGTCTGATGTTG
GTGATA GTG CG G AA GTTG CA GTTAA AATGT
TTG ATG CTTACGTTAATACGTTTTCATCAACTTTTAACGTACCAATG G AAAAACTCAA AACA CTA G TT G
CAA CTG CA G AAGCTG AA CTTG C
AAAGAATGTGTCCTTAGACAATGTCTTATCTACTTTTATTTCAG CAG CTCG G CAAG GGTTTGTTGATTCAG
ATGTAGAAACTAAAGATGTT
GTTG AATGTCTTAAATTGTCACATCAATCT GA CATA GAA GTTA CTGG CGATAGTTGTAATAACTATATG
CT CACCTATAA C AAA GTTG AAA
A CATG ACACCCCGTG ACCTTG GTGCTTGTATTGACTGTAGTGCG CGTCATATTAATGCGCAGGTAG CAAAAA
GT CA CAA CATTG CTTTG A
TATG GAACGTTAAAGATTTCATGTCATTGTCTGAACAACTACGAAAACAAATACGTAGTG CTG CTAAAAAG
AATAA CTTA C CTTTTAA GT
TGACATGTG CAACTACTA GA CAA GTTG TTAATGTTGTAACAA CAAA GATAG CA CTTAAG G
GTGGTAAAATTGTTAATAATTG GTTG AA G
CA GTTAATTAAA GTTA CA CTTGTGTT CCTTTTTGTTG CTG CTATTTTCTATTTAATAA CA
CCTGTTCATGTCATGTCTAAACATA CTG ACTTT
TCAAGTGAAATCATAG GATACAAG G CTATTGATGGTG GTGTCA CTCGT GA CATA G CAT CTA CA
GATA CTTGTTTTG CTAACAAACATG CT
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G ATTTTG A CACATG GTTTAG CCAG CGTG GT G GTA GTTATA CTAAT GACAAA G CTTG
CCCATTGATTG CTGCAGTCATAACAAGAGAAGT
G G GTTTTGTCGTGCCTGGTTTGCCTGG CA CGATATTA CGCA CAA CTAATG GT G ACTTTTT G CATTT
CTTA CCTA GA GTTTTTA GT G CA GTT
G GTAA CATCTGTTA CA CACCATCAAAA CTTATAG A GTAC A CTG A CTTTG CAACATCAG
CTTGTGTTTTGG CTG CTGAATGTACAATTTTTA
AAGATG CTTCTG GTAAG CCAGTACCAT ATT GTTATG ATACCAATGTA CTAGAAGGTT CTGTTG CTTATG
AAAGTTTACGCCCTGACACAC
GTTATGTG CTCATG G AT G G CT CTATTATTCAATTTCCTAA CA CCTACCTTGAA G
GTTCTGTTAGAGTG GTAACAA CTTTTGATTCT GA GTA
CTGTAGG CA CG G CA CTTGTG AAA GATCA G AA G CTG GT GTTTGTGTAT CTACTAGTG GTAGATG
G GTA CTTAA CAAT GATTATTA CA G AT
CTTTACCAG GAGTTTTCTGTG GT GTAG ATG
CTGTAAATTTACTTACTAATATGTTTACACCACTAATTCAACCTATTG GTG CTTTG GA CATA
TCAGCATCTATAGTAG CTG GTGGTATTGTAG CTATCGTAGTAACATG CCTTG CCTACTATTTTATGAG
GTTTAGAAGAG CTTTTGGTGAAT
A CAGTCATGTA GTTG CCTTTAATA CTTTA CTATTCCTTATGTCATTCA CTGTACT CTGTTTAA CACCA
GTTTA CTCATT CTTA CCTG GT GTTT
ATTCTGTTATTTACTTGTACTTGACATTTTATCTTACTAATGATGTTTCT 11111 AG CACATATTCAGTGGATG
GTTATGTTCACACCTTTAG
TA CCTTTCT G G ATAACAATTG CTTATATCATTTGTATTTCCACAAAG CATTTCTATTG GTTCTTTA
GTAATTA CCTAAA GAG AC GTGTA GTC
TTTAATG GTGTTTCCTTTAGTA CTTTTG AA G AA G CTG CG CT GT G CA CCTTTTTGTTAAATAAA
GAAAT GTAT CTAAA G TTG CGTAGTGATG
TG CTATTACCTCTTACG CAATATAATAGATACTTAG CTCTTTATAATAAGTACAAGTATTTTAGTG GAG CAAT
G G ATA CAA CTA G CTACAG
A GAA G CT G CTTGTTGTCATCTCG CAAAG G CT CTCAATG A CTTCA GTAACT CAG
GTTCTGATGTTCTTTACCAACCACCACAAACCTCTATC
ACCTCAG CTGTTTTG CAG A GTGGTTTTAGAAAAATG GCATTCCCATCTGGTAAAGTTG AG GGTTGTATG
GTA CAAGTAACTTGTGGTA CA
A CTA CA CTTAA CG GTCTTTG G CTTG ATG ACGTA GTTTA CT GT CCAA G ACATGTG AT CTG
CA CCTCTG AAG A CAT G CTTAACCCTAATTATG
AAGATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTA CA G GCTGGTAATGTTCAACTCAG G GTTATTG
G A CATTCTATG CAAAATTG
TGTACTTAAGCTTAAG GTTGATACAG CCAATCCTAAG ACACCTAAGTATAAGTTT GTTCGCATT CAACCAGG
ACAG ACTTTTTCA GT GTTA
G CTTGTTACAATG GTTCACCATCTG GT GTTTACCAATGTG CTATGAGG C CCAATTT CA CTATTAAGG
GTTCATTCCTTAATG GTTCATGTG
GTAGTGTTGGTTTTAACATAGATTATGACTGTGTCTCTTTTTGTTACATG CA CCATATG G AATTA CCAA CTG
G AGTT C AT G CTG G CA CAG A
CTTA G AA G GTAACTTTTATG GA CCTTTTGTTG ACA G G CA AACA G CACAAG CA G CTG GTACG
GACACAACTATTACAGTTAATGTTTTAG C
HG GTTGTACGCTGCTGTTATAAATG GAG ACA G GTGGTTTCTCAATCG
ATTTACCACAACTCTTAATGACTTTAACCTTGTG GCTATGAAG
TA CAATTATGAACCTCTAA CACAAGACCATGTTG ACATA CTAG GACCTCTTTCTG CTCAAACTG
GAATTGCCGTTTTAGATATGTGTG CTT
CATTAAAAGAATTACTG CAAAATG GTATGAATG GACGTACCATATTG GGTAGTG
CTTTATTAGAAGATGAATTTACACCTTTTGATGTTG
TTAGACAATG CTCA G GTGTTA CTTT CCAAA GT G CA GTG AAAAG AA CAATCAAG G GTAC A CA
CC ACT G GTTGTTACTCA CAATTTTG A CTT
CA CTTTTAGTTTTA GT CCAG A GTACT CAATG GTCTTTGTTCTTTTTTTTNTATGAAAATG
CCTTTTTACCTTTTGCTATGGGTATTATTGCTA
TGTCTG CTTTTG CAATGATGTTTGTCAAACATAAGCATG CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG
CCACTGTAG CTTATTTTAATA
TG GT CTATATG CCT G CTAGTTG G GT GATG CGTATTATGACATG GTTG
GATATGGTTGATACTAGTTTGTCTG GTTTTAAG CTAAAA G A CT
GTGTTATGTATGCATCAG CTGTAGTGTTACTAATCCTTATGACAG CAAG AACTGTGTATGATGATGGTG CTAG
GA G AG TGTG GACACTT
ATGAATGTCTTGACACTCGTTTATAAAGTTTATTATG GTAATGCTTTAGATCAAGCCATTTCCATGTGG G
CTCTTATAATCTCTGTTACTTC
TAACTACTCAG GTGTAGTTACAACTGTCATGTTTTTGG CCAGAG GTATTGTTTTTATGT GT GTTGAGTATTG
CCCTATTTT CTTCATAA CT G
GTAATACACTTCAGTGTATAATG CTAGTTTATTGTTTCTTAG GCTATTITTGTACTTGTTACTTTGG CCTC. I
I I I GTTTACTCAACCG CTACT
TTA G ACT GA CTCTTG GTGTTTATG ATTA CTTA GTTTCTA C A CAG G A GTTTA GATATATG
AATT CACA G G G ACTA CTCCCACCC AA
GAATAG CATAGATG CCTTCAAACTCAACATTAAATTGTTGG GTGTTG GTGG CAAACCTTGTATCAAAGTAG
CCACTGTACAGTCTAAAAT
GTCAGATGTAAAGTG CACATCAGTA GT CTTA CTCTCAGTTTTG CAACAACTCAG
AGTAGAATCATCATCTAAATTGTGGG CTCAATGTGT
CCA GTTA CACAATG A CATT CTCTTA G CTAAAG ATA CTA CT GAA G CCTTTGAAAAAATG GTTTCA
CTA CTTTCTGTTTT G CTTTCCATG CA G G
GTG CT GTAG ACATAAACAAG CTTTGTGAAGAAATGCTG GACAACAGG G
CAACCTTACAAGCTATAGCCTCAGAGTTTAGTTCCCTTCCAT
CATATGCAG CTTTTGCTACTG CTCAAGAAGCTTATGAG CAG G CTGTTG CTAATGGTG ATTCTG AAGTT
GTT CTTAAAAAGTTGAAG AA GT
CTTTGAATGTGG CTAAATCTGAATTTGACCGTGATGCAG CCATG CAACGTAAGTTG GAAAAGATG
GCTGATCAAGCTATGACCCAAATG
TATAAA CA G G CTA G ATCTG AG G ACA A G AG G GCAAAAGTTACTAGTG CTATGCAG ACAATG
CTTTTCACTATG CTTAG AAA GTTG GATAA
TG AT G CA CTCAA CAA CATTATCAACAATG CAA G A GATG
GTTGTGTTCCCTTGAACATAATACCTCTTACAACAG CAG CCAAA CTAATG GT
TGTCATA CCA G A CTATAA CA CATATAAAAATA CGTGTGATG G TA CAA CATTTA CTTATG
CATCAGCATTGTG G GAAAT CCAA CA G GTTGT
A GATG CA GATA GTAAAATTGTTCAA CTTA GTG AAATTA GTAT G G A CAATT CACCTAATTTAG
CATG G CCT CTTATTGTAA CA G CTTTAAG
G G CCAATTCTG CTGTCAAATTA CAG AATAATG AG CTTAGTCCTGTTG CA CTACGA CAGATGTCTT
GTGCTG CCG GTACTACACAAACTG C
TTG CA CTG ATGACAATGCGTTAG CTTACTACAACACAACAAAGG G AG GTAGGTTT GTA CTTG CA
CTGTTATCCG ATTTACAGGATTTGAA
ATG GG CTAGATTCCCTAAGAGTGATG G AA CTG GTA CTATCTATA CAG AA CTG GAACCACCTTGTAG
GTTTGTTACAG ACA CAC CTAAA G
GTCCTAAAGTGAAGTATTTATACTTTATTAAAG GATTAAACAACCTAAATAGAGGTATG GTACTTG GTAGTTTAG
CTG CCACAGTACGTC
TACAAG CTG GTAATG CAACAGAAGTG CCTG CCAATTCAACTGTATTATCTTTCTGTG CTTTTG CTGTAG
AT G CTG CTAAAG CTTACAAAG A
TTATCTAG CTAGTG GG G GACAACCAATCA CTAATTGTGTTAA GATGTTGTGTA CA CACA CTG GTACTG
GT CAG G CAATAACAGTTACACC
G GAAGCCAATATG G AT CAA GAAT CCTTTG GTG GT G CATCGTGTTGTCTGTACTG CCGTTG
CCACATAGATCATCCAAATCCTAAAG GATT
TTGTG A CTTAAAA G GTAA GTATGTA CAAATA C CTA CAA CTTGTG CTAATGACCCTGTG G GTTTT
ACA CTTAAAAA CA CAGTCT GTA CCGTC
TG CGGTATGTG G AAA GGTTATG G CTGTAGTTGTGATCAACTCCG CGAACCCATGCTTCAGTCAG CTGATG
CACAATCGTTTTTAAACG G
GTTTG CG GTGTAAGTG CAG CCCGTCTTACACCGTG CGG CA CAG G CA CTAGTA CTGATG TCGTATA
CAG G GCTTTTG AC ATCTA CAATGAT
AAA GTA G CT G GTTTTG CTAAATTCCTAAAAACTAATTGTTGTCG CTTCCAAGAAAAG G ACG AA GATG
A CAATTTAATT GATT CTTA CTTTG
TA GTTAAG A GA CA CACTTTCTCTAA CTA CCAA CATG AA G AAA CAATTTATAATTTA CTTAA G G
ATTGTCCA G CTGTT G CTAAA CAT GA CTT
CTTTAAGTTTAGAATAGACG GTGACATG GTACCA CATATAT CACGTCAACGT CTTA CTA AATA CA
CAATG G CAGACCTCGTCTATG CTTTA
AGG CATTTTGATGAAG
GTAATTGTGACACATTAAAAGAAATACTTGTCACATACAATTGTTGTGATGATGATTATTTCAATAAAAAG GAC
TG GTATGATTTTGTAGAAAACCCAGATATATTACG CGTATACGCCAACTTAG GT GAACGT GTACG
CCAAGCTTTGTTAAAAACAGTACAA
TTCTGTGATG CCATGCGAAATG CTG GTATTGTTG GTGTACT GA CATTA G ATAATCAA GATCT CAATG
GTAACTG GTATGATTTCG GT GAT
TTCATACAAACCACGCCAG GTAGTG GAGTTCCTGTTGTAGATTCTTATTATTCATTGTTAATG
CCTATATTAACCTTG AC CAG G GCTTTAA
CTG CAG A GT CACATGTTG A CACT GA CTTAA CAAA G CCTTACATTAAGTG G G
ATTTGTTAAAATAT G A CTTCA CG G AAG A GA G GTTAAAA
CTCTTTGACCGTTATTTTAAATATTG G G AT CAG ACATACCACCCAAATT GTGTTAA CTGTTTGG ATG
ACAG ATG CATTCTG CATTGTGCAA
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A CTTTAATG TTTTATT CTCTA CA GTG TT C C CAC CTA CAA GTTTTG G AC CA CTA G TG AG
AAAAATATTTG TTG ATG GT GTT C CATTTG TA G TT
TCAACTGGATACCACTTCAGAGAG CTAGGTGTTGTACATAATCAG GATGTAAACTTACATAG
CTCTAGACTTAGTTTTAAG GAATTACTT
GTGTATGCTGCTGACCCTG CTATG CACG CTG CTTCTGGTAATCTATTACTAGATAAACG CACTACGTG
CTTTTCAGTAG CTG CA CTTA CTA
A CAATG TTG CTTTTCAAACTGTCAAACCCG GTAATTTTAACAAAGACTTCTATGACTTTG CTGTGTCTAAG G
GTTTCTTTAAG GAAG G AA G
TTCT GTTG AATTAAAACACTTCTT CTTT G CT CAG GATG GTAATG CTG
CTATCAGCGATTATGACTACTATCGTTATAATCTACCAACAATGT
GTGATATCA G ACAACTACTATTTGTA GTTG AA GTTGTTG ATAAGTACTTTGATTGTTACGATG GTG G CT
G TATTAAT G CTAA C CAAG TCAT
C G TCAA CAA C CTAG A CAAATCA G CTG GTTTTCCATTTAATAAATG G G GTAAG G CTAG
ACTTTATTATG ATTCAATG AGTTATG A G GATCA
A GATG CACTTTTCG
CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATGCCATTAGTG CAAA G AATAG
AG CT
CG CACCGTAGCTGGTGTCTCTATCTGTAGTACTATGACCAATAGACAGTTTCATCAAAAATTATTGAAATCAATAG
CCG CCACTAG AGG A
G CTACTGTAGTAATTG GAACAAG CAAATTCTATGGTG GTTG G CAC AACAT GTTAA
AAACTGTTTATAGTG ATGTAGAAAACCCTCACCTT
ATG GGTTGG GATTATCCTAAATGTGATAGAG CCATGCCTAACATGCTTAGAATTATGGCCTCACTTGTTCTTG
CTCG CAAACATACAACG
TGTTGTA G CTTGTCACACCGTTTCTATAG ATTA G CTAATG A GT GT G CTCAA GTATTG AGTG
AAATG GTCAT GT GTG G CG GTTCACTATAT
GTTAAACCAGGTG GAACCTCATCAG GAG ATGCCACAACTGCTTATGCTAATAGTG 1 1 1 1 1
AACATTTGTCAAGCTGTCACGG CCAATGTT
AAT G CACTTTTATCTACTG AT G GTAACAAAATTG CCGATAAGTATGTCCG CAATTTACAACACAG
ACTTTATG A GTGTCTCTATA G AAATA
G AG ATGTTG ACACAGACTTTGTGAATG AGTTTTACG CATATTTGCGTAAACATTTCTCAATGATG
ATACTCTCTG ACGATG CTGTTGTGTG
TTTCAATAG CACTTAT G CATCT CAA G GT CTA GTG G CTA G CATAAA G AA CTTTAA G TCAG
TT CTTTATTATCAAAA CAATG TTTTTATG TCTG
AAG CAAAATGTTG G ACTG A G ACTG ACCTTA CTAAAG GACCTCATGAATTTTG CTCTCAACATACAATG
CTAGTTAAACAGG GTG AT GATT
ATGTGTACCTTCCTTACCCAGATCCATCAAGAATCCTAGG G GCCG G CTGTTTTGTAG AT
GATATCGTAAAAACAG ATG GTACACTTATG A
TTGAACGGTTCGTGTCTTTAG CTATAGATG CTTACCCACTTACTAAACATCCTAATCAG GAGTATG CTG AT
GT CTTTCATTTGTA CTTACAA
TACATAA G AAA G
CTACATGATGAGTTAACAGGACACATGTTAGACATGTATTCTGTTATGCTTACTAATGATAACACTTCAAG
GTATTGG
G AACCTG AGTTTTATG AG G CTATGTACACACCG CATACAGTCTTACAGG CTGTTG G GG
CTTGTGTTCTTTG CAATTCACAG A CTTCATTAA
GATGTG GTG CTTG CATACGTAGACCATTCTTATGTTGTAAATG
CTGTTACGACCATGTCATATCAACATCACATAAATTAGTCTTGTCTGT
TAATCCGTATGTTTG CAATG CTC CA G G TTG TG ATG TCA CAG ATG TG A CTCAA CTTTA CTTA
G GAG G TAT G A G CTATTATTGTAAATCACAT
AAA C CA C C CATTAG TTTTC CATTG TG TG CTAATG G A CAA G TTTTTG G TTTATATAAAA
ATA CATG TG TTG G TAG CG ATAATG TTACTG A CT
TTAATG CAATTG CAA CATGT G A CTG G A CAAAT G CTGGTGATTACATTTTAG CTAA CACCT
GTACTG AAAG A CTCAAG CTTTTTG CA G CA G
AAACG CTCAAAG CTACTGAG GAG ACATTTAAA CTG TCTTATG GTATTG CTACTGTACGTGAAGTG CTG
TCTG ACAG AGAATTA CAT CTTT
CATGG GAAGTTG G TAAA C CTA G AC C A C CA CTTAAC C G AAATTAT GTCTTTA CTG GTTATC
GT GTAA CTA AAAA CAG TAAAG TA CAAATA G
G AG A GTACA C CTTTG AA AAA G GT G A CTATG GTG AT G CT GTT GTTTA C C G AG G TA
CAA CAACTTA CAAATTAAAT GTTG GT G ATTATTTTG
TG CTGACATCACATACAGTAATG CCATTAAGTG CA C CTACACTA G TG C CA CAA G A G
CACTATGTTA G AATTACT G G CTTATACCCAACAC
TCAATATCTCAGATGAGTTTTCTAG CAATGTTGCAAATTATCAAAAGGTTGGTATG CAA AA GTATT CTA
CACTCCAG GGACCACCTG G TA
CTG GTAA G A GTCATTTTG CTATTG G CCTAG CTCTCTACTACCCTTCTG CTCG CATAG TG TATA CA
G CTT GCT CTCATG C C G CTGTTGATG C
A CTAT GT G A G AA G G CATTAAAATATTTG C CTATA G ATAAATG TAG TAG AATTATAC CTG
CA C G TG CT C GT GTA G A GT GTTTTG ATAAATT
CAAAGTG AATTCAA CATTAG AA CAG TATG TCTTTTG TA CTG TAAATG CATTG C CTG AG AC G A
CA G CAG ATATAG TTGTCTTTG ATG A AAT
TTCAATG GCCACAAATTATGATTTGAGTGTTGTCAATGCCAGATTACGTG CTAAG CA CTATG TG TA CATTG
G CG ACCCTG CT CAATTAC CT
G CACCACG CACATTG CTAACTAAG G
GCACACTAGAACCAGAATATTTCAATTCAGTGTGTAGACTTATGAAAACTATAGGTCCAGACATG
TTCCTCG GAACTTGTCGG CGTTGTCCTG CTGAAATTGTTGACACTGTGAGTG CTTTG GTTTATGATAATAAG
CTTAAAG CACATAAAGAC
AAATCAG CTCAATGCTTTAAAATGTTTTATAAG G GTGTTATCACG CATG AT GTTTCATCTG CAATTAACAG
GCCACAAATAG G CGTG GTA
AGAGAATTCCTTACACGTAACCCTG CTTG GAG AAAAGCT GT CTTTATTT CACCTTATAATT CACAG AATG
CTGTAG CCTCAAAGATTTTG G
GACTACCAACTCAAACTGTTGATTCATCACAG GG
CTCAGAATATGACTATGTCATATTCACTCAAACCACTGAAACAGCTCACTCTTGTAA
TG TAAA CAGATTTA ATG TTG CTATTAC CAG AG CAAAAGTAG G CATACTTTG
CATAATGTCTGATAGAGACCTTTATGACAAGTTG CAATT
TA CAAG TCTT G AAATTC CA C GTAG GAATGTG G CAA CTTTA CAA G CTG AAAATGTAA CA G G
A CTCTTTAAA G ATTG TA GTAA G GTAATCAC
TG G GTTACATCCTACACAG G CA CCTACACACCT CA GTGTTG ACACTAAATTCAA AACTG AA G
GTTTAT GT GTTGACATACCTG GCATACC
TAAGG ACATGACCTATAGAAG ACT CATCT CTATGATG G GTTTTAAAATGAATTATCAAGTTAATG
GTTACCCTAACATGTTTATCACCCG C
GAAGAAG CTATAAG ACAT GT ACGTG CATG GATTG G CTTCGATGTCGAG G GGTGTCATG
CTACTAGAGAAG CTGTTG GTACCAATTTACC
TTTACAG CTAGGTTTTTCTACAGGTGTTAACCTAGTTGCTGTACCTACAG GTTATGTTG ATAC
ACCTAATAATACA G ATTTTTCCA G A GTTA
GTGCTAAACCACCG CCTG G AG ATCAATTTAAACACCTCATACCACTTATGTACAAA G G ACTT CCTTG
GAATGTAGTG CGTATAAAGATTG
TACAAATGTTAA GT GACACACTTAAAAATCTCTCTG ACA GA GTCGTATTTGTCTTAT G G G CACATG G
CTTTG AG TTG ACATCTATGAAG T
ATTTTGTGAAAATAG GACCTG A GCG CACCTGTTGTCTATGTGATAGACGTG CCACATG
CTTTTCCACTGCTTCAGACACTTATG CCTGTTG
G CATCATTCTATTG GATTTGATTACGTCTATAATCCGTTTATGATTGATGTTCAACAATG GG GTTTTACAG
GTAACCTACAAAG CAACCAT
G ATCT GTATT GT CAAGTCCATGGTAATG CACATGTAG CTAGTTGTGATG CAATCATGACTAG GTGTCTAG
CTGTCCACGAGTGCTTTGTT
AAG CGTGTTG ACT G G ACTATTG AATAT CCTATAATTG GTG AT GAACT G AA G ATTAATG CG G
CTTG TA GAAAG GTTCAACACATG GTTGTT
AAA G CTG CATTATTA G CA G ACA AATTCCCA GTTCTTCACG ACATTG
GTAACCCTAAAGCTATTAAGTGTGTACCTCAAG CTG AT GTA GAA
TG GAAGTTCTATGATG CACAG CCTTGTAGTGACAAAG CTTATAAAATAG A A GAATTATTCTATT CTTATG
CCACACATTCTGACAAATTCA
CA GATG GTGTATGCCTATTTTG GAATTG
CAATGTCGATAGATATCCTGCTAATTCCATTGTTTGTAGATTTGACACTAGAGTG CTATCTAA
CCTTAACTTG CCTG GTTGTGATG GTG G CAGTTTG TATG TAAATA AA CATG CATTCCA CA CACCA G
CTTTTGATAAAAGTG CTTTTGTTAAT
TTAAAACAATTACCATTTTTCTATTACTCTG ACAGTCCATGTGAGTCTCATG
GAAAACAAGTAGTGTCAGATATAGATTATGTACCACTAA
A GTCT G CTAC G TG TATAA CA C G TTG CAATTTAG GTG GTG CTG TCTG TA G A CATCATG
CTAAT G A G TACAG ATTG TATCTC G ATG CTTATA
ACATGATGATCTCAGCTG G CTTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG G
AACACTTTTACAAG ACTT CAG A GTTT
A GAAAAT GTG GCTTTTAATGTTGTAAATAAGG GACACTTTGATG GACAACAGG GTG AA GTACCA GTTT
CTAT C ATTAATAACA CTGTTTA
CACAAAAGTTGATG GTGTTG ATGTA G AATT GTTTG AAAATAAAAC AACATTACCTGTTAATGTA G
CATTT GA G CTTTG G GCTAAG CG CAA
CATTAAACCAGTACCAGAGGTGAAAATACTCAATAATTTGG GTGTG GACATTG CTG CTAATACTGTGATCTG G
GACTA CAAAAG AG ATG
CTCCAGCACATATATCTACTATTG GT GTTTGTTCTATG ACTGACATA G
CCAAGAAACCAACTGAAACGATTTGTG CACCACTCACTGTCTT
87
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
TTTTGATG GTAGAGTTGATG GT CAAGTAGACTTATTTA GAAATG CCC GTAATG GTG TT CTTATTA
CAGAAGGTAGTG TTAAAG GTTTA CA
ACCATCTGTAG GTCCCAAACAAG CTAGTCTTAATG GA GTCACATTAATTGG AGAAG CCGTAAAAA CA CAG
TT CAATTATTATAAG AAAG T
TG AT G G TG TTG TCC AA CAATTACCT GAAACTTA CTTTA CTCA GA G TA G AAATTTA C AA
GAATTTAAACCCAG G AG TCAAAT G G AAATT GA
TTTCTTAGAATTAG CTATGGATGAATTCATTGAACGGTATAAATTAGAAGG CTATG
CCTTCGAACATATCGTTTATG G AG ATTTTAG TCAT
A GTCA G TTA G GT G G TTTACATCTA CTG ATTG GACTAG CTAAACGTTTTAAG
GAATCACCTTTTGAATTAGAAGATTTTATTCCTATG GA CA
GTACAGTTAAAAACTATTTCATAACAGATG CGCAAACAG G TTCATCTAA GT G TG TG T G TTCT
GTTATTG ATTTATTACTTGATGATTTTGTT
G AAATAATAAAATCCCAA G ATTTATCTG TA G TTT CTAAG G TTG TCAAA G TG A CTATTG
ACTATACA G AAATTT CATTTATG CTTTG G TG TA
AAGATG GCCATG TAG AAA CATTTTACC CAAAATTA CAATCTAG TCAA G CGTGG CAACCG
GGTGTTGCTATG CCTAATCTTTACAAAATG C
AAA G AAT G CTATTAGAAAAGTGTGACCTTCAAAATTATG GTGATAGTG CAACATTACCTAAAG G
CATAATG AT G AATGTCG CAAAATAT
ACTCAA CTG TG TCAATATTTAAA CACATTAA CATTAG CT GTACCCTATAATATG AG
AGTTATACATTTTG GTG CTG GTT CTG ATAAAGG AG
TTG CA CCAG G TA CA G CTG TTTTAA G ACA G TG GTTGCCTACG G GTACG CTG CTTG TCG
ATTCAG ATCTTAAT G A CTTT GTCTCTG AT G CA G
ATTCAACTTTG AUG GTGATTGTG CAA CTGTACATA CAG CTAATAAATGG G ATCTCATTATTAGTGATAT
GTACG ACCCTAAG ACTAAA A
ATGTTACAAAAGAAAATGACTCTAAAGAGGG I I I I TTCACTTACATTTGTG GGTTTATACAACAAAAGCTAG
CTCTTGGAGGTTCCGTG G
CTATAAA G ATAACA G AACATTCTT G G AAT G CT GATCTTTATAA G CTCATG G G A CACTT CG
CATG G TG G A CA G CCTTT GTTA CTAATG TG A
ATGCGTCATCATCTGAAGCATTTTTAATTGGATGTAATTATCTTGGCAAACCACGCGAACAAATAGATGGTTATGTCAT
GCATGCAAATT
ACATATTTTG GAG GAATACAAATCCAATTCAGTTGTCTTCCTATTCTTTATTTG ACATG A
GTAAATTTCCCCTTAAATTAAG GG GTACTG CT
GTTATGTCTTTAAAAGAAG GTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAG G TA GA CTTATAATTA
G AG AAAA CAACA G AG TT
GTTATTTCTAGTGATGTTCTTGTTAACAACTAAACGAACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTAGTCAGTGTGTTAATCT
TACAACCAGAACTCAATTACCCCCTGCATACACTAATTCTTTCACACGTG
GTGTTTATTACCCTGACAAAGTTTTCAG AT CCTCAGTTTTAC
ATTCAACTCAG GACTTGTTCTTACCTTTCTTTTCCAATGTTACTTGGTTCCATG CTATACATGTCTCTG
GGACCAATGGTA CTA AG AG GTTT
G ATAA CCCTG TCCTA CCATTTAATG AT G G TG TTTATTTTG CTTCCA CTG A GAA GT
CTAACATAATAAG A G G CTG G ATTTTT G G TA CTACTT
TAGATTCGAAGACCCAGTCCCTACTTATTGTTAATAACG CTACTAATGTTGTTATTAAAGTCTGTGAATTTCAA
_________ 1111 GTAATGATCCATTT
TTG G GT GTTTATTA CCACAAAAA CAACAAAAG TTG G AT G G AAAG TG A GTT CAG A
GTTTATTCTA G TG CGAATAATTG CACTTTTGAATAT
GTCTCTCAGCCTTTTCTTATGGACCTTGAAG GAAAACAG GGTAATTTCAAAAATCTTAG G
GAATTTGTGTTTAAGAATATTGATG GTTATT
TTAAAATATATTCTAAG CACACG CCTATTAATTTA GT GCG TG ATCTCCCTCA G G GTTTTTCGG
CTTTAG AA CCATT G G TA G ATTTG CCAAT
AG GTATTAACATCACTAG GTTTCAAACTTTACTTG
CTTTACATAGAAGTTATTTGACTCCTGGTGATTCTTCTTCAG GTTGGACAG CTG GT
G CTG CA G CTTATTATGTG G G TTATCTTCAA CCTA G G A CTTTTCTATTAAAATATAATG AAAATG
GAACCATTACAGATG CTG TA GA CTG TG
CACTTGACCCTCTCTCAGAAACAAAGTGTACGTTGAAATCCTTCACTGTAGAAAAAG
GAATCTATCAAACTTCTAACTTTAGAGTCCAACC
AACAGAATCTATTGTTAGATTTCCTAATATTACAAACTTGTG CCCTTTTGGTG AAG TTTTTAACG
CCACCAGATTTG CAT CTGTTTATG CTT
G GAACAG G AAG AG AATCAG CAACT GT GTTG CTGATTATT CT GTCCTATATAATTCCG
CATCATTTTCCACTTTTAAGTGTTATG GAGTGTC
TCCTACTAAATTAAATGATCTCTG CTTTACTAATGTCTATG CA GATT CATTT G TAATTA GA G GT GATG
AAG TCA G ACAAATCG CTCCAG G G
CAAACTG G AAA GATT G CT GATTATAATTATAAATTA CCAG ATG ATTTTA CA G G CTG CGTTATAG
CTTG GAATTCTAACAATCTTGATTCTA
AGGTTG GTG GTAATTATAATTACCTGTATAGATTGTTTAG G AAGTCTAAT CTCAAACCTTTTGAG AG
AGATATTTCAA CTG AAATCTATCA
G G CCG GTAG CA CACCTTG TAATGGTG TTGAAGGTTTTAATTG TTA CTTTCCTTTA CAAT CATATGG
TTTCCAACCCA CTAATG GTGTTG GT
TACCAACCATACAGAGTAGTAGTACTTTC __________________________________________ 1111
GAACTTCTACATGCACCAGCAACTGTTTGTGGACCTAAAAAGTCTACTAATTTGGTTA
AAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CA CAG G T G TTCTTA CT GA GTCTAA
CAAAAA G TTTCT G CCTTTCCAA CAATT
TG G CA G AGA CATTG CTGACACTACTGATG CTGT CCGTGATCCA CA GA CA CTTG A
GATTCTTGACATTA CA CC AT GTTCTTTT G G TG GTGTC
A GT GTTATAA CA CC AG G AACAAATACTTCTAACCAG GTTG CTGTTCTTTATCAG G ATGTTAACT G
CA CA GAA GT CCCTGTTG CTATTCATG
CAGATCAACTTACTCCTACTTG G CGTGTTTATTCTACAG GTTCTAATGTTTTTCAAACACGTG CAG G
CTGTTTAATAGG G G CTG AA CATG T
CAACAACTCATATGAGTGTGACATACCCATTG GTG CA G GTATATG CG
CTAGTTATCAGACTCAGACTAATTCTCCTCG GCGGG CACGTAG
TG TA G CTAG TCAATCCATCATTG CCTA CA CTATG TCA CTTG GTG CAGAAAATTCAGTTG
CTTACTCTAATAACTCTATTG CCATACCCA CAA
ATTTTACTATTAGTGTTACCACAGAAATTCTACCAGTGTCTATGACCAAGACATCAGTAGATTGTACAATGTACATTTG
TG GTGATTCAAC
TGAATG CA G CAATCTTTTGTTG CAATATG G CA GTTTTTG TA CA CAATTAAA CCGT G CTTTAACT
G G AATAG CTG TTG AA CAA G ACAAAAA
CA CCCAA G AA G TTTTTG CACAA GT CAAA CAAATTTACAAAA CA CCACCAATTAAAG ATTTTG G
TG G TTTTAATTTTTC A CAAATATTA CCA
G AT CCAT CAAAACCAA G CAA G AG G TCATTTATTG AAG ATCTA CTTTT CAA CAAA G TG ACA
CTT G CA G ATG CTG G CTTCATCA AA CAATAT
G GTGATTG CCTTG GTGATATTG CTG CTAG AGACCTCATTTGTG CA CAAAAGTTTAACGG
CCTTACTGTTTTG CCACCTTTG CTCACAGATG
AAATGATTG CTCAATACACTTCTGCACTGTTAG CGG GTACAATCACTTCTGGTTG GACCTTTG GTGCAG
GTGCTGCATTACAAATACCATT
TG CTATG CAAATG GCTTATAGGTTTAATG GTATTG G AG TTACA CA GAATG TT CTCTAT GA G AA
CCAAAAATT G ATTG CCAACCAATTTAA
TA GT G CTATT G G CAAAATTCAA GA CTCA CTTT CTTCCA CAG CAAGTG CA CTTG GAAAACTT
CAA G AT GT G G TCAA CCAAAAT G CA CAAG C
TTTAAACACG CTTGTTAAACAACTTAGCTCCAATTTTG GTG CAATTTCAA GT GTTTTAAATGATATCCTTTCA
CG TCTTG ACAAAG TTGAG
G CT GAA G T G CAAATTG ATAG G TTG AT CACA G G CA G ACTTCAAA G TTTG CA GA
CATATG T GA CTCAA CAATTAATTA G AG CTG CA GA AAT
CA GA G CTTCTG CTAATCTTG CTG CTA CTAAAATG TCA GA G TG TG TA CTTG GA CAATCAAAAA
G A GTTG ATTTTT G TG G AAA G GG CTATCA
TCTTATGTCCTTCCCTCAGTCAG CA CCTCATG G TG TA GTCTTCTTG CATGT GA CTTATG TCCCT G
CA CAAG AAAAG AACTTCACAA CTG CTC
CTG CCATTTGTCATGATG G AAAAG CA CA CTTTCCTCGTG AAG GTGTCTTTGTTTCAAATG G CACA CA
CTGGTTTG TAA CA CAAA G GAATT
TTTATG AACCACAAATCATTACTACAG ACAACACATTTGTGTCTG G TAACTGTGATGTTGTAATAG G
AATTGTCAACAA CACAGTTTATG A
TCCTTTG CAACCTGAATTAGACTCATTCAAG G AGG AGTTAG ATAAATATTTTAA
GAATCATACATCACCAGATGTTG ATTTAG GTGACATC
TCTG G CATTAAT G CTT CAG TT GTAAA CATTCAAAAA GAAATTG ACCG CCTCAAT G AG GTTG
CCAAGAATTTAAATGAATCTCTCATCGATC
TCCAAG AA CTTG GAAAG TATG A G CA G TATATAAAATG G CCATG GTACATTTGG CTAG
GTTTTATAG CTGG CTTGATTG CCATAGTAATG
GTGACAATTATG CTTTG CTGTATGACCAGTTG CTG TAG TT GT CT CAAG GG CTG TT GTT CTTGTG
GATCCTGCTG CAAATTTGATGAAGAC
GACTCTGAG CCAGTG CTCAAAGG AGT CAAATTA CATTA CACATAAA CG AA CTTATG
GATTTGTTTATGAGAATCTTCACAATTG GAACTG
TAACTTTGAAG CAAG GTGAAATCAAG GATGCTACTCCTTCAGATTTTGTTCGCGCTACTG CAA CG ATACCG
ATA CAAG CCTCACTCCCTTT
CG GATGGCTTATTGTTGG CGTTG CACTTCTTG CTG TTTTTCAG AG CG
CTTCCAAAATCATAACCCTCAAAAAGAGATG G CAA CTAG CACT
88
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
CTCCAAGG GTGTTCACTTTGTTTG CAACTTG CTGTTGTTGTTTGTAACAGTTTACTCACACCTTTTG
CTCGTTGCTG CTG GCCTTGAAG CCC
CTTTTCTCTATCTTTATG CTTTAGTCTACTTCTTG CAG A GTATAAACTTTGTAAG AATAATAAT GAG G
CTTTG G CTTTG CTG GAAATGCCGT
TCCAAAAACCCATTACTTTATGATGCCAACTATTTTCTTTG CTG G
CATACTAATTGTTACGACTATTGTATACCTTACAATAGTGTAACTTCT
TCAATTGTCATTACTTCAGGTGATG GCACAACAAGTCCTATTTCTGAACATGACTACCAGATTG GTG
GTTATACTGAAAAATG GGAATCT
G GAGTAAAAGACTGTGTTGTATTACACAGTTACTTCACTICAGACTATTACCAG
CTGTACTCAACTCAATTGAGTACAGACACTGGTGTT
G AACATGTTACCTTCTTCATCTACAATAAAATTGTTGATG AG CCTG AAGAACATGTCCAAATTCACACAATCG
ACGTTTCATCCG G AGTTG
TTAATCCAGTAATG GAACCAATTTATGATGAACCGACGACGACTACTAGCGTG CCTTTGTAAG
CACAAGCTGATGAGTACGAACTTATGT
ACTCATTCGTTTCG GAAGAGACAG GTACGTTAATAGTTAATAG CGTACTTCTTTTTCTTG CTTTCGTG
GTATTCTTG CTAGTTACACTAG CC
ATCCTTACTG CG CTTCGATTGTGTGCGTACTG CTG CAATATTGTTAACGTG
AGTCTTGTAAAACCTTCTTTTTACGTTTACTCTCGTGTTAA
AAATCTGAATTCTTCTAGAGTTCCTGATCTTCTG GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTG
GAACTTTAATTTTAGCCAT
G G CAGATTCCAACGGTACTATTACCGTTGAAGAG CTTAAAAAGCTCCTTGAACAATG GAACCTAGTAATAG
GTTTCCTATTCCTTACATG
GATTTGTCTTCTACAATTTG CCTATG CCAACAGGAATAG GTTTTTGTATATAATTAAGTTAATTTTCCTCTGG
CTGTTATG G CCAGTAACTT
TAG CTTG 1111 GTGCTTGCTGCTGTTTACAGAATAAATTG GATCACCG GTGGAATTG CTATCG CAATGG
CTTGTCTTGTAGG CTTGATGTG
G CTCAG CTACTTCATTG CTTCTTTCAGACTGTTTG CGCGTACG CGTTCCATGTG
GTCATTCAATCCAGAAACTAACATTCTTCTCAACGTG C
CACTCCATGG CACTATTCTG ACCAG ACCG CTTCTAG AAA GTGAACTCGTAATCGG
AGCTGTGATCCTTCGTG G ACATCTTCGTATTG CTG
G ACACCATCTAG GACG CTGTGACATCAAGG ACCTG CCTAAAG AAATCACTGTTG CTACATCACG AACG
CTTTCTTATTACAAATTG G GAG
CTTCGCAGCGTGTAGCAGGTGACTCAGGTTTTGCTGCATACAGTCGCTACAGGATTGGCAACTATAAATTAAACACAGA
CCATTCCAGTA
G CAGTGACAATATTG CTTTG
CTTGTACAGTAAGTGACAACAGATGTTTCATCTCGTTGACTTTCAGGTTACTATAGCAG AGATATTACTAA
TTATTATGAG GACTTTTAAAGTTTCCATTTG G
AATCTTGATTACATCATAAACCTCATAATTAAAAATTTATCTAAGTCACTAACTG AG AAT
AAATATTCTCAATTAG ATGAAG AG CAACCAATG GAG ATTG ATTAAACG AACATG
AAAATTATTCTTTTCTTG G CACTGATAA CACTCG CT
ACTTGTG AG CTTTATCACTACCAAG AGTGTGTTAG AGGTACAACAGTACTTTTAAAAG AACCTTGCTCTTCTG
GAACATACG AGG G CAAT
TCACCATTTCATCCTCTAGCTGATAACAAATTTGCACTGACTTGCTTTAGCACTCAATTTGCTTTTGCTTGTCCTGACG
GCGTAAAACACGT
CTATCAGTTACGTGCCAGATCAGTTTCACCTAAACTGTTCATCAGACAAGAG
GAAGTTCAAGAACTTTACTCTCCAATTTTTCTTATTGTTG
CG
GCAATAGTGTTTATAACACTTTGCTTCACACTCAAAAGAAAGACAGAATGATTGAACTTTCATTAATTGACTTCTATTT
GTG CTTTTTA
GCCTTTCTGCTATTCCTTGTTTTAATTATGCTTATTATCTTTTGGTTCTCACTTGAACTGCAAGATCATAATGAAACTT
GTCACGCCTAAACG
AACATGAAATTTCTTGTTTTCTTAGGAATCATCACAACTGTAGCTGCATTTCACCAAGAATGTAGTTTACAGTCATGTA
CTCAACATCAAC
CATATGTAGTTGATGACCCGTGTCCTATTCACTTCTATTCTAAATG GTATATTAGAGTAG G AG CTA G
AAAATCA G CACCTTTAATTGAATT
GTGCGTG G ATG AG G CTG GTTCTAAATCACCCATTCAGTACATCGATATCG
GTAATTATACAGTTTCCTGTTTACCTTTTACAATTAATTG C
CAGGAACCTAAATTG G GTAGTCTTGTAGTG
CGTTGTTCGTTCTATGAAGACTTTTTAGAGTATCATGACGTTCGTGTTGTTTTAGATTTCA
TCTAAACGAACAAACTAAAATGTCTGATAATG GACCCCAAAATCAG CGAAATG CACCCCG CATTACGTTTG
GTG G ACC CTCAGATTCAAC
TG GCAGTAACCAGAATGGAGAACG CAGTG G GG CG CGATCAAAACAACGTCG G CCCCAAG
GTTTACCCAATAATACTG CGTCTTG GTTC
ACCGCTCTCACTCAACATG G CAAG G AAGAC CTTAAATTCCCTCG AG GACAAG G
CGTTCCAATTAACACCAATAG CAGTCCAGATGACCA
AATTGG CTACTACCGAAG AG CTACCAGACGAATTCGTG GTG GTGACG
GTAAAATGAAAGATCTCAGTCCAAGATG GTATTTCTACTACC
TAG G AACTG G G CCAGAAGCTG GACTTCCCTATG GTGCTAACAAAGACG G CATCATATG G GTTG
CAACTG AG G GAG CCTTGAATACACC
AAAAGATCACATTGGCACCCGCAATCCTGCTAACAATGCTGCAATCGTGCTACAACTTCCTCAAGGAACAACATTGCCA
AAAGGCTTCTA
CG CAGAAG G GAG CAGAG GCG G
CAGTCAAGCCTCTTCTCGTTCCTCATCACGTAGTCGCAACAGTTCAAGAAATTCAACTCCAG G CAG CA
GTAG G G GAACTTCTCCTG CTAG AATG G CTG GCAATG GC G GTG ATGCTG CTCTTGCTTTG CTG
CTGCTTG ACAG ATTG AACCAGCTTGAG
AGCAAAATGTCTGGTAAAG G CCAACAACAACAAG G C CAAACTGTCA CTAAG AAATCTGCTGCTG AG
GCTTCTAAG AAGCCTCG G CAAA
AACGTACTG CCACTAAAG CATACAATGTAACACAAG CTTTCG CAGACGTG GTCCAG AACAAACCCAAG G
AAATTTTGG G G ACCAG G A
ACTAATCAGACAAG GAACTGATTACAAACATTGG CCG CAAATTG CACAATTTGCCCCCAG CG CTTCAG
CGTTCTTCG GAATGTCG CG CAT
TG GCATG GAAGTCACACCTTCG GGAACGTG GTTGACCTACACAG GTG
CCATCAAATTGGATGACAAAGATCCAAATTTCAAAGATCAAG
TCATTTTGCTGAATAAGCATATTGACG CATACAAAACATTCCCACCAACAG AG CCTAAAAAG
GACAAAAAGAAGAAGGCTGATGAAACT
CAAG CCTTACCG CAG AG ACAG AAG AAACAGCAAACTGTGACTCTTCTTCCTG CTG CAG ATTTGG ATG
ATTTCTCCAAACAATTG CAACAA
TCCATG AG CAGTGCTGACTCAA CTCAG GCCTAAACTCATGCAGACCACACAAGGCAGATGG GCTATATAAACG
III1C GCTTTTCCGTTT
ACGATATATAGTCTACTCTTGTG CAGAATGAATTCTCGTAACTACATAG CACAA GTAG ATGTAGTTAAC I I
I AATCTCACATAGCAATCTT
TAATCAGTGTGTAACATTAG G GAG GACTTGAAAGAG CCACCACATTTTCACCGAGG CCACGCG
GAGTACGATCGAGTGTACAGTGAAC
AATGCTAG G GAG AG CTG CCTATATG GAA G AG
CCCTAATGTGTAAAATTAATTTTAGTAGTGCTATCCCCATGTGATTTTAATAGCTTCTT
AGGAGAAT
SFQ ID NO: 10
>Severe acute respiratory syndrome coronavirus 2 orf1ab polyprotein of isolate
hCoV-19/Italy/INM11-is1/2020
(Genbank Acc. No: 01A98553)
MESLVPGFNEKTHVQLSLPVLQVRDVLVRGFGDSVEEVLSEARQHLKDGTCGLVEVEKG VLPQLEQPYVF I
KRSDARTAPH G HVMVE LVAE LE
G I QYG RSGETLGVLVPHVG El PVAYRKVLLRKN GN KGAG GHSYGADLKSFDLGDE
LGTDPYEDFQENWNTKHSSGVTR ELM RELN GGAYTRY
VDN NFCG PDGYPLECI KD LLARAGKASCTLSEQLDF I DTKRGVYCCR EH EHEIAWYTERSEKSYELQTP
FEI KLAKKFDTFNG ECP N FVFPLNSI I K
TIQPRVEKKKLDG FM G RI RSVYPVASPN ECN QM CLSTLMKCDHCG ETSWQTGDFVKATCEFCGTEN
LTKEGATTCGYLPQNAVVKIYCPACH
NSEVG PEHSLAEYHN ESG LKTILRKGG RTIAFG GCVFSYVG CH NKCAYWVPRASAN IGCN HTGVVG
EGSEG LN DN LLE I LQKE KVN I N I VG DFK
LN EEI AI I LASFSASTSAFVETVKG LDYKAFKQIVESCG NFKVTKG KAKKGAWN I
GEQKSILSPLYAFASEAARVVRSIFSRTLETAQNSVRVLQKA
AITILDG ISQYSLRLI DAM M FTSDLATNN LVVMAYITGGVVQLTSQWLTN I FGTVYEKLK PVLDWLE
EKFKEGVEFLRDGWEIVKFISTCACE IV
GGQIVICAKEIKESVQTFFKLVNKFLALCADS1 I IG GAKLKALN LG ET FVTHSKG LYR KCVKSRE ETG
LLM PLKAPKEI I FLEG ETLPTEVLTEEVVLIK
TG DLQPLEQPTSEAVEAPLVGTPVCI NG LM LLEI KDTEKYCALAPN M MVTN NTFTLKGGAPTKVTFG
DDTVIEVQGYKSVNITFELDERI DKVL
89
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NEKCSAYTVELGTEVNEFACVVADAVIKTLQPVSELLTPLGIDLDEWSMATYYLFDESGEFKLASHMYCSFYPPDEDEE
EGDCEEEEFEPSTQYE
YGTEDDYQG KP LEFGATSAALQPEEEQEEDWLDDDSQQTVGQQDGSEDN QTTTIQTIVEVQPQLEM
ELTPVVQTI EVNSFSGYLKLTDNVYI
KNADIVEEAKKVKPTVVVNAANVYLKHGGGVAGALNKATN NAM QVESDDYIATN GP LKVGGSCVLSG HN
LAKHCLHVVG P NVN KGEDIQL
LKSAYENFN QHEVLLAPLLSAGI FGADP I HSLRVCVDTVRTNVYLAVFDKN LYDK LVSSFLEM
KSEKQVEQKIAEI PKEEVKP F ITESKPSVEQRKQ
DDKKIKACVEEVTTTLEETKFLTENLLLYI DING N LH PDSATLVSDI DITFLKKDA PYI VG DVVQEG
VLTAVVI PTKKAGGTTEM LAKALRKVPTDN
YITTYPGQGLNGYTVEEAKTVLKKCKSAFYILPSIISN EKQEI LGTVSWN LREMLAHAEETRKLM
PVCVETKAIVSTIQRKYKGI KIQEGVVDYGAR
FYFYTSKTTVASLI NTLN DLN ETLVTM P LGYVTHG LN LEEAARYM RSLKVPATVSVSSP
DAVTAYNGYLTSSSKTPEEHFI ETISLAGSYKDWSYS
G QSTQLG IEFLKRG DKSVYYTSN PTTFH LDG EVITFDNLKTLLSLREVRTI KVFTTVDNI N
LHTQVVDMSMTYG QQFG PTYLDGADVTK 1 KPHNS
HEGKTFYVLPNDDTLRVEAFEYYHTTDPSFLGRYMSALNHTKKWKYPQVNG LTSIKWADNN CYLATALLTLQQI
ELKFNPPALQDAYYRARAG
EAANFCALI LAYCN
KTVGELGDVRETMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQFKKGVQ1PCTCGKQATKYL
VQQESP FVM MSAP PAQYELKHGTFTCASEYTGN YQCG HYKHITSKETLYCI
DGALLTKSSEYKGPITDVFYKENSYTTTI KPVTYKLDGVVCTEID
PKLDNYYKKDNSYFTEQPI DLVPNQPYPNASFDNFKFVCDN I KFADDLN QLTGYKKPASRELKVTFFP DLN
GDVVAI DYKHYTPSFKKGAKLLHK
PI VWHVN N ATN KATYKPNTWCI RCLWSTKPVETSNSFDVLKSEDAQG M DN LACEDLKPVSEEVVEN PTI
QKDVLECNVKTTEVVG DI I LKPAN
NSLKITEEVGHTDLMAAYVDNSSLTIKKPNELSRVLGLKTLATHGLAAVNSVPWDTIANYAKPFLN
KVVSTTTNIVTRCLNRVCTNYMPYFFTLL
LQLCTFTRSTNSRIKASMPTTIAKNTVKSVGKFCLEASFN YLKSPNFSKLI N I I
IWFLLLSVCLGSLIYSTAALGVLMSNLGM PSYCTGY REG YLNST
NVTIATYCTGSI PCSVCLSGLDSLDTYPSLETIQITISSFKWDLTAFGLVAEWFLAYILFTRFFYVLGLAAIM
QLFFSYFAVHFISNSWLM WLI I NLV
QMAPISAMVRMYIFFASFYYVVVKSYVHVVDGCNSSTCMMCYKRN RATRVECTTIVN GVRRSFYVYANGG KG
FCKLHN WNCVNCDTFCAG
STFISDEVARDLSLQFKRPI
NPTDQSSYIVDSVTVKNGSIHLYFDKAGQKTYERHSLSHFVNLDNLRANNTKGSLPINVIVFDG KSKCEESSAKSAS
VYYSQLMCQP 1 LLLDQALVSDVG DSAEVAVKM FDAYVNTFSSTFN VPM EKLKTLVATAEAELAKN
VSLDNVLSTFISAAR QG FVDSDVETKDV
VECLKLSHQSDI EVTGDSCN NYMLTYN KVENMTPRDLGACI DCSAR HI
NAQVAKSHNIALIWNVKDFMSLSEQLRKQIRSAAKKNN LP FKLTC
ATTRQVVNVVTTKIALKGGKIVNNWLKQLI KVTLVFLFVAAI
FYLITPVHVMSKHTDFSSEIIGYKAIDGGVTRDIASTDTCFAN KHADFDTWFS
QRGGSYTN DKACP LIAAVITREVG FVVPG LPGTI LRTTNG DFLHFLPRVFSAVG NI CYTPSKLI
EYTDFATSACVLAAECTI FKDASGKPVPYCYDT
NVLEGSVAYESLRPDTRYVLMDGSI
IQFPNTYLEGSVRVVTTFDSEYCRHGTCERSEAGVCVSTSGRWVLNNDYYRSLPGVFCGVDAVN LLTN
M FTPLIQP IGALDISASIVAGGI VAIVVTCLAYYFM
RFRRAFGEYSHVVAFNTLLFLMSFTVLCLTPVYSFLPGVYSVIYLYLTFYLTN DVSF LAN! Q
WM VM FTPLVPFWITIAYI ICISTKHFYWFFSNYLKRRVVF NGVSFSTFEEAALCTFLLN KEMYLKLRSDVLLP
LTQYN RYLALYN KYKYFSGAMD
TTSYREAACCHLAKALN DFSNSGSDVLYQPPQTSITSAVLQSG FRKMAF PSG KVEGCMVQVTCGTTTLNG
LWLDDVVYCP RHVICTSEDM LN
PNYEDLLIRKSNHNFLVQAGNVQLRVIGHSM QNCVLKLKVDTAN PKTPKYKFVRI QPG QT
FSVLACYNGSPSGVYQCAM RP N FT! KGSFLN GS
CGSVGFNIDYDCVSFCYMHHMELPTGVHAGTDLEGN FYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVI
NGDRWFLNRFTTTLNDFN LVA
MKYNYEPLTQDHVDILGPLSAQTGIAVLDMCASLKELLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQSAVKRTI
KGTHHWLLLTI LTSL
LVLVQSTQWSLFFFXYEN AF LP FAMGI IAMSAFAM MFVKHKHAFLCLFLLPSLATVAYF N MVYM PASWVM
RI MTWLDM VDTSLSGFKLKD
CVMYASAVVLLI LMTARTVYDDGARRVVVTLM NVLTLVYKVYYGNALDQAISMWALI ISVTSNYSG VVTTVM F
LARG IVF MCVEYCP 1 FFITG N
TLQCIM LVYCFLGYFCTCYFGLFCLLN RYFRLTLGVYDYLVSTQEFRYMNSQGLLPPKNSI
DAFKLNIKLLGVGGKPCIKVATVQSKMSDVKCTSV
VLLSVLQQLRVESSSKLWAQCVQLH N DI LLAKDTTEAFEKMVSLLSVLLSM
QGAVDINKLCEEMLDNRATLQAIASEFSSLPSYAAFATAQEAY
EQAVANG DSEVVLKKLKKSLN VAKSEF DRDAAM QRKLEKMADQAMTQMYKQARSEDKRAKVTSA M QTM
LFTM LRKLDN DALN NI I N NA
RDGCVPLN I I P LTTAAK LM VVI P DYNTYKNTCDGTTFTYASALWEIQQVVDADSKIVQLSEISM
DNSPNLAWPLIVTALRANSAVKLQNN ELSP
VALRQMSCAAGTTQTACTDDNALAYYNTTKGGRFVLALLSDLQDLKWARFPKSDGTGTIYTELEPPCRFVTDTP KG
PKVKYLYF 1 KG LN N LN R
GMVLGSLAATVRLQAGNATEVPANSTVLSFCAFAVDAAKAYKDYLASGGQPITNCVKMLCTHTGTGQAITVTPEANMDQ
ESFGGASCCLYC
RCHIDHPNPKGFCDLKGKYVQIPTTCANDPVGFTLKNTVCTVCGMWKGYGCSCDQLREPMLQSADAQSFLN
RVCGVSAARLTPCGTGTSTD
VVYRAFDIYN DKVAG FAKFLKTNCCRFQEKDEDDN LI DSYFVVKRHTFSN YQHE ETI YN
LLKDCPAVAKHDFFKFRI DGDMVPHISRQRLTKYT
MADLVYALR HFDEGN CDTLKEI LVTYNCCDDDYF N KKDWYDFVEN PDI LRVYAN
LGERVRQALLKTVQFCDAM RN AG IVGVLTLDN QDLNG
NWYDFG DFI QTTPGSGVPVVDSYYSLLM PI
LTLTRALTAESHVDTDLTKPYIKWDLLKYDFTEERLKLFDRYFKYVVDQTYHPNCVNCLDDRCIL
HCANFNVLFSTVFPPTSFGPLVRKI FVDG VP FVVSTGYHFR ELGVVHNQDVN LHSSRLSFKELLVYAADPAM
HAASGN LLLDKRTTCFSVAALT
NNVAFQTVKPGNFN
KDFYDFAVSKGFFKEGSSVELKHFFFAQDGNAAISDYDYYRYNLPTMCDIRQLLFVVEVVDKYFDCYDGGC1 NAN
QVIV
NNLDKSAGFPFNKWGKARLYYDSMSYEDQDALFAYTKRNVI PTITQMN LKYAISAKN
RARTVAGVSICSTMTNRQFHQKLLKSIAATRGATVV
IGTSKFYGGWHN MLKTVYSDVEN PHLMGWDYPKCDRAMPN M LRIMASLVLARKHTTCCSLSH RFYRLAN
ECAQVLSEM VM CGGSLYVKP
GGTSSGDATTAYANSVFN I CQAVTANVN ALLSTDG N KIADKYVRN LQH RLYECLYRN
RDVDTDFVNEFYAYLRKHFSMM I LSDDAVVCF NST
YASQGLVASIKNFKSVLYYQN NVFMSEAKCWTETDLTKG PH EFCSQHTM LVKQG DDYVY LPYPDPSRI
LGAGCFVDDIVKTDGTLMIERFVSL
AI DAYPLTKHPN QEYADVFHLYLQYI RKLH DELTGHM LDMYSVM LTN DNTSRYWEP EFYEAM
YTPHTVLQAVGACVLCNSQTSLRCGACI RR
PFLCCKCCYDHVISTSHKLVLSVN
PYVCNAPGCDVTDVTQLYLGGMSYYCKSHKPPISFPLCANGQVFGLYKNTCVGSDNVTDFNAIATCDWT
NAG DYI LANTCTERLKLFAAETLKATEETFKLSYGIATVREVLSDRELHLSWEVG KP RPP LN
RNYVFTGYRVTKNSKVGIG EYTF EKG DYG DAVV
YRGTTTYKLNVGDYFVLTSHTVMP LSAPTLVPQEHYVRITGLYPTLN ISDEFSSN VAN YQKVG M QKYSTLQG
PPGTGKSHFAI GLALYYPSARI V
YTACSHAAVDALCEKALKYLPIDKCSRI I PARARVECFDKFKVNSTLEQYVFCTVNALPETTADIVVFDEI
SMATNYDLSVVNARLRAKHYVYIG D
PAQLPAPRTLLTKGTLEPEYFNSVCRLMKTIGPDMFLGTCRRCPAEIVDTVSALVYDN KLKAHKDKSAQCF KM
FYKGVITHDVSSAI NRPQIGV
VREFLTRNPAWRKAVFISPYNSQNAVASKILGLPTQTVDSSQGSEYDYVIFTQTTETAHSCNVNRFNVAITRAKVGILC
I MSDRDLYDKLQFTSL
El P RRN VATLQAENVTGLFKDCSKVITG LHPTQAPTH LSVDTKEKTEGLCVDI PG I PKDMTYRRLISM
MGF KM N YQVNGYP N M FITREEAI RH
VRAWIGFDVEGCHATREAVGTNLPLQLGFSTGVN
LVAVPTGYVDTPNNTDFSRVSAKPPPGDQFKHLIPLMYKGLPWNVVRIKIVQMLSDTL
KN LSDRVVFVLWAHG FELTSM KYFVKIG PERTCCLCDRRATCFSTASDTYACWH HSI GF DYVYN PFM 1
DVQQWG FTG N LQSN H DLYCQVHG
NA HVASCDAI MTRCLAVHECFVKRVDWTIEYPI IGDELKINAACRKVQHMVVKAALLADKFPVLHDIGN
PKAIKCVPQADVEWKFYDAQPCS
DKAYKIEELFYSYATHSDKFTDGVCLFWNCNVDRYPANSIVCRFDTRVLSNLNLPGCDGGSLYVNKHAFHTPAFDKSAF
VNLKQLPF FYYSDSP
CESHGKQVVSDIDYVPLKSATCITRCNLGGAVCRHHANEYRLYLDAYNMM
ISAGFSLWVYKQFDTYNLWNTFTRLQSLENVAFNVVNKGHF
DG QQG EVPVSI IN NTVYTKVDGVDVELFEN KTTLPVNVAFELWAKRNIKPVPEVKI LN N
LGVDIAANTVIWDYKRDAPAHISTIGVCSMTDIAK
KPTETI CAP LTVFFDG RVDG QVDLFRN ARNGVLITEGSVKG LQPSVGP KQASLNGVTLIG EAVKTQF N
YYKKVDGVVQQLP ETYFTQSRN LQE
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FKPRSQM El DFLELAM DEFI ERYKLEGYAFEHI VYG DFSHSQLGGLHLLIG LAKRFKESPFELEDFI PM
DSTVKNYFITDAQTGSSKCVCSVI DLLL
DDFVEI1KSQDLSVVSKVVKVTIDYTEISFM LWCKDGHVETFYPKLCISSQAWQPGVAM PN LYKM QRM
LLEKCDLQNYG DSATLPKG1M M NV
AKYTQLCQYLNTLTLAVPYN M RVIH FGAGSDKGVAPGTAVLRQWLPTGTLLVDSDLN DFVSDADSTLIG
DCATVHTANKWDLIISDM YDPKT
KNVTKENDSKEG FFTYICG FIQQKLALGGSVAIKITEHSWNADLYKLMG
HFAWWTAFVTNVNASSSEAFLIGCNYLGKPREQIDGYVM HAN YI
FWRNTN PIQLSSYSLFDMSKFPLKLRGTAVMSLKE
SEQ ID NO: 11
>Protei n \ S_2019-nCoV/Italy-IN MI1 (Sprotei NMIn_hCoV191talyI 1is
I2020)(Ge n ban k Acc. No: 0JA98554)
M FVFLVLLPLVSSQCVN LTTRTQLP PAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAI
HVSGTNGTKRFDNPVLPFNDGVYFAS
TEKSN I I RGWI FGTTLDSKTQSLLIVN NATNVVIKVCEFQFCNDPFLGVYYHKNNKSWM ESEFRVYSSAN
NCTFEYVSQPFLM DLEG KQG NFK
N LREFVFKN I DGYFKIYSKHTPI NLVRDLPQGFSALEPLVDLPIG IN ITRFQTLLALHRSYLTPG
DSSSGVVTAGAAAYYVGYLQPRTFLLKYNENGT
1TDAVDCALDPLSETKCTLKSFTVEKGIYQTSN FRVQPTES1VRFP N ITN LCPFG
EVFNATRFASVYAWNRKRISN CVADYSVLYNSASFSTFKCYG
VSPTKLNDLCFTNVYADSFVIRG DEVRQI APGQTG KIADYNYKLPDDFTGCVIAWNSN N LDSKVGG
NYNYLYRLFRKSNLKPFERDISTEIYQAG
STPCNGVEG FNCYFPLQSYG FQPTNGVGYQPYRVVVLSFELLHAPATVCG PKKSTN LVKNKCVNFNFNG
LTGTG VLTESN KKF LP FQQFGR DI
ADTTDAVRDPQTLEI LDITPCSFGGVSV1TPGTNTSN QVAVLYQDVNCTEVPVA1
HADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVN NSY EC
DI P1GAGICASYQTQTNSP RRARSVASQS11AYTMSLGAENSVAYSN
NSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICG DSTECSNLLLQYGSF
CTQLNRALTG I AVEQDKNTQEVFAQVKQIYKTPP I KDFGG FN FSQI
LPDPSKPSKRSFIEDLLFNKVTLADAG Fl KQYG DCLGDI AAR DLI CAQKF
NG LTVLPPLLTDEM IAQYTSALLAGTITSGVVTFGAGAALQIPFAMQMAYRFNG
IGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQ
DVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSR LDKVEAEVQI DR LITG RLQSLQTYVTQQLI
RAAEIRASAN LAATKMSECVLGQSKRVDFC
GKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAH FPREGVFVSN GTHWFVTQRN FY EPQI
ITTDNTFVSG NCDVVIGIVNN
TVYDPLQPELDSFKEELDKYFKN HTSPDVDLG DISG I N ASVVN I QKEIDRLNEVAKN
LNESLIDLQELGKYEQYI KWPWYIWLG Fl AG LIAIVM VT
1M LCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO: 12
>hCoV-19/Fra nce/I D F0372- is1/2020 I EP USL41072012020-01-23
ATTAAAGGTTTATACCTTCCCAGGTAACAAACCAACCAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACGAACTTTA
AAATCTGTGTGG
CTGTCACTCG GCTG CATG CTTAGTG CACTCACG CAGTATAATTAATAACTAATTACTGTCG TTGACAGG
ACACGAGTAACTCGTCTATCTT
CTG CAG G CTG CTTACGGTTTCGTCCGTGTTGCAGCCGATCATCAG CACATCTAGGTTTCGTCCG GGTGTG
ACCGAAAG GTAAG ATG GAG
AGCCTTGTCCCTG G TTTCAACG AGAAAACACA CGTCCAACTCAGTTTG CCTGTTTTACAG GTTCG
CGACGTG CTCGTACGTG G CTTTGG A
G ACTCCGTG G AG G AGGTCTTATCAG AGG CACGTCAACATCTTAAAGATG G CACTTGTGG
CTTAGTAGAAGTTG AAAAAG G CGTTTTG CC
TCAACTTG AACAGCCCTATGTGTTCATCAAACGTTCGG ATG CTCGAACTG CACCTCATG GTCATGTTATG
GTTG AG CTG GTAGCAG AACT
CGAAGGCATTCAGTACGGTCGTAGTGGTGAGACACTTGGTGTCCTTGTCCCTCATGTGGGCGAAATACCAGTGGCTTAC
CGCAAGGTTC
TTCTTCGTAAG AACG GTAATAAAG G AG CTG GTG GCCATAGTTACGG CGCCG
ATCTAAAGTCATTTGACTTAG GCG A CGAG CTTG G CACT
G ATCCTTATG AAG ATTTTCAAGAAAACTGGAACACTAAACATAG CAGTG GTGTTACCCGT GAACTCATG
CGTG AG CTTAACG GAGGGGC
ATACACTCGCTATGTCGATAACAACTTCTGTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGT
GCTGGTAAAGC
TTCATG CACTTTGTCCG AACAACTGGACTTTATTGACACTAAG AGG G GTGTATACTGCTG CCGTG AACATG
AG CATG AAATTG CTTG GTA
CACGGAACGTTCTGAAAAGAGCTATGAATTGCAGACACCTTTTGAAATTAAATTGGCAAAGAAATTTGACACCTTCAAT
GGGGAATGTC
CAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAGGGTTGAAAAGAAAAAGCTTGATGGCTTTAT
GGGTAGAATTC
G ATCTGTCTATCCAGTTGCGTCACCAAATG AATGCAACCAAATGTG CCTTTCAA CTCTCATG AAGTGTG
ATCATTGTG GTGAAACTTCATG
G CAG ACGG G CGATTTTGTTAAAG CCACTTG CG AATTTTGTG GCACTG AGAATTTG ACTAAAG
AAGGTG CCACTACTTGTG G TTACTTA CC
CCAAAATGCTGTTGTTAAAATTTATTGTCCAGCATGTCACAATTCAGAAGTAGGACCTGAGCATAGTCTTGCCGAATAC
CATAATGAATC
TGGCTTGAAAACCATTCTTCGTAAGGGTGGTCGCACTATTGCCTTTGGAGGCTGTGTGTTCTCTTATGTTGGTTGCCAT
AACAAGTGTGC
CTATTG G GTTCCACGTGCTAG CG CTAACATAG GTTGTAACCATACAGGTGTTGTTG GAG AAG GTTCCG
AAG GTCTTAATGACAACCTTCT
TGAAATACTCCAAAAAGAGAAAGTCAACATCAATATTGTTGGTGACTTTAAACTTAATGAAGAGATCGCCATTATTTTG
GCATCTTTTTCT
G CTTCCACAAGTG CIIIIGTG G AAACTGTG AAAG GTTTG GATTATAAAGCATTCAAACAAATTGTTG
AATCCTGTG GTAATTTTAAAGTT
ACAAAAGGAAAAGCTAAAAAAGGTGCCTGGAATATTGGTGAACAGAAATCAATACTGAGTCCTCTTTATGCATTTG
CATCAGAGGCTGC
TCGTGTTGTACGATCAATTTTCTCCCGCACTCTTGAAACTGCTCAAAATTCTGTG CGTGTTTTACAGAAGG CCG
CTATAACAATACTAG AT
G GAATTTCACAGTATTCACTG AG ACTCATTG ATGCTATG ATGTTCACATCTG ATTTG G
CTACTAACAATCTAGTTGTAATGG CCTACATTA
CAGGTG GTGTTGTTCAG TTG ACTTCGCAGTG GCTAACTAACATCTTTG G
CACTGTTTATGAAAAACTCAAACCCGTCCTTG ATTG G CTTG A
AGAGAAGTTTAAGGAAGGTGTAGAGTTTCTTAGAGACGGTTGGGAAATTGTTAAATTTATCTCAACCTGTGCTTGTGAA
ATTGTCGGTG
G ACAAATTGTCACCTGTG CAAAG G AAATTAAGG AGAGTGTTCAGACATTCTTTAAG
CTTGTAAATAAATTTTTG GCTTTGTGTGCTG ACT
CTATCATTATTGGTGGAGCTAAACTTAAAGCCTTGAATTTAGGTGAAACATTTGTCACGCACTCAAAGGGATTGTACAG
AAAGTGTGTTA
AATCCAG AGAAGAAACTGG CCTACTCATG CCTCTAAAAG CCCCAAAAG AAATTATCTTCTTAG AG G GAG
AAACACTTCCCACAG AAGTG
TTAACAG AG GAAGTTGTCTTG AAAACTG GTGATTTACAACCATTAGAACAACCTACTAGTG AAG CTGTTG
AAG CTCCATTGGTTGGTACA
CCAGTTTGTATTAACGGGCTTATGTTGCTCGAAATCAAAGACACAGAAAAGTACTGTGCCCTTGCACCTAATATGATGG
TAACAAACAAT
1111 I 1GGTG ATGACACTGTG ATAG AAGTG CAAG G TTACAAG AGTGTG AATAT
CACTTTTG AACTTG ATGAAAGG ATTG ATAAAG TACTTAATG AG AAGTG CTCTGCCTATACAGTTG
AACTCG GTACAG AAGTAAATGAGTT
CG CCTGTGTTGTGGCAG ATGCTGTCATAAAAACTTTGCAACCAGTATCTGAATTACTTA CACCACTGG G
CATTGATTTA G ATGAGTG GAG
TATG GCTACATACTACTTATTTGATG AGTCTG GTGAGTTTAAATTG
GCTTCACATATGTATTGTTCTTTCTACCCTCCAG ATG AG G ATGAA
G AAG AAG GTGATTGTGAA GAAG AAG AGTTTG AG CCATCAACTCAATATG AGTATGGTACTG AAG ATG
ATTACCAAG GTAAACCTTTG G
AATTTG GTGCCACTTCTGCTG CTCTTCAACCTG AAG AAG AG CAAG AAG AAG ATTG GTTAGATG ATG
ATAGTCAACAAACTGTTG GTCAA
91
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CAAGACGG CA GTGAG GACAATCAGACAACTACTATTCAAACAATTGTTGAG GTTCAA CCTCAATTAG AG
ATG GAA CTTA CA CCAG TTG T
TCA G A CTATT G AA GT G AATA GTTTTA G TG GTTATTTAAAA CTTA CT G A CAATG TATA
CATTAAAAATG CA G A CATTG TG G AA G AA G CTAA
AAAG GTAAAACCAA CA GTG GTTGTTAATG CAGCCAATGTTTACCTTAAACATG G AG G AG GTGTTG
CAGG AG CCTTAAATAAGG CTACTA
A CAATG CCATGCAAGTTGAATCTGATGATTACATAG CTACTAATG GACCACTTAAAGTG G
GTGGTAGTTGTGTTTTAAG CGGACACAATC
TTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAG GTG AAG ACATT CAA CTTCTTAAG
AGTG CTTATGAAAATTTTAATCA
G CAC G AAG TT CTA CTTG CACCATTATTAT CA G CTG GTATTTTTG GTG CTG A
CCCTATACATTCTTTAA G AG TTTG TGTAG ATA CT G TTC G CA
CAAATGTCTACTTAG CTG TCTTT G ATAAAAATCTCTATG A CAAA CTTG TTTCAA G CTTTTTG G
AAATG AA G AGTG A AAA G CAA GTTG AA C
AAAAGATCG CTG AG ATTCCTAA A G AG G AA G TTAA G CCATTTATAA CTG AAA G TAAA CCTT
CA G TTG AA CA G A G AAAA CAAG ATG ATAA G
AAAATCAAAG CTTG TG TTG AA G AAG TTA CAACAA CTCTG G AA G AAA CTAAG TTCCT CACA G
AAAACTTG TTA CTTTATATTG A CATTAAT
G G CAATCTTCATCCAGATTCTG CCA CTCTTG TTA GT G A CATTG A CATCA CTTTCTTAAAG AAA G
ATG CT CCATATATA G TG G G TG ATG TT G
TTCAAGAG GGTGTTTTAACTGCTGTG GTTATACCTACTAAAAAGG CTG GTGG CA CTA CTG AAATG
CTAGCGAAAG CTTTGAGAAAAGTG
CCAACAGACAATTATATAACCACTTACCCG GGTCAG GGTTTAAATG GTTACACTGTAG AG G AG G
CAAAGACAGTG CTTAAAAAGTGTAA
AAGTG CCTTTTA CATT CTA CCAT CTATTAT CTCTAAT G A G AA G CAA G AAATTCTTG G AA
CTG TTTCTTG GAATTTG C G AG AAATG CTTG CA
CATG CA G AAG AAA CA C G CAAATTAAT G CCTG TCT GT GTG G AAA CTAAA G CCATA
GTTTCAACTATA CA G CGTAAATATAAG G GTATTAA
AATACAAGAG GGTGTG GTTGATTATG GTGCTAG ATTTTA CTTTTA CA CCAGTAAAACAACT GTAG
CGTCACTTATCAACA CA CTTAA CG A
TCTAAATGAAACTCTTGTTACAATGCCACTTGG CTATG TAA CA CATG G CTTAAATTTGGAAGAAG CTG
CTCG GTATATG AG ATCTCTCA A
A GTG CCAG CTACA G TTT CT GTTTCTT CACCTG ATG CTGTTACAG C G TATAAT G G TTATCTTA
CTTCTTCTTCTAAAA CACCTG AA G AA CATT
TTATTG AAACCATCTCA CTTG CTG GTTCCTATAAAGATTG GTCCTATT CTG G A CAAT CTACA CAA
CTAG GTATAG AATTT CTTAAGAG AG G
TGATAAAAGTGTATATTACACTAGTAATCCTACCACATTCCACCTAGATG
GTGAAGTTATCACCTTTGACAATCTTAAGACACTTCTTTCTT
TG AG A G AA G TG AG GACTATTAAG GT GTTTA CAA CA G TAG A CAACATTAA CCTC CA CAC
G CAAGTTGTG G ACATG TC AATG A CATATG GA
CAACAGTTTG GTCCAACTTATTTG G ATG G AG CTGATGTTACTAAAATAAAACCTCATAATTCACATGAAG
GTAAAACATTTTATGTTTTAC
CTAATGATGACACTCTACGTGTTGAG G CTTTTGAGTACTACCACACAACTGATCCTAGTTTTCTGG
GTAGGTACATGTCAGCATTAAATCA
CA CTAAAAAG TG GAAATACCCACAAGTTAATGGTTTAACTTCTATTAAATG G G CA G ATAA CAA
CTGTTATCTTG CCA CTG CATT GTTAA CA
CTCCAACAAATAG A GTTG AA G TTTAATCC A CCTG CT CTA CAA G AT G CTTATTA CAG A G C
AA G G G CTG GT G AA G CTG CTAA CTTTT GTG CA
CTTATCTTA G CCTA CTG TAATAA G A CA GTAG G TG AG TTAG GT G ATG TTA G AG AAACAAT
G A G TTA CTTG TTTCAA CAT G CCAATTTA G AT
TCTTG CAAAAGAGTCTTGAACGTGGTGTGTAAAACTTGTG GACAACAG CAGACAACCCTTAAG G GT
GTAGAAG CTGTTATGTACATGG G
CA CACTTTCTTATG AACAATTTAA G AAA G GT GTT CAG ATA CCTTG TA C GT GT G G TAAAC
AA G CTACAAAATATCTAGTACAACAG G AG TC
A CCTTTT GTTATG ATG TCA G CACCACCTG CTCA GTAT G AA CTTAA G CATG
GTACATTTACTTGTG CTA G TG A GTACA CTG GTAATTACCAG
TGTG GT CACTATAA A CATATAA CTTCTAAA G AAA CTTTG TATTG CATAGACG GTG
CTTTACTTACAAAGTCCTCAG AATACAAAG GTCCTA
TTACG G ATG TTTTCTA CAAA G AAAACA G TTA CA CAA CAACCATAAAA CCA GTTACTTATAAATTG
G AT GG TG TTG TTTG TACA G AAATTG
ACCCTAAGTTG G ACAATTATTATAAG AAAG AC AATTCTT ATTTCACAGAG CAA CCAATTG AT
CTTGTACCAAACCAACCATATCCAAACG C
AAG CTTC G ATAATTTTAA G TTTG TATG TG AT AATATCAAATTTG CTG ATG ATTTAAA CCA
GTTAACT G G TTATAA G AAA CCTG CTTCA AG A
GAG CTTAAA GTTA CATTTTTCCCT G A CTTAAATG GTGATGTG GTGG CTATT G ATTATAAA CA CTA
CA CA CCCTCTTTTAA G AAA G GAG CTA
AATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG CAA CTAATAAAG CCA C GTATAAA CCAAATA
CCTG GTGTATACGTTGTCTTTG
GAG CA CAAAACCA G TTG AAA CATCA AATTC G TTTG ATG TA CT G AAG TCA G AG G AC G
CG CAGG GAATG GATAATCTTG CCTG C G AA G AT
CTAAAACCAGTCTCTGAAGAAGTAGTG
GAAAATCCTACCATACAGAAAGACGTTCTTGAGTGTAATGTGAAAACTACCGAAGTTGTAGG
AGACATTATACTTAAACCAG CAAATAATAGTTTAAAAATTACAGAAG AG GTTGG CCACACAGATCTAATGG
CTG CTTATG TAG ACAATTC
TA G TCTTA CTATTAA G AAA CCTAATG AATTATCTA G AG TATTA G GTTTGAAAACCCTTG
CTACTCATG GTTTAG CTG CT GTTA ATA G T G TC
CCTTG G GATACTATAG CTAATTATG CTAAG CCTTTTCTTAA CAAA G TTG TTA G TA CAACTA
CTAACATA G TTA CAC G GTGTTTAAACCGTG
TTTGTACTAATTATATG CCTTATTTCTTTACTTTATTG CTA CAATTG TG TA CTTTTA CTAG AAG TA
CAAATT CTA G AATTAAAG CATCTATG C
C G ACTA CTATA G CAAAG AATA CTG TTAA G AG TG TC G GTAAATTTTGT CTA G AG
GCTTCATTTAATTATTTGAAGTCACCTAATTTTTCTAA
A CTG ATAAATATTATAATTTG GTTTTTACTATTAAGTGTTTGCCTAG G TT CTTTAATCTACT CAA CC G
CTG CTTTAG GT GTTTTAATGTCTAA
TTTAG G CAT G CCTT CTTA CTG TA CTG GTTA CA G A G AA G G CTATTTG AA CTCTA
CTAATG TCA CTATTG CAA CCTA CTG TA CTG GTTCTATAC
CTTG TA G TGTTTG TCTTAG TG G TTTA G ATTCTTTAG ACA CCTATCCTT CTTTA G AAA CTATA
CAAATTA CCATTTCATCTTTTAAATG G GATT
TAA CT G CTTTTG G CTTAGTTG CAG A GT G G TTTTTG G CATATATT CTTTT CA CTA G G
1 1 1 1 1 CTATGTACTTG GATTG G CTG CAATCATG CAA
TTGTTTTTCAG CTATTTTG CA GTACATTTTATTA G TAATT CTTG G CTTATG TG G
TTAATAATTAATCTTG TA CAAATG G CCCCGATTTCAG CT
ATG GTTAG AATG TA CATCTTCTTT G CATCATTTTATTATG TATG G AAA AG TTAT GTG C
ATGTTGTAG AC G G TTGTAATTCATCAA CTTG TAT
GATGTGTTACAAACGTAATAGAG CAACAAGAGTCGAATGTACAACTATTGTTAATG GT
GTTAGAAGGTCCTTTTATGTCTATG CTAATG G
A G G TAAAG G CTTTT G CA AA CTA CACAATTG GAATTGTGTTAATTGTG ATACATTCTGTGCTG
GTAG TA CATTTATTAG TG ATG AA G TTG C
G AG AGACTTGTCACTACAGTTTAAAAG ACCAATAAATCCTACTG ACCAGTCTTCTTACATCGTTG
ATAGTGTTACAGTG AAGAATG
GTTCCATCCATCTTTACTTTGATAAAGCTG
GTCAAAAGACTTATGAAAGACATTCTCTCTCTCATTTTGTTAACTTAGACAACCTGAGAG CT
AATAA CA CTAAA G GTTCATTG CCTATTAATGTTATAGTTTTTG AT G G TAAAT CAAAAT GTG AA G
AATCATCTG CAAAATCAG CGTCTGTTT
A CTA CAG TCA G CTTATG TG TCAA CCTATA CTGTTACTAG ATCAG G CATTA GT GTCT GATGTTG
GTGATAGTG C GG AAG TT G CA G TTAAAA
TGTTTGATG CTTA C G TTAATAC G TTTTCATCAA CTTTTAAC G TA CCAAT G G AAAAA CTCAAAA
CACTAG TTG CAACT G CA G AA G CT G AA CT
TG CAAAG AATG TG TCCTTAG A CAATG T CTTAT CTACTTTTATTTC AG CA G CTCGG CAA G G G
TTTG TTG ATTCA G AT GTAG AAA CTAAAG A
TG TTG TTG AAT GT CTT AAATTG TCA CAT CAATCTG ACATAG AA GTTACTG G
CGATAGTTGTAATAACTATATG CTCACCTATAACAAAG TT
GAAAACATGACACCCCGTGACCTTG GTGCTTGTATTG ACT GTAG TG CG CGTCATATTAATG CG CAG
GTAG CAA AAAGTCA CAA CATTG C
TTTGATATG G AA C GTTAAAG ATTTCATG TCATTG TCTG AA CAA CTAC G AAAACAAATACG TA G
TG CTG CTAAAAAGAATAACTTACCTTTT
AA GTT G A CATG TG CAA CTA CTA G ACAA GTTG TTAAT G TTG TAA CAA C AAA G ATA G
CACTTAAG G GT G GTAAAATT GTTAATAATTG GTTG
AAG CA GTTAATTAAA G TTA CA CTTG TG TTCCTTTTTG TTG CTG CTATTTTCTATTTAATAA CA C
CTG TT CATG TCATG TCTAAA CATACTG A C
TTTTCAAGTGAAATCATAG GATACAAG G CTATTGATG GT G G TG TCA CTC G TG ACATA G
CATCTACAGATACTTGTTTTGCTAACAAACAT
G CTGATTTTGACACATG GTTTAGCCAG C GT G G TG G TA GTTATACTAATG A CAAA G CTTG
CCCATTGATTGCTG CA GTCATAACAAG A G AA
92
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
GTGGGTTTTGTCGTGCCTGGTTTGCCTGGCACGATATTACGCACAACTAATGGTGACTTTTTGCATTTCTTACCTAGAG
TTTTTAGTGCAG
TTGGTAACATCT GTTA CACA CCATCAAAA CTTATA G AGTA CA CTG ACTTTG CAACATCAG
CTTGTGTTTTGG CTG CTGAATGTACAATTTT
TAAAGATG CTTCTG GTAAG CCAGTACCATATTGTTATGATACCAATGTACTAGAAG GTTCTGTTG
CTTATGAAAGTTTACG CCCTGACAC
A CGTTAT GT G CTCATG G AT G G CTCTATTATTCAATTTCCTAA CACCTA CCTT GAAG GTTCT
GTTA GA GTG GTAA CAACTTTTG ATTCTG AG
TA CTGTA G G CA CG G CA CTTGTG AAA GATCA G AA G CTG GTGTTTGTGTATCTACTAGTG
GTAGATG GGTACTTAACAATGATTATTACAG
ATCTTTACCAG GAGTTTTCTGTG GTGTAGATG CT GTAAATTTACTTACTAATATGTTTACACCA
CTAATTCAACCTATTGGTG CTTTG GA CA
TATCAGCATCTATAGTAGCTGGTG GTATTGTAGCTATCGTAGTAACATGCCTTG CCTA CTATTTTATG AG
GTTTAGAAGAG CTTTTGGTG A
ATACAGTCATGTAGTTGCCTTTAATACTTTACTATTCCTTATGTCATTCACTGTACTCTGTTTAACACCAGTTTACTCA
TTCTTACCTG GTGT
TTATT CT GTTATTTACTT GTA CTT GA CATTTTAT CTTA CTA AT GATGTTTCTTTTTTA G
CACATATTCA GTG G AT G GTTATGTTCA CA CCTTTA
GTACCTTTCTG GATAACAATTG
CTTATATCATTTGTATTTCCACAAAGCATTTCTATTGGTTCTTTAGTAATTACCTAAAGAGACGTGTA
GT CTTTAAT G GTGTTT CCTTTA GTACTTTTG AAG AAG CTG CG CTGTG CA CCTTTTTGTTAAATAA
A GAAAT GTATCTAAA GTTG CGTAGTG
ATGTGCTATTACCTCTTACG CAATATAATAGATACTTAG CTCTTTATAATAAGTACAAGTATTTTAGTG GAG C
AAT G G ATA CAA CTA G CTA
CA GA G AA G CTG CTTGTTGTCATCTCG CAAAG G CTCTCAAT GACTT CAGTAA CTCA G GTTCT
GATGTTCTTTA CCAACCA CC ACAAACCTCT
ATCACCTCAG CTGTTTTGCAGAGTG GTTTTAG AA AAATGGCATTCCCATCTG GTAAAGTTGAGG
GTTGTATGGTACAAGTAACTTGTGGT
A CAA CTA CA CTTAACG GTCTTTGG CTTG ATG ACG TA GTTTA CTGTCCAA GA CATGTG AT CT G
CA CCTCTG AAG ACATG CTTAACCCTAATT
ATGAAGATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTACAG G CTG GTAATGTTCAACTCAG G
GTTATTG GACATTCTATG CAAAA
TTGTGTA CTTA A G CTTAAG GTTGATACAG CCAAT CCTAAG A CACCTAA GTATAAGTTT GTTCG
CATT CAA CCA G GA CA GA CTTTTTCA GTG
TTAG CTTGTTACAATGGTTCACCATCTG GTGTTTACCAATGTGCTATGAGG CCCAATTTCACTATTAAG G
GTTCATTCCTTAATG GTTCATG
TG GTAGTGTTGGTTTTAACATAGATTATG ACTGTGTCTCTTTTTGTTACATGCACCATATG
GAATTACCAACTGGAGTTCATG CTG GCA CA
GACTTAGAAG GTAACTTTTATG GACCTTTTGTTGACAG GCAAACAG CA CAAG CAGCTG GTACGG ACA
CAA CTATTA CAGTTAATGTTTTA
G CTTG GTTGTACG CTG CTGTTATAAATG G A G ACA G GT G GTTTCTCAAT CGATTTACCA CAA
CTCTTAATG ACTTTA ACCTTGT G G CTATG A
AGTACAATTATGAACCTCTAACACAAGACCATGTTGACATACTAG GACCTCTTTCTGCTCAAACTGGAATTG CC
GTTTTAGATATGTGTG C
TTCATTAAAAG AATTA CT G CAAAATG GTATGAATG GACGTACCATATTG GGTAGTG
CTTTATTAGAAGATGAATTTACACCTTTTGATGTT
GTTA GA CAAT G CT CA G GTGTTACTTTCCAAAGTG CAGTG AAAA G AA CAATCAA G G GTA CA
CACCA CTG GTTGTTA CTCA CAATTTTGA CT
TCA CTTTTAGTTTTA GT C CAG A GTACT C AATG GTCTTTGTTCTTTTTTTTGTATG AAAATG
CCTTTTTACCTTTTG CTATG G GTATTATTG CT
ATGTCTG CTTTT G CAATG AT GTTTGTCAAA CATAA G CATG
CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG CCACTGTAG CTTATTTTAAT
ATGGTCTATATG CCTG CTAGTTG GGTGATG CGTATTAT GA CATG GTTGGATATG GTTG ATA CTA
GTTTGTCT G GTTTTA AG CTAAAA G A C
TGTGTTATGTATG CATCAG CTGTAGTGTTACTAATCCTTATGACAG CAAG AA CT GT GTATG ATG
ATGGTG CTAGG AG AGTGTG GACACTT
ATGAATGTCTTGACACTCGTTTATAAAGTTTATTATG GTAATG CTTTAGATCAAGCCATTTCCATGTGG G
CTCTTATAATCTCTGTT ACTT C
TAACTACTCAGGTGTAGTTACAACTGTCATGTTTTTGGCCAGAGGTATTGTTTTTATGTGTGTTGAGTATTGCCCTATT
TTCTTCATAACTG
GTAATACACTTCAGTGTATAATGCTAGTTTATTGTTTCTTAGGCTATTTTTGTACTTGTTACTTTGGCCTI. 1111
GTTTACTCAACCGCTACT
TTA G ACT GA CTCTT G GTGTTTAT GATTACTTAGTTTCTA C ACA G
GAGTTTAGATATATGAATTCACAG G G ACTA CTCCCA CCCAA G AATAG
CATAGATG CCTTCAAACT CAA CATTAAATTGTTG GGTGTTG GTG G CAAACCTTGTATCAAAGTAG CCA
CTGTA CA GT CTAAA ATGTCAG A
TGTAAAGTG CA CATCAGTA GT CTTA CTCTCAGTTTTGCAACAA CTCAG AGTAG AAT CAT
CATCTAAATTGTG G GCTCAATGTGTCCAGTTA
CA CAATG ACATT CTCTTAG CTAAAGATACTACTGAAGCCTTTGAAAAAATG GTTTCACTAC ____ I I I
CT GTTTTG CTTTCCATG CAGG GTG CTG
TA GA CATAAACAA G CTTTGTG AA G AAATG CT G G A CAA CA G G G CAA CCTTA CAA G
CTATA G CCTCA G A GTTTA GTTCCCTTCCATC ATATG
CA G CTTTTG CTACTG CTCAAGAAG CTTATG A G CA G G CT GTTG CTAATG GTG ATTCTG AA
GTTGTTCTTAAAAAGTT GAA GAA GT CTTTG A
ATGTGG CTAAATCTGAATTTGACCGTGATGCAG CCATG CAACGTAAGTTG GAAAAGATG GCTGATCAAG
CTATGACCCAAATGTATAAA
CAGG CTAGATCTGAGGACAAGAGG G CAAAAGTTACTAGTG CTATG CAGACAATGCTTTTCACTATG
CTTAGAAAGTTGGATAATGATG C
ACTCAACAACATTATCAACAATGCAAGAGATGGTTGTGTTCCCTTGAACATAATACCTCTTACAACAGCAGCCAAACTA
ATGGTTGTCAT
ACCAGACTATAACACATATAAAAATACGTGTG
ATGGTACAACATTTACTTATGCATCAGCATTGTGGGAAATCCAACAGGTTGTAGATGC
AG ATA GTAAAATTGTTCAACTTAGTG AAATTAGTATG GACAATTCACCTAATTTAG CATG
GCCTCTTATTGTAACAG CTTTAAGG G CCAAT
TCTG CTGTCAAATTACAG AATAATG AG CTTAGTCCTGTTG CA CTA CGACAGATGTCTTGTGCTG CCG
GTACTACACAAACTG CTTG CA CT
GATGACAATGCGTTAG CTTA CTA CAA CA CAACAAAG G GAG GTAG
GTTIGTACTTGCACTGTTATCCGATTTACAGGATTTGAAATG GGC
TAGATTCCCTAAGAGTGATG G AA CTG GTACTATCTATACAGAACTG GAACCACCTTGTAG
GTTTGTTACAGACACACCTAAAGGTCCTAA
A GTGAA GTATTTATA CTTTATTAAAGG ATTAAACAACCTAAATAG AGGTATG GTACTTG GTAGTTTAG
CTG C CA CAGTACGTCTA CA AG C
TG GTAATG CAACAGAAGTG CCTG CCAATTCAACTGTATTATCTTTCTGTG CTTTTG CT GTA G AT G
CTG CTAAAG CTTAC AAA GATTATCTA
G CTAGTG G GG G ACAACCAAT CA CTAATTGTGTTAA GATGTT GTGTA CA CACA CTG GTACTG
GTCAG GCAATAA CAG TTA CA CCGG AAGC
CAATATG GATCAAGAATCCTTTG GTG GT G CAT CGTGTTGTCTGTA CTG CCGTTG CCACATA G AT
CAT CC AAATCCTAAAG G ATTTTGTG A
CTTAAAAGGTAAGTATGTACAAATACCTACAACTTGTGCTAATGACCCTGTGGGTTTTACACTTAAAAACACAGTCTGT
ACCGTCTGCGG
TATGTGGAAAGGTTATGGCTGTAGTTGTGATCAACTCCGCGAACCCATGCTTCAGTCAGCTGATGCACAATCGTTTTTA
AACGGGTTTGC
GGTGTAAGTGCAGCCCGTCTTACACCGTGCGGCACAGGCACTAGTACTGATGTCGTATACAGGGCTTTTGACATCTACA
ATGATAAAGT
AGCTGGTTTTGCTAAATTCCTAAAAACTAATTGTTGTCGCTTCCAAGAAAAGGACGAAGATGACAATTTAATTGATTCT
TACTTTGTAGTT
AAGAGACACACTTTCTCTAACTACCAACATGAAGAAACAATTTATAATTTACTTAAGGATTGTCCAGCTGTTGCTAAAC
ATGACTTCTTTA
AGTTTAGAATAGACGGTGACATGGTACCACATATATCACGTCAACGTCTTACTAAATACACAATGGCAGACCTCGTCTA
TG CTTTAAGG C
ATTTTGATGAAGGTAATTGTGACACATTAAAAGAAATACTTGTCACATACAATTGTTGTGATGATGATTATTTCAATAA
AAAGGACTG GT
ATGATTTTGTAGAAAACCCAGATATATTACG CGTATACG CCAACTTAG GTGAACGTGTACG CCAAG
CTTTGTTAAAAA CA GTACAATTCT
GTGATG CCATG CGAAATG CT G GTATTGTT G GTGTA CTG ACATTAG ATAAT CAA G AT CTCAAT G
GTAA CTG GTATGATTTCG GTGATTTCA
TA CAAA CCA CG CCA G GT AGTG GAGTTCCTGTTGTAGATTCTTATTATTCATTGTTAATG
CCTATATTAACCTTGACCAG GG CTTTAACTG C
AGAGTCACATGTTGACACTGACTTAACAAAG CCTTACATTAAGTGG GATTTGTTAAAATATG ACTTCA CGG
AAG AG AG GTTAAAACTCTT
TGACCGTTATTTTAAATATTGG G AT CAG A CATACCA CCCAAATT GTGTTAACTGTTT GG AT G ACA G
AT G CATTCT GCATTG TG CAAACTTT
AATGTTTTATTCTCTACAGTGTTCCCACCTACAAGTTTTG GA CCACTA GT GA G AAAAATATTTGTTG ATG
GT GTTCCATTTGTA GTTTCAA C
93
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
TG GATACCACTTCAGAGAGCTAG GTGTTGTACATAATCAGGATGTAAACTTACATAGCTCTAGACTTAGTTTTAAG
GAATTACTTGTGTA
TG CTG CTGACCCTG CTATG CACGCTG CTTCTGGTAATCTATTACTAGATAAACGCACTACGTG CTTTT CA
GTAG CTG CACTTACTAACAAT
GTTG CTTTTCAAACTGTCAAACCCG GTAATTTTAACAAAGACTTCTATGACTTTG CT GTG TCTAAG
GGTTTCTTTAAG GAAG GAAGTTCTG
TTGAATTAAAACACTTCTTCTTTG CTCAGGATG GTAATG CTG CTATCAGCG
ATTATGACTACTATCGTTATAATCTACCAACAATGTGTGA
TATCAGACAACTACTATTTGTAGTTGAAGTTGTTGATAAGTACTTTGATTGTTACGATG GTG G CT GTATTAATG
CTAACCAAGTCATCGTC
AACAACCTAGACAAATCAG CTG GTTTTCCATTTAATAAATGG C GTAAG G CTAG ACTTTATTAT GATTCA
ATG AGTTAT GAG GATCAAGAT
G CACTTTTCG CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATGCCATTAGTG
CAAAG AATAG AG CTCG CA
CCGTAGCTGGTGTCTCTATCTGTAGTACTATGACCAATAGACAGTTTCATCAAAAATTATTGAAATCAATAGCCG
CCACTAGAG GAG CTA
CTGTAGTAATTG GAACAAGCAAATTCTATG GT G GTTG G
CACAACATGTTAAAAACTGTTTATAGTGATGTAGAAAACCCTCACCTTATG G
GTTG GGATTATCCTAAATGTGATAGAGCCATG CCTAACATG CTTAGAATTATG GCCTCACTTGTTCTTG CTCG
CAAACATACAACGTGTTG
TAG CTTGTCACACCGTTTCTATAGATTAG CTAATGAGTGTGCTCAAGTATTGAGTGAAATG GTCATGTGTG G
CGGTTCACTATATGTTAA
ACCAG GTG GAACCTCATCAG G AG ATG CCACAACTG CTTATG CTAATAGTGTTTTTAACATTTGTCAAG
CTGTCACGG CCAATGTTAATG C
ACTTTTATCTACTGATG GTAACAAAATTGCCGATAAGTATGTCCG CAATTTACAACACAG ACTTTATG
AGTGTCTCTATAGAAATAG AG AT
GTTGACACAGACTTTGTGAATG AGTTTTACG CATATTTG
CGTAAACATTTCTCAATGATGATACTCTCTGACGATG CTGTTGTGTGTTTCA
ATAGCACTTATG CATCTCAAG GTCTAGTG GCTAG CATAAAG
AACTTTAAGTCAGTTCTTTATTATCAAAACAATGTTTTTATG TCTG AAG C
AAAATGTTG GACTGAGACTGACCTTACTAAAGGACCTCATGAATTTTG CTCTCAACATACAATGCTAGTTAAACAG
GGTG ATGATTATGT
GTACCTTCCTTACCCAGATCCATCAAGAATCCTAGG G GCCG G CTGTTTTGTAGATGATATCGTAAAAACAGATG
GTACACTT ATGATTG A
ACGGTTCGTGTCTTTAGCTATAGATGCTTACCCACTTACTAAACATCCTAATCAG GAGTATG CTG AT
GTCTTTCATTT GT ACTTACAATACA
TAAGAAAG CTACATG AT G AGTTAACAG GACACATGTTAGACATGTATTCTGTTATG
CTTACTAATGATAACACTTCAAGGTATTGG GAAC
CTG AGTTTTATG AG G CTATGTACACACCG CATACAGTCTTACAG GCTGTTGG G
GCTTGTGTTCTTTGCAATTCACAGACTTCATTAAGATG
TG GTGCTTG CATACGTAG ACCATTCTTATGTTGTAAATG CT
GTTACGACCATGTCATATCAACATCACATAAATTAGTCTTGTCTGTTAATC
CGTATGTTTG CAAT G CTC CA G G TTG TG AT GT CAC A G ATGT G A CTCAA CTTTA CTTA G
GAG G TATG AG CTATTATTGTAAATCA CATAAA C
CACCCATTAGTTTTCCATTGTGTG CTAATG GACAAG
_____________________________________________ 11111 GGTTTATATAAAAATACATGTGTTG
GTAG CGATAATGTTACTGACTTTAA
TG CAATT G CAACAT GT GACTG GACAAATGCTGGTGATTACATTTTAG
CTAACACCTGTACTGAAAGACTCAAGCTTTTTG CAG CAGAAAC
G CTCAAAG CTACTGAG G AG ACATTTAAACT GTCTTATG GTATTG CTA CTG TA C GTG AA G TG
CTG TCTG A CAG A G AATTAC ATCTTTCATG
GAAGTTG GTAAACCTAG ACCACCACTTAACCG AA ATTATG TCTTTA CTG GTTATCGTG TAA CTAAAAA
CAG TAAAGTA CAAATAG GAG
AGTACACCTTTGAAAAAG GT GACTATG GTG AT G CT GTT GTTTACCG AG
GTACAACAACTTACAAATTAAATGTTG GT GATTATTTTGTG C
TGACATCACATACAGTAATG CCATTAAGTG CACCTACACTAGTG CCACAAGAG CACTATGTTAGAATTACTG G
CTTATACCCAACACTCA
ATATCTCAGATGAGTTTTCTAG CAATGTTGCAAATTATCAAAAGGTTG GTATG CAAAAGTATTCTACACTCCAG
GG A CCACCTGGTA CTG
GTAAGAGTCATTTTG CTATTGG CCTAGCTCTCTACTACCCTTCTGCTCG CATAGTGTATACAG
CTTGCTCTCATG CCG CTGTTGATG CACTA
T GTG AG AAGG CATTAAAATATTTGCCTATAGATAAATGTAGTAGAATTATACCTG CACGTG CTCGTGTAG
AGTGTTTTGATAAATTC AAA
GTGAATTCAACATTAGAACAGTATGTCTTTTGTACTGTAAATG CATTG
CCTGAGACGACAGCAGATATAGTTGTCTTTGATGAAATTTCA
ATGG CCACAAATTATGATTTGAGTGTTGTCAATG CCAGATTACGTG CTAAG CACTATGTGTACATTGG
CGACCCTGCTCAATTACCTG CA
CCACG CACATTG CTAACTAAG GG
CACACTAGAACCAGAATATTTCAATTCAGTGTGTAGACTTATGAAAACTATAG GTCCAGACATGTTC
CTCG G AA CTTG TC G G CGTTGTCCTG CTG AAATTGTTG A CA CTGT G A G TG CTTTG G
TTTAT G ATAATAAG CTTAAA G CA CATAAA G A CAAA
TCAGCTCAATG CTTTAAAATGTTTTATAAGG GTGTTATCACGCATGATGTTTCATCTGCAATTAACAGG
CCACAAATAG G CGT G GTAAG A
GAATTCCTTACACGTAACCCTG CTTG GAG AAAAGCTGTCTTTATTT CACCTTATAATTCACAG AATG
CTGTAGCCTCAAAGATTTTG G GAC
TACCAACTCAAACTGTTGATTCATCACAGG G
CTCAGAATATGACTATGTCATATTCACTCAAACCACTGAAACAGCTCACTCTTGTAATGT
AAACAGATTTAATGTTG CTATTACCAG AG CAAAAGTAG G
CATACTTTGCATAATGTCTGATAGAGACCTTTATGACAAGTTGCAATTTAC
AAGTCTTGAAATTCCACGTAG GAATGTG G CAACTTTACAAG CT GAAAATG TAACAG
GACTCTTTAAAGATTGTAGTAAG GTAATCACTG
G GTTACATCCTACACAGG
CACCTACACACCTCAGTGTTGACACTAAATTCAAAACTGAAGGTTTATGTGTTGACATACCTG GCATACCTA
AGGACATGACCTATAGAAGACTCATCTCTATGATG GGTTTTAAAATG AATTATCAAGTTAATGGTTA
CCCTAACAT GTTTATCACCCG CG
AAGAAG CTATAAGACATGTACGTG CATG GATTGG CTTCG ATGTCG AG G GGTGTCATG CTACTAGAGAAG
CTGTTG GTACCAATTTACCT
TTACAGCTAG GTTTTTCTACAGGTGTTAACCTAGTTG CTGTACCTACAG
GTTATGTTGATACACCTAATAATACAGAIIIII __ CCAGAGTTA
GTG CTAAACCACCGCCTG G AG ATCAATTTAAACACCTCATACCACTTATGTACAAAGG ACTTCCTTG
GAATGTAGTG CGTATAAAGATTG
TACAAATGTTAAGTGACACACTTAAAAATCTCTCTGACAGAGTCGTATTTGTCTTATG GG CA CAT G G CTTTG
A G TTG AC ATCTATG AA G T
ATTTTGTGAAAATAG GACCTG A GCG CACCTGTTGTCTATGTGATAGACGTG CCACATG
CTTTTCCACTGCTTCAGACACTTATG CCTGTTG
G CAT CATTCTATT G G ATTTG ATTA C G TCTATAATC C G TTTAT G ATT G ATG TTCAA CAATG
G GGTTTTACAG GTAACCTACAAAG CAAC CAT
G ATCT GTATT GT CAA G TC CATG G TAATG CACATG TA G CTAG TT GTG ATG CAATCATG A
CTA G G TG TCTA G CT G TC CA C G A GT G CTTT G TT
AAG CGTGTTGACTGGACTATTGAATATCCTATAATTGGTGATGAACTGAAGATTAATG CG GCTTGTAGAAAG
GTTCAACACATGGTTGTT
AAAG CTG CATTATTAGCAGACAAATTCCCAGTTCTTCACGACATTG
GTAACCCTAAAGCTATTAAGTGTGTACCTCAAG CTG AT GTAGAA
TG GAAGTTCTATGATG CACAG CCTTGTAGTGACAAAG
CTTATAAAATAGAAGAATTATTCTATTCTTATGCCACACATTCTGACAAATTCA
CAGATG GTGTATG CCTATTTTG GAATTG
CAATGTCGATAGATATCCTGCTAATTCCATTGTTTGTAGATTTGACACTAGAGTG CTATCTAA
CCTTAACTTG CCTG GTTGTGATG GTG GCAGTTTGTATGTAAATAAACATGCATTCCACACACCAG
CTTTTGATAAAAGTG CTTTTGTTAAT
TTAAAACAATTACCA _______________________________________________________ 11111
CTATTACTCTGACAGTCCATGTGAGTCTCATGGAAAACAAGTAGTGTCAGATATAGATTATGTACCACTAA
A GT CTG CTAC G TG TATAA CAC G TT G CAATTTA G GTG GTG CTG TCT GTAG A CATCATG
CTAAT G A G TACAG ATTG TATCTC G ATG CTTATA
A CATG ATG ATCTCA G CTG G CTTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG G
AA CA CTTTTACAAG ACTT CAG A GTTT
AGAAAATGTG G CTTTTAATGTTGTAAATAAG G GACACTTTGATG GACAACAG G GT
GAAGTACCAGTTTCTATC ATTAATAACA CTGTTTA
CACAAAAGTTGATG GT GTTGATGTAG AATTGTTT GAAAATAAAAC AACATTACCTGTTAATGTAG
CATTTGAG CTTTG G GCTAAG CG CAA
CATTAAACCAGTAC CAG AG GTGAAAATACTCAATAATTTG G GT GTGG ACATTGCTGCTAATACTG TG
ATCTGG G ACTACAAAAG AG ATG
CTCCAGCACATATATCTACTATTG GT GTTTGTTCTATG ACTGACATAG
CCAAGAAACCAACTGAAACGATTTGTG CACCACTCACTGTCTT
TTTTGATGGTAGAGTTGATGGTCAAGTAGACTTATTTAGAAATGCCCGTAATG
GTGTTCTTATTACAGAAGGTAGTGTTAAAG GTTTACA
94
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ACCATCTGTAG GTCCCAAACAAG CTAGTCTTAATG GA GTCACATTAATTGG AGAAG CCGTAAAAA CA
CAGTTCAATTATTATAAG AAA GT
TG AT G GTGTTGTCC AA CAATTACCT GAAACTTA CTTTA CTCA GA GTA G AAATTTA C AA
GAATTTAAACCCAG GAGTCAAATG G AAATT GA
TTTCTTAGAATTAGCTATG GATGAATTCATTGAACG GTATAAATTAGAAG G CTATGCCTTCGAA
CATATCGTTTAT GG A GATTTTAGT CAT
A GTCA GTTA G GT G GTTTACATCTA CTG ATTG GACTAG CTAAACGTTTTAAG G AATCA
CCTTTTGAATTA G AA G ATTTTATT CCTATG G A CA
GTACAGTTAAAAACTATTTCATAACAGATG CGCAAACAG GTTCATCTAA GT GTGTGT GTTCT GTTATTG
ATTTATTACTTGATGATTTTGTT
GAAATAATAAAATCCCAAGATTTATCTGTAGTTTCTAAG GTTGTCAAA GTG A CTATTG ACTATACA G
AAATTT CATTTATG CTTTG GTGTA
AAGATG GCCATGTAG AAA CATTTTACC CAAAATTACAATCTAGTCAAG CGTGGCAACCGG GTGTTG CTATG
CCTAATCTTTACAAAATG C
AAA G AAT G CTATTAGAAAAGTGTGACCTTCAAAATTATG GTGATAGTG CAACATTACCTAAAG G
CATAATG AT G AATGTCG CAAAATAT
A CTCAA CTGTGTCAATATTTAAA CACATTAA CATTAGCT GTACCCTATAATATG AG AGTTATACATTTTG
GTG CTG GTT CTG ATAAAGG AG
TTG CACCAG GTACAG CTGTTTTAAGACAGTG GTTG CCTACG GGTACG CTG
CTTGTCGATTCAGATCTTAATG ACTTTGTCTCTGATG CA G
ATTCAACTTTG ATTG GTGATTGTGCAACTGTACATACAG CTAATAAATGG G ATCTCATTATTAGTGATAT
GTACG ACCCTAAG ACTAAA A
ATGTTA CAAAAG AAAATG ACTCTAAAGAGGGTTTTTT CA CTTA CATTTGTG
GGTTTATACAACAAAAGCTAG CTCTTGGAGGTTCCGTG G
CTATAAA G ATAA CA GAA CATTCTTG GAATG CTGATCTTTATAAG CTCATGG GACACTTCG CATG GT
G G A CAG CCTTT GTTA CTAATGTG A
ATG CGTCATCATCTGAAG CATTTTTAATTG GATGTAATTATCTTGG CAAAC CACGCG AA CAAATAG ATG
GTTATGT CAT GCATG CAAATT
A CATATTTTG GAG G AATA CAAAT C CAATTCA G TT G TCTT C CTATTCTTTATTTG A CAT G A
G TAAATTTC C C CTTAAATTAAG G G G TA CTG CT
GTTATGTCTTTAAAAGAAG GTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAG G TA G A
CTTATAATTA G AG AAAA CAACA G AG TT
GTTATTTCTAGTGATGTTCTTGTTAACAACTAAACGAACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTAGTCAGTGTGTTAATCT
TACAACCAGAACTCAATTACCCCCTGCATACACTAATTCTTTCACACGTG
GTGTTTATTACCCTGACAAAGTTTTCAGATCCTCAGTTTTAC
ATTCAACTCAG GACTTGTTCTTACCTTTCTTTTCCAATGTTACTTG GTTCCATG CTATA CAT GTCT CTG
GGACCAATG GTACTAAGAGGTTT
G ATAA CCCTGTCCTA CCATTTAATG AT G GTGTTTATTTTG CTTCCA CTG A GAA GT
CTAACATAATAAG A G G CTG GATTTTTGGTACTACTT
TAG ATTCGAAG ACCCAGTCCCTACTTATTGTTAATAACG CTACTAATGTTGTTATTAAAGTCTGTG
AATTTCAATTTTGTAATG ATCCATTT
HG
GGTGTTTATTACCACAAAAACAACAAAAGTTGGATGGAAAGTGAGTTCAGAGTTTATTCTAGTGCGAATAATTGCACTT
TTGAATAT
GTCTCTCAGCCTTTTCTTATGGACCTTGAAG GAAAACAG GGTAATTTCAAAAATCTTAG G
GAATTTGTGTTTAAGAATATTGATG GTTATT
TTAAAATATATTCTAAG CA CACG CCTATTAATTTAGTG CGT GATCTCC CT CAG G GTTTTTCG G
CTTTAGAACCATTG GTAGATTTG CCAAT
AG GTATTAA CATCACTAG GTTT CAAA CTTTACTTG CTTTA CATAGAA GTTATTTGACTC CTG
GTGATTCTTCTTCAG GTTG GACA G CTG GT
G CTG CA G CTTATTATGTG G G TTATCTTCAA CCTA G G A CTTTTCTATTAAAATATAATG AAAATG
G AA C CATTA CAG ATG CTG TA G A CTG TG
CACTTGACCCTCTCTCAGAAACAAAGTGTACGTTGAAATCCTTCACTGTAGAAAAAGGAATCTATCAAACTTCTAACTT
TAGAGTCCAACC
AACAG AATCTATTGTTAGATTTCCTAATATTAC AAA CTT GTGCCCTTTTG GTGAAGTTTTTAACG
CCACCAGATTTGCATCTGTTTATG CTT
G GAACAG GAAGAGAATCAG CAA CTGTGTTG CTGATTATTCTTTCCTATATAATTCCG CATCATTTT CCA
CTTTTAA GT GTTATGG AGTGT C
TCCTACTAAATTAAATGATCTCTG CTTTACTAATGTCTATG CA GATT CATTT GTAATTA GA G GT GATG
AAGTCA G ACAAATCG CTCCAG G G
CAAACTG G AAA G ATTG CTG ATTATAATTATAAATTACCA G AT GATTTTA CAG G CTG
CGTTATAGCTTG GAATTCTAACAATCTTGATTCTA
AGGTTG GTG
GTAATTATAATTACCTGTATAGATTGTTTAGGAAGTCTAATCTCAAACCTTTTGAGAGAGATATTTCAACTGAAATCTA
TCA
G G CCG
GTAGCACACCTTGTAATGGTGTTGAAGGTTTTAATTGTTACTTTCCTTTACAATCATATGGTTTCCAACCCACTAATG
GTGTTG GT
TACCAACCATACAGAGTAGTAGTACTTTCTTTTGAACTTCTACATGCACCAGCAACTGTTTGTG
GACCTAAAAAGTCTACTAATTTG GTTA
AAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CA CAG
GTGTTCTTACTGAGTCTAACAAAAAGTTTCTGCCTTTCCAACAATT
TG G CA G AGA CATTG CTGACA CTA CTG ATG CT GT CCGTG ATCCA CAG A CACTTG AG
ATTCTT GA CATTA CA CCATGTT CTTTTG GTG GTGTC
A GT GTTATAA CA CC AG G AACAAATACTTCTAACCAG GTTG CTGTTCTTTATCAG G ATGTTAACT G
CA CA GAA GT CCCTGTTG CTATTCATG
CA GATCAA CTTA CTCCTA CTTG G CGTGTTTATT CTA CA G GTTCTAATGTTTTTCAAACA CGT G CA
G G CT GTTTAATAG G GG CTG AA CATGT
CAACAACTCATATGAGTGTGACATACCCATTG GTG CAG GTATATG CG CTAGTTATCAG ACT CAG A
CTAATTCTCCTCG GCGGG CACGTAG
TGTAGCTAGTCAATCCATCATTG CCTA CA CTATGTCA CTTG GTG CAGAAAATTCAGTTG
CTTACTCTAATAACTCTATTG CCATACCCA CAA
ATTTTACTATTAGTGTTACCACAGAAATTCTAC CAGTGTCTATG ACCAAG A CATCAGTAG ATTGTA CAATG
TACATTTGTG GTGATTCAAC
TGAATG CAG CAATCTTTTGTTG CAATATGG CAG __ 11111 GTACACAATTAAACCGTG CTTTAACTG
GAATAGCTGTTGAACAAGACAAAAA
CA C CCAA G AA G TTTTTG CACAA GT CAAA CAAATTTACAAAA CA C CAC CAATTAAAG ATTTTG
G TG G TTTTAATTTTTC A CAAATATTA C CA
GATCCATCAAAACCAAG CAAGAG GTCATTTATTGAAGATCTACTTTTCAACAAAGTG ACACTTG CAGATG CTG
G CTTCAT CA AA CAATAT
G GTGATTGCCTTG GTGATATTGCTGCTAGAGACCTCATTTGTG CA CAAAAGTTTAACGG CCTTACTGTTTTG
CCACCTTTG CTCACAGATG
AAATGATTG CTCAATACACTTCTGCACTGTTAG CGG GTACAATCACTTCTGGTTG GACCTTTG GTGCAG
GTGCTGCATTACAAATACCATT
TG CTATG CAAATG GCTTATAGGTTTAATG GTATTG G AGTTACA CA GAATGTT CTCTAT GA G AA
CCAAAAATT G ATTG CCAACCAATTTAA
TA GTG CTATTG G CAAAATTCAAG A CTCA CTTTCTT CCA CA G CAA GTG CA CTT G G AAAA
CTTCAA GATGTG GT CAA CCAAAAT G CACAAGC
TTTAAACACG CTTGTTAAACAACTTAG CTCCAATTTTG GTG CAATTTCAA GTGTTTTAAATG ATATCCTTT
CACGTCTTGA CAAAGTTG A G
G CTGAAGTGCAAATTGATAG GTTG AT CACA G G CA G A CTTCAAA GTTTG CA GA CATATGTG
ACTCAA CAATTAATTAG AG CTG CA G AAAT
CA GA G CTTCTG CTAATCTTG CTG CTA CTAAAATGTCA GA GTGTGTA CTTG GA CAATCAAAAA G A
GTTG ATTTTT GTG G AAA G GG CTATCA
TCTTATGTCCTTCCCTCAGTCAG CACCTCATG GTGTAGTCTTCTTG
CATGTGACTTATGTCCCTGCACAAGAAAAGAACTTCACAACTG CTC
CTG CCATTTGTCATGATG G AAAA G CA CA CTTTCCTCGTG AAG GTGTCTTTGTTTCAAATG G CACA
CA CTG GTTT GTAA CACAAA G GAATT
TTTATG AACCACAAATCATTACTACAG ACAACACATTTGTGTCTG G TAACTGTGATGTTGTAATAG G
AATTGTCAACAA CACAGTTTATG A
TCCTTTGCAACCTGAATTAGACTCATTCAAG GAG
GAGTTAGATAAATATTTTAAGAATCATACATCACCAGATGTTGATTTAG GTGACATC
TCTG G CATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCG CCTCAAT GAG GTTG
CCAAGAATTTAAATGAATCTCTCATCGATC
TCCAAG AA CTTG GAAAGTATG A G CA GTATATAAAATG G CCATG GTACATTTGG CTAG GTTTTATAG
CTGG CTTGATTG CCATAGTAATG
GTGACAATTATG CTTTG CTGTATG A CCAG TTG CTGTAGTTGTCTCAAGG G CTGTTGTTCTT GT G G
ATCCTG CTG CAAATTT GATG AAG AC
GACTCTGAG CCAGTG CTCAAAGG AGT CAAATTA CATTA CA CATAAACG AACTTATGG ATTTGTTTATG
AG AAT CTTCA CAATTG GAACTG
TAACTTTGAAG CAAG GTGAAATCAAG GATGCTACTCCTTCAGATTTTGTTCGCGCTACTG CAA CG ATACCG
ATA CAAG CCTCACTCCCTTT
CG GATG GCTTATTGTTG G CGTTGCA CTTCTTG CT GTTTTTCAG AGC G
CTTCCAAAATCATAACCCTCAAAAAGAGATG G CAA CTAG CACT
CTCCAAGG GTGTTCACTTTGTTTG CAA CTTG CTGTTGTTGTTT GTAA CA GTTTA CTCA CACCTTTTG
CTCGTTGCTG CTG G CCTTGAAG CCC
CA 03168783 2022- 8- 19
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CTTTTCTCTATCTTTATGCTTTAGTCTACTTCTTGCAGAGTATAAACTTTGTAAGAATAATAATGAGGCTTTGGCTTTG
CTGGAAATG CCGT
TCCAAAAACCCATTACTTTATGATGCCAACTATTTTCTTTG CTG G
CATACTAATTGTTACGACTATTGTATACCTTACAATAGTGTAACTTCT
TCAATTGTCATTACTTCAG GTGATGG CACAACAAGTCCTATTTCTGAACATGACTACCAGATTG
GTGGTTATACTGAAAAATGGGAATCT
G GAGTAAAAGACTGTGTTGTATTACACAGTTACTTCACTTCAGACTATTACCAG
CTGTACTCAACTCAATTGAGTACAG ACACTGGTGTT
G AACATGTTACCTTCTTCATCTACAATAAAATT GTTG ATG AG CCTG AAG
AACATGTCCAAATTCACACAATCGACGTTICATCCG G AGTTG
TTAATCCAGTAATG GAACCAATTTATGATGAACCGACGACGACTACTAGCGTG CCTTTGTAAG
CACAAGCTGATGAGTACGAACTTATGT
ACTCATTCGTTTCG GAAGAGACAG GTACGTTAATAGTTAATAGCGTACTTCTTTTTCTTG CTTTCGTG
GTATTCTTG CTAGTTACACTAG CC
ATCCTTACTG CG CTTCGATTGTGTGCGTACTG CTG CAATATTGTTAACGTG
AGTCTTGTAAAACCTTCTTTTTACGTTTACTCTCGTGTTAA
AAATCTGAATTCTTCTAGAGTTCCTGATCTTCTG GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTG
GAACTTTAATTTTAGCCAT
G G CAGATTCCAACG GTACTATTACCGTTGAAGAG
CTTAAAAAGCTCCTTGAACAATGGAACCTAGTAATAGGTTTCCTATTCCTTACATG
GATTTGTCTTCTACAATTTGCCTATG CCAACAG GAATAG GTTTTTGTATATAATTAAGTTAATTTTCCTCTG
GCTGTTATGG CCAGTAACTT
TAG CTTGTTTTGTGCTTGCTGCTGTTTACAGAATAAATTG GATCACCG GTGGAATTG CTATCG CAATGG
CTTGTCTTGTAGG CTTGATGTG
G CTCAG CTACTTCATTGCTTCTTTCAGACTGTTTG CG CGTACG CGTTCCATGTG
GTCATTCAATCCAGAAACTAACATTCTTCTCAACGTG C
CACTCCATG G CACTATTCTG ACCAG ACCG CTTCTAGAAAGTG AACTCGTAATCG GAG CTGTG
ATCCTTCGTG GACATCTTCGTATTG CTG
GACACCATCTAGGACG CTGTGACATCAAG GACCTGCCTAAAGAAATCACTGTTG CTACATCACGAACG
CTTTCTTATTACAAATTG G GAG
CTTCG CAGCGTGTAG CAG GTGACTCAG GTTTTG CTG CATACAGTCG CTACAG GATTG
GCAACTATAAATTAAACACAG ACCATTCCAGTA
G CAGTGACAATATTGCTTTG
CTTGTACAGTAAGTGACAACAGATGTTTCATCTCGTTGACTTTCAGGTTACTATAGCAG AGATATTACTAA
TTATTATG AG GACTTTTAAAGTTTCCATTTG GAATCTTG
ATTACATCATAAACCTCATAATTAAAAATTTATCTAAGTCACTAACTG AGAAT
AAATATTCTCAATTAG ATG AAG AG CAACCAATG G AG ATTG ATTAAACG AACATG
AAAATTATTCTTTTCTTG G CACTG ATAACACTCG CT
ACTTGTG AG CTTTATCACTACCAAG AGTGTGTTAG AG GTACAACAGTACTTTTAAAAG AACCTTG
CTCTTCTG GAACATACG AG G G CAAT
TCACCATTTCATCCTCTAG CTGATAACAAATTTG CACTGACTTG CTTTAG CACTCAATTTG
CTTTTGCTTGTCCTGACG G CGTAAAACACGT
CTATCAGTTACGTGCCAGATCAGTTTCACCTAAACTGTTCATCAGACAAGAGGAAGTTCAAGAACTTTACTCTCCAA
_______ I I I TTCTTATTGTTG
CG
GCAATAGTGTTTATAACACTTTGCTTCACACTCAAAAGAAAGACAGAATGATTGAACTTTCATTAATTGACTTCTATTT
GTG CTTTTTA
G CCTTTCTG CTATTCCTTGTTTTAATTATG CTTATTATCTTTTGGTTCTCACTTGAACTG
CAAGATCATAATGAAACTTGTCACGCCTAAACG
AACATG AAATTTCTTGTTTTCTTAG GAATCATCACAACTGTAGCTGCATTTCACCAAG
AATGTAGTTTACAGTCATGTACTCAACATCAAC
CATATGTAGTTGATGACCCGTGTCCTATTCACTTCTATTCTAAATGGTATATTAGAGTAGGAGCTAGAAAATCAGCACC
TTTAATTGAATT
GTGCGTGGATGAGGCTGGTTCTAAATCACCCATTCAGTACATCGATATCGGTAATTATACAGTTTCCTGTTTACCTTTT
ACAATTAATTGC
CAGGAACCTAAATTG GGTAGTCTTGTAGTG
CGTTGTTCGTTCTATGAAGACTTTTTAGAGTATCATGACGTTCGTGTTGTTTTAGATTTCA
TCTAAACGAACAAACTAAAATGTCTGATAATG GACCCCAAAATCAG CGAAATG CACCCCG CATTACGTTTG
GTG G ACC CTCAGATTCAAC
TG GCAGTAACCAGAATGGAGAACG CAGTG G GG CG CGATCAAAACAACGTCG G CCCCAAG
GTTTACCCAATAATACTG CGTCTTG GTTC
ACCGCTCTCACTCAACATG G CAAG GAAG AC CTTAAATTCCCTCG AG GACAAG G
CGTTCCAATTAACACCAATAG CAGTCCAGATGACCA
AATTGG CTACTACCG AAG AG CTACCAGACGAATTCGTGGTG GTGACG
GTAAAATGAAAGATCTCAGTCCAAGATG GTATTTCTACTACC
TAG G AACTG G G CCAGAAGCTG GACTTCCCTATG GTGCTAACAAAGACG G CATCATATG G GTTG
CAACTG AG G GAG CCTTGAATACACC
AAAAGATCACATTG G CACCCG CAATCCTGCTAACAATGCTGCAATCGTG CTACAACTTCCTCAAG
GAACAACATTG CCAAAAG GCTTCTA
CGCAG AAG G GAG CAG AGG CG GCAGTCAAG CCTCTTCTCGTTCCTCATCACGTAGTCG CAACAGTTCAAG
AAATTCAACTCCAGG CAGCA
GTAG G G GAACTTCTCCTG CTAG AATG G CTG GCAATG GCG GTGATG CTG CTCTT GCTTTG
CTGCTGCTTGACAGATTGAACCAG CTTG AG
AGCAAAATGTCTGGTAAAG G CCAACAACAACAAG G CCAAACTGTCA CTAAG AAATCTGCTGCTG AG
GCTTCTAAG AAGCCTCG G CAAA
AACGTACTGCCACTAAAGCATACAATGTAACACAAGCTTTCG
GCAGACGTGGTCCAGAACAAACCCAAGGAAATTTTGGGGACCAGG A
ACTAATCAGACAAGGAACTGATTACAAACATTGGCCGCAAATTGCACAATTTGCCCCCAGCGCTTCAGCGTTCTTCGGA
ATGTCGCGCAT
TG GCATG GAAGTCACACCTTCG GGAACGTG GTTGACCTACACAG GTG
CCATCAAATTGGATGACAAAGATCCAAATTTCAAAGATCAAG
TCATTTTGCTGAATAAG CATATTGACG CATACAAAACATTCCCACCAACAGAG CCTAAAAAG
GACAAAAAGAAGAAG G CTGATGAAACT
CAAG CCTTACCG CAG AG ACAG AAG AAACAGCAAACTGTGACTCTTCTTCCTG CTG CAGATTTGG
ATGATTTCTCCAAACAATTG CAACAA
TCCATG AG CAGTGCTGACTCAA CTCAG GCCTAAACTCATGCAGACCACACAAGGCAGATGG
GCTATATAAACGTTTTCGCTTTTCCGTTT
ACGATATATAGTCTACTCTTGTG CAGAATG AATTCTCGTAACTACATAG CACAAGTAG ATGTAGTTAAC
___________ I I I AATCTCACATAGCAATCTT
TAATCAGTGTGTAACATTAGGGAGGACTTGAAAGAGCCACCACATTTICACCGAGGCCACGCGGAGTACGATCGAGTGT
ACAGTGAAC
AATGCTAG G GAG AG CTG CCTATATG GAA G AG
CCCTAATGTGTAAAATTAATTTTAGTAGTGCTATCCCCATGTG ATTTTAATAG CTTCTT
AGGAGAATGACAAAA
SEQ ID NO: 13
>Severe acute respiratory syndrome coronavirus 2 orf1ab polyprotein of isolate
hCoV-19/France/IDF0372-
is1/2020
M ESLVPGF N EKTHVQLSLPVLQVRDVLVRG FG DSVEEVLSEARQHLKDGTCG LVEVEKG VLPQLEQPYVF
I KRSDARTAPHGHVMVELVAELE
G IQYG RSGETLGVLVP HVG El
PVAYRKVLLRKNGNKGAGGHSYGADLKSFDLGDELGTDPYEDFQENWNTKHSSGVTRELMRELNGGAYTRY
VDNN FCGPDGYPLECI KDLLARAGKASCTLSEQLDFIDTKRGVYCCREHEHEIAWYTERSEKSYELQTP FEI
KLAKKF DTFNG ECP N FVFPLNSI I K
TIQPRVEKKKLDG FMG RI RSVYPVASPNECNQMCLSTLMKCDHCGETSWQTG DFVKATCEFCGTEN
LTKEGATTCGYLPQNAVVKIYCPACH
NSEVGPEHSLAEYHNESGLKTILRKGGRTIAFGGCVFSYVGCHNKCAYWVPRASAN IGCNHTGVVGEGSEGLN DN
LLEILQKEKVN I N I VG DFK
LN EEIAI I LASFSASTSAFVETVKG LDYKAFKQI VESCG N FKVTKGKAKKGAWN
IGEQKSILSPLYAFASEAARVVRSIFSRTLETAQNSVRVLQKA
AITI LDG ISQYSLRLI DAM M FTSDLATNN LVVMAYITGGVVQLTSQWLTN I FGTVYEKLKPVLDWLEEKF
KEGVEFLRDGWEI VKFISTCACEI V
GG QIVTCAKEI KESVQTFFKLVN KFLALCADSI I I GGAKLKALN LG ETFVTHSKG LYRKCVKSR
EETGLLMPLKAPKEI I FLEG ETLPTEVLTEEVVLK
TGDLQPLEQPTSEAVEAPLVGTPVCI NG LM LLEI
KDTEKYCALAPNMMVINNTFTLIKGGAPTIWTFGDDTVIEVQGYKSVNITFELDERI DKVL
N EKCSAYTVELGTEVN EFACVVADAVI KTLQPVSELLTP LG I DLDEWSMATYYLFDESG EFK LASH
MYCSFYPP DEDEEEGDCEEEEFEPSTQYE
96
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PCT/IB2021/052858
YGTEDDYQGKPLEFGATSAALQPEEEQEEDWLDDDSQQTVGQQDGSEDNQTTTIQTIVEVQPQLEMELTPVVQTIEVNS
FSGYLKLTDNVY1
KNADIVEEAKKVKPTVVVNAANVYLKHGGGVAGALNKATNNAMQVESDDYIATNGPLKVGGSCVLSGHNLAKHCLHVVG
PNVNKGEDIQL
LKSAYENFNQHEVLLAPLLSAGIFGADPIHSLRVCVDTVRTNVYLAVFDKNLYDKLVSSFLEMKSEKCIVEQKIAEIPK
EEVKPFITESKPSVEQRKQ
DDKKI KACVEEVTTTLEETKFLTEN LLLYI DING N LH PDSATLVSDIDITFLKKDAPYI VG
DVVQEGVLTAVVI PTKKAG GTTEM LAKALRKVPTDN
YITTYPGQGLNGYTVEEAKTVLKKCKSAFYILPSIISN EKQE 1 LGTVSWN LREM LAHAEETRKLM
PVCVETKAIVSTI QRKYKG I KIQEGVVDYGAR
FYFYTSKTTVASLINTLNDLNETLVTMPLGYVTHGLNLEFAARYMRSTKVPATVSVSSPDAVTAYNGYLTSSSKTPFEH
FIETISLAGSYKDWSYS
GQSTQLG I EF LKRG DKSVYYTSN PTTFH LDG EVITFDN LKTLLSLREVRTIKVFTTVDNIN
LHTQVVDMSMTYGQQFG PTYLDGADVTK I KPH N S
HEGKTFYVLPN DDTLRVEAFEYYHTTDPSFLG RYMSALN HTKKWKYPQVN G LTSI
KWADNNCYLATALLTLQQI ELKFN PPALQDAYYRARAG
EAANFCALI LAYCN
KTVGELGDVRETMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQFKKGVQ1PCTCGKQATKYL
VQQESPFVM M SAP PAQYELKHGTFTCASEYTG N YQCG HYKHITSKETLYCI
DGALLTKSSEYKGPITDVFYKENSYTTTI KPVTYKLDG VVCTE I D
PKLDNYYKKDNSYFTEQPIDLVPNQPYPNASFDNFKFVCDNIKFADDLNQLTGYKKPASRELKVTFFPDLNGDVVAIDY
KHYTPSFKKGAKLLHK
PI VWHVN NATN KATYKPNTWCIRCLWSTKPVETSNSFDVLKSEDAQGM DN LACE DLK PVSEEVVEN
PTIQKDVLECNVKTTEVVG DI I LKPAN
NSLKITEEVG HTDLMAAYVDNSSLTIKKPN ELSRVLG LKTLATHG
LAAVNSVPWDTIANYAKPFLNKVVSTTTNIVTRCLNRVCTNYM PYF FTLL
LQLCTFTRSTNSR I KAS M PTTIAKNTVKSVGKFCLEASFN YLKSPNFSKLI N I I
IWFLLLSVCLGSLIYSTAALGVLM SNLGM PSYCTGYREGYLNST
NVTIATYCTGSIPCSVCLSGLDSLDTYPSLETIQITISSFKWDLTAFGLVAEWFLAYILFTRFFYVLGLAAIMQLFFSY
FAVHFISNSWLMWLIINLV
QMAPISAMVRMYIFFASFYYVWKSYVHVVDGCNSSTCMMCYKRNRATRVECTTIVNGVRRSFYVYANGGKGFCKLHNWN
CVNCDTFCAG
STFISDEVAR DLSLQFKR PI N PTDOSSYIVDSVTVKN GS! H LYFDKAGQKTYERHS LSH FVN LDN
LRAN NTKGSLP I NVIVF DG KSKCEESSAKSAS
VYYSQLMCQPILLLDQALVSDVGDSAEVAVKMFDAYVNTFSSTFNVPMEKLKTLVATAEAELAKNVSLDNVLSTFISAA
RQGFVDSDVETKDV
VECLKLSHQSDIEVTGDSCNNYMLTYNKVENMTPRDLGACIDCSARHINAQVAKSHNIALIWNVKDFMSLSEQLRKQIR
SAAKKNNLPFKLTC
ATTRQVVNVVTTKIALKGGKIVNNWLKQLIKVTLVFLFVAAIFYLITPVHVMSKHTDFSSEIIGYKAIDGGVTRDIAST
DTCFANKHADFDTWFS
QRGGSYTN DKACP LI AAVITREVG FVVPGLPGTI LRTTN G DF LH FLPRVFSAVG N 1 CYTPSKLI
EYT DFATSACVLAAECT I FKDASG KPVPYCYDT
NVLEGSVAYESLRPDTRYVLMDGSIIQFPNTYLEGSVRVVTTFDSEYCRHGTCERSEAGVCVSTSGRWVLNNDYYRSLP
GVFCGVDAVNLLTN
M FTPLI QP I GALDISASI VAG G IVAIVVTCLAYYFM RFRRAFG
EYSHVVAFNTLLFLMSFTVLCLTPVYSFLPGVYSVIYLYLTFYLTN DVSFLAH I Q
WMVMFTPLVPFWITIAYIICISTKHFYWFFSNYLKRRVVFNGVSFSTFEEAALCTFLLNKEMYLKLRSDVLLPLTQYNR
YLALYNKYKYFSGAMD
TTSYREAACCHLAKALN DFSNSGSDVLYQPPQTSITSAVLQSG FRKMAFPSG KVEGCMVQVTCGTTTLNG
LWLDDVVYCPRHVICTSEDM LN
PNYEDLLIRKSN H NFLVQAG NVQLRVI GHSM QN CVLKLKVDTAN PKTPKYKFVRI
QPGQTFSVLACYNGSPSGVYQCAM R P N FT! KGSFLN GS
CGSVG FN I DYDCVSFCYM H H M ELPTGVHAGTDLEG NFYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVI
NG DRWFLNRFTTTLN DFN LVA
MKYNYEPLTQDHVDILG PLSAQTG IAVLDM CASLKELLQN G M NG
RTILGSALLEDEFTPFDVVRQCSGVTFQSAVKRTI KGTHHWLLLTILTSL
LVLVQSTQWSLFFFLYENAFLPFAMGIIAMSAFAM M FVKHKHAFLCLFLLPSLATVAYFN MVYM PASWVM RI
MTWLDMVDTSLSG FKLKD
CVMYASAVVLLILMTARTVYDDGARRVWTLM NVLTLVYKVYYGNALDQAISMWALIISVTSNYSGVVTTVM FLARG
IVFM CVEYCP I FFITG N
TLQCI M LVYCFLGYFCTCYFGLFCLLNRYFRLTLGVYDYLVSTQEFRYM NSQG LLPP KNS I DAFKLN I
KLLG VGG KP CI KVATVQSKMSDVKCTSV
VLLSVLQQLRVESSSKLWAQCVQLH N DI LLAKDTTEAFEKMVSLLSVLLSMQGAVDI
NKLCEEMLDNRATLQAIASEFSSLPSYAAFATAQEAY
EQAVANG DSEVVLKKLKKSLNVAKSEFDRDAAMQRKLEKMADQAMTQMYKQARSEDKRAKVTSAMQTM LFTM
LRKLDN DALN NI I N NA
RDGCVPLN I I PLTTAAKLMVVI PDYNTYKNTCDGTTFTYASALWEI QQVVDADSKIVQLSEISM DNSPN
LAWPLIVTALRANSAVKLQN N ELSP
VALRQMSCAAGTTQTACTDDNALAYYNTTKGGRFVLALLSDLQDLKWARFPKSDGTGTIYTELEPPCRFVTDTPKGPKV
KYLYFI KG LN NLNR
GMVLGSLAATVRLQAGNATEVPANSTVLSFCAFAVDAAKAYKDYLASGGQPITNCVKMLCTHTGTGQAITVTPEANMDQ
ESFGGASCCLYC
RCH I DH PN P KG FCD LKG KYVQI PTTCAN DPVG FTLKNTVCTVCG MWKGYGCSCDQLREPM
LQSADAQSFLN GFAV
SEQ ID NO: 14
>Protein \S_Human \2019-nCoV (Sprotein_hCoV19Francel DF0372is12020)
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRF
DNPVLPFNDGVYFAS
TEKSNIIRGWIFGTTLDSKTQSLLIVN NATNVVIKVCEFQFCNDPFLGVYYHKN NKSWM ESEFRVYSSAN
NCTFEYVSQPFLM DLEG KQG NFK
N LRE FVFKN I DGYF KlYSKHTPI N LVRDLPQG FSALEPLVDLPI GI NITRFQTLLALHRSYLTPG
DSSSGWTAGAAAYYVGYLQPRTFLLKYN EN GT
ITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFP N ITN LCPFG
EVFNATRFASVYAWNRKRISNCVADYSFLYNSASFSTFKCYG
VSPTKLNDLCFTNVYADSFVIRG DEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNN
LDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAG
STPCNGVFG FNCYFPLQSYGFQPTN GVGYQPYRVVVLSFELLHAPATVCG PKKSTN LVKNKCVNFNFNG
LTGTGVLTESN KKFLPFQQFG RDI
ADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAG
CLIGAEHVNNSYEC
DI P I GAG I CASYQTQTNSP RRARSVASQS I IAYTM SLGAEN SVAYSN NSIAI PTN FTISVTTE I
LPVSMTKTSVDCTMYI CG DSTECSN LLLQYGSF
CTQLN RALTG 1 AVEQDKNTQEVFAQVKQIYKTPP 1 KDFG G FN FSQI
LPDPSKPSKRSFIEDLLFNKVTLADAG Fl KQYG DCLG DIAARDLICAQKF
NG LTVLPPLLTDEM
IAGYTSALLAGTITSGVVTFGAGAALGIPFAMQMAYRFNGIGVTGNVLYENQKLIANGFNSAIGKIQDSLSSTASALGK
LQ
DVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQI DRLITG RLQSLQTYVTQQLI RAAEI
RASANLAATKMSECVLGQSKRVDFC
GKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFV
SGNCDVVIGIVNN
TVYDPLOPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPW
Y1WLGFIAGLIAIVMVT
I M LCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO: 15
>hCoV-19/Austria/CeMM0360/2020 I EPUSL_43812312020-04-05
NNNNNNNNNNNNNNNNNNNNNNNNNNNNNNACCAACCAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACGAACTTTA
AAATCTG
TGTGGCTGTCACTCGGCTGCATGCTTAGTGCACTCACGCAGTATAATTAATAACTAATTACTGTCGTTGACAGGACACG
AGTAACTCGTC
TATCTTCTGCAGGCTGCTTACGGTTTCGTCCGTGTTGCAGCCGATCATCAGCACATCTAGGTTTTGTCCGGGTGTGACC
GAAAGGTAAGA
TGGAGAGCCTTGTCCCTGGTTTCAACGAGAAAACACACGTCCAACTCAGTTTGCCTGTTTTACAGGTTCGCGACGTGCT
CGTACGTGGCT
97
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TTGGAGACTCCGTGGAGGAGGTCTTATCAGAGGCACGTCAACATCTTAAAGATGGCACTTGTGGCTTAGTAGAAGTTGA
AAAAGGCGT
TTTGCCTCAACTTGAACAG CCCTATG TGTTCATCAAACGTTCG G AT G CT CG AA CTG CACCT CAT G
GTCATGTTATG GTTG AG CTG GTAG C
AGAACTCGAAG GCATTCAGTACG GTCGTAGTG GTGAGACACTTGGTGTCCTTGTCCCTCATGTG G
GCGAAATACCAGTG GCTTACCG CA
AGGTTCTTCTTCGTAAGAACGGTAATAAAG GAG CTG GTGG CCATAGTTACG G
CGCCGATCTAAAGTCATTTGACTTAG G CG ACG AG CTT
G G CACTG ATCCTTATGAAGAIIII CAAGAAAACTG GAACACTAAACATAG CAGTGGTGTTACCCGTG
AACTCATGCGTG AG CTTAACG G
AGG G GCATA CA CTCGCTAT GTCG ATAACAA CTTCTGTG G CCCTGATGG
CTACCCTCTTGAGTGCATTAAAGACCTTCTAG CACGTG CTG G
TAAAG CTTCATG CA CTTTGTCCG AA CAA CTG GACTTTATTG A CACTAA G AG G G GTGTATACTG
CTG CCGTG AA CATG AG CATGAAATTG C
TTG GTACACG G AACGTTCTG AAAAG AG CTATGAATTGCAGACACCTTTTGAAATTAAATTG
GCAAAGAAATTTGACACCTTCAATG GG G
AATGTCCAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAG G GTTGAAA A GAAAAA G
CTTGATGG CTTTATGG GTA
GAATTCGATCTGTCTATCCAGTTG CGTCACCAAATGAATG CAA CCAAATGTG CCTTTCAA CTCT CATG AA
GT GTG ATCATT GTG GTGAAA
CTTCATG G CAGACGG G CGATTTTGTTAAAG CCACTTGCGAATTTTGTG GCA CTG AG
AATTTGACTAAAGAAGG TG CCACTACTTGTGG TT
A CTTA CCCCAAAATG CT GTTGTTAAAATTTATT GTCCA G CATGTCA CAATT CAG AA GTA G G
ACCT GA G CATAGTCTTGCCGAATACCATAA
TGAATCTGG CTTGAAAACCATTCTTCGTAAG GGTG GTCG CA CTATT G CCTTTG GAG
GCTGTGTGTTCTCTTATGTTG GTTG CCATAA CAA
GTGTGCCTATTGG GTTCCACGTG CTAG CG CTAA CATA G GTTGTAA CC ATACA G GT GTTGTTG GA
GAA G GTTCC G AA G GT CTTAATGA CA
ACCTTCTTG AAATACT CCAAAAAG AGAAAGTCAACAT CAATATTGTTG GTG ACTTTAAACTTAATG AAGAG
ATCG CCATTATTTTGG CATC
TTTTTCTG CTTCCACAAGTG CTTTTGTGGAAACTGTGAAAG GTTTG GATTATAAAG
CATTCAAACAAATTGTTGAATCCTGTG GTAATTTT
AAA GTTA CAAAA G G A AAA G CTAAAAAAG GTG CCTGGAATATTG GT GAA CAG A AATCA ATA
CTG AGTC CTCTTTATG CATTTG CATCAG A
G G CTG CTCGTGTTGTACG AT CAATTTTCTCCCG CA CTCTTG AAA CTG
CTCAAAATTCTGTGCGTGTTTTACAGAAG G CCG CTATAACAATA
CTAGATG G AATTTC A CAGTATT CACT GA G ACT CATTG AT G CTATG ATGTTCA CATCTG ATTTG
G CTACTAACAATCTAGTTGTAATGG CCT
A CATTACA G GT G GTGTTGTT CAGTTG A CTTCG CAGTG G CTAACTAACATCTTTG G CA CT
GTTTATGAAA AACT CAAA CC CGT CCTTG ATTG
G CTTG AA G A GAA GTTTAA G G AAG GTGTA GA GTTTCTTA GA G ACG GTTG G
GAAATTGTTAAATTTATCTCAACCTGTGCTTGTGAAA
TTGTCGGTGGACAAATTGTCACCTGTGCAAAGGAAATTAAGGAGAGTGTTCAGACATTCTTTAAGCTTGTAAATAAAT
_____ I I I I GGCTTTGT
GTGCTGACTCTATCATTATTGGTGGAGCTAAACTTAAAGCCTTGAATTTAGGTGAAACATTTGTCACGCACTCAAAGGG
ATTGTACAGAA
AGTGTGTTAAATCCAGAGAAGAAACTGGCCTACTCATGCCTCTAAAAGCCCCAAAAGAAATTATCTTCTTAGAGGGAGA
AACACTTCCCA
CAGAA GT GTTAA CAGAG GAAGTTGTCTTGAAAACTG GT GATTTACAACCATTAG AACAACCTA CTA
GTGAAGCT GTTGAAG CTCCATTG
GTTG GTACACCAGTTTGTATTAACGG G CTTATGTTG CTCGAAATCAAAGACACAGAAAAGTACTGTG CCCTTG
CA CCTAATATGATG GTA
A CAAA CAATACCTTCA CA CTCAAAG GCG GTG CACCAACAAAGGTTACTTTTG
GTGATGACACTGTGATAGAAGTGCAAG GTTACAAGAG
TGTG AATATCA CTTTTGAA CTTG ATG AAAGG ATTG ATAAA GTA CTTAATG AG AA GTG CTCTG
CCTATA CAGTTG AA CTCGGTA CAGAA GT
AAATG A GTTCG CCTGT GTT GT G G CA GATG CTGTCATAAAAACTTTG
CAACCAGTATCTGAATTACTTACACCACTG G G CATTG ATTTA GA
TGAGTGGAGTATGGCTACATACTACTTATTTGATGAGTCTGGTGAGTTTAAATTGGCTTCACATATGTATTGTTCTTTT
TACCCTCCAGAT
GAGGATGAAGAAGAAGGTGATTGTGAAGAAGAAGAGTTTGAGCCATCAACTCAATATGAGTATGGTACTGAAGATGATT
ACCAAGGTA
AACCTTTGGAATTTGGTGCCACTTCTGCTGCTCTTCAACCTGAAGAAGAGCAAGAAGAAGATTGGTTAGATGATGATAG
TCAACAAACT
GTTGGTCAACAAGACGGCAGTGAGGACAATCAGACAACTACTATTCAAACAATTGTTGAGGTTCAACCTCAATTAGAGA
TGGAACTTAC
ACCAGTTGTTCAGACTATTGAAGTGAATAGTTTTAGTGGTTATTTAAAACTTACTGACAATGTATACATTAAAAATGCA
GACATTGTGGA
AGAAGCTAAAAAG GTAAAACCAACAGTGGTTGTTAATG CAG CCAATGTTTACCTTAAACATG GAG G AG
GTGTTG CAG G AG CCTTAAATA
A G G CTACTAACAATG CCATG CA A GTTG AATCT GATG ATTA CATA G CTA CTAATG GA CCA
CTTAAAGTG G GTG G TA GTT GTGTTTTAAG CG
GACACAATCTTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAG
GTGAAGACATTCAACTTCTTAAGAGTG CTTATG AAA
ATTTTAATCA G CA CG AAGTTCTACTT G CA CCATTATTATCA G CTG GTATTTTTG GTG CTGA
CCCTATA CATTCTTTAA G A GTTTGTGTAG AT
ACTGTTCG CACAAATGTCTACTTAG CTGTCTTTGATAAAAATCTCTATGACAAACTTGTTTCAAG CTTTTTG
GAAATGAAGAGTGAAAAG C
AAGTTGAACAAAAGATCGCTGAGATTCCTAAAGAGGAAGTTAAGCCATTTATAACTGAAAGTAAACCTTCAGTTGAACA
GAGAAAACAA
GATGATAAGAAAATCAAAGCTTGTGTTGAAGAAGTTACAACAACTCTGGAAGAAACTAAGTTCCTCACAGAAAACTTGT
TACTTTATATT
GACATTAATG G CAATCTT CAT CCAG ATTCT GCCA CT CTT GTTA GTG A CATTG A
CATCACTTTCTTAAA GAAAG ATG CTCCATATATAGTG G
GTGATGTTGTTCAAGAGG GTGTTTTAACTG CTGTG GTTATACCTACTAAAAAG GCTGGTG G
CACTACTGAAATGCTAG CGAAAGCTTTG
AGAAAAGTG CCAACAGACAATTATATAACCACTTACCCGG GTCAGG GTTTAAATGGTTACACTGTAGAG GAG
GCAAAGACAGTGCTTAA
AAAGTGTAAAAGTGCCTTTTA CATTCTACCATCTATTATCT CTAATG AG AAG CAAGAAATTCTTG G AA
CTGTTTCTTG GAATTTG CGAGAA
ATGCTTG CACATG C A GAA GAAA CACG CAAATTAATG CCTGTCTGTGTG GAAACTAAAG CCATAGTTT
CAA CTATA CA G CGTAA ATATAA
G G GTATTAAAATA CAA GA G GGTGTG GTTGATTATG GT GCTAG ATTTTACTTTTA CA CCAGTAAAA
CAA CT GTAG CGTCA CTTATCAA CAC
A CTTAACGATCTAAATG AAA CTCTTGTTA CAATGCCACTTG G CTATGTAACACATG
GCTTAAATTTGGAAGAAGCTG CTCG GTATATGAG
ATCTCTCAAAGTG CCAGCTACAGTTTCTGTTTCTTCACCTGATG CTGTTACAG
CGTATAATGGTTATCTTACTTCTTCTTCTAAAACACCTG
AAGAACATTTTATTGAAACCATCTCACTTGCTGGTTCCTATAAAGATTGGTCCTATTCTGGACAATCTACACAACTAGG
TATAGAATTTCT
TAAGAGAGGTGATAAAAGTGTATATTACACTAGTAATCCTACCACATTCCACCTAGATGGTGAAGTTATCACCTTTGAC
AATCTTAAGAC
ACTTCTTTCTTTGAGAGAAGTGAGGACTATTAAGGTGTTTACAACAGTAGACAACATTAACCTCCACACGCAAGTTGTG
GACATGTCAAT
GACATATGGACAACAGTTTGGTCCAACTTATTIGGATGGAGCTGATGTTACTAAAATAAAACCTCATAATTCACATGAA
GGTAAAACATT
TTATGTTTTACCTAATGATGACACTCTACGTGTTGAGGCTTTTGAGTACTACCACACAACTGATCCTAGTTTTCTGGGT
AGGTACATGTCA
G CATTAAATCACACTAAAAAGTG GAAATA CCCA CAA GTTAATG GTTTAACTTCTATTAAATG GG CA
GATAA CAA CTGTTATCTTG CCA CT
G CATT GTTAACA CTCCAACAAATA GA GTTG AA GTTTAATCCA CCTG CTCTACAAGATG CTTATTA
CAG A G CAA G G G CTG GTGAAGCTG CT
AACTTTTGTG CACTTATCTTAG CCTACT GTAATAA GA CA GTAG GTGAGTTAG GT GATGTTA G AG
AAACAATG AGTTA CTT GTTTCAACAT
G CCAATTTAG ATTCTT G CAAAA G AGTCTTG AA CGTG GTGTGTAAAACTTGTG G A CAA CA G CA
G ACAA CCCTTAA G G GTGTA GAA G CT GT
TATGTA CAT G G G CACA CTTT CTTATG AA CAATTTAA GAAA G GTGTTCA GATACCTTGTA CGTGT
G GTAAA CA AG CTACAAAATATCTAGT
A CAA CA G G A GT CACCTTTTGTTATG ATGT CA G CA CCA CCTG CT CAGTATG AACTTAAG
CATG GTA CATTTACTTGTG CTAGTG A GTACACT
G GTAATTA CCA GT GT G GTCA CTATAAA CATATAACTTCTAAA G AAA CTTT GTATT GCATA G
ACG GTG CTTTA CTTA CAAAGTCCTC A G AAT
A CAAA G GTCCTATTACG G ATGTTTTCTACAAA GAAAA CA GTTA CA CA A CAACCATAAAA CCA
GTTACTTATAAATTG GATG GTGTTGTTT
98
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G TACAG AAATTG ACCCTAAG TTG G ACAATTATTATAAG AAAG ACAATTCTTATTTCA CAG AG
CAACCAATTG ATCTTGTACCAAACCAAC
CATAT CCAAA C G CAA G CTTCGATAATTTTAAGTTTGTATGTGATAATATCAAATTTG
CTGATGATTTAAACCAGTTAACTGGTTATAA G AA
A CCTG CTTCAAG A GA G CTTAAAGTTACATTTTTCCCTGACTTAAATG GT G ATG TG GTGG CTATTG
ATTATAAACA CTA CA CACCCTCTTTT
AAGAAAG GAG CTAAATTGTTACATAAACCTATTGTTTG G CATGTTAA CAATG CAA CTAATAAAG
CCACGTATAAA CCAAATACCTG GT GT
ATA CG TT GTC I I I GG AG CA CAAAACCAGTTG AAA CAT CAAATTCGTTTG AT GTACTG AAG
TCAG AG GACGCG CAGG GAATG G AT AATCT
TG CCTG C G AA G ATCTAAAACCA G TCTCTG AAG AAG TA G TG G AAAATCCTA CCATA CAG
AAA G AC G TT CTTG AG TG TAAT GT GAAAA CTA
CCGAAGTTG TAG G AG ACATTATA CTTAAACCAG CAAATAATAG TTTAAAAATTACAGAAG AG GTTG G
CCA CA CAGATCTAATG GCTG CT
TATG TA G A CAATTCTA G TCTTA CTATTAA G AAA CCTAAT G AATTATCTA G AG TATTAG G
TTTG AAAA CCCTTG CTA CT CATG GTTTAG CTG
CTGTTAATAGTGTCCCTTGG GATACTATAG CTAATTATG CTAAG CCTTTTCTTAA CAAAGTTG TTAGTA
CAA CTA CTAA CATAG TTACA CG
GTGTTTAAACCGTGTTTGTACTAATTATATG CCTTATTTCTTTACTTTATTG CTAC AATTG TG TA
CTTTTACTAG AA GTA CAAATTCTA G AAT
TAAAG CATCTATG CCGACTACTATAG CAAAGAATACTGTTAAGAGTGTCG GTAAATTTT GT CTAGAG G
CTTCATTTAATTATTTG AAGT CA
CCTAATTTTTCTAAACTG ATAAATATTATAATTTG G TTTTTA CTATTAA GT GTTTG
CCTAGGTTCTTTAATCTACTCAACCG CTG CTTTAG GT
GTTTTAATGTCTAATTTAG GCATG CCTTCTTA CTGTACTG GTTACAG AG AAG G CTATTTG AA CTCTA
CTAAT GTCA CTATTG CAACCTA CTG
TA CTG GTTCTATA CCTTGTA GT GTTTG TCTTA G TG GTTTAG ATT CTTTA G ACA CCTAT
CCTTCTTTAG AAACTATA CAA ATTA CCATTTCATC
TTTTAAATGGGATTTAACTGC _________________________________________________ I I I
TG G CTTAG TTG CAG AG TG GTTTTTGG CATATATT CTTTTCA CTAG G TTTTTCTATG TA CTTG G
ATTG G
CTG CAATCATG CAATTGTTTTTCAG CTATTTTG CAGTACATTTTATTAGTAATTCTTGGCTTATGTG
GTTAATAATTAATCTTGTACAAATG
G CCCCGATTTCAG CTATG GTTAG AATG TA CATCTTCTTTG CATCATTTTATTATGTATG G AAAA
GTTAT GTG CATG TTG TAG ACG GTTG TA
ATTCATCAACTTGTAT G ATG TG TTA CAAA C G TAATAG A G CAA CAAG AG TC G AATG TA CAA
CTATTG TTAATG G TG TTA G AA G GT CCTTTT
ATGTCTATGCTAATG GAG GTAAAG GCTTTTG CAAA CTA CA CAATT G G AATTGT GTTAATT GT G
ATA CATTCTG T G CTG GTAG TA CATTTAT
TAGTGATGAAGTTG CG AG AGACTTGTCACTACAGTTTAAAAG ACCAATAAATCCTACTG
ACCAGTCTTCTTACATCGTTG ATAGTGTTAC
A GT G AA GAATG GTTCCATCCATCTTTACTTTGATAAAGCTG G TCAAAA G ACTTATG AAA G A
CATTCTCT CTCTCATTTT GTTAACTTAG A C
AACCTG AG AG CTAATAACACTAAAG GTTCATTG CCTATTAATGTTATAG
_____________________________ I I I I TGATGGTAAATCAAAATGTGAAGAATCATCTG CAAAA
TC A G CGT CTG TTTA CTA CA GTCA G CTTATG TG TCAA CCTATA CTG TTA CTA G AT CAG
GCATTAGTGTCTGATGTTG GTGATAGTG CG G AA
GTTG
CAGTTAAAATGTTTGATGCTTACGTTAATACGTTTTCATCAACTTTTAACGTACCAATGGAAAAACTCAAAACACTAGT
TGCAACTG
CA G AA G CT GAACTTG CAAAG AATGTGTCCTTAG ACAATGTCTTATCTACTTTTATTTC A G CA G
CTCGG CAA G G GTTTGTT G ATTCA G AT GT
AGAAACTAAAGATGTTGTTGAATGTCTTAAATTGTCACATCAATCTGACATAGAAGTTACTGG
CGATAGTTGTAATAACTATATGCTCAC
CTATAACAAAGTTGAAAACATG ACACCCCGTGACCTTG GTG CTTG TATTG ACT GTAG TG CG
CGTCATATTAATG CG CAG GTAGCAAAAA
GTCACAACATTG CTTTGATATG G AA C GTTAAA G ATTTCATG TCATTG TCTG AACAA CTA C G
AAAACAAATA C G TA GTG CTG CTAAAA AG A
ATAA CTTACCTTTTAA GTT G A CATG TG CAA CTA CTA G A CAA GTT GTTAATG TTGTAA
CAACAAAG ATA G CA CTTAA G GGTG GTAAAATTG
TTAATAATTG GTTG AA G CAG TTAATTAAA GTTACA CTT GTG TT C CTTTTTGTTG CTG
CTATTTTCTATTTAATAA CA C CTGTTCATG TCATG T
CTAAACATA CTG A CTTTTCAA G TG AAATCATA G G ATA CAA G G CTATTG AT G G TG G TG
TCA CTC G TG A CATA G CAT CTACA G ATA CTT G TT
TTG CTAA CAAA CAT G CT G ATTTTG ACA CATG GTTTAGCCAG C GT G G TG G TA GTTATA
CTAATG A CAAA G CTTG CCCATTGATTGCTG CA G
TCATAACAA G A G AAG TG G GTTTTGTCGTG CCTG GTTTG CCTGG CA C G ATATTAC G CA CAA
CTAATG GTG A CTTTTTG CATTTCTTACCTAG
A GTTTTTA G TG CA GTT G G TAA CAT CTG TTA CA CA CCATCAAAA CTTATA G AGTA CA CTG
ACTTTG C AA CAT CAG CTTGTGTTTTG G CT G CT
GAATGTACAATTTTTAAAG ATG CTTCTG GTAAG CCAGTACCATATTGTTATGATACCAATGTACTAG AA G
GTTCTGTTG CTTATG AAAG TT
TACGCCCTGACACACGTTATGTG CTCATG GATG G CTCTATTATTCAATTTCCTAACACCTACCTTGAAG
GTTCTGTTAGAGTG GTAACAAC
TTTTGATTCTGAGTACTGTAG G CACG G CACTT GT GAAAG
ATCAGAAGCTGGTGTTTGTGTATCTACTAGTGGTAG ATGG GTACTTAACAA
TGATTATTACAGATCTTTACCAG GAGTTTTCTGTG GTGTAGATG
CTGTAAATTTACTTACTAATATGTTTACACCACTAATTCAACCTATTG
GTGCTTTG GACATATCAG CATCTATAGTAG CTG GT G GTATT GTA G CTATCGTAGTAACATG CCTTG
CCTACTATTTTAT GA G GTTTA G AA G
A G CTTTTG G TG AATA CA GT CATG TA G TTG C CTTTAATA CTTTACTATTC CTTATG TCATTCA
CTG TA CTCTG TTTAA CA C CAG TTTA CTCATT
CTTACCTG G TG TTTATTCT GTTATTTA CTTG TA CTTG A CATTTTATCTTA CTAATG ATG TTT
CTTTTTTA G C A CATATTCA G TG G ATG GTTAT
GTTCACACCTTTAGTACCTTTCTG GATAACAATTG CTTATATCATTTGTATTTCCACAAAG CATTTCTATTG
GTTCTTTAGTAATTACCTAAA
G AG ACGTGTAGTCTTTAATGGTGTTTCCTTTAGTAL
_____________________________________________ 1111 GAAGAAG CTG CGCTGTG
CACCTTTTTGTTAAATAAAGAAATGTATCTAAAG
TTG CGTA GT GATGTG CTATTACCTCTTACG CAATATAATAGATACTTAG
CTCTTTATAATAAGTACAAGTATTTTAGTG GAG CAATGGATA
CAACTAG CTA CAG A G AA G CTG CTTG TT G TCATCTC G CAAAG G CT CTCAATG ACTT CAG
TAA CTCA G G TTCT G ATG TTCTTTA CCAACCA CC
A CAAA CCTCTATCA CCT CAG CTG TTTTG CA G AG TG GTTTTAGAAAAATG G CATTCCCATCTG G
TAAA G TTG AG G GTTG TAT G G TA CAAG T
AACTT GT G G TA CAACTACACTTAA C G G TCTTTG G CTTG ATG A C G TAG TTTACT GT CCAA
G ACATG TG AT CTG CA CCT CT G AA G ACATG CTT
AACCCTAATTATGAAGATTTA CTCATTCGTAA GT CTAATCATAATTTCTTG GTACAG G CTG
GTAATGTTCAACTCAG GGTTATTG GACATT
CTATG CAAAATTG TG TA CTTAAG CTTAAG GTTG ATACAG CCAATCCTAAG ACACCTAA
GTATAAGTTTG TTCG CATTCAACCAG G ACAG A
CTTTTTCAGTGTTAG CTTGTTACAATG GTTCACCATCTGGTGTTTACCAATGTG CTATG AG G
CCCAATTTCACTATTAAG GGTTCATTCCTT
AAT G G TT CAT GT G G TA G TGTTG GTTTTAACATAG ATTAT G A CT GT GT CTCTTTTTG TTA
CAT G CA C CATATG G AATTA C CAACT G G A GTTC
ATGCTGG CA CAG ACTTAG AAG GTAACTTTTATG GACCTTTTGTTGACAG G CAAACAG CA CAAG CAG
CT GGTACG GACA CAA CTATTA CA
GTTAATGTTTTAG CTTG G TTG TA C G CT G CT GTTATAAATG G AG A CAG GTG GTTTCTCAATC
G ATTTA C CA CAA CTCTTAATG A CTTTA A C C
TT GTG G CTAT G AA GTACAATTATG AA C CTCTAA CA CAA G AC CATG TTG A CATA CTAG G
A CCT CTTTCT G CTCAAA CT G G AATTG CCGTTTT
AGATATGTGTG CTTCATTAAAAG AATTACTG CAAAATG GTATG AATGG ACGTACCATATTG G GTAGTG
CTTTATTAGAAGATGAATTTAC
A CCTTTTG ATG TTG TTA G ACA ATG CT CA G G TG TTA CTTTCCAAA G TG CAG TG AAAA G
AA CAAT CAA G G G TA CA CACCA CTG G TTG TTA CT
CA CAATTTTG A CTTCA CTTTTA GTTTTA G TCCA G AG TA CTCAATG GT CTTTG TTCTTTTTTTTG
TATG AAAATG CCTTTTTACCTTTTG CTATG
G GTATTATTG CTATGTCTG CTTTT G CAATG AT GTTTG T CAAA CATAAG CATG
CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG CCACTGTA
G CTTATTTTAATATG GTCTATATG CCTG CTAGTTG G G TG AT G CGTATTATG ACATG GTTGGATATG
GTTGATACTAGTTTGTCTGGTTTTA
A G CTAAAAG A CTG TG TTATG TATG CATCA G CTG TA GT G TTACTAATCCTTATG A CA G CAA
G A A CTG T G TATG ATG ATG GT GCTAG GAGA
G TGT G G ACA CTTATG AATG TCTT G A CA CTC G TTTATAAAG TTTATTATG GT AATG
CTTTAGATCAAG CCATTTCCATGTG G G CT CTTATAA
TCTCTGTTACTTCTAACTACTCAG GTG TAGTTA CAA CTG TCAT GTTTTTG G CCAG AG
GTATTGTTTTTATGTGTGTTGAGTATTG CCCTATT
99
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TTCTTCATAACTGGTAATACACTTCAGTGTATAATGCTAGTTTATTGTTTCTTAGGCTATTTTTGTACTTGTTACTTTG
GCCTCTTTTGTTTAC
TCAACCGCTACTTTAGACTGACTCTTG GTGTTTATGATTACTTAGTTTCTACACAG GAGTTTAG ATATATG
AATTCACAGGG ACTA CTCCC
A CCCAA G AATA G CATA GATG CCTTCAAACTCAACATTAAATTGTTG G GT GTT G GTG G
CAAACCTTGTATCAAAGTAG CCACTGTACAGTC
TAAAATGTCA G AT GTAAA GT G CA CATCA GTAGTCTTA CT CTCA GTTTTG CAACAA CTCA GA
GTA GAATCATCATCTAAATTGTG GG CTCA
ATGT GT CCAGTTA CA CAATG A CATTCTCTTAG CTAAAG ATA CTA CTG AA G CCTITG
AAAAAATGGTITCACTACTTTCTGTTITG CTTTCCA
TG CA G GGTG CTGTAG ACATAAACAAGCTTTGTGAAGAAATG CTG G A CAACAG G G CAA CCTTACA
A G CTATAG CCTCA GA GTTTAGTTCC
CTTCCATCATATG CAG CTTTTG CTACTG CTCAAGAAG CTTATG A G CAG G CTGTTG CTAATGGTG
ATTCTG AA GTT GTTCTTAAAAAGTTG A
A GAA GT CTTTG AATGTG G CTAAATCT GAATTTG A CCGT GATG CA G CCATG CAACGTAA GTTG
G AAAA G AT G G CTGATCAAG CTATG A CC
CAAATGTATAAACAGG CTAGATCTGAG G ACAAG AG GG CAAAAGTTACTAGTG CTATG
CAGACAATGCTTTTCACTATG CTTAGAAAGTT
G GATAATGATG CA CTCA ACAA CATTATCAACAATG CAA G AG ATG
GTTGTGTTCCCTTGAACATAATACCTCTTACAACAG CAG CCAAA CT
AAT G GTTGTCATA CCA GA CTATAA CACATATAAAAATA CGT GT GATG GTA CAA CATTTA CTTAT
G CATCA G CATT GT G G G AAATCCAA CA
G GTTGTAGATG CAGATAGTAAAATTGTTCAACTTAGTGAAATTAGTATGG A CAATT CACCTAATTTAG CATG
GCCTCTTATTGTAACAGC
TTTAAG GG CCAATTCTG CTGTCAAATTACAGAATAATGAGCTTAGTCCTGTTG CACTACGACAGATGTCTTGTG
CTG CCG GTACTA CA CA
AACTGCTTGCACTG ATGACAATG CGTTAGCTTA CTACAACA CAA CAAAG G GAG GTAG GTTTGTACTTG
CA CTGTTATCCG ATTTA CAGG A
TTTGAAATGG G CTAGATTCCCTAAGAGTGATG G AA CTG GTACTATCTATACAGAACTG
GAACCACCTTGTAGGTTTGTTACAGACACACC
TAAAG GTCCTAAAGTGAAGTATTTATACTTTATTAAAGG ATTAAACAACCTAAATAG AG GTATG
GTACTTGGTAGTTTAG CT GCCACA GT
A CGTCTACAA G CT GGTAATG CA A CAG AA GTG CCTG CCAATTCAACTGTATTATCTTTCTGTG
CTTTT G CT GTAG AT G CTG CTAAAG CTTAC
AAAGATTATCTAGCTAGTGGG G GACAACCAATCA CTAATTGT GTTAAG ATGTTGTGTACA CA
CACTGGTACTG GTCAG G CAATAACAGT
TA CA CCG GAAG CCAATATGGATCAAGAATCCTTTG GTG GT G CATCGTGTT GTCTGTA CTG CCGTTG
CCACATAGATCATCCAAATCCTAA
AGGATTTTGTGACTTAAAAGGTAAGTATGTACAAATACCTACAACTTGTG CTAATGACCCTGTGG GTTTTACA
CTTAAAAACA CA GT CTG
TACCGTCTG CGGTATGTG GAAAGGTTATG G CTGTAGTTGTGATCAACTCCG CGAACCCATGCTTCAGTCAG
CTGATG CA CAATCGTTTTT
AAACG GGTTTGCG GTGTAAGTG CAGCCCGTCTTACACCGTGCG G CACAG G
CACTAGTACTGATGTCGTATACAGG GCI I I I GACATCTA
CAATGATAAAGTAG CTG GTTTTG CTAAATTCCTAAAAACTAATTGTTGTCGCTTCCAAGAAAAG G AC G AAG
ATG ACAATTTAATTG ATTC
TTACTTTGTAGTTAAG AG A CACACTTTCTCTAACTACCAACATG AAG AAACAATTTATAATTTACTTAAGG
ATTGTCCAG CTGTTG CTAAA
CATGACTTCTTTAAGTTTAGAATAGACG GT GA CATG GTA CCA CATATAT CA CGT
CAACGTCTTACTAAATACA CAATG G CA GA CCTCGTCT
ATGCTTTAAGG CATTTTGATGAAG GTAATTGTGA CA CATTAAAA G AAATA CTTGTCA CATACAATTGTT
GTG ATG AT GATTATTTCAATAA
AAA G GA CTG GTATGATTTTGTAGAAAACCCAGATATATTACG CGTATACG CCAACTTAG GTG AA CGTG
TA CG CCAA G CTTTGTTAAAAAC
A GTA CAATTCTGTG AT G CC ATG CGAAATG CTG GTATT GTT G GTGTA CTG ACATTAG ATAAT C
AA G AT CTCAATG GTAACTG GTATGATTT
CG GTGATTTCATACAAACCACG CCAG GTAGTGGAGTTCCTGTTGTAGATTCTTATTATTCATTGTTAATG
CCTATATTAACCTTGACCAG G
G CTTTAACTG CAGAGTCACATGTTGACACTGACTTAACAAAG CCTTACATTAAGTGG
GATTTGTTAAAATATGACTTCACG GAAGAGAGG
TTAAAACTCTTTG A CC GTTATTTTAAATATTG GGATCAGACATACCACCCAAATTGTGTTAACTGTTTG GATG
A CAG ATG CATTCTG CATT
GTGCAAACTTTAATGTTTTATTCTCTACAGTGTTCCCACTTACAAGTTTTG GACCA CTA GTG AG
AAAAATATTTGTTG ATG GT GTTCCATTT
GTAGTTTCAACTG GATACCACTTCAGAGAG CTAGGTGTTGTACATAATCAG G ATGTAAA CTTA CATAGCT
CT AG ACTTAGTTTT AAG GAA
TTACTTGTGTATG CTG CTG A CCCTG CTATG CA CG CTG CTTCT GGTAATCTATTA CTA G ATAAA
CG CA CTA CGTG CTTTTC A GTA G CT G CA C
TTACTAACAATGTTGCTTTTCAAACTGTCAAACCCGGTAA ______________________________ 1111
AACAAAGACTTCTATGACTTTGCTGTGTCTAAGGGTTTCTTTAAGGA
A G G AAGTT CTGTTG AATTAAAACA CTT CTTCTTT G CT CAG G AT G GTAATG CTG CTATCAG
CG ATTATG A CTACTAT CGTTATAATCTA CCA
ACAATGTGTGATATCAGACAACTACTATTTGTAGTTGAAGTTGTTGATAAGTACTTTGATTGTTACGATGGTG G
CTGTATTAATG CTAA CC
AAGTCATCGTCAACAACCTAGACAAATCAG CTG GTTTTCCATTTAATAAATG GGGTAAG G CTA GA
CTTTATTATG ATTC AAT GA GTTATG
AG G ATCAAG ATG CACTTTTCG
CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATG CCATTA GTG CAAAG A
ATAGAGCTCGCACCGTAGCTGGTGTCTCTATCTGTAGTACTATGACCAATAGACAGTTTCATCAAAAATTATTGAAATC
AATAGCCGCCA
CTAGAGGAGCTACTGTAGTAATTGGAACAAGCAAATTCTATGGTGGTTGGCACAACATGTTAAAAACTGTTTATAGTGA
TGTAGAAAAC
CCTCACCTTATG G GTTGG G ATTATCCTAAATGTGATAG AG CCATG CCTAACATGCTTAGAATTATGG
CCTCACTTGTTCTTG CTCG CAAAC
ATACAACGTGTTGTAG CTTGTCACACCGTTTCTATAGATTAG CTAATGAGTGTG CTCAAGTATTGAGTGAAATG
GTCATGTGTG G CGGTT
CACTATATGTTAAACCAGGTG GAACCTCATCAG GAG ATGC CACAACTGCTTATGCTAATAGTG 11111
AACATTTGTCAAGCTGTCACG G
CCAATGTTAATG CA CTTTTAT CTA CTG ATG GTAACAAAATTG CCGATAA GTAT GT CCG CAATTTA
CAACA C A G ACTTTATG A GT GTCTCTA
TAGAAATAGAG AT GTT GA CA CAG ACTTTGTG AATG AGTTTTACG CATATTTG CGTAAA
CATTTCTCAATG ATGATA CTCTCTGACG ATG CT
GTTGTGTGTTTCAATA G CA CTTATG CATCTCAAG GTCTAGTG GCTAG
CATAAAGAACTTTAAGTCAGTTCTTTATTATCAAAACAATGTTT
TTATGTCTG AA G CA AAATGTT G G A CTG AG A CTG A CCTTA CTAAA G G ACCT CATG
AATTTT G CTCT CAA CATACAATG CTAGTTAAACAG G
GTGATGATTATGTGTACCTTCCTTACCCAGATCCATCAAGAATCCTAG GG G CCGG
CTGTTTTGTAGATGATATCGTAAAAACAGATGGTA
CACTTATGATTGAACGGTTCGTGTCTTTAGCTATAGATGCTTACCCACTTACTAAACATCCTAATCAGGAGTATGCTGA
TGTCTTTCATTTG
TACTTACAATACATAAGAAAGCTACATGATGAGTTAACAGGACACATGTTAGACATGTATTCTGTTATGCTTACTAATG
ATAACACTTCAA
GGTATTGGGAACCTGAGTTTTATGAGGCTATGTACACACCGCATACAGTCTTACAGGCTGTTGGGGCTTGTGTTCTTTG
CAATTCACAGA
CTTCATTAAGATGTGGTGCTTGCATACGTAGACCATTCTTATGTTGTAAATGCTGTTACGACCATGTCATATCAACATC
ACATAAATTAGT
CTTGTCTGTTAATCCGTATGTTTGCAATGCTCCAGGTTGTGATGTCACAGATGTGACTCAACTTTACTTAGGAGGTATG
AGCTATTATTGT
AAATCACATAAACCACCCATTAGTTTTCCATTGTGTG CTAATGG A C AAGTTTTTG GTTTATATAAAAATA
CAT GT GTTG GTA G CGATAATG
TTA CTG A CTTTAATG CAATTG CAA CATGTG A CTG GA CAAATG CT G GTG ATTACATTTTA G
CTAA CA CCTGTA CT GAAA G A CTCA A G CTTTT
TG CAG CAGAAACG CTCAAAG CTACTGAG GAG ACATTTA AA CTG TCTTATG GTATTG
CTACTGTACGTGAAGTG CTGTCTGACAG AG AAT
TA CAT CTTTCATG G GAAGTTG GTAAA CCTA GA CCA CCACTTAAC CG AAATTATG TCTTTA CTG
GTTAT CGT GTAA CTAAAA A CAGTAAA GT
A CAAATAGG AG AGTACACCTTTG AAAAAGGTG ACTATG GTGATG
CTGTTGTTTACCGAGGTACAACAACTTACAAATTAAATGTTG GTG
ATTATTTTGT G CTG A CATCACATA CA GTAATG CCATTAAGTG CA CCTA CACTAGTG CCA CA A G
AG CA CTATGTTA GAATTA CTG G CTTATA
CCCAA CA CTCAATAT CTCAGATG AGTTTTCTAG CAATGTTG CAAATTATCAAAAGGTTGGTATG
CAAAAGTATTCTACACTCCAG G GACC
A CCTG GTA CTG GTAAGAGTCATTTTGCTATTGG CCTAG CTCTCTA CTA CCCTT CTG CT CG CATA
GTGTATA CA G CTTG CTCTCATGCCG CT
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GTTG AT G CACTATGTG AG AAG G CATTAAAATATTTG CCTATAGATAAATGTAGTAGAATTATACCTG
CACGTG CTCGTGTA GA GTGTTTT
GATAAATTCAAAGTGAATTCAACATTAGAACAGTATGTCTTTTGTACTGTAAATG CATTG CCTGAGACGACAG
CAGATATAGTTGTCTTT
GATGAAATTTCAATGG CCACAAATTATGATTTGAGTGTTGTCAATGCCAGATTACGTG CTAAG
CACTATGTGTACATTGG CGACCCTG CT
CAATTACCTGCACCACGCACATTG CTAACTAAG GG CA CACTA G AACC A G AATATTTCAATTCA
GTGTGTA GACTTATG AAAACTATA G GT
CCAGACATGTTCCTCG GAACTTGTCG G CGTTGTCCTG CT GAAATTGTTG ACACT GTG A GTG CTTTG
GTTTATG ATAATA A G CTTAAAG CA
CATAAAGACAAATCAGCTCAATG CTTTAAAATGTTTTATAAG G GT GTTATCACG CATG ATGTTTCATCT G
CAATTA ACA G G CCACAAATA
G G CGTG GTAAGAGAATTCCTTACACGTAACCCTG CTTG GAGAAAAG
CTGTCTTTATTTCACCTTATAATTCACAGAATGCTGTAG CCTC A
AAGATTTTGG GACTACCAACTCAAACTGTTGATTCATCACAG G
GCTCAGAATATGACTATGTCATATTCACTCAAACCACTGAAACAG CT
CACTCTTGTAATGTAAACAGATTTAATGTTG CTATTACCA GA G CAAAAGTAG G CATACTTTG CATAATG
TCTG ATA GA G ACCTTTATG ACA
AGTTGCAATTTACAAGTCTTGAAATTCCACGTAG GAATGTG G CAACTTTACAAG
CTGAAAATGTAACAGGACTCTTTAAAGATTGTAGTA
A G GTAATCACT G G GTTACATCCTACACAG G CACCTACACACCTCA GTGTTG ACACTAAATTCAAAACTG
AA G GTTTATGTGTTG ACATAC
CTG G CATACCTAAG G AC ATG ACCTATA G AA GACTCATCTCTATG ATG
GGTTTTAAAATGAATTATCAAGTTAATG GTTACCCTAACATGTT
TATCACCCGCGAAGAAGCTATAAGACATGTACGTGCATG GATTG GCTTCGATGTCGAGG G GT GTCATG
CTACTAG AG AAG CTGTTGGTA
CCAATTTACCTTTACAG CTAGGTTTTTCTACAGGTGTTAACCTAGTTG
CTGTACCTACAGGTTATGTTGATACACCTAATAATACAGATTTT
TCCAGAGTTAGTG CTAAACCACCG CCTG G AG ATCAATTTAAACACCTCATACCACTTAT GTACAAAG
GACTTCCTTG GAATGTAGTG CGT
ATAAA G ATTGTACAAAT GTTAAGTG ACACACTTAAAA ATCTCTCT GACA GA G TCGTATTTGTCTTATG
G G CACATG G CTTTGAGTTGACA
TCTATGAAGTATTTTGTGAAAATAG GACCTGAG CG CACCTGTTGTCTATGTGATAGACGTG
CCACATGCTTTTCCACTG CTTCAGACACTT
ATG CCTGTTG GCATCATTCTATTGGATTTGATTACGTCTATAATCCGTTTATGATTGATGTTCAACAATG GG
GTTTTACAG GTAACCTACA
AAG CAACCATGATCTGTATTGTCAAGTCCATG GTAATGCACATGTAGCTAGTTGTGATG
CAATCATGACTAGGTGTCTAG CTGTCCACG A
GTGCTTTGTTAAGCGTGTTGACTG GACTATTGAATATCCTATAATTG GT GATG AACTG AA G ATTAATG CG
G CTTGTAG AAA G GTTCAACA
CATGGTTGTTAAAGCTGCATTATTAG CA GACAAATTCCCA GTTCTTCACG ACATT G GTAACCCTAAA G
CTATTAAGTGTGTACCTCAAG CT
GATGTAG AATG G AA GTTCTATG ATG CACAG CCTTG TA GT G A CAAA G CTTATAAAATA G AA G
AATTATT CTATTCTTATG CCACACATTCT
GACAAATTCACAGATG GT GTATGCCTATTTTG GAATTG CAATGTCGATAGATATCCTG
CTAATTCCATTGTTTGTAGATTTGACACTAGAG
TG CTATCTAACCTTAACTTG CCT G GTT GT GATG GTG G CA GTTTGTATGTAAATAAACAT G CATTCC
ACACACCAG CTTTTGATAAAAGTG C
TTTTGTTAATTTAAAA CAATTA C CATTTTTCTATTA CT CTG ACA G TCCATG TG AG TCTCATG G
AAAACAA G TA GT GT CA G ATATA G ATTAT
G TACCACTAAA GT CTG CTACGTGTATAACACGTTG CAATTTAG GTG GTG CTG TCTG TAG ACATCATG
CTAATG AG TACAG ATTGTATCTC
GATG CTTATAACATGATGATCTCAG CTG GCTTTAGCTTGTGG GTTTACAAACAATTTGATACTTATAACCTCTG
GAACACTTTTACAAGAC
TTCAGAGTTTAGAAAATGTG G CTTTTAATGTTGTAAATAAG GGACACTTTGATG GACAACAG
GGTGAAGTACCAGTTTCTATCATTAATA
ACACTGTTTACACAAAAGTTGATG GTGTTGATGTAGAATTGTTTGAAAATAAAACAACATTACCTGTTAATGTAG
CATTTG AG CTTTGGG
CTAAG CG CAACATTAAACCA GTACCAG A G GTGAAAATACTCAATAATTTG GGTGTG GACATTG CTG
CTAATACT GT GATCTG G GACTAC
AAAAGAGATG CTCCAG CACATATATCTACTATTG
GTGTTTGTTCTATGACTGACATAGCCAAGAAACCAACTGAAACGATTTGTG CACCA
CTCACTGTCTTTTTTGATGGTAGAGTTGATG
GTCAAGTAGACTTATTTAGAAATGCCCGTAATGGTGTTCTTATTACAGAAGGTAGTGTTA
AAG GTTTACAACCATCTGTAG GTCCCAAACAAG CTAGTCTTAATGGAGTCACATTAATTG
GAGAAGCCGTAAAAACACAGTTCAATTATT
ATAAG AAA GTTG ATG GT GTT GTCCAACAATTACCTG AAACTTACTTTACTCA G A GTAG
AAATTTACAAG AATTTAAACCCA G G A GTCAAA
TG GAAATTGATTTCTTAGAATTAG CTATG G AT G AATTCATTG AA C G G TATAAATTA G AA G G
CTAT G CCTTC G AA CAT AT C GTTTATG GAG
ATTTTAGTCATAGTCAGTTAG GTG GTTTACATCTACTGATTGGACTAGCTAAACGTTTTAAG
GAATCACCTTTTGAATTAGAAGATTTTAT
TCCTATG G ACA GTACAGTTAAAAACTATTTCATAACA G AT G CG CAAA CA G GTTCATCTAA GT GT
GTGTGTTCT GTTATTG ATTTATTACTT
GATGATTTTGTTGAAATAATAAAATCCCAAGATTTATCTGTAGTTTCTAAG
GTTGTCAAAGTGACTATTGACTATACAGAAATTTCATTTA
TG CTTTG GTGTAAAGATGG CCATGTA GAAACATTTTACCCAAAATTACAATCTAGTCAAGCG TG G CAACCG
GGTGTTG CTATG CCTAATC
TTTACAAAATG CAAAGAATGCTATTAGAAAAGTGTGACCTTCAAAATTATG GTG ATA GT G
CAACATTACCTAAA G G CATAATGATGAAT
GTCG CAAAATATACTCAACTGTGTCAATATTTAAACACATTAACATTA G CT GTACCCTATAATATG AG A
GTTATACATTTTG GT G CTG GTT
CTGATAAAG GAGTTG CACCAG GTACAG CTGTTTTAAGACAGTG GTTG CCTACG G GTACGCTG CTT GTC
G ATTCAG AT CTTAATGACTTTG
TCTCTGATG CA G ATTCAA CTTT G ATTG GTGATTGTG CAACTGTACATACAGCTAATAAATG G G
ATCTCATTATTA GT GATATGTACG ACCC
TAAGACTAAAAATGTTACAAAAGAAAATGACTCTAAAGAGG GIIII1TCACTTACATTTGTG
GGTTTATACAACAAAAG CTAG CTCTTGG
AG GTTCCGTG G CTATAAAG ATAA CAG AA CATTCTTG G AATG CTGATCTTTATAAG CT CATG
GGACACTTCG CATGGTG GACAG CCTTTGT
TA CTAAT GTG AATG CGTCATCATCTGAAG CATTTTTAATTG GATGTAATTATCTTG G
CAAACCACGCGAACAAATAGATG GTTAT GT CAT
G CATG CAAATTACATATTTTG GAG GAATACAAATCCAATTCAGTTGTCTTCCTATTCTTTATTTGACATG AG
TAAATTTCCCCTTAAATTAA
G G G GTA CTG CT GTTATGT CTTTAAAAG AAG
GTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAGGTAGACTTATAATTAGAGAAA
ACAACAGAGTTGTTATTTCTAGTG ATGTTCTTGTTAACAACTAAAC GAACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTAGTCA
GTGTGTTAATCTTACAACCAGAACTCAATTACCCCCTGCATACACTAATTCTTTCACACGTGGTGTTTATTACCCTGAC
AAAGTTTTCAGAT
CCTCAGTTTTACATTCAACTCAGGACTTGTTCTTACCTTTCTTTTCCAATGTTACTTG GTTCCATG
CTATACATGTCTCTG GGACCAATG G TA
CTAAG A G GTTTG ATAACCCTGTCCTACCATTTAATG AT G GTGTTTATTTTG CTTCCACTG AG A A
GTCTAACATAATAA G AG G CTG GATTTT
TG GTACTACTTTAGATTCGAAGACCCAGTCCCTACTTATTGTTAATAACG
CTACTAATGTTGTTATTAAAGTCTGTGAATTTCAATITTGTA
ATGATCCATTTTTG GGTGTTTATTACCACAAAAACAACAAAAGTTGGATG GA AA GTG A GTTCA
GAGTTTATTCTA GT G CG AATAATTG CA
CTTTTGAATATGTCTCTCAG CCTTTTCTTATG GACCTTGAAGGAAAACAGG GTAATTTCAAAAATCTTAG G
GAATTTGTGTTTAAG AATAT
TG AT G G TTATTTTAAAATATATTCTAA G CACACG CCTATTAATTTAGTG CGTGATCTCCCTCAG G
GTTTTTCG G CTTTAG AACCATTG G TA
GATTTG CCAATAG G TATTAA CAT CACTA G G TTT CAAA CTTTA CTT G CTTTA CATAG
AAGTTATTTG A CTCCTG GTGATTCTTCTTCAG GTTG
GACAG CTG GT G CTG CA G CTTATTATGTG GGTTATCTTCAACCTAG
GACTTTTCTATTAAAATATAATGAAAATG GAACCATTACAGATGC
TGTAGACTGTG CACTTGACCCTCTCTCAGAAACAAAGTGTACGTTGAAATCCTTCACTGTAGAAAAAG G A
ATCTAT C AAA CTTCTAA CTTT
AG AG KCCAACCAACAGAATCTATTGTTAGATTTCCTAATATTACAAACTTGTG CCCTTTTG
GTGAAGTTTTTAACGCCACCAGATTTG CAT
CTGTTTATG CTTGGAACAG GAA G AG AATCAG CAACTGTGTTG CTGATTATTCTGTCCTATATAATTCCG
CATCATTTTCCACTTTTAAGTGT
TATG GA GTGTCTCCTACTAAATTAAAT GATCTCT G CTTTACTAATGTCTATG CAG ATTCATTT
GTAATTAG A G GTG ATG AA GTCA G ACAAA
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TCG CTCCAGG G CAAACTG GAAAGATTG CTGATTATAATTATAAATTACCAGATGATTTTACAG G CT G C
G TTATA G CTTG G AATTCTAA CA
ATCTTGATTCTAAGGTTGGTG GTAATTATAATTACCTGTATAGATTGTTTAG G
AAGTCTAATCTCAAACCTTTTGAG AG AG ATATTTCAAC
TGAAATCTATCAG GCCG GTAG CACACCTTGTAATG GTGTTGAAG
GTTTTAATTGTTACTTTCCTTTACAATCATATG GTTTCCAACCCA CT
AATGGTGTTG GTTA CCAACCATA CA GA GTA GTAGTA CTTT CTTTT GAA CTTCTA CATG CAC CA G
CAA CTGTTTGTG G A CCTAAAAA GT CTA
CTAATTTG GTTAAAAA CAA ATGTGTCAATTTCAA CTTCAAT G GTTTAACA G G CA CA G GTGTT
CTTACTG AGTCTAACAAAAA GTTTCTG CC
TTTCCAACAATTTG GCAG A GACATTG CTGACACTACTGATG CTGTCCGT GATCCACAG ACA CTTG AG
ATTCTTG ACATTACACCATGTTCT
TTTG GTG GT GT CAGTGTTATAA CACCA G GAACAAATACTTCTAACCAG GTTG CTGTTCTTTATCAG G
GT GTTAA CTG CA CAG AAGTCCCT
GTTG CTATTCATG CAGATCAACTTACTCCTACTTG GCGTGTTTATTCTACAG GTTCTAATGTTTTTCAAA CA
CGTG CAG G CTGTTTAATAG G
G G CT GAACAT GT CAA CAA CTCATATG AGTGTG A CATA CCCATTG GT G CA G GTATATG CG
CTA GTTAT CA GA CT CAG A CTAATT CTCCTCG
G CGG G CACGTAGTGTAG CTAGTCAATCCAT CATTGCCTA CA CTATGTCA CTTG
GTGCAGAAAATTCAGTTGCTTACTCTRATAACTCTATT
G
CCATACCCACAAATTTTACTATTAGTGTTACCACAGAAATTCTACCAGTGTCTATGACCAAGACATCAGTAGATTGTAC
AATGTACATTT
GTGGTGATTCAACTGAATGCAG CAATCTTTTGTTG CAATATGG CAGTTTTTGTACACAATTAAACCGTG
CTTTAACTGGAATAG CTGTTG A
A CAA G ACAAAAA CA CCCAA G AA GTTTTTG CACAA GT CAAACAAATTTACAAAA CACCA
CCAATTAAA GATTTTG GTG GTTTTAATTTTT CA
CAAATATTACCAG AT CCATCAAAACCAAGCAAG AG GTCATTTATTGAAGATCTACTTTTCAA CAAAGTGA CA
CTTG CAGATG CTG G CTTC
ATCAAACAATATGGTGATTGCCTTGGTGATATTGCTGCTAGAGACCTCATTTGTGCACAAAAGTTTAACGGCCTTACTG
TTTTGCCACCTT
TGCTCACAGATGAAATGATTGCTCAATACACTTCTGCACTGTTAGCGGGTACAATCACTTCTGGTTGGACCTTTGGTGC
AGGTGCTGCAT
TACAAATACCATTTGCTATGCAAATGGCTTATAGGTTTAATGGTATTGGAGTTACACAGAATGTTCTCTATGAGAACCA
AAAATTGATTG
CCAACCAATTTAATAGTG CTATTG G CAAAATT CAA G A CT CA CTTTCTT CCACA G CAAGTG CA
CTTG GAAAACTTCAAGATGTG GT CAA CC
AAAATG
CACAAGCTTTAAACACGCTTGTTAAACAACTTAGCTCCAATTTTGGTGCAATTTCAAGTGTTTTAAATGATATCCTTTC
ACGTCTT
GACAAAGTTGAG GCTGAAGTGCAAATTGATAG GTTGATCACAG G
CAGACTTCAAAGTTTGCAGACATATGTGACTCAACAATTAATTAG
A G CTG CA G AAATCA GA GTTTCT G CTAATCTTG CT G CTACTAAAATGTCAGAGTGTGTACTTG GA
CAATCAAAAAG A GTTGATTTTTG TG G
AAA G GG CTATCATCTTAT GT C CTTC C CTCA GT CAG CA C CTCATG GT GTA G TCTT CTTG
CAT GT G A CTTATG TC C CTG CA CAAG AAAAG AA C
TTCA CAA CTG CTCCTG CCATTTGTCATGATG GAAAAG CA CA CTTTC CTCGT GAA G
GTGTCTTTGTTTCAAAT G G CA CACA CTG GTTTGTAA
CA CAAA G G AATTTTTAT GAA CCACAAATCATTA CTA CA G A CAA CA CATTTGTGTCTG
GTAACTGTGATGTTGTAATAG GAATT GT CAA CA
ACACAGTTTATGATCCTTTGCAACCTGAATTAGACTCATTCAAGGAGGAGTTAGATAAATATTTTAAGAATCATACATC
ACCAGATGTTG
ATTTAGGTGACATCTCTGGCATTAATGCTTCAGTTGTAAACATTCAAAAAGAAATTGACCGCCTCAATGAGGTTGCCAA
GAATTTAAATG
AAT CT CTCATC G ATCT CCAA G AA CTTG G AAA G TATG AG CA GT ATATAAAAT G G CCATG
G TA CATTTG G CTA G GTTTTATA G CT G G CTTG A
TTG CCATAGTAATG GTGACAATTATG CTTTG CTGTATGACCAGTTG CTGTAGTTGTCTCAAG G
GCTGTTGTTCTTGTG G AT CCT G CT G CAA
ATTTG ATG AAG ACG ACT CTG AG CCAGTGCTCAAAGGAGTCAAATTACATTACACATAAACGAACTTATG
GATTT GTTTATG AG AAT CTTC
A CAATTG G AACTG TAA CTTTG AA G CAA G G TG AAATCAA G G ATG
CTACTCCTTCAGATTTTGTTCG CG CTA CT G CAA CG ATA CC G ATACAA
G CCTCACTCCCTTTCG GATGGCTTATTGTTGG CGTTG CA CTTCTTG CTGTTTTTCAGAG CG
CTTCCAAAATCATAACCCT CAAAAAG AG AT
G G CAA CTA G CACTCTCCAAG G G TG TT CA CTTTGTTTG CAA CTT G CTG TT GTT GTTTG
TAACA G TTTA CTCA CACCTTTTG CTCGTTG CTG CT
G G CCTTGAAG CCCCTTTTCTCTATCTTTATG CTTTAGTCTACTTCTTG CAGAGTATAAACTTTG TAAG
AATAATAATG AG G CTTTGG CTTTG
CTG GAAATG CCGTTCCAAAAACCCATTACTTTATGATG CCAACTATTTTCTTTG CTG G CATA CTAATTG
TTACG ACTATTG TATACCTTA CA
ATA GTG TAA CTTCTTCAATT GT CATTA CTTCA G GTG ATG G CA CAA CAA G TCCTATTT CT G
AA CATG ACTA C CAG ATTGGTG GTTATACTG A
AAAATG GGAATCTG G A G TAAAA G ACTG TG TTG TATTACA CA GTTA CTTCA CTTCA G A
CTATTACCA G CTG TA CT CAA CTCAATTG A GTA C
AGACACTG GT GTTGAA CATGTTACCTTCTTCATCTACAATAAAATTG TTGATG AG CCTGAAGAACAT
GTCCAAATTCA CACAATCG ACG G
TTCATCCG G AG TTG TTAATCCAGTAATG GAACCAATTTATGATGAACCGACG ACGACTACTAG CGTG
CCTTTGTAAGCACAAG CT GATG A
G TAC G AA CTTATG TA CTCATTC G TTTC G G AA G AG M CA G GTACGTTAATAGTTAATAG C G
TA CTTCTTTTTCTTG CTTTC GT G G TATTCTTG
CTAGTTACACTAG CCATCCTTACTG CG CTTC G ATTGT GT G C G TACT G CTG CAATATTGTTAA C
GTG A G TCTTG TAAAA CCTTCTTTTTAC G T
TTACTCTCGTGTTAAAAATCTGAATTCTTCTAGAGTTCCTGATCTTCTG
GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTGGAACT
TTAATTTTAG CCATG G CA G ATTCCAACG G TA CTATTA CCGTTGAA G AG CTTAAA AA G
CTCCTTGAACAATG GAACCTAGTAATAG GTTTC
CTATTCCTTA CAT G G ATTT GT CTTCTA CAATTTG CCT AT G CC AA CAG GAATAG
GTTTTTGTATATAATTAAGTTAATTTTCCTCTGG CTGTT
ATGG CCAGTAACTTTAG CTTGTTTTGTG CTTG CTG CT GTTTA CAG AATAAATTG G AT CACCG
GTGGAATTG CTATCGCAATG G CTT GT CTT
GTAG G CTTGATGTG GCTCAG CTACTTCATTG CTTCTTTCAGACTGTTTGCG CGTACGCGTTCCATGTG GTC
ATTCAATCCAG AAACTAA CA
TTCTTCTCAACGTG CCACTCCATG G CACTATTCTGACCAGACCG CTTCTAG AAAGTG AA CTCGTAATCGG
AGCTGTG ATCCTTCGTG GAC
ATCTTCGTATTG CTG G ACACCATCTA GG A CGCTGTGACATCAAG
GACCTGCCTAAAGAAATCACTGTTGCTACATCACGAATG CTTTCTTA
TTACAAATTGG GAG CTTCG CA G CGTGTA G CAG GTG ACT CAG GTTTTGCTG CATACAGTCG CTA
CA G G ATTG G CAA CTATAAATTAAA CA
CA GA CCATTCCA GT AG CA GT GACAATATTG CTTTG CTTGTA CA GTAA GTG ACAA CA GATGTTT
CATCT C GTTGACTTTCA GGTTA CTATA G
CAGAG AT ATTACTAATTATTATGAG GACTTTTAAAGTTTCCATTTG
GAATCTTGATTACATCATAAACCTCATAATTAAAAATTTATCTAAG
TCACTAACTGAGAATAAATATTCTCAATTAGATGAAGAG CAACCAATG G A G ATTG ATTAAACG AA CATG
AAAATTATTCTTTTCTTG G CA
CTGATAACACTCG CTACTTGTG AG CTTTATCACTACCAAGAGTGTGTTAGAG
GTACAACAGTACTTTTAAAAGAACCTTG CTCTTCTG G AA
CATA CG AG GG CAATTCACCATTTCATCCTCTAG CTGATAACAAATTTG CACTGACTTG CTTTAG CA
CTCAATTTG CTITTG CTTG TC CTG AC
G G CGTAAAA CACGTCTATCA GTTACGTG CCAG AT CAG TTT CACCTAAA CTG TTC ATCAG
ACAAGAG GAAGTTCAAGAACTTTACTCTCCA
ATTTTTCTTATTGTTGCG G CAATAGTGTTTATAA CA CTTTG CTTCA CA CTCA AAAG AAAGACA G
AATG ATTG AACTTT CATTAATTG ACTTC
TATTTGTG CTTTTTAG CCTTTCTGCTATTCCTTGTTTTAATTATGCTTATTATCTTTTGGTTCTCACTTGAACTG
CAAGATCATAATGAAACTT
GTCA CG CCTAAA CG AA C ATG AAATTT CTTGTTTT CTTA G GAATCATCA CAA CTGTA G CTG
CATTTCA CCAA G AATG TA GTTTACA G TCATG
TA CTCAACATCAACCATAT GTAGTTG ATG ACCCGTGTCCTATT CA CTT CTATTCTAAATG
GTATATTAGAGTAG GAG CTAGAAAATCAG CA
CCTTTAATTGAATTGTGCGTG GATGAG GCTGGTTCTAAATCACCCATTCAGTACATCGATATCG
GTAATTATACAGTTTCCTGTTTACCTTT
TA CAATTAATTG CCAG GAACCTAAATTG G GTA GTCTTGTA GT G CGTTGTTCGTT CTAT GAA GA
CTTTTTA GA GTATCATG ACGTTCGTGTT
GTTTTAGATTTCATCTAAACGAACAAACTAAAATGTCTGATAATG GACCCCAAAATCAGCGAAATG CACCCCG
CATTACGTTTGGTG GAC
CCTCAGATTCAACTG GCAGTAACCAGAATG G AG AACG CA GTGG G GCG CGATCAAAACAACGTCG G
CCCCAAG GTTTACCCAATAATACT
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GCGTCTTGGTTCACCGCTCTCACTCAACATGGCAAGGAAGACCTTAAATTCCCTCGAGGACAAGGCGTTCCAATTAACA
CCAATAGCAGT
CCAGATGACCAAATTGGCTACTACCGAAGAGCTACCAGACGAATTCGTGGTGGTGACGGTAAAATGAAAGATCTCAGTC
CAAGATGGT
ATTTCTACTACCTAGGAACTGGGCCAGAAGCTGGACTTCCCTATGGTGCTAACAAAGACGGCATCATATGGGTTGCAAC
TGAGGGAGCC
TTGAATACACCAAAAGATCACATTGGCACCCGCAATCCTGCTAACAATGCTGCAATCGTGCTACAACTTCCTCAAGGAA
CAACATTGCCA
AAAGGCTTCTACGCAGAAGGGAGCAGAGGCGGCAGTCAAGCCICTTCTCGTTCCTCATCACGTAGTCGCAACAGTICAA
GAAATTCAAC
TCCAGGCAGCAGTAAACGAACTTCTCCTGCTAGAATGGCTGGCAATGGCGGTGATGCTGCTCTTGCTTTGCTGCTGCTT
GACAGATTGAA
CCAGCTTGAGAGCAAAATGTCTGGTAAAGGCCAACAACAACAAGGCCAAACTGTCACTAAGAAATCTGCTGCTGAGGCT
TCTAAGAAGC
CTCGGCAAAAACGTACTGCCACTAAAGCATACAATGTAACACAAGCTTTCGGCAGACGTGGTCCAGAACAAACCCAAGG
AAATTTTGGG
GACCAGGAACTAATCAGACAAGGAACTGATTACAAACATTGGCCGCAAATTGCACAATTTGCCCCCAGCGCTTCAGCGT
TCTTCGGAAT
GTCGCGCATTGGCATGGAAGTCACACCTTCGGGAACGTGGTTGACCTACACAGGTGCCATCAAATTGGATGACAAAGAT
CCAAATTTCA
AAGATCAAGTCATTTTGCTGAATAAGCATATTGACGCATACAAAACATTCCCACCAACAGAGCCTAAAAAGGACAAAAA
GAAGAAGGCT
GATGAAACTCAAGCCTTACCGCAGAGACAGAAGAAACAGCAAACTGTGACTCTTCTTCCTGCTGCAGATTTGGATGATT
TCTCCAAACAA
TTGCAACAATCCATGAGCAGTGCTGACTCAACTCAGGCCTAAACTCATGCAGACCACACAAGGCAGATGGGCTATATAA
ACGTTTTCGCT
TTTCCGTTTACGATATATAGTCTACTCTTGTGCAGAATGAATTCTCGTAACTACATAGCACAAGTAGATGTAGTTAACT
TTAATCTCACATA
GCAATCTTTAATCAGTGTGTAACATTAGGGAGGACTTGAAAGAGCCACCACATTTTCACCGAGGCCACGCGGAGTACGA
TCGAGTGTAC
AGTGAACAATGCTAGGGAGAGCTGCCTATATGGAAGAGCCCTAATGTGTAAAATTAATTTTAGTAGTGCTATCCCCATG
TGATTTTAATA
G CTTCTTAG GAG NATGACANNNNNNNNNNNNNN
SEQ ID NO: 16
>Severe acute respiratory syndrome coronavirus 2 orflab polyprotein of isolate
hCoV-
19/Austria/CeM M0360/2020
M ESLVPGFNEKTHVQLSLPVLQVRDVLVRG FG DSVEEVLSEARQHLKDGTCG LVEVEKG VLPQLEQPYVF I
KRSDARTAPHGHVMVELVAELE
G IQYG RSGETLGVLVPHVG El PVAYRKVLLRKN GNKGAGG HSYGADLKSFDLG
DELGTDPYEDFQENWNTKHSSGVTRELM RELN GGAYTRY
VDNN FCGPDGYPLECI KDLLARAG KASCTLSEQLDF I DTKRGVYCCR EHEHEI AWYTERSEKSYELQTP F
El KLAKKEDTENG ECPN FVFPLNSII K
TIQPRVEKKKLDG FMG RI RSVYPVASPNECNQMCLSTLMKCDHCGETSWQTG DFVKATCEFCGTEN
LTKEGATTCGYLPQNAVVKIYCPACH
NSEVGPEHSLAEYHNESGLKTILRKGGRTIAFGGCVFSYVGCHNKCAYWVPRASANIGCN
HTGVVGEGSEGLNDNLLEILQKEKVNINIVGDFK
LN EEI AI I LASFSASTSAFVETVKG LDYKAFKQIVESCG N F KVTKG KAKKGAWN I GEQKSI
LSPLYAFASEAARVVRSI FSRTLETAQNSVRVLQKA
AITILDG ISQYSLRLI DAM M FTSDLATNNLVVMAYITGGVVQLTSQWLTN I FGTVY EKLKPVLDWLEEKF
KEGVEFLR DGWEI VKFISTCACEI V
GGQIVTCAKEIKESVQTFFKLVN KFLALCADSI II GGAKLKALN LG ETFVTHSKG LYRKCVKSREETGLLM
PLKAPKEI I FLEG ETLPTEVLTEEVVLK
TG DLQPLEQPTSEAVEAPLVGTPVCI NG LM LLEI KDTEKYCALAPN M MVTNNTFTLKGGAPTKVTFG
DDTVIEVQGYKSVNITFELDERI DKVL
NEKCSAYTVELGTEVNEFACVVADAVIKTLQPVSELLTPLG I DLDEWSMATYYLFDESG EFK LASH
MYCSFYPP DEDEEEGDCEEEEFEPSTQYE
YGTEDDYQGKPLEFGATSAALQPEEEQEEDWLDDDSQQTVGQQDGSEDNQTTTI QTIVEVQPQLEM
ELTPVVQTIEVNSFSGYLKLTDNVYI
KNADIVEEAKKVKPTVVVNAANVYLKHGGGVAGALNKATN NAM QVESDDYI ATN GP LKVGGSCVLSG
HNLAKHCLHVVG PNVN KGEDIQL
LKSAYEN FN QHEVLLAPLLSAGI FGADP I HSLRVCVDTVRTNVYLAVFDKN LYDK LVSSFLEM
KSEKQVEQKIAEIPKEEVKPFITESKPSVEQRKQ
DDKKIKACVEEVTTTLEETKFLTENLLLYI DING N LH PDSATLVSDI DITFLKKDA PYI VG
DVVQEGVLTAVVIPTKKAGGTTEM LAKALRKVPTDN
YITTYPGQGLNGYTVEEAKTVLKKCKSAFYILPSIISNEKQEILGTVSWNLREM LAHAEETRKLM
PVCVETKAIVSTI QRKYKG I KIQEGVVDYGAR
FYFYTSKTTVASLINTLNDLNETLVTM PLGYVTHG LN LEEAARYM RSLKVPATVSVSSPDAVTAYN
GYLTSSSKTPEEHFI ETISLAGSYKDWSYS
GQSTQLG I EFLKRG DKSVYYTSNPTTFH LDG EVITFDNLKTLLSLR EVRTI KVFTTVDN I
NLHTQVVDMSMTYGQQFG PTYLDGADVTK I KPHNS
HEGKTFYVLPNDDTLRVEAFEYYHTTDPSFLG RYMSALN HTKKWKYPQVN G LTSI
KWADNNCYLATALLTLQQI ELKFNPPALQDAYYRARAG
EAANFCALILAYCNKTVG ELG
DVRETMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQFKKGVQ1PCTCGKQATKYL
VQQESPFVM MSAPPAQYELKHGTFTCASEYTGNYQCG HYKHITSKETLYCI DGALLTKSSEYKGP ITDVFYK
ENSYTTTI KPVTYKLDGVVCTEID
PKLDNYYKKDNSYFTEQPIDLVPNQPYPNASFDNFKFVCDNIKFADDLNQLTGYKKPASRELKVIFFPDLNGDVVAIDY
KHYTPSFKKGAKLLHK
PIVWHVNNATNKATYKPNTWCIRCLWSTKPVETSNSFDVLKSEDAQG M DN
LACEDLKPVSEEVVENPTIQKDVLECNVKTTEVVG DI I LKPAN
NSLKITEEVG HTDLMAAYVDNSSLTIKKPNELSRVLG LKTLATHG
LAAVNSVPWDTIANYAKPFLNKVVSTTTNIVTRCLNRVCTNYM PYF FTLL
LQLCTFTRSTNSRIKASMPTTIAKNTVKSVGKFCLEASFN YLKSP N FSKLI N I I
IWELLLSVCLGSLIYSTAALGVLMSNLGM PSYCTGYREGYLNST
NVTIATYCTGSI PCSVCLSG LDSLDTYPSLETIQITISSFKWDLTAFG LVAEWFLAYILFTRFFYVLG LAAIM
QLFFSYFAVHFISNSWLM WLI I NLV
QMAPISAMVRMYIFFASFYYVWKSYVHVVDGCNSSTCM M CYKRNRATRVECTTIVNGVRRSFYVYANGGKG
FCKLHNWNCVN CDTFCAG
STFISDEVARDLSLQFKRPI N PTDQSSYIVDSVTVKN GS!
HLYFDKAGQKTYERHSLSHFVNLDNLRANNTKGSLPI NVIVFDG KSKCEESSAKSAS
VYYSQLMCQP I LLLDQALVSDVG DSAEVAVKM FDAYVNTESSTENVPM
EKLKTLVATAEAELAKNVSLDNVLSTFISAARQG FVDSDVETKDV
VECLKLSHQSDI EVTGDSCN NYM LTYN KVEN MTPRDLGACI DCSARH I NAQVAKSHN
IALIWNVI<DEMSLSEQLRKQI RSAAKKNNLPFKLTC
ATTRQVVNVVTTKIALKGGKIVN NWLKQLIKVTLVFLEVAAIFYLITPVHVMSKHTDFSSEI
IGYKAIDGGVTRDIASTDTCFANKHADFDTWFS
QRGGSYTN DKACP LI AAVITREVG FVVPGLPGTI [RUN GDF LH FLPRVESAVG NICYTPSKLI EYT
DFATSACVLAAECT I FKDASGKPVPYCYDT
NVLEGSVAYESLRPDTRYVLM DGSI I QFPNTYLEGSVRVVTTFDSEYCRHGTCERSEAGVCVSTSGRWVLN
NDYYRSLPGVFCGVDAVN LLTN
M FTPLIQPIGALDISASIVAGGIVAIVVTCLAYYFM R
FRRAFGEYSHVVAFNTLLFLMSFTVLCLTPVYSFLPGVYSVIYLYLTFYLTN DVSF LAN! Q
WM VM FTP LVPFWITI AYI ICISTKHEYWFFSN YLKRRVVENGVSFSTFEEAALCTELLN
KEMYLKLRSDVLLPLTQYN RYLA LYN KYKYFSGAM D
TTSYREAACCHLAKALN DFSNSGSDVLYQP PQTSITSAVLQSGFRKM AFPSGKVEGCM VQVTCGTTTLNG
LWLDDVVYCPRHVICTSEDM LN
PNYEDLLIRKSNHNFLVQAG NVQLRVIG HSM QNCVLKLKVDTAN PKTPKYKEVRI
QPGQTFSVLACYNGSPSGVYQCAM R P N FT! KGSFLN GS
CGSVG FN I DYDCVSFCYM H H M ELPTGVHAGTDLEG NFYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVI
NG DRWFLNRFTTTLNDFN LVA
M KYNYEPLTQDH VD! LG PLSAQTGIAVLDMCASLKELLQNG M NG RTI LGSALLEDEFTP
FDVVRQCSGVTFQSAVKRTIKGTHHWLLLTI LTSL
LVLVQSTQWSLFF FLY ENAFLPFAMG I I AMSAFAM M FVKHKHAFLCLFLLPSLATVAYFN MVYM
PASWVM RI MTWLDMVDTSLSG FKLKD
CVMYASAVVLLILMTARTVYDDGARRVWTLM NVLTLVYKVYYGNALDQAISMWALIISVTSNYSGVVTTVM FLARG
IVFM CVEYCP I FFITG N
103
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TLQCIM
LVYCFLGYFCTCYFGLFCLLNRYFRLTLGVYDYLVSTQEFRYMNSQGLLPPKNSIDAFKLNIKLLGVGGKPCIKVATVQ
SKMSDVKCTSV
VLLSVLQQLRVESSSKLWAQCVQLH N DI LLAKDTTEAFEKMVSLLSVLLSMQGAVDI
NKLCEEMLDNRATLQAIASEFSSLPSYAAFATAQEAY
EQAVANG DSEVVLKKLKKSLNVAKSEFD RDAAM QRKLEKMADQAMTQMYKQARSEDKRAKVTSA MQTM LFTM
LRKLDN DALN NIIN NA
RDGCVPLN I I P LTTAAK LM VVI P DYNTYKNTCDGTTFTYASALWEIQQVVDADSKIVQLSEISM
DNSPNLAWPLIVTALRANSAVKLQNN ELSP
VALRQMSCAAGTTQTACTDDNALAYYNTTKGGRFVLALLSDLQDLKWARFPKSDGTGTIYTELEPPCRFVTDTPKGPKV
KYLYFI KG LN NLNR
GMVLGSLAATVRLQAGNATEVPANSTVLSFCAFAVDAAKAYKDYLASGGQPITNCVKMLCTHTGTGQAITVTPEANMDQ
ESFGGASCCLYC
RCHIDHPNPKGFCDLKGKYVQIPTTCAN DPVGFTLKNTVCTVCGMWKGYGCSCDQLREPM LQSADAQSFLNGFAV
SEQ ID NO: 17
>SARS-CoV-2_S_MedUniWien (Sprotein_hCoV19AustriaCeM M03602020)
MFVFLVLLPLVSSQCVN
LTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDN PVLPFN
DGVYFAS
TEKSNIIRGWIFGTTLDSKTQSLLIVN NATNVVIKVCEFQFCNDPFLGVYYHKN NKSWMESEFRVYSSAN
NCTFEYVSQPFLMDLEG KQGNFK
N LREFVFKN I DGYFKIYSKHTPI N LVRDLPQGFSALEP LVDLPIG I N ITRFQTLLALHRSYLTPG
DSSSGVVTAGAAAYYVGYLQPRTFLLKYN ENGT
1TDAVDCALDP LSETKCTLKSFTVEKG 1YQTSN FRXQPTES1 VRFP N ITN LCPFG EVFNATRFASVYAWN
RKR1SNCVADYSVLYNSASFSTFKCYG
VSPTKLNDLCFTNVYADSFVIRGDEVRQ1APGQTGKIADYNYKLPDDFTGCVIAWNSNN
LDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAG
STPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCG PKKSTN LVKN KCVN FN FNG
LTGTG VLTESN KKF LP FQQFGRDI
ADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQGVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAG
CLIGAEHVNNSYEC
DI PIGAGICASYQTQTNSP RRARSVASQSI lAYTMSLGAENSVAYSXNSIAIPTNFTISVTTEI
LPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFC
TQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQ1LPDPSKPSKRSFI
EDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFN
GLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQI P FAMQMAYRFN GI GVTQNVLYENQKLIANQFN
SAIGKIQDSLSSTASALGKLQD
VVN QNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQI DRLITG RLQSLQTYVTQQLI
RAAEIRVSAN LAATKMSECVLGQSKRVDFCGK
GYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSG
NCDVVIGIVNNTV
YDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGI NASVVN IQKEIDRLNEVAKNLN
ESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIM
LCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT
SEQ ID NO: 18
>Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-
2/hunnan/England/ex-SA/2021, EVAg Ref-
SKU:004V-04071 (SA_P2) complete genome. South-African B.1.351 lineage
ATTAAAGGTTTATACCTTCCCAGGTAACAAACCAACCAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACG
AACTTTAAAAT
CTGTGTGGCTGTCACTCG GCTG CATG CTTAGTG CACTCACGCAGTATAATTAATAACTAATTACTGTCGTTG
ACAGG ACAC
G AG TAACTCTTCTATCTTCTG CAGG CTGCTTACG GTTTCGTCCGTGTTG CAG CCGATCATCAG
CACATCTAG GTTTTGTCCG
GGTGTG ACCG AAAG GTAAG ATG G AG AG CCTTGTC CCTG GTTTCAACG AG AAAACACACG
TCCAACTCAG TTTG CCTGTTTT
ACAG GTTCGCG ACGTGCTCGTACGTG GCTTTGG AG ACTCCGTG G AG G AG GTCTTATCAG AG G CAC
GTCAACATCTTAAAG
ATG GCACTTGTG G CTTAGTAG AAGTTG AAAAAG G C GTTTTG CCTCAACTTG AACAG CC CTATG
TGTTCATCAAACGTTCG G
ATG CTCG AACTG CACCTCATG GT CATGTTATG GTTG AG CTG GTAG CAGAACTCG
AAGGCATTCAGTACGG TCGTAGTG GT
GAG ACACTTGGTGTCCTTGTCCCTCATGTGGG CGAAATACCAGTG G CTTACCGCAAGGTTCTTCTTCGTAAG
AACG GTAAT
AAAG G AG CTG GTG GCCATAGTTACG GCG CCGATCTAAAGTCATTTG ACTTAG G CG AC G AG CTTG
G CACTG ATC CTTATG A
AG ATTTTCAAG AAAACTG G AACACTAAACATAG CAGTGGTGTTACCCGTGAACTCATG CGTG AG
CTTAACG G AG G G G CAT
ACACTCGCTATGTCGATAACAACTTCTGTGG CCCTGATG G CTACCCTCTTG AGTG CATTAAAG ACCTTCTAG
CAC GTG CTG G
TAAAGCTTCATG CACTTTGTCCGAACAACTG G ACTTTATTG ACACTAAG AG G G GTG TATACTG CTG
CC GTG AACATG AG CA
TGAAATTG CTTG GTACACG G AACGTTCTGAAAAG AG CTATG AATTGCAGACACCTTTTG AAATTAAATTG
GCAAAGAAATT
TGACATCTTCAATGGGG AATGTCCAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAG
GGTTGAAAAG
AAAAAG CTTG ATGG CTTTATG G G TAG AATTCG ATCTGTCTATC CAGTTG CGTCACCAAATG AATG
CAACCAAATG TGCCTTT
CAACTCTCATG AAG TGTG ATCATTGTG GT G AAACTTCATG G CAG ACG GGCG
ATTTTGTTAAAGCCACTTGCGAATTTTGTG
G CACTG AG AATTTGACTAAAGAAGGTGCCACTACTTGTG GTTACTTACCCCAAAATG
CTGTTGTTAAAATTTATTGTCCAGC
ATGTCACAATTCAGAAGTAGGACCTG AG CATAGTCTTG C CG AATACCATAATGAATCTGG
CTTGAAAACCATTCTTCGTAA
GGGTGG TCGCACTATTGCCTTTGG AG G CTG TG TGTTCTCTTATGTTG G TTG C CATAACAAGTG TG
CCTATTG GGTTCCACGT
GCTAGCG CTAACATAGGTTGTAACCATACAG GTGTTGTTGG AG AAG GTTCCG
AAGGTCTTAATGACAACCTTCTTG AAATA
CTCCAAAAAG AG AAA GTCAACATCAATATTGTTG GTG ACTTTAAACTTAATGAAG AG ATC G
CCATTATTTTG G CATCTTTTT
CTG CTTCCACAAGTGCTTTTGTGG AAACTGTG AAAGGTTTG GATTATAAAGCATTCAAACAAATTGTTG
AATCCTGTG GTA
ATTTTAAAGTTACAAAAGGAAAAGCTAAAAAAGGTGCCTGG AATATTGGTGAACAG
AAATCAATACTGAGTCCTCTTTATG
CATTTGCATCAG AG G CTG CTCGTGTTG TACG
ATCAATTTTCTCCCGCACTCTTGAAACTGCTCAAAATTCTGTG CGTGTTTTA
CAGAAGGCCGCTATAACAATACTAGATG G AATTTCACAGTATTCACTG AG ACTCATTG ATG CTATG
ATGTTCACATCTG ATT
TGG CTACTAACAATCTAGTTGTAATG GCCTACATTACAGGTGGTGTTGTTCAGTTG ACTTCGCAG
TGGCTAACTAACATCTT
TGG CACTGTTTATGAAAAACTCAAACCCGTCCTTGATTGGCTTGAAG AGAAGTTTAAGGAAG
GTGTAGAGTTTCTTAGAGA
CGGTTGG GAAATTGTTAAATTTATCTCAACCTGTG CTTGTGAAATTGTCGGTG
GACAAATTGTCACCTGTGCAAAG GAAAT
TAAG G AG AGTG TTCAG ACATTCTTTAAGCTTGTAAATAAATTTTTGG
CTTTGTGTGCTGACTCTATCATTATTGGTGG AG CT
104
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AAACTTAAAG CCTTG AATTTAG G TGAAACATTTGTCACG CACTCAAAG G G ATTG TAC AG AAAG TG
T G TTAAATC CA G AG AA
GAAACTG G CCTACTCATG CCTCTAAAAG CC CCAAAAG AAATTATCTT CTTAG AG G GAG
AAACACTTCCCACAG AAGTGTTA
ACAG AG GAAGTTGTCTTGAAAACTG GTGATTTACAACCATTAG AACAACCTACTAGTGAAG CTGTTGAAG
CTCCATTG G TT
G GTACACCAGTTTGTATTAACG G G CTTATGTTG CTCG AAATC AAAG AC ACAG AAAAG TA CTGTG
CCCTTG CAC CTAATATG
ATG GTAACTAACAATACCTTCACACTCAAAG G CG GTG CAC CAACAAAG GTTACTTTTG G TG AT
GACACTGTG ATAG AAGTG
CAAG GTTAC AAG AG TG TG AATAT CACTMG AA CTTG ATGAAAG GATT GATAAAGTACTTAAT G AG
AAG TG CT CTG CCTAT
ACAGTTGAACTCG G TAC AG AAG TAAATG AG TT CG C CTG TG TT G TG G C AG ATG CTG
TCATAAAAACTTTG CAACCAG TATCT
G AATTACTTAC AC CACTG G G CATTGATTTAGATG AG TG G AG TATG G CTACATACTACTTATTTG
ATG AG TCT G GTG AG TTTA
AATTG G CTTCAC ATATG TATT G TTCTTTTTAC C CTC CA G ATG AG GATGAAG AAG AA G GTG
ATTG TG AA G AAG AAG A G TTTG
AG CCATCAACTCAATATG AG TATG GTACTGAAG ATGATTACCAAG GTAAACCTTTG G AATTTG
GTGCCACTTCTG CTG CTCT
TCAAC CTG AAG AAG A G CAAG AAGAAG ATTG GTTAG ATG AT G ATA G TC AAC AAACT G TTG
G TC AACAAG AC G G CAG TG AG
G AC AATCAG ACAACTACTATTCAAAC AATTGTTG AG GTTCAACCTCAATTAG AG ATG G AA CTTAC
AC CAG TTG TTCAG ACTA
TTG AAGTGAATAGTTTTAGTG GTTATTTAAAACTTACTG ACAATGTATACATTAAAAATG CAG A CATTG TG
G AAG AA G CTA
AAAAG G TAAAAC CAA CAGTG G TT G TTAATG C AG CCAATGTTTACCTTAAACATG GAG G AG
GTGTTG C AG GAG CCTTAAAT
AAG G CTACTAACAATG CCATG CAA G TTG AATCTGATG ATTACATAG CTACTAATG G AC CA
CTTAAAG TG G GTG G TA G TTG T
GTTTTAAG CG G ACACAATCTTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAG GTG
AAGACATTCAACTTC
TTAAG AG T G CTTATG AAAATTTTAATCAG C AC G AAG TT CTACTTG CA C CATTATTATCAG CTG
GTATTTTTG GTG CTG A C C CT
ATACATTCTTTAAG AG TTTG T G TAG ATACTGTTCG CACAAATGTCTACTTAG CT G TCTTTG
ATAAAAATCTCTATG A CAAACT
TGTTTCAAG CTTTTTG GAAATGAAG A G TG AAAAG C AAG TT G AACAAAAG AT C G CT G AG
ATTC CTAAAG AG G AAGTTAAG C
CATTTATAACTG AAA G TAAAC CTTCA G TTG AACAG AG AAAAC AAG ATG ATAAG AAAATCAAAG
CTTG TG TTG AAG AAG TT
ACAACAACTCTG G AAG AAACTAAG TTC CT CACAG AAAACTT G TTACTTTATATT G ACATTAATG G
CAATCTTC ATC CA G ATT
CTG C CACT CTTG TTAG TG AC ATTG ACATCACTTTCTTAAAGAAAG ATG CTCCATATATAGTG G GTG
ATG TTG TT CAAG AG G G
TGTTTTAACTG CTGTG G TT ATAC CTACTAAAAAG G CTG GTG G C ACTA CTG AAAT G TTAG
CGAAAG CTTTG AG AAAAGTG CC
AACAG ACAATTATATAACCACTTACCCG G GTCAG G GTTTAAATG GTTACACTG TAG AG GAG G
CAAAGACAG TG CTTAAAA
AG T G TAAAAG TG CCTTTTACATTCTACCATCTATTATCT CTAAT G AG AA G CAAG AAATTCTTG G
AACTGTTTCTTG GAATTTG
CG AG AAATG CTTG CACATG CAG AAG AAA CAC G CAAATTAATG CCTGTCTGTGTG G AAACTAAAG
CCATAGTTTCAACTATA
CAG CGTAAATATAAG G G TATTAAAATAC AAG AG G GTGTG GTTG ATTATG GTG CTAG
ATTTTACTTTTAC A C C AG TAAAACA
ACTG TAG CGTCACTTATCAACACACTTAACGATCTAAATGAAACTCTTGTTACAATG CCACTTG G
CTATGTAACACATG G CT
TAAATTTG GAAGAAG CTG CTCG G TATATG A GATCTCTCAAAGTG CCAG CTACAG TTTCTG TTTCTT
CAC CT G ATG CTGTTAC
AG CGTATAATG GTTATCTTACTTCTTCTTCTAAAACACCTGAAG AA CATTTTATTG A AACCAT
CTCACTTGCTGGTTCCTATA
AAGATTG GTCCTATTCTG G A CAATCTACACAACTAG G TATAG AATTTCTTAAG A G AG G TG
ATAAAAG TG TATATTA CA CTA
G TAATC CTAC CACATTC CA C CTAG ATG G TG AAG TTAT CAC CTTTG ACAATCTTAAG AC
ACTTCTTTCTTT G AG A G AAG T G AG
GACTATTAAG G T G TTTACAA C AG TAG ACAAC ATTAAC CTC C AC AC G CAAGTTGTG G ACATG
TCAAT G AC ATATG GACAACA
GTTTG G TC CAA CTTATTTG G ATG G AG CT G ATG TTA CTAAAATAAAAC CTCATAATTCA CATG
AAG G TAAAACATTTTATG TT
TTACCTAATGATG ACACT CTAC G TG TTG AG G CTTTTG A G TACTAC CAC ACAACT G ATC CTAG
TTTT CTG G G TAG GTACATGT
CAG CATTAAATCACACTAAAAATTG G AAATACCCACAAGTTAATG GTTTAACTTCTATTAAATGG G CA G
ATAACAA CTG TTA
TCTTG CCACTG C ATTG TTAAC ACTC C AACAAATAG AG TTG AAG TTTAATC CAC CT G
CTCTACAAG ATG CTTATTACAG AG CA
AG G G CTG GTG AAG CT G CTAACTTTTGTG CA CTTATCTTAG C CTACT G TAATAAG AC A G
TAG G TG A GTTA G GTG ATG TTAG A
G AAA CAATG AG TTACTTG TTTC AACATG CCAATTTAG ATTCTTG C AAAAG AG T CTT G AAC G
TG G TG TG TAAAACTTG TG GA
CAACAG CAGACAACCCTTAAG G GTG TAG AAG CTGTTATGTACATG G G
CACACITTCTTATGAACAATTTAAGAAAG GTG TT
CAG ATAC CTTG TA C G TG TG GTAAACAAG CTAC AAAATAT CTAG TACAAC AG G AG TCAC
CTTTT G TTATG ATG TCAG CAC CA
C CT G CTCA G TAT G AACTTAAG CATG G TAC ATTTACTTG T G CTAG TG A G TACA CTG G
TAATTACCAGTGTG GTCACTATAAAC
ATATAACTTCTAAAGAAACTTTGTATTG CATAG AC G GTG CTTTACTTACAAAG TC CT CAG AATACAAAG
GT CCTATTACG GA
TG TTTTCTACAAAG AAAAC AG TTACACAAC AACCATAAAACCAGTTACTTATAAATTG GATG GTGTTG
TTTGTACAG AAATT
G AC C CTAAG TTG G ACAATTATTATAAGAAAG ACAATT CTTATTTCAC AG AG CAAC C AATTG
ATCTTG TAC CAAAC CAAC CAT
ATCCAAACG CAAG CTTCG ATAATTTTAAGTTTGTATGTG ATAATATCAAATTTG CTG
ATGATTTAAACCAGTTAACTG G TTA
CAAG AAAC CT G CTT CAAG A G AG CTTAAAGTTACATTTTTCCCTGACTTAAATG GTG ATGTG GT G
G CTATTG ATTATAAAC AC
TA CA CACCCTCTTTTAAG AAAG G AG CTAAATTGTTACATAAACCTATTGTTTG G CATG TTAA CA ATG
CAA CTAATA AA G C CA
C G TATAAA C CAAAT AC CTG G TG TATAC G TT G TCTTTG GAG C ACAAAAC CAG TTG AAA
CATCAAATTC G TTTG ATG TACTG AA
G TC AG AG G AC G CG CAG G GAATG GATAATCTTG CCTG CGAAG ATCTAAAAC CA G TCT CTG
AA G AAG TAG T G GAAAATCCTA
C CATACAG AAAG AC G TTCTT G AG TG TAATG T G AAAACTA C C G AAG TTGTAG GAG
ACATTATACTTAAACCAG CAAATAATA
G TTTAAAAATTACAG AAG AG GTTG G CCACACAG ATCTAATG G CTG
CTTATGTAGACAATTCTAGTCTTACTATTAAGAAAC
CTAATGAATTATCTAGAGTATTAG GTTTG AAAACC CTTG CTACTCATG GTTTAG CTG CTGTTAATAG
TGTCCCTTG G G ATAC
TATA G CTAATTATG CTAAG C CTTTTCTTAACAAAG TT G TTAG TAC AACTACTAACAT AG TTAC AC
G G TG TTTAAA C C GT G TTT
G TA CTAATTATATG CCTTATTTCTTTACTTTATTG CTAC AATTG TG TA CTTTTACTAG AAG TA C
AAATT CTAG AATTAAA G CAT
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CTATG CC G ACTA CTATAG CAAAG AATACTG TTAAG AG TG TCG GTAAATTTTG TCTAG AG G
CTTCATTTAATTATTTGAAGTC
AC CTAATTTTTCTAAACTG ATAAATATTATAATTTG GTTTTTACTATTAAGTGTTTG CCTAG GTTCTTTAAT
MTACTCAACCG
CTG CTTTAG GTGTTTTAATGTCTAATTTAG G CATG CCTTCTTACTGTACTG G TTACAG AG AAG G
CTATTTGAACTCTACTAAT
GTCACTATTG CAACCTACTGTACTG G TTCTATAC CTTG TAG T G TTTG T CTTAG TG G TTTA G
ATT CTTTAG ACA C CTAT C CTT CT
TTAGAAACTATACAAATTACCATTTCATCTTTTAAATG G GATTTAACTG CTTTTG G CTTAGTTG CAG AGTG
GTTTTTG G CATA
TATTCTTTTCACTAGGTTTTTCTATGTACTTG GATTG G CTG CAATCATG CAATTGTTTTTCAG CTATTTTG
CAG TA CATTTTAT
TAG TAATT CTTG G CTT ATG TG GTTAATAATTAATCTTGTACAAATG G CCCCGATTTCAG CTATG
GTTAGAATGTACATCTTCT
TTG CATCATTTTATTATGTATG GAAAAGTTATGTG CATG TTG TAG AC G
GTTGTAATTCATCAACTTGTATGATGTGTTACAA
AC G TAATAG AG CAACAAG A G TC G AATGTACAACTATTGTTAATG GTGTTAGAAG
GTCCTTTTATGTCTATG CTAATG G AG G
TAAAG G CTTTTG CAAACTACACAATTG GAATTGTGTTAATTGTGATACATTCTGTG CTG G TAG TAC
ATTTATTAG T G AT G AA
GTTG CG AG AG ACTTG TCACTACAGTTTAAAAG ACCAATAAATCCTACTG ACCAGTCTTCTTACATC GTTG
ATAG TGTTACAG
TGAAGAATG G TT C CATC CAT CTTTACTTTG ATAAAG CTG GTCAAAAGACTTATG AAAG AC ATTCT
CTCT CT CATTTTG TTAAC
TTAG ACAAC CTG AG AG CTAATAACACTAAAG GTTCATTG C CTATTAATG TTATAG TTTTTG AT G
GTAAATCAAAATGTG AAG
AATCATCTG CAAAATCAG C G TCT G TTTACTA CAG TC AG CTTATGTGTCAACCTATACTGTTACTAG
ATCAG G CATTAGTGTC
TG ATG TT G GTG ATAGTG CG GAAGTTG C AG TTAAAATG TTTG ATG CTTA C G TTAATAC G
TTTTCAT CAA CTTTTAACG TAC CA
ATG GAAAAACTCAAAACACTAGTTG CAACTG CA G AAG CT G AACTTG CAAAGAATGTGTCCTTAG AC
AATGT CTTATCTACT
TTTATTTCAG CAG CTCG G CAAG G GTTTGTTG ATTC AG ATG TAG AAACTAAAGATGTTGTTG
AATGTCTTAAATTGTCACATC
AATCTGACATAGAAGTTACTG G CGATAGTTGTAATAACTATATG CTCACCTATAACAAAGTTGAAAACATG
ACACCCCGTG
AC CTTG GTG CTTGTATTG ACTGTAGTG CG CGTCATATTAATG C G CAG GTAG
CAAAAAGTCACAACATTG CTTTG ATATG GA
AC G TTAAAG ATTT CATG TCATTG TCTG AA CAACTA C G AAAACAAATAC G TAG TG CTG
CTAAAAAGAATAACTTACCTTTTAA
G TT G ACAT G TG CAACTACTAG ACAAGTTGTTAATGTTGTAACAACAAAG ATAG CACTTAAG G GTG
GTAAAATTGTTAATAA
TT G GTTGAAG CA G TTAATTAAAG TTACACTT G TG TTC CTTTTT G TTG CTG
CTATTTTCTATTTAATAACAC CTG TT C ATG TC AT
GTCTAAACATACTG ACTTTTCAAGTGAAATCATAG GATACAAG G CTATTGATGGTG
GTGTCACTCGTGACATAG CAT CTAC
AG ATACTT G TTTTG CT AACAAA CATG CTG ATTTT G AC AC ATG GTTTAG CCAG CGTG GTG G
TAG TTATACTAATG ACAAAG CT
TG CCCATTGATTG CTG CAGTCATAACAAG AG AAGTG G GTTTTGTCGTG CCTG GTTTG CCTG G CAC
G ATATTACG CA CAACT
AATG GTG ACTTTTTG CATTTCTTAC CTAG AG TTTTTAG T G CAGTTG G TAAC ATCTG TTAC ACAC
C ATCAAAACTTATAG A GTA
CACTGACTTTG C AACATC AG CTTGTGTTTTG G CT G CT G AATG TACAATTTTTAAAG ATG CTTCTG
GTAAG C CA G TAC C ATAT
TGTTATG ATACCAATGTACTAG AAG GTTCTGTTG CTTATG AAAGTTTACG C C CT G ACA CAC G
TTATG TG CT CATG GATG G CT
CTATTATTCAATTTCCTAACACCTACCTTGAAG G TT CTG TTAG AG TG GTAACAACTITTGATTCTG AG
TACTG TAG G CA C G G
CACTTGTG AAAGATCAGAAG CTG GTGTTTGTGTATCTACTAGTG G TAG ATG G GTACTTAACAATG
ATTATTACAG ATCTTTA
CCAG G AG TTTTCT G TG G TG T AG ATG
CTGTAAATTTATTTACTAATATGTTTACACCACTAATTCAACCTATTG GTG CTTTG GA
CATATCAG CATCTATAG TAG CTG GTG GTATTG TAG CTATCG TAG TAACATG CCTTG
CCTACTATTTTATG AG GTTTAG AAG A
G CTTTTG GTG AATAC AG TCATG TA G TTG C CTTTAATACTTTACTATTC CTTATG TCATT CACT G
TACT CTG TTTAA CAC CAG TT
TACT CATT CTTAC CTG G TG TTTATT CTG TTATTTACTT G TACTTG AC ATTTTATCTTACTAAT G
ATG TTT CTTTTTTAG CAC ATA
TTC AG TG GATG G TTATG TTCACA C CTTT AG TAC CTTTCTG GATAACAATTG
CTTATATCATTTGTATTTCCACAAAG CATTTCT
ATTG GTTCTTTAGTAATTACCTAAAG AG AC GTG TAG TCTTTAATG GTGTTTCCTTTAGTACTTTTG AAG
AAG CTG CG CTGTG
CAC CTTTTTG TTAAATAAAG AAATG TATCTAAAGTT G C G TAG TG ATGTG CTATTAC CT CTTAC G
CAATATAATAGATACTTA
G CT CTTTATAATAAG TACAAG TATTTTAG T G GAG CAATG GATACAACTAG CTACAG A G AAG CTG
CTTGTTGTCATCTCG CA
AAG G CTCTCAATG ACTT CAG TAACTCA G GTTCTG ATG TTCTTTAC CAAC CAC C ACAAAC
CTCTATCAC CTCAG CTGTTTTG CA
G AG TG GTTTTAGAAAAATG G CATT C C CAT CTG GTAAAGTTG AG G GTTGTATG G TA CAA G
TAACTT G TG GTACAACTACACT
TAACG GTCTTTG G CTTGATG AC G TAG TTTACTG T C CAAG ACATGTGATCTG CA C CTCTG AAG
AC ATG CTTAACCCTAATTAT
GAAG ATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTACAG G CTG GTAATGTTCAACTCAG G
GTTATTG G ACATTCTA
TG CAAAATTGTGTACTTAAG CTTAG G GTTGATACAG CCAATC CTAAG ACAC CTAAG TATAAG TTTG
TTCG CATTCAACCAG
G ACAG ACTTTTTCAGTGTTAG CTTGTTACAATG GTTCACCATCTG GTGTTTACCAATGTG CTATG AG G
CCCAATTTCACTATT
AAG G G TT CATTC CTTAATG GTTCATGTG G TAG TGTTG
GTTTTAACATAGATTATGACTGTGTCTCTTTTTKTTACATG CA C CA
TATG GAATTACCAACTG G AG TT CATG CTG G CACAG ACTTAGAAG GTAACTITTATG G AC
CTTTTGTTG AC AG G CA AAC AG C
ACAAG CAG CTG GTACG G ACACAACTATTA C AG TTAATG TTTTAG CTTG G TTG TA C G CTG
CTGTTATAAATGG AG ACA G G TG
GTTTCTCAATCG ATTTACCACAACTCTTAATG ACTTTAACCTTGTG G CTATG AA GTACAATTATG
AACYTCTAA CA CAA G ACC
ATG TTG A CATACTAG G A C CT CTTTCT G CT CAAACT G GAATTG C C G TTTTAG ATATG TG
TG CTTCATTAAAAGAATTACTG CA
AAATG GTATGAATG G AC G TAC CATATTG G G TAG T G CTTTATTA G AAG AT G AATTTAC AC
CTTTT G ATG TTGTTA G ACAATG
CTC AG GTGTTACTTTCCAAAGTG CA G TG AAAAG AAC AATCAA G G G TACAC AC CACT G G TTG
TTACTCA CAATTTTG A CTTCA
CTTTTAG TTTTAG TC CAG AG TACTC AATG GTCTTTGTTCTTTTTTTTGTATG AAAATG
CCTTTTTACCTTTTG CTATG G GTATT
AUG CTATGTCTGCTTTTG CAATG ATGTTTGTCAAACATAAG CATG
CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG CCA CT
G TAG CTTATTTTAATATG GTCTATATG CCTG CTAGTTG G GTGATG CGTATTATG ACATG GTTG
GATATG G TTG ATACTAG TT
TG NNNNN NAAG CTAAAAGACTGTGTTATGTATG CATCAG CTGTAGTGTTACTAATCCTTATGACAG
CAAGAACTGTGTAT
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GATGATG GTG CTAG G AG AGTGTG GACACTTATGAATGTCTTGACACTCGTTTATAAAGTTTATTATG
GTAATG CTTTAG AT
CAAG CCATTTCCATGTG G G CT CTTATAATCT CTG TTACTT CTAACTACTCAG G T G TA G
TTACAACTG T CATG TTTTTG G CCAG
AG G TATT G TTTTTAT G TG TG TTG AG TATT G CCCTATTTTCTTCATAACTG G TAATACACTTC
AG TG TATAAT G CTAGTTTATT
GTTTCTTAG G CTATTTTTGTACTTGTTACTTTG G CCTCTTTTGTTTACTCAACCG CTA CTTTAG ACTG
ACT CTTG GTGTTTATG
ATTACTTAGTTTCTACACAG GAGTTTAGATATATG AATTCACAG G GACTAYTCCCACCCAAGAATAG CATAG
AT G CCTTCAA
ACTCAACATTAAATTGTTG G GTGTTG GTG G CAAACCTTGTAT CAAAG TAG
CCACTGTACAGTCTAAAATGTCAGATGTAAA
GTG CACAT CAG TAG TCTTACT CTCA G TTTTG C AACAACT CAG A G TAG
AATCATCATCTAAATTGTG G G CT CAATG TG TC CAG
TTACACAATGACATTCTCTTAG CTAAAG ATACTACTG AAG CCTTTG AAAAAATG
GTTTCACTACTTTCTGTTTTG CTTTC CAT
G CAG G GTG CTG TAG ACATAAAC AAG CTTTGTGAAG AAATG CTG G ACAACAG G G
CAACCTTACAAG CTATAG CCTC AG AG T
TTAGTTCCCTTCCATCATATG CA G CTTTTG CTACTG CTCAAG AAG CTTATG AG CAG G CTGTTG
CTAATG G TGATTCTG AAGT
TGTTCTTAAAAAGTTG AAGAAGTCTTTGAATGTG G CTAAATCTG AATTTG ACC GTGATG CAG CCATG
CAACG TAAG TT G GA
AAAG ATG G CTGATCAAG CTATGACCCAAATGTATAAACAG G CTAG ATCT G AG G ACAAG AG G G
CAAAAGTTACTAGTG CTA
TG C AG ACAATG CTTTTCACTATG CTTAGAAAGTTG G ATAAT G AT G
CACTCAACAACATTATCAACAATG CAAG AG ATG GTT
GTGTTCCCTTG AACATAATACCTCTTACAAC AG C AG CCAAACTAATG G TT G TCATACCAG
ACTATAACACATATAAAAATAC
GTGTGATG GTACAACATTTACTTATG CAT CAG CATTGTG G GAAATCCAACAG GTTG TAG ATG
CAGATAGTAAAATTGTTCA
ACTTAGTGAAATTAGTATG G ACAATTCACCTAATTTAG CATG G CCTCTTATTGTAACAG CTTTAAG G G
CCAATTCTG CT G TC
AAATTACAG AATAAT G AG CTTAGTCCTGTTG CACTACGACAG ATGTCTTGTG CT G CC G
GTACTACACAAACTG CTTG CACT
G AT G ACAAT G CGTTAG CTTACTACAACACAACAAAG G G AG G TAG G TTTG TACIT G
CACTGTTATCCG ATTTACAG G ATTTG
AAATG G G CTAGATTCCCTAAG AG TG AT G G AACTG G TA CTATCTATAC AG AACTG G AACCAC
CTTG TAG G TTTG TTAC AG AC
ACACCTAAAG GTCCTAAAGTGAAGTATTTATACTTTATTAAAG GATTAAACAACCTAAATAG AG GTATG
GTACTTG G TAG T
TAG CTG CCACAGTACGTCTACAAG CTG GTAATG CAACAG AAGTG CCTG
CCAATTCAACTGTATTATCTTTCTGTG CTITTG
CTG TAG ATG CTG CTAAAG CTTACAAAGATTATCTAG CTAGTG GGGG
ACAACCAATCACTAATTGTGTTAAG ATG TTG TG TA
CACACACTG G TA CTG GTCAG G CAATAA CAG TTAC AC C G GAAG CCAATATG G ATCAAG
AATCCTTTG GTG GTG CATCG T G TT
G TCTG TA CTG CCGTTG CCACATAGATCATCCAAATCCTAAAG GATTTTGTGACTTAAAAG
GTAAGTATGTACAAATACCTAC
AACTTGTG CTAATG ACC CTGTG G GTTTTACACTTAAAAACACAGTCTGTACCGTCTG CG GTATGTG
GAAAG GTTATG G CTG
TAG TTGTG ATCAA CTCCG CGAACCCATG CTTCAGTCAG CTGATG CAC AATCGTTTTTAAAC G G
GTTTG CG GTGTAAGTG CA
G CC CGTCTTACAC CGTG CG G CACAG G CACTAGTACTGATGTCGTATACAG GG CTTTTG AC AT
CTACAATG ATAAAG TAG CT
G GTTTTG CTAAATTCCTAAAAACTAATTGTTGTCG CTTCCAAGAAAAG G A CG AAG ATG AC
AATTTAATTG ATTCTTACTTTG
TAG TTAAG AG ACA CACTTTCTCTAACTACCAAC ATG AAG AAACAATTTATAATTTACTTAAG G ATTGT
CC AG CTGTTG CTAA
ACATGACTTCTTTAAGTTTAG AATAG AC G GTG AC ATG G TACCAC ATATAT CAC G TCAAC G
TCTTACTAAATAC ACAATG G CA
GACCTCGTCTATG CTTTAAG G CATTTTGATGAAG G TAATTG T G ACACATTAAA AG AAATACTTG T
CAC ATA CAATTG TTG TG
ATG ATGATTATTTCAATAAAAAG GACTG G TATG ATTTTG TAG AAAACCCAG ATATATTACG CGTATACG
CCAACTTAG GTG
AACGTGTACG CCAAG CTTTG TTAAAAAC AG TAC AATTCTGTG ATG CCATGCGAAATG CTG
GTATTGTTG GTG TACTGACAT
TAG ATAATCAAGATCTCAATG GTAACTG GTATG ATTTCG GTGATTTCATACAAACCACG CCAG GTAGTG G
AG TTCCTG TTG
TAG ATTCTTATTATTCATTGTTAATG CCTATATTAACCTTG AC C AG G G CTTTAACTG CAG AG T CA
CATG TTG AC ACTG ACTTA
ACAAAG CCTTACATTAAGTG G GATTTGTTAAAATATGACTTCACG GAAG AG AG G TTAAAACTCTTTG AC
C G TTATTTTAAAT
ATTG G GATCAG ACATACCACCCAAATTGTGTTAACTGTTTG GATGACAGATG CATTCTGCATTGTG
CAAACTTTAATGTTTT
ATTCTCTACAGTGTTCCCACTTACAAGTTTTG G ACCACTAG T G AG AAAAATATTTG TTG ATG G TG TT
CCATTTG TAG TTTCAA
CTG G ATACCACTT CAG A G AG CTAG GTG TTGTACATAATCAG G ATGTAAACTTACATAG
CTCTAGACTTAGTTTTAAG GAAT
TACTTGTGTATG CTG CTG AC CCTG CTATG CAC G CTG CTTCTG GTAATCTATTACTAGATAAACG CA
CTAC G TG CTTTTCAGT
AG CTG CA CTTACTAACAATG TTG CTTTTCAAACTGTCAAACCC G
GTAATTTTAACAAAGACTTCTATGACTTTG CTGTGTCTA
AG G GTTTCTTTAAG G AAG G AA G TT CTG TTG AATTAAAA CACTT CTTCTTTG CTC AG G AT G
GTAATG CT G CTATCAG CGATTA
TGACTACTATCGTTATAATCTACCAACAATGTGTGATATCAG
ACAACTACTATTTGTAGTTGAAGTTGTTGATAAGTACTTT
GATTGTTACGATG GT G G CTGTATTAATG CTAACCAAGTCATCGTCAACAACCTAG ACAAATCAG CT G
GTTTTCCATTTAATA
AATG G G GTAAG G CTAG ACTTTATTATG ATTCAATG AG TTAT G AG GATCAAG ATG CACTTTTCG
CATATACAAAACGTAATG
TCATCCCTACTATAACTCAAATGAATCTTAAGTATG CCATTAGTG CAAAG AATAG AG CTCG CACCG TAG
CTG GTGTCTCTAT
CTG TAG TACTATG ACCAATAG AC AG TTTCATC AAAAATTATTG AAATC AATAG CCG CCACTAG AG
G AG CTACTGTAGTAAT
TG G AA CAA G CAAATTCTATG GTG GTTG G CA CAA C ATG TTA AAAA CTG TTTATA G TG ATG
TA G AAAA CC CTCA CCTTATG CC
TTG G GATTATCCTAAATGTG ATAG AG CCATG CCTAACATG CTTAGAATTATG G CCTCACTTGTTCTTG
CTCG CAAACATACA
AC G TG TT G TAG CTTG TCAC ACC G TTTCT ATA G ATTAG CTAAT G AG T G TG CTCAA G
TATTG AG TG AAATG GTCATGTGTG GC
G GTTCACTATATGTTAAACCAG GTG G AACCTCATCAG G AG ATG CC ACAACT G CTTATG
CTAATAGTGTTTTTAACATTTGTC
AAG CTGTCACG G CCAATGTTAATG CACTTTTATCTACTG ATG GTAACAAAATTG CCG ATAAGTATGTCCG
CAATTTACAAC
ACAG ACTTTATG A G TG T CTCTATAG AAATAG AG ATG TTG A CACAG ACTTT G TG AATG AG
TTTTAC G CATATTTG CGTAAAC
ATTTCTCAATG AT G ATACT CT CTG A C G ATG CTG TTG T G TG TTTCAATAG CACTTATG
CATCTCAAG GTCTAGTG G CTAG CAT
AAAG AACTTTAAG TCAG TTCTTTATTATCAAAA C AAT G TTTTTAT G TCTG AAG CAAAATGTTG G
ACTG AG ACT G ACCTTACT
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AAAG GACCTCATG AATTTTG CTCTCAACATACAATG CTAGTTAAACAG G G TG ATG ATTATG TG TA
CCTT CCTTA CCCAG ATC
CATCAAGAATCCTAG G G G CCG G CTGTTTTGTAG ATG ATATCG TAAAAAC AG ATG
GTACACTTATGATTGAACG GTTCGTGT
CTTTAG CTATAG ATG CTTAC CCACTTACTAAACAT CCTAATC AG G AG TATG
CTGATGTCTTTCATTTGTACTTACAATACATA
AG AAAG CTA CATG ATG AG TTAAC AG G A CACATG TTAG ACATGTATTCTGTTATG
CTTACTAATGATAACACTTCAAG GTATT
G GG AACCTG AG TTTTATG AG G CTATG TACA CAC CG CATACAGTCTTACAG G CTGTTG G G G
CTTGTGTTCTTTG CAATT CAC
AG ACTTCATTAAG ATG TG GIG CTTG CATAC G TAG ACCATTCTTATGTTGTAAATG CTG TTAC G A
CCATG TCATATC AAC ATC
ACATAAATTAGTCTTGTCTGTTAATCCGTATGTTTGCAATG CTTCAG GTTGTG ATGTCACAG ATGTG ACT
CAACTTTACTTAG
GAG G TAT G AG CTATTATTG TAAATC ACATAAACCACC CATTA G TTTTCC ATTG T G TG CTAATG
GACAAGTTTTTG GTTTATAT
AAAAATACATGTGTTG GTAG CGATAATGTTACTGACTTTAATG CAATTG CAACATGTGACTG G AC AAATG
CTG GTGATTAC
ATTTTAG CTAACAC CT G TACTG AAAGACTCAAG CTTTTTG C AG CAG AAACG CT CAAA G CTAC
TG AG G AG A CATTTAAA CTG
TCTTATG GTATTG CTA CTG TA C G TG AAGTG CTG T CTG AC AG AG AATTACATCTTTCATG G
GAAGTTG GTAAAC CTAG A CCA
CCACTTAA CC G AAATTATG TCTTTACTG GTTATCGTGTAACTAAAAACAGTAAAGTACAAATAG G AG A G
TACA CCTTTG AA
AAAG G TG A CTATG GTG AT G CTG TT G TTTACC G AG GTACAACAACTTACAAATTAAATGTTG G
TG ATTATTTTG TG CTGACAT
CACATACAGTAATG CCATTAAGTG C ACCTAC A CTAG TG CCA CAAG AG CACTATGTTAGAATTACTG G
CTTATACCCAACACT
CAATATCT CAG ATG AG TTTT CTAG CAATGTTG CAAATTATCAAAAG GTTG GTATG
CAAAAGTATTCTACACTCCAG G G ACCA
CCTG G TA CTG GTAAG AG TC ATTTTG CTATTG G CCTAG CT CTCTACTAC C CTT CTG CTCG
CATAGTGTATACAG CTTG CTCT CA
TG CCG CT G TT G ATG CACTATGTG AG AAG G CATTAAAATATTTG CCTATAG ATAAAT G TAG
TAG AATTATACCTG CAC G TG C
TC G TG TAG AG T G TTTTG ATAAATTCAAAG TGAATTCAACATTAG
AACAGTATGTCTTTTGTACTGTAAATG CATT G CCT G AG
AC G A CAG CA G ATATAG TT G TCTTTG ATG AAATTTC AATG G CCACAAATTAT G ATTTG AG
TG TT G T CAATG CC AG ATTAC GT
G CTAAG CACTATGTGTACATTG G CGACCCTG CTCAATTACCTG CACCACG CAC ATTG CTAACTAAG G
G CA CACTAG AACCA
G AATATTT CAATTCAGTGTG TAG ACTTATG AAAACTATAG GTCCAG ACATGTTCCTCG G AACTTGTCG
G CGTTGTCCTG CTG
AAATT G TT G ACACT G TG AG TG CTTTG GTTTATG ATAATAAG CTTAAAG
CACATAAAGACAAATCAG CTCAATG CTTTAAAAT
GTTTTATAAG G GTGTTATCACG CAT G ATG TTTCATCTG CAATTAAC AG G CCACAAATAG G CGTG G
TAAG AG AATTCCTTAC
AC G TAACC CTG CTTG G AG AAAAG CT G T CTTTATTTC ACCTTATAATTCAC AG AATG CT G
TAG CCTCAAAG ATTTTG G G ACTA
CCAACTCAAACTGTTGATTCATCACAG G G CTC AG AATATG ACTATG T CATATTCACT C AAAC CACTG
AAACAG CTCACTCTT
GTAATGTAAACAG ATTTAATGTTG CTATTAC CAG AG CAAAAG TAG G CATACTTTG CATAATG TCTG
ATAG AG ACCTTTATG
ACAAGTTG CAATTTACAA G T CTTG AAATTCCA C G TA G GAATGTG G CAA CTTTA CAAG CTG
AAA ATG TAACAG G ACTCTTTA
AAG ATTG TAG TAA G GTAATCACTG G GTTACATCCTACACAG G CACCTA CAC ACCTC AG TG TTG
AC A CTAAATTCAAAACTG
AAG GTTTATGTGTTG AC ATACCTG G CATACCTAAG G AC ATG A CCTATAG AA G
ACTCATCTCTATGATG G G TTTTAAAATG A
ATTATCAAGTTAATG GTTACCCTAACATGTTTATCACCCG CGAAGAAG CTATAAGACATGTACGTG CATG
GATTG G CTTCG
ATG TCG AG G G GTGTCATG CTACTAG AG AAG CTGTTG GTACCAATTTACCTTTACAG CTAG G
TTTTTCTAC AG GTGTTAACCT
AG TTG CT G TAC CTACA G GTTATGTTGATACACCTAATAATACAG ATTTTTC CAG AG TTAG TG
CTAAACC ACC G CCTG G AG AT
CAATTTAAACACCTCATACCACTTATGTACAAAG G ACTTC CTTG GAATGTAGTG CGTATAAAG
ATTGTACAAATGTTAAGTG
ACACA CTTAAAAATCT CT CTG A CAG AG TC G TATTTG TCTTATG G G CAC ATG G CTTT G AG
TT G ACAT CTAT G AAG TATTTTG T
GAAAATAG G ACCTG AG CG CACCTGTTGTCTATGTGATAG ACGTG CCACATG CTTTTCCACTG CTTCAG
AC ACTTATG CCTGT
TG G CATCATTCTATTG GATTTGATTACGTCTATAATCCGTTTATG ATTG ATG TT CAACAATG G G G
TTTTAC AG GTAACCTACA
AAG C AACCATG AT CTG TATTG TCAAG T CCATG GTAATG CACATG TAG CTAGTTGTGATG
CAATCATGACTAG GTGTCTAG C
TGTCCACG AGTG CTTTGTTAAG CGTGTTGACTG G ACTATTGAATATCCTATAATTG GTGATG AACTGAAG
ATTAATG CG GC
TTG TAG AAAG GTTCAACACATG GTTGTTAAAG CTG CATTATTAG CAG A CAAATT CCCAG TTCTTCAC
G ACATTG GTAACCC
TAAAG CTATTAAGTGTGTACCTCAAG CTG ATG TAG AAT G G AAG TT CTAT G ATG CACAG CCTTG
TAG T G ACAAAG CTTATAA
AATAG AAGAATTATTCTATTCTTATG CC ACACATTCTG ACAAATTCACAGATG GTGTATG CCTATTTTG
GAATTG CAATGTC
GATAGATATCCTG CTAATTCCATTG TTTG TAG ATTTG ACA CTAG A GTG CTATCTAACCTTAACTTG
CCTG GTTGTG ATG GTG
G CAGTTTGTATGTAAATAAACATG CATTCCACACACCAG CTTTTG ATAAAAGTG
CTTTTGTTAATTTAAAACAATTACCATTT
TTCTATTACTCTGACAGTCCATGTG AG T CTCAT G G AAAACAAG TAG T G TCA G ATAT AG ATTATG
TACCA CTAAA G TCTG CTA
CGTGTATAACACGTTG CAATTTAG GT G GTG CTG TCTG TAG ACATCATG CTAATG AG TACAG
ATTGTATCTCGATG CTTATAA
CATG ATG ATCTC AG CT G G CTTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG G
AACACTTTTAC AAG A CTTC
AG AG TTTA G AAAAT G TG G CTTTTAATGTTGTAAATAAG G G ACACTTTGATG G A CAACAG G
GTG AAG TACCAG TTTCTAT CA
TTA ATAA CA CTG TTTA C A CAAAA G TTG ATG G TG TTG AT G TA G AATT G TTT G AA
AATAAAA C AA CATTACCT G TTAATG TA G C
ATTTG AG CTTTG G G CTAAG CG CAACATTAAACCAGTACCAG AG GTGAAAATACTCAATAATTTG G
GTGTG G ACATTG CT G C
TAATACTG TG AT CTG G G ACT ACAAAAG AG ATG CTCCAG CA CATAT ATCTA CTATTG
GTGTTTGTTCTATGACTG ACATAG CC
AAG AAACCAACTG AAA C G ATTTG T G CACCACTCACTGTCTTTTTTG ATG G TAG AG TTG ATG G
TCAAG TAG ACTTATTTAG A
AATG CCCGTAATG GTGTTCTTATTACAGAAG GTAGTGTTAAAG GTTTACAACCATCTG TAG
GTCCCAAACAAG CTAGTCTT
AATG G AG T CACATTAATTG G A G AAG CC G TAAAAACA CAG TT CAATTATTATAAG AAAG TT G
ATG GTGTTG TCCAACAATTA
CCT G AAACTTACTTTA CT CAG AG TAG AAATTTACAAG AATTTAAACCCA G G AG TCAAATG G AA
ATTG ATTTCTTAG AATTAG
CTATG GATGAATTCATTGAACG GTATAAATTAGAAG G CTATG CCTTCG AACATATCGTTTATG G AG
ATTTTAG TCATAGTCA
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GTTAG GTG GTTTAC AT CTACTG ATTG GACTAG CTAAACGTTTTAAG G AATCACCTTTTGAATTAG AAG
ATTTTATTCCTATG
G AC AG TAC AG TTAAAAACTATTT CATAAC AG ATG CG CAAACAG
GTTCATCTAAGTGTGTGTGTTCTGTTATTGATTTATTAC
TTG ATG ATTTTGTTG AAATAATAAAATCCCAAG ATTTATCTG TAG TTTCTAAG
GTTGTCAAAGTGACTATTG ACTATACAG A
AATTTCATTTATG CTTTGGTGTAAAG ATG G C CATG TAG AAA CATTTTACC CAAAATTA CAATCTAG
TCAAG CGTG G CAACCG
G GT G TT G CTATG CCTAATCTTTACAAAATG CAAAG AATG CTATTAG AAAAGTGTG AC CTT
CAAAATTATG GTG ATAGTG CA
ACATTACCTAAAG G CATAAT G AT G AAT G TC G CAAAATATACTCAACTG TG TCAATATTTAAA CA
C ATTAACATTAG CT G TAC
C CTATAATATG AG A G TTATACATTTTG GTG CT G G TT CTG ATAAAG G AG TT G CAC C AG G
TA CAG CT G TTTTAAG A CAG TG GT
TG CCTACG G GTACG CTG CTTGTCGATTCAGATCTTAATGACTTTGTCTCTGATG CAGATTCAACTTTGATTG
GTGATTGTG C
AACTGTACATACAG CTAATAAATG G GATCTCATTATTAGTGATATGTACG AC C CTAAG
ACTAAAAATGTTACAAAAGAAAA
TG ACTCTAAAG AG G GTTTTTTCACTTACATTTGTG G GTTTATACAACAAAAG CTAG CTCTTG GAG
GTTCCGTG G CTATAAAG
ATAA CAG AA CATTCTTG GAATG CTG ATCTTTATAAG CTCATG G GACACTTCG C AT G GTG GACAG
C CTTTG TTACTAATG TG A
ATG CGTCATCATCTGAAG CATTTTTAATTG G AT G TAATTATCTTG G CAAAC C AC G CGAACAAATAG
AT G GTTATGTCATG CA
TG CAAATTACATATTTTG GAG G AATAC AAATC CAATT CAG TT G TCTTC CTATTCTTTATTTG A
CATG AG TAAATTT CC C CTTA
AATTAAG G G G TA CTG CTGTTATGTCTTTAAAAG AAG GTCAAATCAATG ATATG
ATTTTATCTCTTCTTAG TAAAG G TAG ACT
TATAATTAG AG AAAACAACAG AGTTGTTATTTCTAG TG ATGTTCTTGTTAACAACTAAACG AACAATG
TTTG TTTTTCTTGTT
TTATTG C CACTA GTCT CTAG TCAG T G TG TTAAT CTTA CAAC CA G AACT CAATTAC C C C
CTG CATACACTAATTCTTTCA CAC G
TG G TG TTTATTACC CT G ACAAAG TTTTCAG ATC CT CAG TTTTAC ATTCAACTCAG G ACTTG TT
CTTAC CTTT CTTTTCCAAT G T
TACTTG GTTCCATG CT ATA CAT G TCT CTG G G AC C AATG G TACTAAG AG GTTTG CTAAC C
CT G TC CTAC CATTTAAT G ATG GT
GTTTATTTTG CTTC CACTG A G AAG TCTAAC ATAATAAG AG G CTG GATTTTTG G TA CTACTTTAG
ATTCG AAG AC C CAG TC C C
TACTTATTGTTAATAACG CTACTAATGTTGTTATTAAAGTCTGTGAATTTCAATTTTGTAATGATCCATTTTTG G
GTGTTTATT
AC CAC AAAAACAACAAAAG TTG GATG G AAAGTG AG TTCAG AG TTTATTCTAGTG CGAATAATTG
CACTTTTG AATATGTCT
CTCAG CCTTTTCTTATG G AC CTTG AA G GAAAACAG G GTAATTTCAAAAATCTTAG G
GAATTTGTGTTTAAG AATATTG AT G
GTTATTTTAAAATATATTCTAAG CACACG CCTATTAATTTAGTG CGTG GTCTCCCTCAG GGTTTTTCG G
CTTTAGAACCATTG
G TAG ATTTG CCAATAG GTATTAACATCACTAG G TTTC AAA NNNNNN CTTTACATAGAAGTTATTTG
ACTCCTG GT G ATT CTT
CTTCAG GTTG G ACAG CTG GTG CT G CAG CTTATTATGTG G GTTATCTTCAACCTAG G A
CTTTTCTATTAAAATATAAT G AAA
AT G G AACCATTACAG ATG CT G TAG ACTGTG CACTTG A C C CTCTCTCA G AAACAAAG TG TAC
G TTG AAAT C CTTCACTG TAG
AAAAAG G AAT CTAT CAAACTTCTAA CTTTAG AG T C CAA C CAACAG AATCTATTGTTAG
ATTTCCTAATATTACAAACTTGTG
CCCTTTTG GTG AAGTTTTTAACG C C AC CAG ATTTG CATCTGTTTATG CTTG GAACAG GAAG AG
AAT CA G C AACTG TG TT G CT
GATTATTCTGTCCTATATAATTCCG CATCATTTTCCACTTTTAAGTGTTATG G AG T G TCT C CTA
CTAAATTAAATG AT CTCT G C
TTTACTAATGTCTATG CAG ATTCATTTG TAATTAG AG GTG ATG AAG T CAG AC AAAT C G CTC C
AG GG CAAACTG GAAATATT
G CTGATTATAATTATAAATTACCAGATGATTTTACAG G CTG CGTTATAG CTTG GAATTCTAACAATCTTG
ATTCTAAG GTTG
GT G GTAATTATAATTACCTGTATAG ATTGTTTAG GAAG TCTAATCTC AAAC CTTTTG AG AG AG
ATATTTCAACTG AAAT CTA
TCAG G CCG GTAG CACACCTTGTAATG GTGTTAAAG GTTTTAATTG TT ACTTTC CTTTACAATCATATG
GTTTCCAACC CA CTT
ATG GTGTTG G TTAC C AAC CATACAG A G TAG TAG TACTTT CTTTTG AA CTTCTACATG CAC C
AG CAACTGTTTGTG G AC CTAA
AAAGTCTACTAATTTG GTTAAAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CACAG G TG TT
CTTACTG AG TCT
AACAAAAAGTTTCTG CCTTTCCAACAATTTG G CAG AG ACATTG CTG ACACTACTG ATG CT G TC C G
TG ATC CA CA G ACA CTTG
AG ATTCTTG ACATTACAC CATG TTCTTTTG GTG GTGTCAGTGTTATAACACCAG G
AACAAATACTTCTAACCAG GTTG CTGT
TCTTTATC AG G GTGTTAACTG CACAG AA G TC C CTG TT G CTATT CAT G CAG
ATCAACTTACTCCTACTTG G CGTGTTTATTCTA
CAG G TTCTAATG TTTTTCAAAC AC G T G CAG G CTGTTTAATAG G G G CTG AACATG TC
AACAACT CATATG AG T G TG ACATAC
CCATTG GTG CAG GTATATG CG CTAGTTATCAGACTCAG ACTAATTCTCCTCG G CG G G CAC GTAG
TG TAG CTAG TCAATC CA
TCATTG CCTACACTATGTCACTTG G TG TAG AAAATTC AG TTG CTTACTCTAATAACTCTATTG
CCATACCCACAAATTTTACT
ATTAGTGTTACCACAGAAATTCTACCAGTGTCTATG AC CAAG ACATC AG TAG
ATTGTACAATGTACATTTGTG G TGATTCAA
CTG AATG CAG CAATCTTTTGTTG CAATATG G CAGTTTTTGTACACAATTAAACCGTG CTTTAACTG G
AATAG CTGTTGAACA
AG AC AAAAACAC C CAAG AAG TTTTTG CACAAG T CAAAC AAATTTACAAAAC AC C AC C
AATTAAA G ATTTTG GIG GTTTTAA
TTTTTCA CAAATATTAC C AG ATC CATCAAAAC CAA G CAAG AG GTCATTTATTG AAG AT
CTACTTTT CAACAAA G TG A CACTT
G C AG ATG CTG G CTTCATCAAACAATATG GTGATTG CCTTG GTGATATTG CTG CTAG AG AC
CTCATTTG TG CAC AAAAG TTT
AACG G CCTTACTGTTTTG CCACCTTTG CT CACAG ATG AAATGATTGCTCAATACACTTCTG CACTGTTAG
CG G GTACAAT CA
CTTCTG GTTGG ACCTTTG GTG CAG GTG CTG CATTA CAA ATACCATTTG CTATG CAAATG G
CTTATAG GTTTAATG GTATTG G
AG TTACACA G AATG TTCT CTAT G AG AA C C AAAAATTG ATTG CCAACCAATTTAATAGTG
CTATTG G CAAAATTCAAGACTCA
CTTTCTTCCACAG CAA G TG CA CTTG GAAAACTTCAAGATGTG GTCAACCAAAATG CACAAG CTTTAAAC
AC G CTTGTTAAAC
AACTTAG CT C CAATTTTG GTG CAATTTCAAGTGTTTTAAATG ATATC CTTT CAC G T CTTG ACAAAG
TTG AG G CTG AAGTG CA
AATTGATAG G TT G ATCACAG G CAGACTTCAAAGTTTG CAG ACATATGTG ACTCAACAATTAATTAG AG
CT G CAG AAATCAG
AG CTTCTG CTAATCTTG CTG CTACTAAAATG TCAG A G TG T G TACTT G G ACAATCAAAAAG AG
TTG ATTITTG TG GAAAG G G
CTATCATCTTATGTCCTTCCCTCAGTCAG C AC CT CATG G TG TAG TCTTCTTG CATGT G ACTT ATG
TC C CT G CAC AAG AAAAG A
ACTT CACAACTG CT C CTG C CATTTG TC ATG AT G G AAAAG CAC ACTTT C CTC G TG AA G
G TG TCTTTG TTTCAAATG G CACACA
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CTG GTTTGTAACACAAAG G AATTTTTATG AACCACAAATCATTACTA CAG AC AACA CATTTG TG TCTG
G TAACT G TG ATG TT
GTAATAG G AATTGTCAACAACACAGTTTATG ATCCTTTG CAACCTG AATTAG ACTCATTCAAG GAG G AG
TTAG ATAAATAT
TTTAAG AATCATA CATCACCAG AT G TT G ATTTAG G TG AC ATCTCTG G CATTAATG CTT CAG
TTG TAAACATTCAAA AAG AAA
TTG ACCG CCTC AATG AG GTTG CCAAGAATTTAAATGAATCTCTCATCGATCTCCAAGAACTTG G AAAG
TATG AG CAG TATA
TAAAATG G CCATG GTACATTTG G CTAG GTTTTATAG CTG G CTTGATTG CC ATA G TAATG GTG
ACAATTATG CTTTG CTG TAT
G ACC AG TT G CTG TAG TTG TCTCAAG G G CT G TTG TTCTTG T G G AT CCTG CTG CA
AATTT G ATG AAG AC G A CTCTG AG CCAGT
G CT CAAAG G AG T CAAATTACATTACACATAAAC G AA CTTATG G ATTTGTTTATG AG AAT CTTCA
CAATT G G AA CTG TAACTT
TGAAG CAAG GTGAAATCAAG G ATG CTACTCCTTCAGATTTTGTTCG CG CTACTG
CAACGATACCGATACAAG CCTCACTCC
CTTTCG G ATG G CTTATTGTTG G CGTTG CACTTCTTG CTGTTTTTCATAG CG CTTCC AAAATC
ATAACC CTC AAAAAG A G ATG
G CAA CTAG CACTCTCCAAG G GTGTTCACTTTGTTTG CAACTTG
CTGTTGTTGTTTGTAACAGTTTACTCACACCTTTTG CTCG
TTG CTG CTG G CCTTG AAG CC CCTTTTCTCTATCTTTAT G CTTTAGTCTACTTCTTG CA G AG
TATAAACTTTG TAAG AATAATA
ATG AG G CTTTG G CTTTG CTG GAAATG CCGTTCCAAAAACCCATTACTTTATGATG
CCAACTATTTTCTTTG CTG G CATACTAA
TTGTTACGACTATTGTATACCTTACAATAGTGTAACTTCTTCAATTGTCATTACTTTAG GTGATG G
CACAACAAGTCCTATTT
CTG AACATG ACTACCAGATTG GTG GTTATACTGAAAAATG G GAATCTG G AG TAAAAG ACTGTGTTG
TATTACACAGTTA CT
TCACTTC AG ACTATTACCAG CTG TACT CAACTC AATTG AG TA CAG AC ACTG
GTGTTGAACATGTTACCTTCTTCATCTACAAT
AAAATTGTTGATG AG CCTGAAGAACATGTCCAAATTCACACAATCG AC G GTTCATCCG G AG TTG TT
AATCCAGTAATG G AA
CCAATTTATG AT G AACC G AC G AC G ACTACTAG CGTG CCTTTGTAAG CACAAG CTG AT G AG
TAC G AACTTATGTACTCATTC
GTTTCG G AAG A G ACA G GTACGTTAATAGTTAATAG CGTACTTCTTTTTCTTG CTTTCGTG
GTATTCTTG CTAGTTACACTAG C
CATCCTTACTG CG CTTCGATTGTGTG CGTACTG CTG CAATATTGTTAACGTG AG TCTTGTAAAACCTT
CTTTTTAC GTTTACT
CTCGTGTTAAAAATCTG AATTCTTCTAG AG TTCTTG AT CTTCTG
GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTG G
AACTTTAATTTTAG CCATG G CAGATTCCAACG GTACTATTACC GTT G AAG AG CTTAAAAAG CTCCTTG
AACAATG GAACCTA
GTAATAG GTTTCCTATTCCTTACATG GATTTGTCTTCTACAATTTG CCTATG CC AACAG G AATAG
GTTTTTGTATATAATTAA
GTTAATTTTCCTCTG G CTGTTATG G CCAGTAACTTTAG CTTGTTTTGTG CTG CTG CTGTTTACAG
AATAAATTG G ATCA CC G
GTG GAATTG CTATCG CAATG G CTTG TCTTG TAG G CTTGATGTG G CTCAG CTACTTCATTG
CTTCTTTCAGACTGTTTG CG CG
TACG CGTTCCATGTG GTCATTCAATCCAGAAACTAACATTCTTCTCAACGTG CC A CTCC ATG G
CACTATTCTGACCAG ACC G
CTTCTAGAAAGTG AACTCGTAATCG GAG CT G TG ATCCTT C GT G GACATCTTCGTATTG CTG G A
CACCAT CTAG G AC G CTGT
G AC ATCAAG G A CCTG CCTAAAGAAATCACTGTTG CTACAT CAC G AA C G
CTTTCTTATTACAAATTG G GAG CTTCG CAG CGT
G TAG CAG GTGACTCAG GTTTTG CTG CATACAGTCG CTACAG GATTG G CAA CTATAAATTAAACACAG
ACCATTCCAG TAG C
AG T G ACAATATT G CTTTG CTTGTACAGTAAG CG ACAAC AG AT G TTT CATCTC G TTG ACTTTC
AG GTTACTATAG C AG AG ATA
TTA CTAATTATTATG A G GACTTTTAAAGTTTCCATTTG GAATCTTG
ATTACATCATAAACCTCATAATTAAAAATTTATCTAA
G TC ACTAA CTG AG AATAAATATTCTCAATTAG ATG AA G AG CAACCAATG GAG ATTG
ATTAAACGAACATG AAAATTATTCT
TTTCTTG G CACTGATAACACTCG CTACTTG T G AG CTTTATCACTACCAAG AG TG TG TTAG AG
GTACAACAGTACTTTTAAAA
GAACCTTG CTCTTCTG G AACATAC G AG G G CAATTCACCATTTCATCCTCTAG CTGATAACAAATTTG
CACTG ACTT G CTTTA
G CACTCAATTTG CTTTTG CTTGTCCTG ACG G CGTAAAACACGTCTATCAGTTACGTG C CAG AT CAG
TTTCACCTAAA CTG TTC
ATCA G ACAA G AG G AAG TT CAAG AACTTTACTCTCCAATTTTTCTTATTG TTG CG G
CAATAGTGTTTATAACACTTTG CTTC AC
ACTCAAAAG AAAG AC AG AAT G ATT G AACTTTC ATTAATTG A CTTCTATTTG TG CTTTTTAG
CCTTTCTG CTATTCCTTGTTTTA
ATTATG CTTATTATCTTTTG G TT CTCACTTG AACTG CAAG ATCATAATG AA ACTTG TCAC G
CCTAAACG AACATG AAATTT CT
TGTTTTCTTAG G AATC ATCAC AACTG TA G CT G CATTTCACCAAG AATG T AG TTTACAG TCAT G
TACT CAACAT CAACC ATAT
G TA G TTG ATG ACCCGTGTCCTATTCACTTCTATTCTAAATG G TATATTA G AG TAG GAG
CTAGAAAATCAG CACCTTTAATTG
AATTGTG CGTG GATG AG G CTG G TTCTA AAT CAC CCATT CAG TA CATC G ATATCG
GTAATTATACAGTTTCCTGTTTACCTTTT
ACAATTAATTG CCAG GAACCTAAATTG G G TAG TCTT G TAG TG C G TTG TTC G TT CTATG AAG
ACTTTTTAG AG TATCATG AC G
TTCGTGTTGTTTTAG ATTTTATCTAAACG AACAAACTAAAATGTCTGATAATG G ACCCCAAAATCAG
CGAAATG CAC CCC G C
ATTACGTTTGGTG G ACCCTC AG ATT CAACTG G CAGTAACCAGAATG G AG AACG CAGTGG G G CG
CGATCAAAACAACGTCG
G CC CCAAG GTTTACCCAATAATACTG CGTCTTG GTTCACCG CTCTCACTCAACATG G CAAG G AAG
ACCTTAAATTCCCTCG A
G GACAAG G CGTTCCAATTAACACCAATAG CAGTCCAGATGACCAAATTG G CTACTACCGAAG AG
CTACCAGACG AATTCG
TG GTG G TG AC G GTAAAATG AAAG AT CTCAG TCCAAG ATG GTATTTCTACTACCTAG G AACTG G
G C CAG AA G CTG G ACTT
CCCTATG GTG CTAACAA AG AC G G CAT CATAT G G GTTG CAACTG AG G G AG
CCTTGAATACACCAAAAG ATCACATTG G CAC
CCG CAATCCTG CTAACAATG CTG CAATCGTG CTA CAA CTTCCTCAAG G AA CA ACATTG CCAAAAG
G CTTCTACGCAG AAG G
GAG CAG AG G CG G CAGTCAAG CCTCTTCTCGTTCCTCATCACGTAGTCG CAACAG TT CAAG
AAATTCAA CTCCAG G CAG CAG
TAG G G GAATTTCTCCTG CTAG AATG G CTG G CAATG GCG GTGATG CTG CTCTTG CTTTG CTG
CTG CTTG ACAGATTGAACCA
G CTTG AG AG CAAAATGTCTG GTAAAG G CCAACAACAACAAG G CCAAACTG TCACTAAGAAATCTG
CTG CTG AG G CTTCTA
AG AA G CCTCG G CAAAAACGTACTG CC ACTAAAG CATACAATGTAACACAAG CTTTCG G CAG AC G
TG GTCCAGAACAAACC
CAAG GAAATTTTG G G G ACCAG GAACTAATCAG AC AAG GAACTGATTACAAACATTG G CC G
CAAATTG CAC AATTTG C CC C
CAG CG CTTCAG CGTTCTTCG G AATGTCG CG CATTG G CATG G AAG TCACACCTTC G G GAACGTG
GTTG ACCTACACAG GTG
CCATCAAATTG G AT G ACAAAG ATCCAAATTTCAAAGATCAAGTCATTTTG CT G AATAAG CATATTG
ACG CATACAAAACATT
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CCCACCAACAG AG CCTAAAAAG GACAAAAAG AAGAAG G CTGATGAAACTCAAG CCTTACCG CAGAG
ACAGAAGAAACAG
CAAACTGTGACTCTTCTTCCTG CTG CAGATTTG GATG ATTTCTCCAAACAATTG CAACAATCCATG AG
CAGTGCTGACTCAA
CTCAGGCCTAAACTCATGCAGACCACACAAGGCAGATGGGCTATATAAACGTTTTCGCTTTTCCGTTTACGATATATAG
TCT
ACTCTTGTGCAGAATGAATTCTCGTAACTACATAGCACAAGTAGATGTAGTTAACTITAATCTCACATAGCAATCTITA
ATC
AGTGTGTAACATTAG G G AG GACTTGAAAGAG CCACCACATTTTCACCG AG G CCACG CG
GAGTACGATCGAGTGTACAGTG
AACAATGCTAGGGAGAGCTGCCTATATGGAAGAGCCCTAATGTGTAAAATTAATTTTAGTAGTGCTATCCCCATG
NNNNN
NNNNNNNNNNNNNNNNNNNNNNN NAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
SEQ ID NO: 19
>SA_P2_gp02 surface glycoprotein, from genome accession SA_P2_t0.9_q20
M FVFLVLLPLVSSQCVN LTTRTQLPPAYTNSFTRGVYYPDKVF RSSVLHSTQDLFL PF FS NVTW F HAI
HVSGTNGTKRFAN PVLP F
N DGVYFASTE KSNIIRGWI FGTTLDSKTQSLLIVN NATNVVI KVCEFQFCN DPFLGVYYH KN N KSW M
ESE F RVYSSAN NCTFEYV
SQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRGLPQGFSALEPLVDLPIGINITRFQXXXLHRSYLTP
GDSSSGWT
AGAAAYYVGYLQPRTFLLKYN E NGTITDAVDCALDPLSETKCTLKSFTVEKG IYQTSNFRVQPTESIVRF PN
ITN LCPFG EVFNATR
FASVYAWN R KRISNCVADYSVLYNSASFSTFKCYGVSPTKLN DLCFTNVYADSFVI RG DEVRQIAPGQTG N
IADYNYKLPDDFTG
CVIAWNSN N LDSKVGG NYNYLYRLFRKSN LKP F E R DISTE IYQAGSTPCNGV KG FNCYFPLQSYG
FQPTYGVGYQPYRVVVLSFE
LLHAPATVCG PKKSTN LVKN KCVN FN F NG LTGTGVLTESN KKFL PFQQFG RDIADTTDAVRD PQTLE
1 LDITPCSFGGVSVITPGT
NTSNQVAVLYQGVNCTEVPVAI HADQLTPTWRVYSTGSNVFQTRAGC LI GAEHVN NSYECDI PI GAG
ICASYQTQTNSPRRARS
VASQS1lAYTMSLGVENSVAYSN NSIAI PTN FTISVTTEILPVSMTKTSVDCTMYICG DSTECSN
LLLQYGSFCTQLN RALTG IAVEQ
D KNTQEVFAQVKQIYKTPP 1 KD FGG F NFSQ1 L PD PS KPSKRSF 1 EDLLFN KVTLADAG Fl
KQYG DCLG DIAAR DL ICAQKF NG LTVL
PP LLTD E M IAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNG IGVTQNVLYENQKLIANQFNSAIG
KIQDSLSSTASALG
KLQDVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQIDRLITG RLQSLQTYVTQQL1
RAAEIRASAN LAATKMS EC
VLGQSKRVDFCG KGYH L MSF PQSAP HGVVF LHVTYVPAQE KN FTTAPAI CH DG KAH F PR EG
VFVSNGTHWFVTQRN FYEPQII
TTDNTFVSG NC DVVI G IVN NTVYDPLQPE LDSFKEELDKYFKN HTSPDVDLG DI SGINASVVN IQKE
1 DR LN EVAKN LN ESLI DLQE
LG KYEQYI KWPWYIWLG FIAG LIAIVMVTI M LCCMTSCCSCLKGCCSCGSCCKFD EDDSE
PVLKGVKLHYT
SEQ ID NO: 20
>MW520923.1 Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-
2/h u n/USA/M N-M DH-
2399/2021, complete genome, example fo Brazilian P1 lineage.
CAACTTTCGATCTCTTGTAGATCTGTTCTCTAAACGAACTTTAAAATCTGTGTGGCTGTCACTCGGCTGCATGCTTAGT
G
CACTCACG CAGTATAATTAATAACTAATTACTGTCGTTGACAG GACACGAGTAACTCGTCTATCTTCTG CAG G
CTG CTTA
CGGTTTCGTCCGTGTTGCAGCCGATCATCAGCACATCTAGGTTTTGTCCG GGTGTGACCGAAAGGTAAGATG
GAGAG CCT
TGTCCCTG GTTTCAACGAGAAAACACACGTCCAACTCAGTTTG CCTGTTTTACAG GTTCG CGACG TG
CTCGTAC GTG G CT
TTG GAGACTCCGTGG AG GAG GTCTTATCAGAG G CACGTCAACATCTTAAAG ATG G CACTTGTG G
CTTAGTAG AAGTTGAA
AAAGGCGTTTTGCCTCAACTTGAACAGCCCTATGTGTTCATCAAACGTTCGGATGCTCGAACTGCACCTCATGGTCATG
T
TATGGTTGAGCTGGTAGCAGAACTCGAAGGCATTCAGTACGGTCGTAGTGGTGAGACACTTGGTGTCCTTGTCCCTCAT
G
TG G G CG AAATACCAGTG G CTTACCG CAAG GTTCTTCTTCGTAAGAACGGTAATAAAG GAG CTG GTG
G CCATAGTTACG G C
G CCGATCTAAAGTCATTTGACTTAG G CGACGAG CTTG G CACTGATCCTTATGAAG ACTTTCAAG
AAAACTG GAACACTAA
ACATAG CAGTG GTGTTACCCGTG AACTCATG CGTGAG CTTAACG G AG G G G CATACACTCG
CTATGTCGATAACAACTTCT
GTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGTGCTGGTAAAGCTTCATGCACTTTGTCCGA
A
CAACTG GACTTTATTGACACTAAGAG G G GTGTATACTG CTG CCGTGAACATG AG CATGAAATTG CTTG
GTACACG GAACG
TTCTGAAAAGAGCTATGAATTGCAGACACCTTTTGAAATTAAATTGGCAAAGAAATTTGACACCTTCAATGGGGAATGT
C
CAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAGGGTTGAAAAGAAAAAGCTTGATGGCTTTAT
G
GGTAGAATTCGATCTGTCTATCCAGTTGCGTCACCAAATGAATGCAACCAAATGTGCCTTTCAACTCTCATGAAGTGTG
A
TCATTGTG GTG AAACTTCATG G CAG ACG G G CG ATTTTGTTAAAG CCACTTG CGAATTTTGTG G
CACTGAGAATTTG ACTA
AAGAAGGTGCCACTACTTGTGGTTACTTACCCCAAAATGCTGTTGTTAAAATTTATTGTCCAGCATGTCACAATTCAGA
A
GTAGGACCTGAGCATAGTCTTGCCGAATACCATAATGAATCTGGCTTGAAAACCATTCTTCGTAAGGGTGGTCGCACTA
T
TG CCTTTG GAG G CTGTGTGTTCTCTTATGTTG GTTG CCATAACAAGTGTG CCTATTG G GTTCCACGTG
CTAG CG CTAACA
TAG GTTGTAACCATACAG GTGTTGTTG GAG AAG GTTCCGAAG GTCTTAATG ACAACCTTCTTG
AAATACTCCAAAAAGAG
AAAGTCAACATCAATATTGTTGGTGACTTTAAACTTAATGAAGAGATCGCCATTATTTTGGCATCTTTTTCTGCTTCCA
C
AAGTGCTTTTGTGGAAACTGTGAAAGGTTTGGATTATAAAGCATTCAAACAAATTGTTGAATCCTGTGGTAATTTTAAA
G
TTACAAAAG GAAAAG CTAAAAAAG GTG CCTG G AATATTG GTGAACAG
AAATCAATACTGAGTCCTCTTTATG CATTTG CA
TCAG AG G CTG CTCGTGTTGTACGATCAATTTTCTCCCG CACTCTTGAAACTG CTCAAAATTCTGTG
CGTGTTTTACAG AA
GGCCGCTATAACAATACTAGATGGAATTTCACAGTATTCACTGAGACTCATTGATGCTATGATGTTCACATCTGATTTG
G
CTACTAACAATCTAGTTGTAATG G CCTACATTACAG GTG GTGTTGTTCAGTTGACTTCG CAGTG G
CTAACTAACATCTTT
1 1 1
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PCT/IB2021/052858
GGCACTGTTTATGAAAAACTCAAACCCGTCCTTGATTG G CTT G AAG A G AAG TTTAA G G AA G G TG
TAG A G TTT CTTAG AG A
CG GTTG G GAAATTGTTAAATTTATCTCAACCTGTG CTTGTG AAATTGTCG GTG GACAAATTGTCACCTGTG
CAAAG G AAA
TTAAG GAG AG TG TTCAG ACATTCTTTAAG CTTG TA AATAAATTTTTG G CTTTGTGTG CTG
ACTCTATCATTATTG GTG GA
G CTAAACTTAAAG CCTTG AATTTAG GTGAAACATTTGTCACG CACTCAAAG G G ATTGTAC AG AAAG
TGTGTTAAATCCA G
AG AA G AAACT G G CCTACTCATG CCTCTAAAAG C CCCAAAA G AAATTAT CTTCTTAG AG G GAG
AAACA CTTCCC ACAG AA G
TG TTAAC AG AG GAAGTTGTCTTGAAAACTG GTGATTTACAACCATTAGAACAACCTACTAGTG AAG CT G
TTG AAG CT CCA
TTG GTTG GTACACCAGTTTGTATTAACG G G CTTATGTTG CTCGAAATCAAAG ACACAGAAAAGTACTGTG
CCCTTG CACC
TAATATGATG GTAACAAACAATACCTTCACACTCAAAG G CG GTG CACCAACAAAG GTTACTTTTG GTGATG
ATACTGTG A
TAG AAGTG CAAG G TTA CAAG A G TG TG AATATCACTTTT G AACTTG ATG AAA G G ATTG
ATAAAGTACTTAATG AG AAG TG C
TCTG CCTATACAGTTG AACTCG G TA CAG AA G TAAATG AG TTC G CCTG TG TT G TG G CA G
ATG CTGTCATAAAAACTTTG CA
ACCAGTATCTGAATTACTTACACCACTG G G CATTGATTTAG ATG AG TG G AG TAT G G
CTACATACTACTTATTTG AT G AG T
CTG GTG AG TTTAAATTG G CTTCA CATAT G TATTG TT CTTTTTAC CCTC CAG AT G AG G
ATGAAGAAG AAG G TG ATTG TG AA
GAAG AAG AG TTT G AG CC ATCAA CTCAATATG A G TATG G TA CTG AA G ATG
ATTACCAAGGTAAACCTTTG GAATTTG GTG C
CACTTCTG CTG CTCTT CAACCT G AAG AAG AG CAAGAAG AAGATTG G TTAG ATG AT G ATAG
TCAA C AAACT G TTG GTCAAC
AAGACG G CAGTG AG G ACAATCAG ACAA CTACTATTCAAACAATTG TTG AG GTTC AACCT CAATTAG
AG ATG G AA CTTACA
CCAGTTGTTCAGACTATTG AAGTG AATAGTTTTAGTG G TTATTTAAAA CTTACTG AC AATG TATAC
ATTAAAAATG CAG A
CATTGTG GAAGAAG CTAAAAAG GTAAAACCAACAGTG GTTGTTAATG CAG CCAATGTTTACCTTAAACATG
G AG G AG G TG
TTG CAG G AG CCTTAAATAAG G CTACTAACAATG CCATG CAAGTTG AATCTG ATGATTACATAG
CTACTAATG G A CCACTT
AAAGTG G GTG GTAG TTG TG TTTTAAG C G G AC ACAATCTTG CT AAACACTGTCTTCATG TTG
TCG G CCCAAATGTTAACAA
AG GTGAAG ACATTCAACTTCTTAAG A G TG CTTATGAAAATTTTAATCAG CAC G AAG TTCTACTTG
CAC CATTATTATCAG
CTG GTATTTTTG GT G CTG ACCCTATAC ATTCTTTAAG AG TTTG T G TAG ATACTG TT C G CA
CAAATG TCTACTTA G CTG TC
TTT G ATAAAAATCTCTATG AC AAACTTG TTTTAAG CTTTTTG G AAATG AA G AG T G AAAAG
CAAGTTGAACAAAAGATCG C
TG AG ATTCCTAAAG AG G AAGTTAAG C CATTTATAACTG AAA GTAAACCTT CAG TTG AAC AG AG
AAAACAAG ATG ATAAG A
AAATCAAAG CTTGTGTTGAAGAAGTTACAACAACTCTG
GAAGAAACTAAGTTCCTCACAGAAAACTTGTTACTTTATATT
GACATTAATG G CAATCTTCATCCAGATTCTG CCACT CTTG TTAG TG AC ATTG ACATCACTTTCTTAAAG
AAAG ATG CTCC
ATATATAGTG G G TG ATGTTG TTCAAG AG G GTGTTTTAACTG CTGTG GTTATACCTACTAAAAAG G
CTG GTG G CACTACTG
AAATG CTAG CGAAAG CTTTG AG AAAAGTG CCAA CAG AC AATTATATAAC CACTTACCCG G GTCAG
G GTTTAAATG GTTAC
ACTG TAG AG GAG G CAAAG ACAGTG CTTAAAAAGTGTAAAAGTG
CCTTTTACATTCTACCATCTATTATCTCTAATG AG AA
G C AA G AAATTCTTG GAACTGTTTCTTG GAATTTG C G AG AAATG CTTG CACATG CAGAAG
AAACACG CAAATTAATG CCTG
TCTGTGTG GAAACTAAAG CCATAGTTTCAACTATACAG CGTAAATATAAG G G TATTAAAATAC AAG AG G
GTGTG G TTG AT
TAT G GTG CTAG ATTTTACTTTTA CACCA G TAAAACAACT G TAG C G T CACTTATCAA CA
CACTTAAC G ATCTAAATG AAAC
TCTTGTTACAATG CCACTTG G CTATGTAACACATG G CTTAAATTTG GAAGAAG CTG CTCG GTATATG
AG AT CTCT CAAAG
TG CCAG CTACAGTTTCTGTTTCTTCACCTG ATGCTGTTACAGCGTATAATG
GTTATCTTACTTCTTCTTCTAAAACACCT
G AAG AA CATTTTATTG AAACCATCTCACTTG CTGGTTCCTATAAAGATTG GTCCTATTCTG
GACAATCTACACAACTAG G
TATAG AATTTCTTAAG A G AG GTGATAAAAG TGTATATTACACTAGTAATCCTACCACATTCCACCTAG ATG
G TG AA G TTA
TCAC CTTT G ACAAT CTTAAG ACACTTCTTTCTTTG AG AG AAG TG AG GACTATTAAG G TG TTTA
C AACAG TAG AC AACATT
AACCTCCACACG CAAGTTGTG G AC ATGTCAATG ACATATG G ACAAC AG TTT G GTCCAACTTATTTG
GATG GAG CTG ATGT
TACTAAAATAAAACCTCATAATTCACATGAAG G TAAAAC ATTTTATG TTTTAC CTAAT G ATG A
CACTCTAC GT G TTG AG G
CTTTTG A G TACTACCAC ACAACT G ATC CTAG TTTT CTG G G TAG G TACAT G T C AG
CATTAAATCACACTAAAAAGTG G AAA
TACCCACAAGTTAATG GTTTAACTTCTATTAAATG G G C AG ATAACAACTGTTATCTTG CCACTG
CATTGTTAACACTCCA
ACAAATAG AG TTG AA G TTTAATCCA CCTG CTCTAC AAG AT G CTTATTACA G AG CAAG G G
CTG GTGAAG CTG CTAACTTTT
GTG CACTTATCTTAG CCTACTGTAATAAG ACAG TAG G T G AG TTAG GTG AT G TTAG AG
AAACAAT G AGTTACTTG TTTC AA
CATG CCAATTTAG ATTCTTG C AAAAG A G TCTTG AA C G TG GTGTGTAAAACTTGTG G AC AACAG
C AG ACAA C CCTTAA G G G
TG TAG AAG CTGTTATGTACATG G G CACACTTTCTTATGAACAATTTAAGAAAG
GTGTTCAGATACCTTGTACGTGTG G TA
AACAAG CTACACAATATCTAGTACAACAG G AG T C AC CTTTT G TTATG ATG T CA G CACCACCTG
CT CAG TATG AACTTAAG
CATG GTACATTTACTTGTG CTAG T G AG TACACT G GTAATTACCAGTGTG
GTCACTATAAACATATAACTTCTAAAGAAAC
TTTGTATTG C ATAG AC G GTG CTTTACTTACAAAGTCCTCAGAATACAAAG GTCCTATTACGG ATG
TTTTCTACAAA G AAA
A CAG TTA CA CAA CAAC CATA AAACCAG TTA CTTATAA ATTG GATG GTG TTG TTTG TA CAG
AAATTG ACCCT AA GTTG G AC
AATTATTATAAG AAA G ACAATTCTTATTT CACAG A G CAACCAATTG ATCTTG TA CCAAACC AACCAT
ATCCAAAC G CAAG
CTTCG ATAATTTTAAG TTTG TATG TG ATAATATCAAATTTG CTGATG ATTTAAACCAGTTAACTG
GTTATAAGAAACCTG
CTT CAAG AG AG CTTAAAGTTACATTTTTCCCTG ACTTAAATG G TG AT G TG GTG G
CTATTGATTATAAACACTACACACCC
TCTTTTAAGAAAG GAG CTAAATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG CAACTAATAAAG C
CACGTATAA
ACCAAATACCTG GTGTATACGTTGTCTTTG GAG CACAAAACCG
GTTGAAACATCAAATTCGTTTGATGTACTGAAGTCAG
AG G ACG CG CAG G G AATG GATAATCTTG CCTG CGAAGATCTAAAACCAGTCTCTGAAGAAGTAGTG
GAAAATCCTACCATA
CAG AAAG AC G TTCTTG AG TG TAATG TG AAAACT ACC G AA G TTG TAG G AG
ACATTATACTTAAAC CAG CAAATAATAGTTT
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AAAAATTACAG AAG AG GTG G C CA CACAG ATCTAATG G CTG CTTATG TA G ACAATTCTAG
TCTTAC TATTAAG AAA C CTA
ATG AATTATCTAG AG TG TTAG GTTTGAAAACCCTTG CTACTCATG GTTTAG CTG
CTGTTAATAGTGTCCCTTG G GATACT
ATAG CTAATTATG CTAAG C CTTTTCTTAACAAAG TT G TTAG TAC AACTACTAACATAG TTACAC G
GTGTTTAAACCGTGT
TTGTACTAATTATATG
CCTTATTTCTTTACTTTATTGCTACAATTGTGTACTTTTACTAGAAGTACAAATTCTAGAATTA
AAG CATCTATG CC G ACTA CTATAG CAAAG AATACTG TTAAG AG TG TCG GTAAATTTTGTCTAG AG
GCTTCATTTAATTAT
TTG AAG T CAC CTAATTTTTCTAAACT G ATAAATATTATAATTTG GTTTTTACTATTAAGTGTTTG CCTAG
GTTCTTTAAT
CTACTCAACCG CTG CTTTAG GTGTTTTAATGTCTAATTTAG G CAT G CCTTCTTACTGTACTG G TTAC
AG AG AAG G CTATT
TGAACTCTACTAATGTCACTATTG CAA C CTACTG TACTG G TTCTATAC CTTG TAG TG TTTG TCTT
AG TG GTTTAGATTCT
TTAGACACCTATCCTTCTTTAG AAACTATACAAATTACCATTTCATCTTTTAAATG G GATTTAACTG CTTTTG
G CTTAGT
TG CAG AG TG GTTTTTG GCATATATTCTTTTCACTAG G TTTTTCTATGTACTTG GATTG G CTG
CAATCATG CAATTGTTTT
TCAG CTATTTTG C AG TACATTTTATTAG TAATTCTTG G CTTATGTG
GTTAATAATTAATCTTGTACAAATG G C CC C G ATT
TCAG CTATG GTTAG AAT G TAC AT CTTCTTT G CAT CATTTTATTATG TATG G AAAAGTTATGTG C
ATG TT G TAG AC G GTTG
TAATTCATCAACTTGTATG ATG TGTTACAAACGTAATAG AG CAACAAG AG TCG
AATGTACAACTATTGTTAATG G TGTTA
GAAG GTCCTTTTATGTCTATG CTAATG G AG GTAAAG G CTTTTG CAAACTACACAATTG
GAATTGTGTTAATTGTGATACA
TTCTGTG CTG GTAGTACATTTATTAGTG ATGAAGTTG CG AG AG ACTTGTCACTA CAG TTTAAAAGAC
CAATAAATCCTAC
TG A C CAG T CTTCTTAC ATC G TTG ATAG T G TTA CA G TG AAGAATG G TTC C ATC CAT
CTTTACTTTG ATAAAG CTG GTCAAA
AG ACTTAT G AAAG ACATTCTCTCTCTCATTTTGTTAACTTAG ACAAC CTG A G AG
CTAATAACACTAAAG GTTCATTG C CT
ATTAATGTTATAGTTTTTGATG G TAAAT C AAAATG TG AA G AATC ATCT G CAAAATCAG
CGTCTGTTTACTACAGTCAG CT
TATG TGTCAAC CTATACTG TTACTAG AT CAG G CATTAGTGTCTGATGTTG GTG ATAGTG CG
GAAGTTG CAGTTAAAATGT
TTG ATG CTTACGTTAATACGTTTTCATCAACTTTTAACGTACCAATG G AAAAACTCAAAACACTAGTTG
CAACTG CAG AA
G CT G AACTTG CAAAGAATGTGTCCTTAG ACAATGTCTTATCTACTTTTATTTCAG CAG CTCG G CAAG G
GTTTGTTGATTC
AG ATGTAG AAACTAAAGATGTTGTTGAATGTCTTAAATTGTCACATCAATCTGACATAGAAGTTACTG G CG
ATAGTTG TA
ATAACTATATG CT CAC CTATAACAAAG TTG AAAACATG ACACCCCGTGACCTTG GTG CTTG TATTG
ACTG TAG TG CG CGT
CATATTAATG CG CAG GTAG CAAAAAG TC AC AACATTG CTTTGATATG GAACGTTAAAG
ATTTCATGTCATTGTCTGAACA
ACTA C G AAAA CAAATAC G TAG TG CT G CTAAAAAGAATAACTTACCTTTTAAGTTG ACATGTG
CAACTACTAGACAAGTTG
TTAATG TT G TAAC AACAAAG ATAG CACTTAAG G GTG GTAAAATTGTTAATAATTG G TTG A AG
CAGTTAATTAAAGTTACA
CTTGTGTTCCTTTTTGTTG CT G
CTATTTTCTATTTAATAACACCTGTTCATGTCATGTCTAAACATACTGACTTTTCAAG
TGAAATCATAG GATACAAG G CTATTGATG GTG GTGTCACTCGTGACATAG CATCTACAGATACTTGTTTTG
CTAACAAAC
ATG CTG ATTTTG ACACATG GTTTAG CCAG CGTG GTG G TAG TTATA CTAATG ACAAAG CTTG
CCCATTG ATTG CTG CAGTC
ATAAC AAG AG AA G TG G GTTTTGTCGTG CCTG GTTTG C CT G G CA C G ATATTAC G
CACAACTAATG GTGACTTITTG CATTT
CTTACCTAG AG TTTTTA G TG C AG TT G G TAACATCT G TTACACA C C ATCAAAACTTATAG AG
TAC ACTG ACTTTG CAACAT
CAG CTTGTGTTTTG G CT G CTG AATG TACAATTTTTAA AG ATG CTTCTG GTAAG C CA G TAC C
ATATT GTTATG ATA C CAAT
G TA CTAG AAG GTTCTGTTG CTTATGAAAATTTACG CCCTG AC ACACG TTATG TG CTCATG GATG G
CT CTATTATTC AATT
TCCTAACACCTACCTTGAAG GTTCTGTTAG AG TG GTAACAACTTTTG ATTCTG AG TACTG TAG G CAC
G G CACTTGTG AAA
G AT CAG AAG CTG GTGTTTGTGTATCTACTAGTG G TAG ATG G GTACTTAACAATG ATTATTACAG AT
CTTTACCAG G AG TT
TTCTGTG GTG TAG ATG CTG TAAATTTACTTACTAATATG TTTA CAC CACTAATT CAAC CTATTG GTG
CTTTG G ACATATC
AG CATCTATAG TA G CTG GTG G TATTG TA G CTATCGTAGTAACATG CCTTG CCTACTATTTTATG
AG GTTTAG AAG AG CTT
TTG GTG AATA CAGTCATG TAG TTG C CTTTAATACTTTACTATTC CTTATGTCATTCACTG TACTCTG
TTTAACACCAG TT
TACT CATT CTTAC CTG GTGTTTATTCTGTTATTTACTTGTACTTG
ACATTTTATCTTACTAATGATGTTTCTTTTTTAG C
ACATATTCAGTG GATG G TTATG TT CACAC CTTTAG TA C CTTT CTG GATAACAATTG
CTTATATCATTTGTATTTCCACAA
AG CATTTCTATTG G TTCTTTAG TAATTA C CTAAA G AG A C G TG TAG TCTTTAATG G TG TTTC
CTTTAG TACTTTTG AAG AA
G CTG CG CTGTG CAC CTTTTTG TTAAATAAAG AAATG TATCTAAAG TTG CGTAGTG ATG TG
CTATTACCTCTTACG CAATA
TAATAGATACTTAG CTCTTTATAATAAGTACAAGTATTTTAGTG GAG CAATG G ATACAACTAG CTAC A G
AG AAG CT G CTT
G TT G TCATCTC G CAAAG G CT CTCAAT G ACTT CAG TAACTC AG GTTCTG ATG TTCTTTAC
CAA C CAC CA CAAAC CTCTAT C
AC CT CAG CTGTTTTG CAG AG TG GTTTTAGAAAAATG G CATTCCCATCTG G TAAAG TTG AG G
GTTGTATG GTACAAGTAAC
TTGTG GTACAACTACACTTAACG GTCTTTG G CTTGATG AC G TA G TTTACTG TC CAAG ACATG TG
AT CTG C AC CTCT G AAG
ACATG CTTAACCCTAATTATGAAGATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTACAG G CTG G
TAATG TT C AA
CTCAG G GTTATTG GACATTCTATG CAAA ATTG TG TA CTTAAG CTTAAG GTTGATACAG C CAATC
CTAAG A CACCTAAG TA
TAAGTTTGTTCG CATT CAAC CA G G ACA G ACTTTTTC AG TG TTA G CTTGTTACAATG
GTTCACCATCTG GTGTTTACCAAT
GTG CTAT G AG G CCCAATTTCACTATTAAG G GTTCATTCCTTAATG GTTCATG TG G TAG T G TTG
GTTTTAACATAGATTAT
GACTGTGTCTCTTTTTGTTACATG CAC C ATATG GAATTACCAACTG G AGTTCATG CTG G
CACAGACTTAG AAG GTAACTT
TTATG GACCTTTTGTTGACAG G CAAACAG CACAAG CAG CTG GTACG G AC ACAACTATTAC AG
TTAATG TTTTAG CTTG GT
TGTACG CTG CTGTTATAAATG G AG AC AG GT G GTTTCTCAATCG ATTT AC CACAA CT CTTAATG
ACTTTAACCTTGTG G CT
ATG AAG TAC AATTATG AAC CTCTAACACAA G AC CAT G TT G ACATACTAG G AC CT CTTT CTG
CTCAAACTG G AATTGTCGT
TTTAGATATGTGTG CTTCATTAAAAGAATTACTG CAAAATG G TATG A ATG G AC G TAC CATATTG G
G TA G TG CTTTATTAG
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AAG ATG AATTTACAC CTTTTG AT G TTG TTAG ACAATG CTCAG GTGTTACTTTCCAAAGTG CAG TG
AAA AG AACAATCAAG
G GTACACAC C ACT G G TTG TT ACTCA CAATTTTG A CTTCA CTTTTAG TTTTAG TC CAG AG TA
CTCAATG G T CUTG TT CTT
TTTTTTGTATG AAAATG CCTTTTTACCTTTTG CTATG G GTATTATTG CTATGTCTG CTTTTG CAATG AT
G TTT G TC AAAC
ATAAG CATG CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG C CACT G TAG CTTATTTTAATATG
GTCTATATG CCTG CT
AG TTG G G TG AT G CGTATTATGACATG GTTG GATATG GTTGATACTAGTTTG AAG CTAAAAG
ACTGTGTTATGTATG CATC
AG CT G TAG TG TTACTAATC CTTATG A CAG CAA G AACT GTG TATG ATG ATG GTG CTAG G
AG AG TG T G GACACTTATGAATG
TCTTGACACTCGTTTATAAAGTTTATTATG GTAATG CTTTAGATCAAG CCATTTCCATGTG G G CT
CTTATAATCTCTG TT
ACTT CTAACTACT CAG G TG TAG TTAC AACTG TCAT G TTTTTG G CCAG AG G TATTG TTTTTAT
GTG TG TT G AG TATTG CCC
TATTTTCTTCATAACTG GTAATACACTTCAGTGTATAATG CTAGTTTATTGTTTCTTAG G
CTATTTTTGTACTTGTTACT
TTG G C CT CTTTTG TTTACT CAAC C G CTACTTTAG ACTG A CTCTTG GTGTTTATG
ATTACTTAGTTTCTACACAG G AG TTT
AG ATATATG AATT CACAG G G ACTACTCC CAC CCAAG AATAG CATAG ATG
CCTTCAAACTCAACATTAAATTGTTG G GTGT
TG GTG G CAAAC CTTG TATCAAA G TAG CCACTGTACAGTCTAAAATGTCAGATGTAAAGTG CACATCAG
TAG TCTT ACTCT
CAGTTTTG CAAC AACTC AG A G TAG AAT CATCATCTAAATTG TG G G CTCAATG TG TC C
AGTTACAC AAT G ACATT CT CTTA
G CTAAAGATACTACTGAAG CCTTTG AAAAAATG GTTTCACTACTTTCTGTTTTG CTTTCCATG C AG G
GTG CTG TAG A CAT
AAACAAG CTTTGTGAAGAAATG CTG G A CAACAG G G CAACCTTACAAG CTATAG C CTC AG AG
TTTAG TTC C CTTC CATC AT
ATG CAG CTTTTG CTACTG CTCAAGAAG CTTAT G AG CA G G CT G TTG CTAATG GTG
ATTCTGAAGTTGTTCTTAAAAAGTTG
AAGAAGTCTTTG AATGTG G CTAAATCTGAATTTG AC C G TG ATG C AG CCATG CAA C G TAA G
TTG GAAAAGATG G CTG ATCA
AG CTATG A C C CAAATG TATAAACAG G CTAG ATCTG A G GACAAG AG G G CAAAAGTTACTAGTG
CTATG CAG ACAATG CUT
TCACTATG CTTAG AAAGTTG GATAATG ATG CACTC AA CAACATTATCAA CAATG CAAG AG ATG
GTTGTGTTCCCTTGAAC
ATAATAC CT CTTA CAACAG CAG CCAAACTAATG GTTGTCATACCAG
ACTATAACACATATAAAAATACGTGTG ATG GTAC
AACATTTACTTATG CATCAG CATTGTG G G AAATCCAACAG GTTG TAG ATG CAG ATAG TAAAATTG
TTCAACTTAGTG AAA
TTAGTATG GACAATTCACCTAATTTAG CATG G C CT CTTATTG TAACAG CTTTAAG G G CCAATTCTG
CTGTCAAATTACAG
AATAATG AG CTTAGTCCTGTTG CACTACGACAGATGTCTTGTG CTG CCG GTACTACACAAACTG CTTG
CACTGATG ACAA
TG CGTTAG CTTATTACAACACAACAAAG G GAG GTAG GTTTGTACTTG C ACTG TTATC C G ATTTAC
AG GATTTGAAATG G G
CTAG ATTCCCTAAG AG TG AT G G AACTG GTACTATCTATACAG AACTG G AAC CAC CTT G TAG G
TTTG TTACAG AC A CAC CT
AAAG GTCCTAAAGTGAAGTATTTATACTTTATTAAAG G ATTAAACAA C CTAAATAG AG G TAT G
GTACTTG G TAG TTTAG C
TG CCACAGTACGTCTACAAG CTG GTAATG CAA CAG AAG TG CCTG
CCAATTCAACTGTATTATCTTTCTGTG CTTTTG CTG
TAG ATG CTG CTAAAG CTTACAAAGATTATCTAG CTAGTG GG GG AC AAC CAAT CACTAATTG
TGTTAAG ATG TTG TG TACA
CACACTG GTACTG GTCAG G CAATAACA G TTAC AC C G G AAG CCAATATG G AT CAAG AATC
CTTTG GTG G TG CAT C G TG TTG
TCTGTACTG CC GTTG CCACATAG ATCATCCAAATCCTAAAG G ATTUGTGACTTAAAAG
GTAAGTATGTACAAATACCTA
CAACTTGTG CTAATG AC CCTG TG G GTTTTACACTTAAAAACACAGTCTGTACCGTCTG CG GTATGTG G
AAAG GTTATG G C
TG TAG TTG TG AT CAACTC CG CG AACCCATG CTTCAGTCAG CTGATG CACAATCGTTTTTAAACG G
GTTTG CG GTGTAAGT
G CAG CCCGTCTTACACCGTG CG G CA CAG G CACTAG TACTG ATG TCG TATAC AG G G
CTTTTGACATCTACAATGATAAAGT
AG CT G GTTTTG CTAAATTCCTAAAAACTAATTGTTGTCG CTTCCAAGAAAAG G AC G AAG AT G A
CAATTTAATTG ATTCTT
ACTTTG TAG TTAAG AG A CACACTTT CTCTAA CTAC C AACATG AAG AAA
CAATTTATAATTTACTTAAG G ATT G TC C AG CT
GTTG CTAAACATG ACTT CTTTAAG TTTAG AATAGACG GTGACATG GTAC CAC ATATATCACG TCAAC
GTCTTACTAAATA
CACAATG G C AG AC CTC G T CTATG CTTTAAG G CATTTTG AT G AAG
GTAATTGTGATACATTAAAAG AAATACTTGTCACAT
ACAATTG TT G TG ATG AT G ATTATTTCAATAAAAAG G A CTG G TATG ATTTTG TAG AAAAC C
CAG ATATATTACG CGTATAC
G CCAACTTAG G T G AAC G TG TA C G CCAAG CTTTG TTAAAAAC A G TAC AATTCTG TG ATG
CCATG CGAAATG CTG GTATTGT
TG GTGTACTG ACATTAGATAATCAAGATCTCAATG GTAACTG G TAT G ATTTC G G TG ATTTC
ATACAAAC CAC G CCAG G TA
GTG G AG TTC CTG TT G TAG ATTCTTATTATTCATTGTTAATG C CTATATTAAC CTTG AC CAG G G
CTTTAACTG CAG AG TCA
CATGTTG ACACTG ACTTAACAAAG CCTTACATTAAGTG G GATTTGTTAAAATATG ACTTC AC G G AAG
AG AG GTTAAAACT
CTTTG AC C G TTATTTTAAATATTG G G AT CAG AC ATAC C AC C CAAATTG TG TTAACTG TTTG
G AT G ACAG ATG CATTCTG C
ATTGTG CAAACTTTAATGTTTTATTCTCTACAG TGTTCCCACTTACAAGTTTTG G AC CACTAG TG AG
AAAAATATTTG TT
G AT G G TG TTC C ATTTG TAG TTTCAACTG G ATAC C ACTTC AG AG AG CTAG
GTGTTGTACATAATCAG GATGTAAACTTACA
TAG CTCTAGACTTAGTTTTAAG G AATTACTT G TG TAT G CT G CT G ACC CT G CTATG C AC G
CT G CTTCTG GTAATCTATTAC
TAG ATAAACG CACTACGTG CTTTTC AG TAG CTG CACTTACTAACAATGTTG
CTTTTCAAACTGTCAAACCCG GTAATTTT
AA CAA A G A CTTCTAT G A CTTTG CTGTGTCTAAG G G TTTCTTTA A G G AA G G AA G TTCT
G TTG AATTAAAACACTTCTTCTT
TG CTCAG GATG GTAATG CT G CTATCAG C G ATTATG ACTACTATC G TTATAATCTAC CAACAATG
TG TG ATATCA G AC AAC
TACTATTTGTAGTTG AAGTTGTTGATAAGTACTTTG ATTGTTACGATG GTG G CTGTATTAATG
CTAACCAAGTCATCGTC
AACAACCTAG ACAAATCAG CTG GTTTTCCATTTAATAAATG G G GTAAG G
CTAGACTTTATTATGATTCAATG AG TTATG A
G GATCAAG ATG CACTUTCG CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATG
CCATTA
GTG CAAAG AATAG AG CT C G CAC C G TA G CTG GTGTCTCTATCT G TA G TACTATG AC
CAATAG ACAGTTTCATCAAAAATTA
TTG AAATCAATAG CCG CCAC TAG AG GAG CTACTGTAGTAATTG GAACAAG CAAATTCTATG GTG
GTTG G CA CAACATG TT
AAAAACTGTTTATAGTG ATG TAG AAAACCCTC AC CTTATG G GTTG G G ATTATCCTAAATGTGATAG
AG CCATG CCTAA CA
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TG CTTAG AATTATG G CCTCACTTGTTCTTG CTCG CAAACATACAACGTGTTGTAG
CTTGTCACACCGTTTCTATAGATTA
G CTAATGAGTGTG CT CAAG TATTG AG TG AAATG GTCATGTGTG G CG GTTCACTATATGTTAAACCAG
GTG G AACCTCATC
AG G AG AT G CCACAACTG CTTATG CTAATAGTG __ 1 1 1 1 1 AACATTTGTCAAG CTGTCACG G
CCAATGTTAATG CACTTTTAT
CTACTGATG GTAACAAAATTG CC G ATAAGTATGTCCG CAATTTACAACACAG ACTTTATG AG
TGTCTCTATAG AAATAG A
G AT G TTG ACACA G ACTTTG T G AAT G AG TTTTA C G CATATTTG
CGTAAACATTTCTCAATGATG ATACT CT CT G AC G ATGC
TG TTG TG TG TTTC AAT AG CACTTATG CATCTCAAG GTCTAGTG G CTAG
CATAAAGAACTTTAAGTCAGTTCTTTATTATC
AAAACAATGTTTTTATGTCTG AAG CAAAATGTTG G ACTG AG ACT G ACCTTACTAAAG G
ACCTCATGAATTTTG CT CTCAA
CATACAATG CTAGTTAAACAG G GTGATGATTATGTGTACCTTCCTTACCCAGATCCATCAAGAATCCTAG G G
G CCG G CTG
TTTTG TAG ATG ATATCGTAAAAACAG ATG GTACACTTATG ATTG AACG GTTCGTGTCTTTAG
CTATAGATG CTTACC CAC
TTACTAAACATCCTAATCAG G AG TATG CTG ATG TCTTTC ATTT G TACTTACAATACATAAG AAA G
CTA CATG ATG AG TTA
ACAG G ACAC ATG TTAG A CATG TATTCTG TTATG CTTACTAATG ATAACACTTCAAG GTATTG G G
AACCT G AG TTTTATG A
G GCTATGTACACACCG CATACAGTCTTAC AG G CTGTTGG G G CTTGTGTTCTTTG
CAATTCACAGACTTCATTAAGATGTG
GTG CTTG CATA C G TAG ACCATTCTTATG TTG TAAATG CTGTTAC G A CCATG TCATATCAAC
ATCACATAAATTAG TCTTG
TCTGTTAATCCGTATGTTTG CAATG CTCCAG GTTGTGATGTCACAGATGTG ACTCAACTTTACTTAG GAG
GTATG AG CTA
TTATTGTAAATCACATAAACCACCCATTAGTTTTCCATTGTGTG CTAATG G AC AAG TTTTTG
GTTTATATAAAAATACAT
GTGTTG G TAG CGATAATGTTACTG ACTTTAATG CAATTG CAACATGTG ACTG G ACAAATG CTG
GTGATTACATTTTAG CT
AACACCTGTACTG AAAGACTCAAG CTTTTTG C AG C AG AAACG CTCAAAG CTACTG AG G AG AC
ATTTAAACTG TCTTATG G
TATTG CTACTGTACGTGAAGTG CTGTCTG ACAG A G AATTACATCTTTCATG G G AAG TTG G
TAAACCTAG ACC ACCACTTA
ACC G AAATTATGTCTTTACTG G TTAT C G TG TAAC TAAAAAC AG TAAAG TAC AAATA G G AG A
G TAC ACCTTTG AAA AAG GT
GACTATG GTGATG CTGTTG TTTACCG AG GTACAACAACTTACAAATTAAATGTTG GTGATTATTTTGTG
CTGACATCACA
TACAGTAATG CCATTAAGTG CA CCTAC ACTAG TG C C AC AAG A G CA CTATG TTAG AATTACT G
G CTTATACCCAACACTCA
ATATCTCAG ATG AG TTTTCTAG CAATGTTG CAAATTATCAAAAG GTTG GTATG
CAAAAGTATTCTACACTCCAG G GACCA
CCTG G TA CTG GTAAG AG TC ATTTT G CTATTG G CCTAG CTCTCTACTACC CTTCTG CT C G
CATAGTGTATACAG CTTG CTC
TCATG CCG CTGTTGATG CACTATG TG AG AAG G CATTAAAATATTTG CCTATAGATAAATGTAGTAG
AATTATACCTG CAC
GTG CTC G TG TAG ATT G TTTTG ATAAATTC AAAG TG AATTC AACATTAG AA CAG TAT G
TCTTTTG TACTG TAAATG CATTG
CCTG AG AC G ACAG CAGATATAGTTGTCTTTGATG AAATTTCAATG G CCACAAATTATGATTTG AG TG
TTGTCAATG CCAG
ATTACGTG CTAAG CACTATGTGTACATTG G C G AC CCTG CTCAATTACCTG CA CCAC G CA CATTG
CTAACTAAG G G CACAC
TAG AACCAG AATATTTCAATTCAGTGTG TAG ACTTATG AAAACTATAG GTCCAG ACATGTTCCTCG
GAACTTGTCG G CGT
TGTCCTG CTGAAATTGTTG ACACTG TG AG TG CTTTG GTTTATGATAATAAG CTTAAAG
CACATAAAGACAAATCAG CTCA
ATG CTTTAAAATGTTTTATAAG G GTGTTATCACG CATGATGTTTCATCTG CAATTAACAG G CCACAAATAG
G CGTG GTAA
G AG AATTCCTTA CACGTAACCCTG CTTG G AG AAAAG CTGTCTTTATTTCACCTTATAATTCAC AG
AATG CTG TAG CCTCA
AAGATTTTG G G ACTACCAACTCAAACTGTTGATTCATCACAG G G CT CAG AATATG
ACTATGTCATATTCACTCAAACCAC
TGAAACAG CTCACTCTT G TAAT G TAAACAG ATTTAATG TT G CTATTAC C AG AG CAAAAG TAG G
CATACTTTG CATAATGT
CTG ATAG AG ACCTTTATG ACAAG TT G CAATTTACAAG TCTTG AAATTCCA C G TAG GAATGTG G
CAACTTTACAAG CT G AA
AATGTAACAG G ACT CTTTAAAG ATTG TAGTAA G GTAATCACTG G GTTACATCCTACACAG G
CACCTACA C AC CTCA G TG T
TG A CACTAAATTCAAAA CTG AAGGTTTATGTGTTG A CATAC CTG G CATACCTAAG G ACATG
ACCTATAG AA G ACT CATCT
CTATGATG G GTTTTAAAATG AATTATCAAGTTAATG GTTACCCTAACATGTTTATCACCCG CG AAGAAG
CTATAAGACAT
G TA C G TG CATG GATTG G CTTC G AT G TC G AG G G GTGTCATG CTACTAG AG AAG CTG
TT G G TA CCAATTTAC CTTTAC AG CT
AG GTTTTTCTACAG GTGTTAACCTAGTTG CTG TACCTACAG G TTATG TT G AT ACACCTAATAATACA
G ATTTTTCC AG AG
TTAGTG CTAAACC ACC G CCTG G AG AT CAATTTAAACAC CTCATACCACTTAT G TACAAAG
GACTTCCTTG G AATG TAG TG
CGTATAAAG ATTG TACAAATG TTAAGTG ACA CACTTAAAAAT CTCTCTG AC AG AGTCGTATTTG
TCTTATG G G CACATG G
CTTTG AG TTG AC ATCTATG AAG TATTTTG T G AAAATAG G A CCTG AG CG
CACCTGTTGTCTATGTG ATA G AC G TG CCACAT
G CTTTTCCACTG CTTCAGACACTTATG CCTGTTG G CAT CATTCTATTG
GATTTGATTACGTCTATAATCCGTTTATG ATT
GATGTTCAACAATG G G GTTTTACAG GTAACCTACAAAG CAACCATG ATCTGTATTGTCAAGTCCATG
GTAATG CAC ATGT
AG CTAG TT G TG ATG CAATCAT G ACTA G GTGTCTAG CTG TCCAC G AG T G CTTTGTTAAG C
G TG TTG A CTG G A CTATT G AAT
ATCCTATAATTG GTG ATG AA CTG AAG ATTAATG CG G CTTGTAG AAAG GTTCAACACATG
GTTGTTAAAG CTG CATTATTA
G CAG ACAAATTCCCAG TT CTTC ACG AC ATTG GTAACCCTAAAG CTATTAAGTGTGTACCTCAAG CTG
ATGTAGAATG G AA
G TT CTATG ATG CA CAG CCTTGTAGTGACAAAG CTTATAAAATAG AAGAATTATTCTATTCTTATG CCA
CA CATTCTG A CA
AATTCACAG ATG GTGTATG CCTATTTTG G AATTG CAATGTCGATAGATATCCTG CTAATTCCATTG TTT
G TAG ATTT G AC
ACTAGAGTG CTATCTAACCTTAACTTG CCTG GTTGTGATG GTG G CAGTTTGTATGTAAATAAACATG
CATTCCACACACC
AG CTTTTGATAAAAGTG CTTTTGTTAATTTAAAACAATTACCATTTTTCTATTACTCTG ACAGTCCATGTG AG
T CT CATG
G AAAACAAG TAG TG TCAG ATATAG ATTATG TACCACTAAAG TCTG CTACGTGTATAACACGTTG
CAATTTAG GTG GTG CT
G TCTG TA G ACAT CATG CTAAT G AG TACAG ATTG TATCT C G ATG CTTATAACATG AT G AT
CT CAG CTG G CTTTAG CTTGTG
G GTTTACAAACAATTTG ATACTTATAACCTCTG G AA CACTTTTAC AAG ACTTCAG AG TTTAG AAAATG
T G G CTTTTAATG
TTGTAAATAAG G G ACACTTTGATG GACAACAG G GTG AAG TACCAG TTTCTATCATTAATAACACTG
TTTAC ACAAAAG TT
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GATG GTGTTG ATG TAG AATTGTTTG AAAATAAAAC AACATTAC CTG TTAATG TAG CATTTG AG
CTTTG G G CTAAG CG CAA
CATTAAAC CA G TAC CAG AG GTG AAAATACTCAATAATTTG G G TGTG GACATTG CTG
CTAATACTGTG ATCTG G G A CTACA
AAAG AG ATG CTC C AG CACATATATCTACTATTG GTGTTTGTTCTATGACTGACATAG CCAAG AAA C
CAACTG AAAC G ATT
TGTG CAC CACTCA CTGTCTTTTTTG ATG G TAG AGTTG ATG G TCAAG TAG ACTTATTTAG AAATG
CCCGTAATG G TGTTCT
TATTACAG AAG G TAG TG TTAAA G G TTTACAAC CATCT G TAG GTCCCAAACAAG CTAGTCTTAATG
G A G TCAC ATTAATTG
GAG AAG CCGTAAAAACACAGTTCAATTATTATAAGAAAGTTGATG
GTGTTGTCCAACAATTACCTGAAACTTACTTTACT
CAG A G TAG AAATTTACAAG AATTTAAACCCAG G AG TCAAATG G AAATTG ATTTCTTAGAATTAG
CTATG G ATGAATTCAT
TGAACG GTATAAATTAGAAG G CTATG CCTTC G AACATATC G TTTAT G G AG
ATTTTAGTCATAGTCAGTTAG GTG GTTTAC
ATCTACTG ATTG G ACTA G CTAAACGTTTTAAG G AATCAC CTTTT G AATT AG AAG
ATTTTATTCCTATG G AC AG TAC AG TT
AAAAACTATTTCATAACAG AT G CG CAAACAG G TT CATCTAAG TG TG T G TG TTCTG TTATTG
ATTTATTACTT G ATG ATTT
TGTTGAAATAATAAAATCCCAAG ATTTATCTGTAGTTTCTAAG GTTGTCAAAGTGACTATTGACTATACAG
AAATTTCAT
TTATG CTTTG GTGTAAAGATG G CCATGTAGAAACATTTTACCCAAAATTACAATCTAGTCAAG CGTG G
CAACCG G GTGTT
G CTATG CCTAATCTTTACAAAATG CAAAG AATG CTATTAG AAAA G TG T G AC CTTCAAAATTAT G
GT G ATAG TG CAACATT
AC CTAAAG G CATAATG AT G AATG TC G
CAAAATATACTCAACTGTGTCAATATTTAAACACATTAACATTAG CTG TA C C CT
ATAATATG A G AG TTATAC ATTTTG GTG CTG G TT CTG ATAAAG G AG TTG CAC CAG GTACAG
CTGTTTTAAG AC AG TG GTTG
CCTACG G GTACG CTG CTTGTCG ATTC AG ATCTTAATG A CTTTG TCT CTG AT G
CAGATTCAACTTTGATTG GTG ATTGTG C
AACTGTACATACAG CTAATAAATG G G AT CTCATTATTAG TG ATAT G TAC G AC C CTAAG A
CTAAAAATG TTACAAAAG AAA
ATG ACTCTAAAG AG G G ____ 111111CA CTTAC ATTTGTG G GTTTATACAACAAAAG CTAG CT
CTTG GAG GTTCCGTG G CT ATA
AAGATAACAG AA CATTCTTG GAATG CTG ATCTTTATAAG CT C ATG G GACACTTCG CATG GTG G
ACAG CCTTTGTTACTAA
TGTGAATG CGTCATCATCTG AAG CATTTTTAATTG GATGTAATTATCTTG G CAAACCACG
CGAACAAATAGATG GTTATG
TCATG CAT G CAAATTACATATTTTG G AG G AATACAAATC CAATTCAG TTG TCTT C
CTATTCTTTATTT G ACATG AG TAAA
TTTCCCCTTAAATTAAG G G GTACTG CTGTTATGTCTTTAAAAG AAGGTCAAATCAATGATATG
ATTTTATCTCTTCTTAG
TAAAG G TA G ACTTATAATTA G AG AAAACAACAG A G TTG TTATTTCTAG TG
ATGTTCTTGTTAACAACTAAACGAACAATG
TTTGTTTTTCTTGTTTTATTG C CACTAG T CTCTAG TC AG TG TG TTAATTTTAC AAACAG AACT
CAATTAC C CT CTG CATA
CACTAATTCTTTCACACGTG GTGTTTATTACCCTG ACAAAG TTTT CAG AT C CTC AG TTTTAC
ATTCAACTCAG G ACTT G T
TCTTACCTTTCTTTTCCAATGTTACTTG GTTCCATG CTATACATGTCTCTG G G AC CAATG GTACTAAG AG
GTTTGATAAC
C CT G TC CTACCATTTAAT G ATG GTGTTTATTTTG CTTC CA CTG AG AAGT CTAAC ATAATAA G
AG G CTG G ATTTTTG GTAC
TACTTTAG ATTC G AAG A C C CAG TC C CTACTTATTG TTAATAAC G
CTACTAATGTTGTTATTAAAGTCTGTG AATTTCAAT
TTTGTAATTATCCATTTTTG G G TG TTTATTAC CACAAAAACAACAAAAG TT G GATG GAAAGTG AGTT
CAG AG TTTATTCT
AGTG CGAATAATTG CACTTTTG AATATG TCTCTC AG CCTTTTCTTATG G AC CTTG AAG GAAAACAG
G GTAATTTCAAAAA
TCTTAG T G AATTTG T GTTTAAG AATATT G AT G GTTATTTTAAAATATATTCTAAG CACACG
CCTATTAATTTAGTG CGTG
ATCT C C CT CAG G GTTTTTCG G CTTTAG A AC CATTG G TAG ATTTG CCAATAG G TATTAAC
AT CACTAG GTTTCAAACTTTA
CTTG CTTTACATAGAAGTTATTTGACTCCTG GTGATTCTTCTTCAG GTTG GACAG CTG GTG CTG
CAGCTTATTATGTG G G
TTATCTTCAACCTAG G ACTTTTCTATTAAAATATAATGAAAATG G AACCATTACAGATG CTG TA G ACT G
T G CACTT G AC C
CTCTCTC AG AAA CAAAG TG TACGTTG AAATCCTTCACTGTAG AAAAAG G
AATCTATCAAACTTCTAACTTTAGAGTCCAA
C CAA CAG AATCTATTG TTAG ATTTC CTAATATTAC AAACTTG TG CCCTTTTG GTG AAGTTTTTAACG
C CAC CA G ATTTG C
ATCTGTTTATG CTTG GAACAG GAAG AG AAT CAG CAACTGTGTTG CT G ATTATTCT G TC C
TATATAATT C CG CATCATTTT
CCACTTTTAAGTGTTATG G AG T G TCTC CTACTAA ATTAAATG ATCTCTG CTTTACTAATGTCTATG
CAG ATTCATTTG TA
ATTAG AG G TG AT G AA G TCAG ACAAATCG CT C CAG G G CAAACTG GAACG ATTG CTG
ATTATAATTATAAATTACCAGATG A
TTTTACAG G CT G CGTTATAG CTTG GAATTCTAACAATCTTGATTCTAAG GTTG GTG G
TAATTATAATTAC CT G TATAG AT
TGTTTAG G AAG TCTAATCTC AAAC CTTTTG AG AG AG ATATTT CAACTG AAAT CTATCAG G CCG
G TAG CAC AC CTTG TAAT
G GTGTTAAAG GTTTTAATTGTTACTTTCCTTTACAATCATATG GTTTCCAACCCACTTATG GTGTTG
GTTACCAACCATA
CAG AG TAG TAG TACTTTCTTTTG AACTT CTACAT G CAC CAG CAACTGTTTGTG G AC CTAAAAAG
T CTACTAATTTG GTTA
AAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CACAG G TG TTCTTACT G AG T
CTAACAAAAAG TTT CT G C CT
TTCCAACAATTTG G CAG AG AC ATTG CTG A CACTA CTG AT G CT G TC C G TG ATC C AC AG
AC ACTTG AG ATTCTT G ACATTAC
AC CATG TT CTTTTG GTG GTGTCAGTGTTATAACACCAG GAACAAATACTTCTAATCAG GTTG
CTGTTCTTTATCAG G GTG
TTAACTG CACAGAAGTCCCTGTTG CTATTCATG CAG AT CAACTTACTC CTACTTG G
CGTGTTTATTCTACAG G TT CTAAT
GTTTTTCAAACACGTG CAG G CTGTTTAATAG G G G CTG AATATGTCAA CAA CTCATATG AG TGTG
ACATACCCATTG GTG C
AG GTATATG CG CTAGTTATCAG ACTC AG ACTAATT CTCCTC G G CG G G CACGTAG TG TAG CTA
GTCAATC CAT CATTG C CT
ACACTATGTCACTTG GTG CAG AAAATTCAGTTG CTTACTCTAATAACTCTATTG
CCATACCCACAAATTTTACTATTAGT
G TTAC CAC AG AAATT CTAC C AG TG TCTAT G AC CAA G ACAT C AG TAG ATT G TACAATG
TACATTTG TG GTG ATTC AA CTG A
ATG CAG CAATCTTTTGTTG CAATATG G CAGTTTTTGTACACAATTAAAC CGTG CTTTAACTG GAATAG
CTGTTG AACAAG
ACAAAAACACCCAAGAAGTTTTTG CACAAGTCAAACAAATTTACAAAACACCACCAATTAAAG ATTTTG GTG
GTTTTAAT
TTTTCAC AAATATTAC C AG ATC CATCAAAAC CAA G CAAG AG
GTCATTTATTGAAGATCTACTTTTCAACAAAGTG ACACT
TG CAGATG CTG G CTTCATCAAACAATATG GTGATTG CCTTG GTGATATTG CTG CTAG AG AC
CTCATTTGTG CACAAAAGT
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TTAACG G CCTTACTGTTTTG CCACCTTTG CTCACAGATGAAATGATTG CTCAATACACTTCTG CA CTG
TTAG CG G GTACA
ATCACTTCTG GTTG G AC CTTTG GTG CAG G TG CTG CATTACAAATACCATTTGCTATG CAAATG G
CTTATAG GTTTAATGG
TATTG G A G TTA CACAG AATGTTCTCTATG AG AAC C AAAAATTG ATTG CCAACCAATTTAATAGTG
CTATTG G CAAAATTC
AAG A CTCACTTTCTTCCAC AG CAA G TG CACTTG GAAAACTTCAAGATGTG GTCAACCAAAATG
CACAAG CTTTAAACACG
CTTGTTAAACAACTTAG CTCCAATTTTG GTG CAATTTC AAG TG TTTTAAAT G ATAT C CTTTCAC G
TCTT G ACAAAG TT G A
G GCTGAAGTG CAAATTG ATAG GTTG ATCACAG G CA G ACTT CAAAG TTTG CAG AC ATAT G TG
ACTCAACAATTAATTAG AG
CTG CAGAAATCAG AG CTTCTG CTAATCTTG CTG CTATTAAAATG TCAG A G TG T G TACTTG G
ACAATCAAAAAG AG TTG AT
TTTTGTG GAAAG G G CTATCATCTTATGTCCTTCCCTCAGTCAG C AC CTC ATG G TG TAG TCTTCTT
G CAT G TG ACTTATG T
CCCTG CACAAGAAAAGAACTTCACAACTG CT CCTG CCATTTGTCATGATG GAAAAG CAC A CTTT CCTC
G TG AAG GTGTCT
TTGTTTCAAATG G CAC ACACTG GTTTGTAACACAAAG GAATTTTTATG AACCACAAATCATTACTACAG
ACAACACATTT
GTGTCTG G TAACTG TG AT G TT G TAAT AG G AATTGTCAACAACACAGTTTATGATCCTTTG
CAACCTGAATTAGACTCATT
CAAG GAG G AG TTAG ATAAATATTTTAA G AAT CATACATCACC AG ATG TTG ATTTAG
GTGACATCTCTG G CATTAATG CTT
CATTTG TAAACATTCAAAAAG AAATTG AC C G CCTCAATG AG GTTG
CCAAGAATTTAAATGAATCTCTCATC GATCTCCAA
GAACTTG G AAAG TATG AG CAGTATATAAAATG G CCATG GTACATTTG G CTAG GTTTTATAG CT G
G CTTGATTG CCATAGT
AATG GTG ACAATTATG CTTTG CTGTATG A CCAG TTG CTG TA G TTG TCTCAAG G G CTG TT G
TT CTTG TG G AT CCT G CT G CA
AATTTG AT G AAG AC G ACTCTG AG CC AG TG CTCAAAG G AG TCAA ATTAC ATTAC ACATAAAC
G AA CTTAT G GATTTGTTTA
TG A G AATCTTCAC AATTG GAACTGTAACTTTG AAG CAAG GTG AAATCAAG G ATG CTACTC CTTC
AG ATTTTG TTC G CG CT
ACTG CAACG ATACCGATACAAG CCTCACTCCCTTTCG GATG G CTTATTGTTGG CGTTG CACTTCTTG CT
G TTTTT C AG AG
CG CTTCCAAAATCATAACCCTCAAAAAG AG ATG G CAACTAG CACTCTCCAAG G GTGTTCACTTTGTTTG
CAA CTTG CTGT
TGTTGTTTGTAACAGTTTACTCACACCTTTTG CTCGTTG CTG CTG G CCTTG AAG CC
CCTTTTCTCTATCTTTAT G CTTTA
GTCTACTTCTTG CAG AGTATAAACTTTG TAAG AATAATAATG AG G CTTTG G CTTTG CTG G AAATG
CCGTTC CAA AAACCC
ATTACTTTATGATG CC AACTATTTT CTTT G CTG G
CATACTAATTGTTACGACTATTGTATACCTTACAATAGTGTAACTT
CTTCAATTGTCATTACTTCAG GTGATG G CA CAACAAG TCCTATTT CTG AACATG ACTACC AG ATTG
GT G G TTATAC TG AA
AAATG G GAATCTG G AG TAAAAG ACTG TG TT G TATTACAC AG TTACTT CACTT CAG
ACTATTACCAG CTGTACTCAACTCA
ATT G AG TACAG AC ACTG G TG TTG AA CATG TTACCTTCTT CATCTAC AAT AAAATT G TT G
ATG AG CCTGAAG AACATGTCC
AAATTCACA CAATC G AC G GTTCACCCG G AG TTG TTAAT CC AG TAATG GAACCAATTTATGATG
AACCGACGACG ACTACT
AG CGTG CCTTTGTAAG CACAAG CTG ATG AG TAC G AACTTATG TA CTCATTC G TTTC G GAAG
AG ACAG GTACGTTAATAGT
TAATAG CGTACTTCTTTTTCTTG CTTTCGTG GTATTCTTG CTAG TTACACTAG CCATCCTTACTG
CGCTTCGATTGTGTG
CGTACTG CTG CAATATTGTTAACGTG AG TCTTG TAAAACCTTCTTTTT AC G TTTACTCTC G T G
TTAAAAATCTG AATTCT
TCTAG AG TTCCT G ATCTTCT G GTCTAAACGAACTAAATATTATATTAGTTTTTCTGTTTG
GAACTTTAATTTTAG CC ATG
G CAG ATTCCAACG GTACTATTAC CGTTG AAG AG CTTAAAAAG CTCCTTGAACAATG G
AACCTAGTAATAG GTTTCCTATT
CCTTACATG GATTTGTCTTCTACAATTTG CCTATG C CAAC AG G AATAG G TTTTTG TATATAATTAAG
TTAATTTTC CTCT
G GCTGTTATG G CCAGTAACTTTAG CTTG TTTTG TG CTTG CTG CT G TTTACAG AATAAATT G
GATCACCG GTG GAATTG CT
ATCG CAATG G CTTG TCTTG TAG G CTTG ATGTG G CTCAG CTACTTCATTG CTTCTTTCAG
ACTGTTTG CG CGTACG CGTTC
CATGTG GTCATTCAATCCAGAAACTAACATTCTTCTCAACGTG CCACTCCATG G CACTATTCTGACCAGACCG
CTTCTAG
AAAGTGAACTCGTAATCG GAG CTGTGATCCTTCGTG G ACATCTTCGTATTG CTG GACACCATCTAG G AC
G CT G TG ACATC
AAG G ACCTG CCTAAAGAAATCACTGTTG CTACATCACGAACG CTTTCTTATTACAAATTG G GAG CTTC G
CAG C G TG TAG C
AG G TG ACT CAG GTTTTGCTG CATAC AG TCG CTAC AG GATTG G CAACTATAAATTAAACAC AG
ACCATTC CA G TAG CAGTG
ACAATATTG CTTTG CTTGTAC AG TAAG TG AC AACAG ATGTTTCATCTCGTTG ACTTTCAG
GTTACTATAG CAG AG ATATT
ACTAATTATTATG AG GACTTTTAAAGTTTCCATTTG
GAATCTTGATTACATCATAAACCTCATAATTAAAAATTTATCTA
AG T CACTAA CTG AG AATAAATATTCTCAATTAGATGAAG AG CAA C CAATG GAG ATTG ATTAAAC G
AA CAT G AAAATTATT
CTTTTCTTG G CACTG ATAACACTCG CTACTTG T G AG CTTTATCACTACCAA G AG T G TG TTAG
AG GTACAACAGTACTTTT
AAAAG AACCTTG CTCTTCTG G AACATAC G AG G G CAATTCACCATTTCATCCTCTAG CTG
ATAACAAATTTG CACTG ACTT
G CTTTAG CACTCAATTTG CTTTTG CTTGTCCTGACG G CGTAAAACACGTCTATCAGTTACGTG CCAG
ATCAGITTCACCT
AAACT G TT CATCAG ACAAG AG G AAG TT CAAG AA CTTTACTCT CCAATTTTT CTTATTG TTG CG
G CAATAGTGTTTATAAC
ACTTTG CTTCAC ACTCAAAAG AAA G ACAG AATGATTGAACTTTCATTAATTG ACTT CTATTTG TG
CTTTTTAG CCTTTCT
G CTATTCCTTGTTTTAATTATG CTTATTATCTTTTG G TTCTCA CTTG AA CTG C AAG ATCATAAT G
AAACTTG TCAC G CCT
AA A C G AA CAT G AAATTTCTTG TTTTCTTA G G AATC ATCA CA A CTG TA G CT G
CATTTCACCAAG AATGTA G TTTA CA G TCA
TG TACTC AACATC AACCATATG TAG TT G ATG ACCCGTGTCCTATTCACTTCTATTCTAAATG
GTATATTAG A G TA G GAG C
TAG AAAATC AG CAC CTTTAATTG AATTGTG CGTG GATG AG G CTG
GTTCTAAATCACCCATTCAGTACATCGATATCG G TA
ATTATACAGTTTCCTGTTTACCTTTTACAATTAATTG CCAGAAACCTAAATTG G GTAGTCTTGTAGTG
CGTTGTTCGTTC
TAT G AAG A CTTTTTAG AG TAT CATG AC G TTC G T G TTG TTTTAG ATTTCATCTAAAC G AAC
AAACAAACTAAAATG TCTG A
TAATG G AC CCCAAAAT CAG CGAAATG CACCCCG CATTACGTTTG GTG GACCCTCAG ATTCAACTG
GCAGTAACCAGAATG
GAG AACG CAGTG G G G CG CG ATCAAAACAACGTCG G CCCCAAG GTTTACCCAATAATACTG
CGTCTTG GTTCACCG CT CTC
ACTCAACATG G CAA G GAAG ACCTTAAATT CCCT C G AG GACAAG G CGTTCCAATTAACACCAATAG
CA G TC G AG AT G ACCA
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AATTG G CTACTACCGAAG AG CTACCAGACGAATTCGTG GTG GTGACG
GTAAAATGAAAGATCTCAGTCCAAG ATG GTATT
TCTACTACCTAG G AACTG G G CCAGAAG CTG GACTTCCCTATG GTG CTAACAAAGACG G CATCATATG
G GTTG CAACTGAG
G GAG CCTTGAATACACCAAAAG ATCACATTG G CACCCG CAATCCT G CTAACAATG CTG CAATCGTG
CTACAACTTCCTCA
AG G AACAACATTG CCAAAAG G CTTCTACG CAG AAG G G AG CAG AG G
CGGCAGTCAAGCCTCTTCTCGTTCCTCATCACGTA
GTCGCAACAGTTCAAGAAATTCAACTCCAGGCAGCTCTAAACGAACTTCTCCTGCTAGAATGGCTGGCAATGGCGGTGA
T
GCTGCTCTTGCTTTGCTGCTGCTTGACAGATTGAACCAGCTTGAGAGCAAAATGTCTGGTAAAGGCCAACAACAACAAG
G
CCAAACTGTCACTAAG AAATCTG CTG CTG AG G CTTCTAAGAAG CCTCG G CAAAAACGTACTG
CCACTAAAG CATACAATG
TAACACAAGCTTTCGGCAGACGTGGTCCAGAACAAACCCAAGGAAATTTTGGGGACCAGGAACTAATCAGACAAGGAAC
T
GATTACAAACATTG G CCG CAAATTG CACAATTTG CCCCCAG CG CTTCAG CGTTCTTCG G AATGTCG
CG CATTG G CATG GA
AGTCACACCTTCGGGAACGTGGTTGACCTACACAGGTGCCATCAAATTGGATGACAAAGATCCAAATTTCAAAGATCAA
G
TCATTTTG CTGAATAAG CATATTGACG CATACAAAACATTCCCACC AACAGAG CCTAAAAAGG ACAAAAAG
AAGAAG G CT
GATGAAACTCAAG CCTTACCG CAG AG ACAGAAG AAACAG CAAACTGTGACTCTTCTTCCTG CTG
CAGATTTG G ATG ATTT
CTCCAAACAATTG CAACAATCCATGAG CAGTG CTGACTCAACTCAG G CCTAAACTCATG
CAGACCACACAAGG CAG ATG G
G CTATATAAACGTTTTCG CTTTTCCGTTTACGATATATAGTCTACTCTTGTG
CAGAATGAATTCTCGTAACTACATAG CA
CAAGTAGATGTAGTTAACTTTAATCTCACATAG CAATCTTTAATCAGTG TGTAACATTAG GG AG GACTTG
AAAGAG CCAC
CACATTTTCACCG AG G CCACG CG GAGTACG ATCG AGTGTACAGTGAACAATG CTAG G GAGAG CTG
CCTATATG GAAGAG C
CCTAATGTGTAAAATTAATTTTAGTAGTGCTAACCCCATGTGATTTTAATAGCTTCTTA
SEQ ID NO: 21
>QQX12069.1 surface glycoprotein, from genonne accession MW520923
M FVF LVLLP LVSSQCVN FTN RTQLPSAYTNSFTRGVYYPDKVFRSSVLHSTQDLF LPFFSNVTWF 1-1A11-
1VSGTNGTK RFD N PVLP
FN DGVYFASTE KSNIIRGW 1 FGTTLDSKTQSLLIVN NATNVVIKVCEFQFCNYPF LGVYYH KN N KSWM
ESE F RVYSSAN NCTF EY
VSQPFLMDLEGKQGNFKNLSEFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYL
TPGDSSSG
WTAGAAAYYVGYLQPRTF LLKYN ENGTITDAVDCALD PLSETKCTLKSFTVEKGIYQTSN FRVQPTESIVRFP
N ITNLCPFG EVEN
ATRFASVYAWN RKRISNCVADYSVLYNSASFSTFKCYGVSPTKLN DLCFTNVYADSFVI RG
DEVRQIAPGQTGTIADYNYKLPDD
FTGCVIAWNSN N LDSKVGG NYNYLYRLFRKSN LKPF E RD ISTE IYQAGSTPCNGVKG FNCYFPLQSYG
FQPTYGVGYQPYRVVVL
SF ELLHAPATVCG PKKSTN LVKN KCVN FN F NG LTGTGVLTESN KKF LP FQQFG
RDIADTTDAVRDPQTLEILDITPCSFGGVSVIT
PGTNTSNQVAVLYQGVNCTEVPVAI HADQLTPTWRVYSTGSNVFQTRAGCLI GAEYVN NSYECD 1 P IGAG
ICASYQTQTNSPRR
ARSVASQSI IAYTMSLGAENSVAYSN NSIAI PTN FT ISVTTEIL PVS MTKTSVDCT MYICG DSTECSN
LLLQYGSFCTQLN RALTG IA
VEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLI
CAQKFNGL
TVLP PL LTD E M IAQYTSALLAGTITSGWTFGAGAALQI PFAM QMAYR F NG 1 GVTQNVLYE NQKL
IANQF NSAI G KIQDSLSSTAS
ALG KLQDVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQI DRLITG RLQSLQTYVTQQL 1
RAAE 1 RASAN LAAIKM
SECVLGQSKRVDFCG KGYH L MS F PQSAP HGVVF LHVTYVPAQEKN FTTAPAICH DG KAH FP RE
GVF VSN GT HW FVTQR N FYE
PQIITTDNTFVSGNCDVVIGIVNNTVYDPLCIPELDSFKEELDKYFKNHTSPDVDLGDISGINASFVNIQKEIDRLNEV
AKNLNESLID
LQE LG KYEQYIKWPWYIWLG FIAG LIAIVMVTI M LCCMTSCCSCLKGCCSCGSCCKFDE
DDSEPVLKGVKLHYT
SEQ ID NO: 22
> Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-
2/human/England/MIG457/2020, EVAg
Ref-SKU:004V-04032, complete genonne. UK B 1.1.7 lineage
ATTAAAGGTTTATACCTTCCCAGGTAACAAACCAACCAACTTTCGATCTCTTGTAGATCTGTICTCTAAACGAACTTTA
AAAT
CTGTGTGGCTGTCACTCGGCTGCATGCTTAGTGCACTCACGCAGTATAATTAATAACTAATTACTGTCGTTGACAGGAC
AC
GAGTAACTCGTCTATCTTCTG CAG G CTG CTTACG GTTTCGTCCGTGTTG CAG CCGATCATCAG
CACATCTAG GTTTTGTCCG
G GTGTG ACCGAAAG GTAAGATG GAG AG CCTTGTCCCTG GTTTCAACG
AGAAAACACACGTCCAACTCAGTTTG CCTGTTTT
ACAG GTTCG CG ACGTG CTCGTACGTG GCTTTG GAGACTCCGTG GAG GAG GTCTTATCAGAG
GCACGTCAACATCTTAAAG
ATGGCACTTGTGGCTTAGTAGAAGTTGAAAAAGGCGTTTTGCCTCAACTTGAACAGCCCTATGTGTTCATCAAACGTTC
GG
ATG CTCGAACTG CACCTCATG GTCATGTTATG GTTG AG CTG GTAG CAGAACTCG AAG G
CATTCAGTACG G TCGTAGTG GT
GAG ACACTTG GTGTCCTTGTCCCTCATGTG G G CG AAATACCAGTG G CTTACCG C AAG
GTTCTTCTTCGTAAG AACG GTAAT
AAAGGAGCTGGTGGCCATAGTTACGGCGCCGATCTAAAGTCATTTGACTTAGGCGACGAGCTTGGCACTGATCCITATG
A
AGATTTTCAAGAAAACTG G AACACTAAACATAG CAGTG GTGTTACCCGTGAACTCATG CGTGAG CTTAACG
GAG G G G CAT
ACACTCGCTATGTCGATAACAACTTCTGTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGTGC
TGG
TAAAG CTTCATG CACTTTGTCTGAACAACTG GACTTTATTGAC ACTAAG AG G G GTGTATACTG CTG
CCGTGAACATG AG CA
TGAAATTGCTTGGTACACGGAACGTTCTGAAAAGAGCTATGAATTGCAGACACCTTTTGAAATTAAATTGGCAAAGAAA
TT
TGACACCTTCAATGGGGAATGTCCAAATTTTGTATTTCCCTTAAATTCCATAATCAAGACTATTCAACCAAGGGTTGAA
AAG
AAAAAGCTTGATGGCTTTATGGGTAGAATTCGATCTGTCTATCCAGTTGCGTCACCAAATGAATGCAACCAAATGTGCC
TTT
CAACTCTCATGAAGTGTGATCATTGTG GT GAAACTTCATG GCAGACG GG CG ATTTTGTTAAAGCCACTT G
CGAATTTTGTG
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G CACTG AG AATTTGACTAAAGAAG GTG CCACTACTTGTG GTTACTTACCCCAAAATG
CTGTTGTTAAAATTTATTGTCCAG C
ATG TCACAATTCA G AAG TAG G A CCTG AG CATAGTCTTG CCGAATACCATAATGAATCTG
GCTTGAAAACCATTCTTCGTAA
G GGTG G TCG CA CTATTG CCTTTG G AG G CTGTGTGTTCTCTTATGTTG GTTG
CCATAACAAGTGTGCCTATTG G GTTCCACGT
G CTAG CG CTAACATAG GTTGTAACCATACAG GTGTTGTTG GAG AAG GTTCCG AAG GTCTTA ATG AC
AACCTT CTTG AAATA
CTCCAAAAAG AG AAAG TCAA CATCAATATT G TTG GTG ACTTTAAACTTAATG AAG AG ATCG
CCATTATTTTG G CATCTTTTT
CTG CTTCCACAAGTG CTTTTGTG G AAACTGTG AAAG GTTTG GATTATAAAG CATT CAAAC AAATTG
TT G AATCCTGTG G TA
ATTTTAAAGTTACAAAAG GAAAAG CTAAAAAAG GTG CCTG G AATATTG GTGAACAG
AAATCAATACTGAGTCCTCTTTATG
CATTTG CATCA G AG G CTG CTCGTGTTGTACG ATCAATTTT CTC CC G CACTCTTG AAACTG
CTCAAAATTCTGTG CGTGTTTTA
CAGAAG G CCG CTATAACAATACTAGATG G AATTTCACAG TATTCACTG AG ACTCATTG ATG
CTATGATGTTCACATCTGATT
TG G CTACTAACAATCTAGTTGTAATG G CCTACATTACAG GTG G TG TT G TTC AG TTG ACTT C G
CAG TG G CTAACTAACATCTT
TG G CACTGTTTATGAAAAACTCAAACCCGTCCTTGATTG G CTTG AAG AG AA G TTTAAG GAAG G T G
TAG A G TTT CTTAG AGA
CG GTTG G GAAATTGTTAAATTTATCTCAACCTGTG CTTGTGAAATTGTCG GTG GACAAATTGTCACCTGTG
CAAAG GAAAT
TAAG G AG A G TG TTCAG ACATTCTTTAAG CTTGTAAATAAATTTTTG G CTTTGTGTG CTG ACT
CTATC ATTATTG GTG G AG CT
AAACTTAAAG CCTTGAATTTAG GTGAAACATTTGTCACG CACTCAAAG G G ATTGTAC AG AAAG TG TG
TTAAATCCAG AG AA
G AAA CTG G CCTACTCATG CCT CTAAAAG CCCCAAAAG AAATTATCTT CTTAG AG G GAG
AAACACTTCCCACAGAAGTGTTA
ACAG AG GAAGTTGTCTTGAAAACTG GTGATTTACAACCATTAG AACAACCTACTAGTGAAG CTGTTGAAG
CTCCATTG G TT
G GTACACCAGTTTGTATTAACG G G CTTATGTTG CTCGAAATCAAAGACACAGAAAAGTACTGTG CC CTTG
CACCTAATATG
ATG GTAACAAACAATACCTTCACACTCAAAG G CG GTG CACCAACAAAG GTTACTTTTG
GTGATGACACTGTG ATAG AAGTG
CAAG GTTAC AAG AG TG TG AATAT CACTTTTG AA CTTG ATGAAAG G ATT G ATAAAG TACTTAAT
G AG AAG TG CT CTG CCTAT
ACAGTTG AACTCG G TA CAG AAG TAAAT G AG TTCG CCTG TG TT G TG G CAG ATG CTG
TCATAAAAACTTTG CAA CCAG TATCT
GAATTACTTACACCACTG G G CATTG ATTTAGATG AG TG G AG TATG G CTACATACTACTTATTTGATG
AG TCTG G T G AG TTTA
AATTG G CTTCACATATGTATTGTTCTTTTTACCCTCCAGATG AG GATGAAG AAG AA G GTG ATTG TG
AA G AAG AAG A G TTTG
AG CCATCAACTCAATATG AG TATG GTACTGAAG ATGATTACCAAG GTAAACCTTTG G AATTTG
GTGCCACTTCTG CTG CTCT
TCAA CCTG AAG AAG A G CAAG AAGAAG ATTG GTTAG ATGATGATAGTCAACAAACTGTTG G TC AA
CAAG AC G G CAG TG AG
G AC AATCAG ACAACTATTATTCAAACAATT G TT G AG GTTCAACCTCAATTAG A G AT G G AA
CTTACACCAG TTG TTCAG ACTA
TTG AAGTGAATAGTTTTAGTG GTTATTTAAAACTTACTGACAATGTATACATTAAAAATG C AG ACATTG T G
G AA G AAG CTA
AAAAG GTAAAACCAACAGTG GTTGTTAATGCAG CCAATGTTTACCTTAAACATG GAG G AG G TG TT G
CAG GAG CCTTAAAT
AAG G CTACTAACAATG CCATG CAA G TTG AATCTGATG ATTACATAG CTACTAATG G
ACCACTTAAAGTG G GTG G TA G TTG T
GTTTTAAG CG G ACACAATCTTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAG GTG
AAGACATTCAACTTC
TTAAG AG TG CTTATG AAAATTTTAATCAG CA C G AAG TTCTACTTG CACCATTATTATCAG CTG
GTATTTTTG GTG CTG AC CCT
ATACATTCTTTAAG AG TTTG T G TAG ATACTGTTCG CACAAATGTCTACTTAG CT G TCTTTG
ATAAAAATCTCTATG A CAAACT
TGTTTCAAG CTTTTTG GAAATGAAG A G TG AAAAG C AAG TT G AACAAAAG AT C G CT G AG
ATTCCTAAAG AG G AAGTTAAG C
CATTTATAACTGAAAGTAAACCTTCAGTTG AACAG A G AAAACAAG ATG ATAAG AA AAT CAAA G CTTG
TGTTGAAG AAG TT
ACAACAACTCTG GAAGAAACTAAGTTCCTCACAGAAAACTTGTTACTTTATATTGACATTAATG G
CAATCTTCATCCAGATT
CTG CCACT CTTG TTAG TG AC ATTG ACATCACTTTCTTAAAGAAAG ATG CTCCATATATAGTG G GTG
ATG TTG TT CAAG AG G G
TGTTTTAACTG CTGTG GTTATACCTACTAAAAAG G CTG GTG G CACTACTGAAATG CTAGCG AAAG
CTTTG AG AAAAGTG CC
AACAG ACAATTATATAACCACTTACCCG G GTCAG G GTTTAAATG GTTACACTGTAG AG GAG G
CAAAGACAGTG CTTAAAA
AG T G TAAAAG TG CCTTTTACATTCTACCATCTATTATCT CTAAT G AG AA G CAAG AAATTCTTG G
AACTGTTTCTTG GAATTTG
CG AG AAATG CTTG CACATG CAGAAG AAACACG CAAATTAATG CCTGTCTGTGTG G AAA CTAAAG
CCATAGTTTCAACTATA
CAG CGTAAATATAAG G G TATTAAAATAC AAG AG G GTGTG GTTGATTATG GTG CTAG
ATTTTACTTTTAC ACC AG TAAAAC A
ACTG TAG CGTCACTTATCAACACACTTAACGATCTAAATGAAACTCTTGTTACAATG CCACTTG G
CTATGTAACACATG G CT
TAAATTTG G AAGAAG CTG CTCG G TATAT G AG AT CTCT CAAAG T G CCAG CTA CAG TTT CT
G TTTCTT CACCTG ATG CTGTTAC
AG CGTATAATG G TTATCTTACTTCTTCTTCTAAAAC AC CTG AAG AAC ATTTTATT G AAAC CAT CT
CACTTG CT G G TTCCTATA
AAGATTG GTCCTATTCTG G A CAATCTACACAACTAG G TATAG AATTTCTTAAG A G AG G TG
ATAAAAG TG TATATTA CA CTA
GTAATCCTACCACATTCCACCTAGATG GTGAAGTTATCACCMG ACAAT CTTAAG ACACTTCTTT CTTTG AG
AG AAGTG AG
GACTATTAAG GTGTTTACAACAGTAGACAACATTAATCTCCACACG CAAG TT GTG G
ACATGTCAATGACATATG G ACAACA
GTTTG GTCCAACTTATTTG G ATG G AG CT G ATG TTA CTAAAATAAAACCTCATAATTCA CATG AAG
G TAAAACATTTTATG TT
TTACCTAATGATG ACA CT CTACG TG TTG AG G CTTTTG AG TA CTACCA CA CAA CTG
ATCCTAGTTTTCTG G G TAG G TA CATGT
CAG CATTAAATCACACTAAAAAGTG G AAATACCCACAAGTTAATG GTTTAACTTCTATTAAATG G G CAG
ATAACAA CTG TT
ATCTTG CC ACTG CATT G TTAA CACTC CAACAAATAG AG TTG AAGTTTAATCCACCTG CTCTACAAG
ATG CTTATTACAG AG C
AAG G G CTG GTG AAG CTG ATAACTTTTGTG CACTTATCTTAGCCTACTGTAATAAG ACAG TAG GTG
AG TTAG GTGATGTTAG
AG AAA CAATG AG TTACTTGTTTCAACATG CCAATTTAG ATTCTTG C AAAAG AG TCTT G AAC G TG
GTGTGTAAAACTTGTG G
ACAAC AG CAG ACAACCCTTAAG G GTGTAG AAG CTGTTATG TA CATG G G CAC ACTTT CTTATG
AACAATTTAAG AAAG GTGT
TCAG ATACCTTGTACGTGTG GTAAACAAG CTACAAAATATCTAG TA CAACAG G AG T CACCTTTTG
TTAT G ATG TCAG CACCA
CCTG CTC AG TATG AA CTTAAG CAT G G TA CATTTACTTG TG CTAG T G AG TACACTG G
TAATTACC AG TG TG GT CACTATAAAC
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ATATAACTTCTAAAGAAACTTTGTATTG CATAG AC G GTG CTTTACTTACAAAG TC CT CAG AATACAAAG
GTCCTATTACG GA
TG TTTTCTACAAAG AAAAC AG TTACACAAC AACCATAAAACCAGTTACTTATAAATTG GATG GTGTTG
TTTGTACAG AAATT
G AC CCTAAGTTG G AC AATTATTATAAG AAAG ACAATT CTTATTTTAC AG AG CAAC CAATTG
ATCTTG TACCAAAC CAAC CAT
ATCCAAACG CAAG CTTCG ATAATTTTAAGTTTGTATGTG ATAATATCAAATTTG CTG
ATGATTTAAACCAGTTAACTG G TTA
TAAG AAACCTG CTTCAAG AG AG CTTAAAGTTACATTTTTCCCTG ACTTAAATG GTG ATGTG GTG G
CTATTG ATTATAAAC AC
TACA CAC C CTCTTTTAA G AAAG GAG CTAAATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG
CAACTAATAAAG C CA
CGTATAAACCAAAT AC CTG GTGTATACGTTGTCTTTG GAG CACAAAACCAG TTG AAA CATC
AAATTCGTTTG ATG TACTG AA
G TC AG AG G AC G CG CAG G GAATG GATAATCTTG CCTG CGAAG ATCTAAAAC CA G TCT CTG
AA G AAG TAG T G GAAAATCCTA
C CATACAG AAAG AC G TTCTT G AG TG TAATG TG AAAACTACCG AAG TT GTAG GAG
ACATTATACTTAAAC CA G CAAATAATA
G TTTAAAAATTAC AG AAG AG GTTG G C CACAC AG ATCTAATG G CT G CTTATG TAG
ACAATTCTAG TC TTACTATTAAG AAAC
CTAATG AATTATCTAG A G TATTAG GTTTG AAAACC CTTGTTACTCATG GTTTAG CTG CT G
TTAATAG TG TC C CTTG G G ATAC
TATAG CTAATTATG CTAAG C CTTTT CTTAA CAAAG TTG TTAG TACAACTACTAAC ATAG TTAC AC
G GTGTTTAAACCGTGTTT
G TA CTAATTATATG CCTTATTTCTTTACTTTATTG CTA CAATT G TG TACTTTTACTAG AA G
TACAAATTCTAG AATTAAA G CAT
CTATG CC G ACTA CTATAG CAAAG AATACTG TTAAG AG TG TCG GTAAATTTTG TCTAG AG G
CTTCATTTAATTATTTGAAGTC
AC CTAATTTTTCTAAACT G ATAAATATTACAATTTG GTTTTTACTATTAAGTG ITT G CCTAG
GTTCTTTAATCTACTCAACCG C
TG CTTTAG GTGTTTTAATGTCTAATTTAG G CAT G CCTTCTTACTGTACTG G TTAC AG AG AAG G
CTATTTGAACTCTACTAATG
TCACTATTG CAACCTACTGTACTG G TTCTATAC CTT G TAG TG TTT G TCTTAG T G GTTTAG
ATTCTTTAG AC AC CTATC CTTCTT
TAG AAACTATACAAATTACCATTTCATCTTTTAAATG G G ATTTAACTG CTTTTG G CTTAGTTG CAG AG
TG GTTTTTG G CATAT
ATTCTTTTCACTAG GTTTTTCTATGTACTTG GATTG G CTG CAATCATG CAATTGTTTTTCAG CTATITTG
CA GTAC ATTTTATT
AG TAATTCTTG G CTTATGTG GTTAATAATTAATCTTGTACAAATG G CC C CG ATTTCAG CTATG
GTTAGAATGTACATCTTCTT
TG CATCATTTTATTATGTATG GAAAAGTTATGTG CATG TTG TAG AC G G TTG TAATTCATC AACTT G
TAT G ATG TGTTACAAA
CGTAATAG AG CAAC AAG AG TC G AATG TAC AACTATTG TTAAT G GTGTTAGAAG
GTCCTTTTATGTCTATG CTAATG G AG GT
AAAG G CTTTTG CAAACTACACAATTG G AATTGTGTTAATTGTGATACATTCTGTG CT G G TAG TAC
ATTTATTA G TG AT G AAG
TTG C G AG AG ACTTG TC ACTAC AG TTTAAAAG AC CAATAAATC CTACTG ACCAG TCTT CTTA
CATC G TTG ATAGT G TTA C AG T
GAAG AATG G TT C CAT C CATCTTTACTTTG ATAAAG CTG GTCAAAAGACTTATG AAAG A
CATTCTCTCTCT C ATTTT G TTAACT
TAG ACAAC CT G AG A G CTAATAACACTAAAG G TT C ATTG CCTATTAATGTTATAGTTTTTGATG
GTAAATCAAAATGTGAAG
AATCATCTG CAAAATCAG C G TCT G TTTACTA CAG TC AG CTTATGTGTCAACCTATACTGTTACTAG
ATCAG G CATTAGTGTC
TGATGTTG GTGATAGTG CG G AAG TT G CAGTTAAAATGTTTGATG CTTA C G TTAATAC G TTTTCAT
CAA CTTTTAACG TAC CA
ATG GAAAAACTCAAAACACTAGTTG CAACTG CA G AAG CT G AACTTG CAAAGAATGTGTCCTTAG AC
AATGT CTTATCTACT
TTTATTTCAG CAG CTCG G CAAG G GTTTGTTG ATTC AG ATG TAG AAACTAAAGATGTTGTTG
AATGTCTTAAATTGTCACATC
AATCTGACATAGAAGTTACTG G CGATAGTTGTAATAACTATATG CTCACCTATAACAAAGTTGAAAACATG
ACACCCCGTG
AC CTTG GTG CTTGTATTG ACTGTAGTG CG CGTCATATTAATG CG CAG GTAG
CAAAAAGTCACAACATTG CTTTG ATATG GA
AC G TTAAAG ATTT CATG TCATTG TCTG AA CAACTA C G AAAACAAATAC G TAG TG CTG
CTAAAAAGAATAACTTACCTTTTAA
GTTGACATGTG CAACTACTAG ACAAGTTGTTAATGTTGTAACAACAAAGATAG CACTTAAG G GTG
GTAAAATTGTTAATAA
TTG G TT G AAG C AG TTAATTA AAG TTACACTTG TG TTC CTTTTTG TTG CT G CTATTTT
CTATTTAATAACAC CTG TT CATG T CAT
GTCTAAACATACTG ACTTTTCAAGTGAAATCATAG GATACAAG G CTATTGATGGTG
GTGTCACTCGTGACATAG CAT CTAC
AG ATACTTGTTTTG CT AACAAAC ATG CTGATTTTG AC ACATG GTTTAG CCAGCGTG GTG
GTAGTTATACTAATG ACAAAG CT
TG CCCATTGATTG CTG CAGTCATAACAAG AG AAG TG G GTTTTGTCGTG CCTG GTTTG CCTG G
CACGATATTACG CACA ACT
AATG GTG ACTTTTTG CATTTCTTAC CTAG AG TTTTTAG T G CAGTTG G TAAC ATCTG TTAC ACAC
C ATCAAAACTTATAG A GTA
CACTGACTTTG CAACATCAG CTTGTGTTTTG G CT G CT G AATGTACAATTITTAAAG ATG CTTCTG
GTAAG CCAGTACCATAT
TGTTATG ATACCAATGTACTAG AAG GTTCTGTTG CTTATGAAAGTTTACG C C CTG AC ACAC G TTATG
TG CTCATG GATG G CT
CTATTATTCAATTTCCTAACACCTACCTTGAAG G TT CTG TTAG AG TG GTAACAACTTTTGATTCTG AG
TACTG TAG G CA C G G
CACTTGTG AAAGATCAGAAG CTG GTGTTTGTGTATCTACTAGTG G TAG ATG G GTACTTAACAATG
ATTATTACAG ATCTTTA
CCAG G AG TTTT CTGTG GTGTAG ATG CTGTAAATTT ACTTA CTAATATG TTTACACCACTAATTC AAC
CT ATTG GTG CITTG GA
CATATCAG CATCTATAG TAG CTG GTG GTATTG TAG CTATCG TAG TAACATG CCTTG
CCTACTATTTTATG AG GTTTAG AAG A
G CTTTTG GTG AATAC AG TC ATG TAG TT G C CTTTAATACTTTACTATTC CTTATG TCATTCACTG
TA CTCTG TTTAA CAC C AG TT
TACT CATT CTTAC CTG GTGTTTATTCTGTTATTTACTTGTACTTG
ACATTTTATCTTACTAATGATGTTTCTTTTTTAG CAC ATA
TTCAGTG GATG GTTATG TTCA CA CCTTTAGTACCTTTCTG GATAACAATTG CTTATAT CATTTGTATTTC
CA CAAAG CATTTCT
ATTG GTTCTTTAGTAATTACCTAAAG AG AC GTG TAG TCTTTAATG GTGTTTCCTTTAGTACTTTTG AAG
AAG CTG CG CTGTG
CAC CTTTTTG TTAAATAAAG AAATGTATCTAAAGTTG C G TA G TG ATGTG CTATTAC CT CTTAC G
CAATATAATAG ATACTTA
G CT CTTTATAATAAG TACAAG TATTTTAG T G GAG CAATG GATACAACTAG CTACAG A G AAG CTG
CTTGTTGTCATCTCG CA
AAG G CTCTCAATG ACTT CAG TAACTCA G GTTCTG ATG TTCTTTAC CAAC CAC C ACAAAC
CTCTATCAC CTCAG CTGTTTTG CA
G AG TG GTTTTAG AAAAATG G CATTCCCATCTG GTAAAGTTG AG G GTTGTATG
GTACAAGTAACTTGTG GTACAACTACACT
TAACG GTCTTTG G CTTGATG AC G TAG TTTACTG T C CAAG ACATGTGATCTG CA C CTCTG AAG
AC ATG CTTAACCCTAATTAT
GAAG ATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTACAG G CTG GTAATGTTCAACTCAG G
GTTATTG G ACATTCTA
120
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TG CAAAATTGTGTACTTAAG CTTAAG GTTGATACAG CCAATC CTAAG AC AC CTAAGTATAAG
TTTGTTCG CATTCAACCAG G
ACAG ACTTTTTC AG TG TTAG CTTGTTACAATG GTTCACCATCTG GTGTTTACCAATGTG CTATG AG G
CCCAATTTCACTATTA
AG G GTTCATTCCTTAATG GTTCATGTG G TAG T G TTG GTTTTAACATAGATTATG
ACTGTGTCTCTTTTTGTTACATG CA C CAT
ATG GAATTACCAACTG G AG TTCAT G CTG G CAC AG ACTTAGAAG GTAACTTTTATG G AC CTTTT
G TTG ACAG G CAAAC AG CA
CAAG CAG CT G GTACG G ACACAACTATTACAGTTAATGTTTTAG CTTG GTTGTACG CTG CT G
TTATAAATG GAG AC AG GTG G
TTTCTCAATCGATTTACCACAACTCTTAATG ACTTTAACCTTGTG G CTATG AA G TACAATTAT G AAC
CTCTAACACAAG AC CA
TG TTG AC ATACTAG G AC CTCTTTCT G CTCAAACTG GAATTG CCGTTTTAGATATGTGTG
CTTCATTAAAAGAATTACTG CAA
AATG GTATGAATG GACGTACCATATTG G GTAGTG CTTTATTAG AAG ATG AATTTAC AC CTTTTG ATG
TTGTTAG ACAATG CT
CAG GTGTTACTTTCCAAAGTG CA G T G AAAAG AACAATCAAG G G TA CACAC C ACTG
GTTGTTACTCACAATTTTGACTTCACT
TTTAG TTTTAG TC CA G AG TACTC AATG G TCTTTG TTCTTTTTTTTG TAT G AAAAT G
CCTTTTTACCTTTTG CTATG G GTATTAT
TG CTATGTCTG CTTTTG CAATGATGTTTGTCAAACATAAG CATG
CATTTCTCTGTTTGTTTTTGTTACCTICTCTTG CCACTGT
AG CTTATTTTAATATG GTCTATATG CCTG CTAGTTG G G TG AT G C G TATTATG ACATG GTTG G
ATATG G TT G ATACTAGTTTG
AAG CTAAAAG ACTGTGTTATGTATG CATCAG CTG TAG T G TTACTAATC CTTATG A CAG CAAG
AACTGTGTATG ATG AT G GT
G CTAG G A G AG T GTG G ACACTTATG AATGTCTTG ACACTCGTTTATAAAGTTTATTATG GTAATG
CTTTAG AT CAAG CCATTT
C CAT G TG G G CT CTTATAATCT CTG TTACTTCTAA CTACT CAG
GTGTAGTTACAACTGTCATGTTTTTG G CCAG AG G TATTG TT
TTTATG T G TG TTG A G TATTG CCCTATTTTCTTCATAACTG GTAATACACTTCAGTGTATAATG
CTAGTTTATTGTTTCTTAG GC
TATTTTTGTACTTGTTACTTTG G C CT CTTTTG TTTACT CAAC C G CTA CTTTAG ACT G A CT
CTTG GTGTTTATGATTACTTAGTTT
CTACACAG G AG TTTAG ATATAT G AATT CACAG G G ACTACTC C CAC C CAAG AATAG C ATAG
AT G CCTTCAAACTCAACATTA
AATTGTTG G GTGTTG GTG G CAAACCTTG TATCAAAG TAG CCA CTG TACAGT CTAAAATG TC AG
ATG TAAAG TG CACAT CA R
TAG TCTTACTCT CAG TTTTG CAACAACTCA G AG TAG AAT CATC ATCTAAATTG TG G G CTC
AATG T G TC C AG TTACA CAATG A
CATTCTCTTAG CTAAA G ATACTA CTG AA G CCTTTGAAAAAATG GTTTCACTACTTTCTGTTTTG CTTT
C CAT G CAG G GTG CTG
TAG ACATAAACAAG CTTTGTGAAGAAATG CTG GACAACAG G G CAACCTTACAAG CTATAG CCTCAG AG
TTTAG TTCC CTTC
CAT CATAT G CAG CTTTTG CTACTG CTCAAG AAG CTTATG AG CAG G CT G TTG CTAATG G TG
ATTCTG AAG TTG TT CTTAAAAA
GTTGAAG AAGTCTTTG AATGTG G CTAAATCTGAATTTGACCGTGATG CAG CCATG CAACGTAAGTTG
GAAAAGATG G CT G
ATCAAG CTATG AC C CAAAT G TATAAACAG G CTAG ATCT G AG GACAAG AG G G
CAAAAGTTACTAGTG CTATG CAG ACAATG
CTTTTC A CTATG CTTAG AAAG TT G G ATAATG AT G CACTCAACAACATTATCAACAATGCAAG AG
ATG G TT GTG TTC C CTTG A
ACATAATAC CTCTTACAAC A G CAG CCAAACTAATG G TT G TCATAC CAG
ACTATAACACATATAAAAATACGTGTGATG G TA
CAACATTTACTTATG CAT CAG CATTGTG G G AAATCCAACAG GTTG TAG ATG CAG ATAG TAAAATTG
TT CAACTTAGTG AAA
TTA G TAT G G AC AATT CAC CTAATTT AG CATG G CCTCTTATTGTAACAG CTTTAAG G G
CCAATTCTG CTG TCAAATTAC AG AA
TAATG AG CTTAGTCCTGTTG CACTACG AC AG ATG TCTTGTG CTG CCG GTACTACACAAACTG CTTG
CA CTG ATGACAATG C
GTTAG CTTACTACAACACAACAAAG G GAG G TAG GTTTGTACTTG C ACT G TTATC C G ATTTACAG
GATTTGAAATG G G CTAG
ATT C C CTAAG AG T G ATG GAACTG GTACTATCTATACAGAACTG G AAC CAC CTTG TA G
GTTTGTTACAG ACACACCTAAAG G
TCCTAAAGTGAAGTATTTATACTTTATTAAAG G ATTAAACAAC CTAAAT AG AG GTATG GTACTTG G TAG
TTTAG CTG CCACA
G TA C G TCTACAAG CTG GTAATG CAACAGAAGTG CCTG C CAATTCAA CT G TATTAT CTTT CTG
T G CTTTTG CTG TAG ATG CTG
CTAAAG CTTACAAAG ATTATCTAG CTAGTG GG GG AC AAC CAATCACTAATTG TG TTAAG ATGTTGT
GTA CAC ACACTG G TA
CTG GTCAG G CAATAACAG TTAC AC C G G AAG CCAATATG G AT CAAG AATC CTTTG GTG GTG
CATCGTGTTG TCT G TACT G CC
GTTG CCACATAG ATCATCCAAATCCTAAAG GATTTTGTG ACTTAAAAG
GTAAGTATGTACAAATACCTACAACTIGTG CTAA
TGACCCTGTG G GTTTTACACTTAAAAACACAGTCTGTACCGTCTG CG GTATGTG GAAAG GTTATG G CTG
TAGTTG TG AT CA
ACTCCG CG AACCCATG CTTCAGTCAG CTG ATG CACAATCGTTTTTAAACG G GTTTG CG GTGTAAGTG
CAG CC C GTCTTACA
CCGTG CG G CACAG G CACTAGTACTG ATGTCGTATACAG G G CTTTTGACATCTACAATGATAAAGTAG
CTG GTTTTG CTAAA
TTCCTAAAAACTAATTGTTGTCG CTTCCAAG AAAAG G AC G AA G ATG ACAATTTAATTG
ATTCTTACTTT G TAG TTAAG AG AC
ACACTTTCTCTAACTACCAACATG AAG AAA CAATTTATAATTTACTTAAG G ATT G TC C AG CT G TTG
CTAAACATG ACTTCTTT
AAGTTTAG AATAG AC G GTGACATG G TAC CAC ATATAT CA C G T CAAC G TCTTACTAAATACAC
AATG G CAG AC CTC G TCTAT
G CTTTAAG G CATTTTGATG AAG GTAATTGTG ACACATTAAAAG
AAATACTTGTCACATACAATTGTTGTGATG ATGATTATT
TCAATAAAAAG GACTG G TAT G ATTTTG TAG AAAAC C CAG ATATATTACG CGTATACG CCAACTTAG
GTGAACGTGTACG CC
AAG CTTTG TTAAAAACA G TACAATTCTG TG AT G C CAT G CGAAATG CTG GTATTGTTG
GTGTACTG ACATTAGATAATCAAG
ATCTCAATG GTAACTG GTATG ATTTCG GTGATTTCATACAAACCACG CCAG G TAG TG G AGTTC CTG
TTG TAG ATT CTTATTA
TTCATTGTTAATG CCTATATTAACCTTG A C CA G G G CTTTAA CT G CA G A G TCA C ATG TTG
A CA CTG A CTTAA CAA A G CCTTAC
ATTAAGTG G GATTTGTTAAAATATG ACTT CAC G G AAG A G AG GTTAAAACTCTTTG AC C G
TTATTTTAAATATT G G G ATCAG
ACATAC CAC C CAAATT G TG TTAACTG TTTG G ATG AC AG ATG CATTCTG CATTGTG CAAA
CTTTAATG TTTTATTC TCTAC AG T
GTTCCCACTTACAAGTTTTG G AC CACTAG TG AG AAAAATATTTG TTG ATG G TG TTCCATTTGTAG
TTT CAACTG GATAC CAC
TTC AG AG A G CTAG GTGTTGTACATAATCAG GAT GTAAACTTACATAG CTCTA G A CTTAG TTTTAA
G GAATTACTTGTGTATG
CTG CTG A C C CTG CTATG CAC G CTG CTTCTG GTAATCTATTACTAGATAAACG C ACTAC G TG
CTTTT CAG TA G CTG CACTTACT
AACAATG TT G CTTTTCAAACTGTCAAACCTG GTAATTTTAACAAAGACTTCTATGACTTTG CT G
TGTCTAAG G GTTTCTTTAA
G GAAG G AA G TTCTG TTG AATTAAAAC ACTTCTTCTTTG CTCAG G ATG GTAATG CTG CTATCAG
CG ATTATGACTACTATCGT
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TATAATCTACCAACAATGTGTGATATCAG ACAACTACTATTTG TAG TT G AAGTTGTTGATAAGTACTTTG
ATTGTTACG ATG
GTG G CTGTATTAATG CTAAC CAA G TC AT C G TCAAC AACCTA G ACAAAT CAG CTG
GTTTTCCATTTAATAAATG G G GTAAG G
CTAG ACTTTATTATG ATTCAAT G AG TTATG AG GATCAAG ATG CACTTTTCG
CATATACAAAACGTAATGTCATCCCTACTAT
AACTCAAATG AATCTTAAGTATG CCATTAGTG CAAAG AATAG A G CTCG CAC C G TAG CTG G TG T
CTCTATCTG TAG TACTAT
GACCAATAG ACAGTTTCATCAAAAATTATTGAAATCAATAG CCG CCACTAG AG GAG CTACTGTAGTAATTG
GAACAAG CAA
ATTCTATG GTG GTG G C AC AACATG TTAAAAACTG TTTATAG T G ATG TAG AAAACCCT
CATCTTATG G G TT G G GATTATCCT
AAAT G TG ATAG AG CCATG CCTAACATG CTTAGAATTATG G CCTCACTTGTTCTTG CTCG C
AAACATACAAC G TG TTG TA G CT
TGTCACACCGTTTCTATAGATTAG CTAATG AG TGTG CTC AAG TATTG AG TG AAATG GTCATG TG TG
G CG GTTCACTATATGT
TAAACCAG GTG G AAC CT CATCA G GAG ATG CCACAACTG CTTATG
CTAATAGTGTTTTTAACATTTGTCAAGCTGTCACG G C
CAATGTTAATG CA CTTTTATCTACTG ATG GTAACAAAATTG CC G ATAAGTATGTCCG CAATTTACAAC
ACAG ACTTTATG AG
TGTCTCTATAGAAATAG AG ATG TTG ACACAG ACTTTGTG AATG A G TTTTAC G CATATTTG C G
TAA ACATTT CTCAATG AT G A
TACT CTCT G AC G ATG CTGTTGTGTGTTTCAATAG CACTTATG CATCTCAAG G TCTAGTG G CTAG
CATAAAGAACTTTAAGTC
AG TTCTTTATTATCAAAACAATG TTTTTAT G TCT G AAG CAAAATGTTG G ACT G AG A CTG A
CCTT ACTAAA G G AC CTCATG AA
TTTTG CT CTCAA CATACAATG CTAGTTAAACAG GGTGATG
ATTATGTGTACCTTCCTTACCCAGATCCATCAAG AATCCTAG
GGGCCG C CTG TTTTG TAG ATG ATATCGTAAAAAC AG ATG GTACACTTATGATTGAACG
GTTCGTGTCTTTAG CTATAGATG
CTTACCCACTTACTAAACATCCTAATCAG G AG TATG CTG AT G TCTTTCATTTG TACTTACAATACATAAG
AAAG CTAC ATG AT
G AG TTAAC AG G A C ACATG TTAG ACATGTATTCTGTTATG CTTACTAATG ATAA CAC CTCAAG
GTATTG G G AACCT G AG TTTT
ATG AG G CTATG TACAC ACC G CATACAGTCTTACAG G CTGTTG G G G CTTGTGTTCTTTG CAATTC
ACAG A CTTCATTAAG ATG
TG GTG CTTG C ATAC G TAG AC CATTCTTAT G TTG TAAAT G CTG TTAC G ACCATG TC ATATC
AACATC A CATAAATTAG TCTTG T
CTGTTAATCCGTATGTTTG CAATG CTCCAG GTTGTGATGTCACAGATGTG ACTCAACTTTACTTAG GAG
GTATG AG CTATTA
TTGTAAATCACATAAACCACCCATTAGTTTTCCATTGTGTG CTAATG G ACAAGTTTTTG G
TTTATATAAAAATAC AT G TG TTG
G TAG CGATAATGTTACTGACTTTAATG CAATTG CAACATGTG ACTG GACAAATG CTG
GTGATTACATTTTAG CTAACACCTG
TACTGAAAG ACTCAAG CTTTTTG CAG CAGAAACG CT CAAAG CTACTG AG G AG
ACATTTAAACTGTCTTATG GTATTG CTAC
TGTACGTG AAGTG CTGTCTG ACAG AG AATTACATCTTTCATG G GAAGTTG
GTAAACCTAGACCACCACTTAACCGAAATTA
TGTCTTTACTG G TTATC G T G TAACTAAAAA CAG TAAAG TA CAAATA G GAG A G TAC ACCTTTG
AAAAAG GTGACTATG G TG A
TG CTG TT G TTTACC G AG GTACAACAACTTACAAATTAAATGTTG GTG ATTATTTTGTG CTG AC
ATCACATACA G TAATG CCA
TTAAGTG CACCTACACTAGTG CC ACAAG AG CACTATGTTAGAATTACTG G CTTATA CCC
AACACTCAATATCTCAG AT G AG
TTTTCTAG CAATGTTG CAAATTATCAAAAG GTTGGTATG CAAAAG TAIT CTACA CTCCAG G G
ACCACCTG GTACTG GTAAG
AG T CATTTTG CTATT G G CCTAG CTCTCTACTACCCTTCTG CTCG CATAGTGTATACAG CTTG
CTCTCATG CC G CTG TTG AT G C
ACTATGTG AG AAG G CATTAAAATATTTG C CTATA G ATAAATG TAG TAG AATTATACCTG CA C G
TG CTC G T G TAG AG TGTTT
TGATAAATTCAAAGTGAATTCAACATTAG AACAG TATG T CTTTTG TA CTG TAAATG CATTG CCTG AG
AC G ACAG CA G ATAT
AG TTG TCTTTG ATGAAATTTCAATG G CCACAAATTATGATTTG AG TG TTG T CAATG CCAG
ATTACGTG CTAAG CACTATGTG
TACATTG G C G AC CCTG CTCAATTACCTG CACCACG CACATTG CTAACTAAG G GCACACTAG
AACCAG AATATTTCAATTCAG
TGTGTAG ACTTATGAAAACTATAG GTCCAGACATGTTCCTCG GAACTTGTCG G CGTTGTCCTG
CTGAAATTGTTGACACTGT
G AG TG CTTTG GTTTATGATAATAG G CTTAAA G CACATAAAG A CAAATCA G CTCAATG
CTTTAAAATGTTTTATAAG G GTGT
TATC AC G CATGATGTTTCATCTG CAATTAACAG G CCACAAATAG G CGTG GTAAG AG
AATTCCTTACAC G TAACC CTG CTTG
GAG AAAAG CTGTCTTTATTTCACCTTATAATTCACAG AATG CT G TAG CCTCAAAG ATTTTG G G ACTA
CCAACT CAAACTG TT
GATTCATCACAG G G CTC AG AATATG ACTATG TCATATTCACTCAAAC CACTG AAAC AG
CTCACTCTTGTAATGTAAACAG AT
TTAATGTTG CTATTAC CAG AG CAAAA G TAG G CATACTTTG C ATAATG T CTG ATAG A G
ACCTTTAT G AC AA G TTG CAATTTAC
AAGTCTTG AAATTC CAC G TAG GAATGTG G CAACTTTACAAG CT G AAAAT G TAACAG G A
CTCTTTAAAG ATTGTAG TAAG CT
AATCACTG G G TTAC ATC CTACAC AG G C ACCTA CAC ACCTCAG TG TT G ACACTAAATTCAAAA
CTG AA G G TTTAT G TG TT G AC
ATACCTG G CATACCTAAG GACATGACCTATAG AAG ACT CATCTCTAT GATG G
GTTTTAAAATGAATTATCAAGTTAATG CU
ACCCTAACATGTTTAT CAC CCG CG AAGAAG CTATAAGACATGTACGTG CATG G ATTG G CTTCG
ATGTCG AG G G GTGTCATG
CTACTAG AG AAG CTGTTG GTACCAATTTACCTTTACAG CTAG G TTTTTCTAC AG GTGTTAACCTAGTTG
CTGTACCTACAG G
TTATGTTGATACACCTAATAATACAGATTTTTCCAG AG TTAG TG CTAAACCACCG CCTG GAG
ATCAATTTAAACACCTCATA
CCACTTATGTACAAAG GACTTCCTTG G AATG TAG TG CGTATAAAG ATTGTAC AAATG TTAAG TG AC
ACA CTTAAAAAT CTCT
CTG ACAG A G TC G TATTTG T CTTAT G G G CACATG G CTTTG AG TT G ACAT CTAT G
AAGTATTTTGTGAAAATAG G ACCTG AG C
G CAC CTG TTGTCTATG TG ATAG A CG TG C CA CATG CTTTTCCACTG CTTCAG ACACTTATG
CCTGTTG G CATCATTCTATTG GA
TTTGATTACGTCTATAATCCGTTTATG ATTG ATG TT CAACAATG G G G TTTTAC AG GTAACCTACAAAG
CAACCATG AT CTG T
ATTGTCAAGTCCATG GTAATG CACATG TAG CTAGTTGTG ATG CAATCATGACTAG GTGTCTAG CT G
TCC AC G AG T G CTTTG
TTAAG CGTGTTG ACTG GACTATTGAATATCCTATAATTG GTGATGAACTGAAG ATTAATG CG G CTTG
TAG AAAG GTTCAAC
ACATG GTTGTTAAAG CTG CATTATTAG CAG ACAAATTCCCAGTTCTTCACGACATTG GTAACCCTAAAG
CTATTAAGTGTGT
ACCTCAAG CTG AT G TAG GATG G AAG TTCTATG AT G CACAG CCTTG TA GTG A CAAAG
CTTATAAAATAG AAGAATTATTCTA
TTCTTATG CCAC ACATT CTG AC AAATT CACAG ATG GTGTATG CCTATTTTG G AATTG
CAATGTCGATAGATATCCTG CTAATT
CCATTG TTTG TAG ATTTG ACA CTAG AGTG CTATCTAACCTTAACTTG CCTG GTTGTGATG G TG G
CAG TTTG TATGTAAATAA
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ACATG CATTCCACACACCAG CTTTTG ATAAAAGTG
CTTTTGTTAATTTAAAACAATTACCATTTTTCTATTACTCTGACAGTCC
ATG TG AG TCTC ATG G AAAACAAG TAG TG TC AG ATATAG ATTATG TACC A CTAAAG TCTG
CTAC G TGTATAAC AC GTT G CAA
TTTAG GTG GTG CTGTCTGTAG ACATCATG CTAATG AG TACAG ATTGTAT CTCG ATGCTTATAACATG
ATG ATCTC AG CTG GC
TTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG GAACACTTTTACAAG ACTT C AG AG
TTTAG AAAATGTG G
CTTTTAATGTTGTAAATAAG G GACACTTTG ATG G ACAACAG G
GTGAAGTACCAGTTTCTATCATTAATAACACTGTTTACAC
AAAAGTTG ATG G TG TTG AT G TAG AATTG TTT G AAAATAAAACAACATT ACCTG TTAATG TAG C
ATTT G AG CTTTG G G CTAA
G CG CAACATTAAAC CAG TACCAG AG GTG AAAATACTCAATAATTTG G GTGTG G AT ATTG CTG
CTAATACTGTG ATCTG G GA
CTACAAAAG AG ATG CTCCAG CAC ATATATCTACTATTG GTGTTTGTTCTATG ACTG ACATAG
CCAAGAAACCAACTGAAAC
GATTTGTG CACCACTCACTGTCTTTTTTG ATG G TAG AG TTG ATG G TCAAG TAG ACTTATTTAG
AAATG CCCGTAATG GTG TT
CTTATTAC AG AAG G TAG TG TTAAAG G TTTACAACCATCTG TAG GTCCCAAACAAG CTAGTCTTAATG
G AG TC ACATTAATT
G GAG AAG CCG TAAAAACA CAG TT CAATTATTATAAG AAAG TTG ATG GTG TTG TCCAAC AATTAC
CTG AAA CTTACTTTACTC
AG AG TAG AAATTTACAAG AATTTAAACCC AG G A G TCAAATG G AAATTGATTTCTTAGAATTAG
CTATG G ATG AATTCATTG
AACG GTATAAATTAGAAG G CTATG CCTTCGAACATATCGTTTATG G AG ATTTTAG TC ATAG TCAG
TTAG GTG GTTTACATCT
ACTG ATTG GACTAGCTAAACGTTTTAAG GAATCACCTTTTGAATTAGAAG ATTTTATTCCTATG G ACAG TA
CAG TTAAAAAC
TATTTCATAACAG ATG CG CAAAC AG G TTC AT CTAAG TG TG TG T GTTCTG TTATTG
ATTTATTACTTG ATGATTTTGTTG AAAT
AATAAAATCCCAAG ATTTATCT G TAG TTT CTAAG G TT G TCAAA G TG A CTATT G ACTATACAG
AAATTTCATTTATG CTTTGTG
TAAAGATG G CCATGTAG AAACATTTTACCCAAAATTACAATCTAGTCAAGCGTG G CAACCG G GTGTTG
CTATG CCTAATCT
TTACAAAATG CAAAG AATG CTATTAGAAAAGTGTGACCTTCAAAATTATG GTGATAGTG
CAACATTACCTAAAG G CATAAT
GATGAATGTCG CAAAATATACTCAACTGTGTCAATATTTAAACACATTAACATTAG CTGTACCCTATAATATG AG
AG TTATA
CATTTTG GTG CTG GTTCTG ATAAAG G AG TTG CAC CAG GTACAG CTGTTTTAAG ACAGTG GTTG
CCTACG G GTACG CTG CTT
G TC G ATT CAG AT CTTAATG ACTTTG TCTCTG AT G CAGATTCAACTTTGATTG GTG ATTGTG C
AA CTG TACATACAG CTAATA
AATG G G ATCTC ATTATTAG TG ATATG TA C G ACCCTAAG A CTAAAAATG TTACAAAAG AAAATG
ACTCTAAAG AG G GTTTTT
TCACTTACATTTGTG G GTTTATACAACAAAAG CTAG CTCTTG GAG GTTCCGTG G CTATAAAGATAACAG
AACATTCTTG GA
ATG CTGATCTTTATAAG CTCATG G G A CACTTC G CATG GTG GACAG CCTTTGTTACTAATGTG AATG
CGTCATCATCTGAAG C
ATTTTTAATTG G ATGTAATTATCTTG G CAAACCACG C G AACAAATAG AT G G TT ATG T CATG
CATG CAAATTACATATTTTG G
AG G AATACAAATCCAATTC AG TTGTCTTCCTATTCTTTATTTG ACATG AG TAAATTTC
CCCTTAAATTAAG G G GTACTG CTGT
TATGTCTTTAAAAGAAG GTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAG G TAG ACTTATAATTAG
AG AAAACAAC
AG AG TTG TTATTTCTAGTG ATGTTCTTG TTAACAACTAAACG AACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTAG
TCAG TGTGTTAATCTTACAAC CAG AA CTCAATTACC CCCTG CATACACTAATTCTTTCACACGTG G
TGTTTATTACCCTG ACA
AAG TTTT CAG AT CCTCA G TTTTACATTCAACTC AG G ACTT G TT CTTAC CTTT CTTTTCCAATG
TTACTTG G TTCC AT G CTATCT
CTG G G AC CAATG G TACTAAG AG GTTTGATAACCCTGTCCTACCATTTAATG ATG GTGTTTATTTTG
CTTC CACTG AG AAG TC
TAAC ATAATAAG AG G CTG GATTTTTG GTACTACTTTAGATTCG AAG ACC CAG T CCCTA CTTATTG
TTAATAA C G CT ACTAAT
G TT G TTATTAAA G TCTG TG AATTTCAATTTTGTAATG ATCCATTTTTG G
GTGTTTACCACAAAAACAACAAAAGTTG G ATG G
AAAG TG AG TTCAG AG TTTATTCTAGT G CGAATAATTG CACTTTTGAATATGTCTCTCAG
CCTTTTCTTATG GACCTTG AAG G
AAAAC AG G GTAATTTCAAAAATCTTAG G G AATTT G TG TTTAA G AATATTG AT G
GTTATTTTAAAATATATTCTAAG CACACG
CCTATTAATTTAGTG CGTGATCTCCCTCAG G GTTTTTCG G CTTTAG AA CCATT G G TAG ATTTG
CCAATAG GTATTAACATCAC
TAG GTTTCAAACTTTACTTG CTTTACATAGAAGTTATTTGACTCCTG GTG ATTCTTCTTCAG GTTG GACAG
CTG GTG CTG CA
G CTTATTATGTG G GTTATCTTCAACCTAG GACTTTTCTATTAAAATATAATGAAAATG G AACCATTACAG
ATG CTG TA G ACT
GTG CACTTG ACC CTCT CTCAG AAACAAA G TG T AC GTTG AAATCCTT CACTG TAG AAAAAG G
AATCTATCAAACTTCTAACTT
TAG AG TC CAACCAACAG AATCTATTG TTAG ATTTCCTAATATTACAAACTTGTG CCCTTTTG
GTGAAGTTTTTAACG CCACCA
GATTTG CATCTGTTTATG CTTG G AACAG G AAG AG AATCAG CAACTGTGTTG
CTGATTATTCTGTCCTATATAATTCCG CATC
ATTTTCCACTTTTAAGTGTTATG G AG TG T CTCCTACTAAATTAAAT G ATCTCTG
CTTTACTAATGTCTATG C AG ATT CATTT G T
AATTAG AG GTGATGAAGTCAG ACAAATCG CT CCAG G GCAAACTG G AAAG ATTG CTG
ATTATAATTATAAATTAC CAG AT G
ATTTTACAG G CTG CGTTATAG CTTG G AATTCTAACAATCTTG ATTCTAAG GTTG GTG
GTAATTATAATTACCTGTATAG ATT
GTTTAG G AAGTCTAAT CTCAAAC CTTTTG AG AG AG ATATTTCAACTG AAATCTAT CAG G CCG G
TAG CACACCTTGTAATGG
TGTTGAAG GTTTTAATTGTTACTTTCCTTTACAATCATATG GTTTCCAACCCACTTATG GTGTTG GTTACCAAC
CATACAG AG
TAG TAG TACTTTCTTTTG AACTTCTACATG CACC AG CAACTG TTTG T G
GACCTAAAAAGTCTACTAATTTG GTTAAAAACAA
ATG TG TC AATTT CAA CTTCAATG GTTTAACAG G CACAG GTGTTCTTA CT G AGTCTAA CAAAAAG
TTTCTG CCTTTCCAA CAA
TTTG G CAG AG AC ATTG ATG AC ACTACTG ATG CTGTCCGTG ATCCACAG ACA CTTG AG
ATTCTTGACATTACACCATGTTCTT
TTG GTG GTGTCAGTGTTATAACACCAG G AA CAAATACTTCTAACCAG GTTG CTGTTCTTTATCAG G
GTGTTAACTG CACAG
AAGTCCCTGTTG CTATTCATG CAG AT CAACTTACTC CTACTTG G CGTGTTTATTCTACAG
GTTCTAATGTTTTTCAAACACGT
G C AG G CT G TTTAATAG G G G CTG AAC ATG T CAACAACTCATAT G AG TG TG
ACATACCCATTG GTG CAG GTATATG CG CTAGT
TAT CAG ACT CAG ACTAATTCTCATC G G CG G G CACG TAGTG TAG CTAGTCAATCCATCATTG
CCTACACTATGTCACTTGGTG
CAG AAAATTC AG TT G CTTACTCTAATAACTCTATTG CC ATACCC ATAAATTTTA CTATT AG TG
TTACC ACAG AAATTCTA CCA
G TG TCTATG AC CAAG AC ATCAG TAG ATTG TACAAT G TACATTTG TG GTGATTCAACTGAATG
CAG CAATCTTTT G TT G CAAT
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ATG G CAG TTTTTG TA CACAATTAAACC G TG CTTTAACTG GAATAG CTG TT G AA CAAG
ACAAAAACACCCAAG AAGTTTTTG
CACAAGTCAAACAAATTTACAAAACACCACCAATTAAAG ATTTTG GTG
GTTTTAATTTTTCACAAATATTACCAGATCCATCA
AAACCAAG CAAG AG GTCATTTATTGAAG ATCTACTTTTCAACAAAGTGACACTTG C AG ATG CTG G
CTTCATCAAACAATAT
G GT G ATTG CCTTG GTGATATTG CTG CTAG AG ACCTCATTTG T G CAC AAAAG TTTAAC G G
CCTTACTG -FITT G CCACCTTTG C
TCAC AG ATG AAATG ATTG CTCAATACACTTCTG CACTGTTAG CG G GTACAATCACTTCTG GTTG G
ACCTTTG GTG CAG GTG
CTG CATTACAAATACCATTTG CTATG CAAATG G CTTATAG GTTTAATG GTATTG G A G TTA CACAG
AATGTTCTCTATG AG AA
CCAAAAATTG ATTG CCAACCAATTTAATAGTG CTATTG G CAAAATTCAAG ACT CACTTTCTTCCAC AG
CAAGTG CACTTG GA
AAACTTCAAG ATGTG GTCAACCAAAATG CACAAG CTTTAAAC AC G CTTGTTAAACAACTTAG
CTCCAATTTTG GIG CAATTT
CAAGTGTTTTAAATGATATCCTTG C AC G T CTTG ACAAAGTTG AG G CTGAAGTG CAAATTGATAG G
TT G ATC ACAG G CAG AC
TTCAAAGTTTG C AG ACATATG TG ACTCAAC AATTAATTAG AG CT G CAG AAATCA G AG CTTCTG
CTAATCTTG CTG CTACTAA
AATGTCAG AG TG TG TACTT G G AC AATCAAAAAG AG TTG ATTTTTGTG GAAAG G G CTAT
CATCTTATG TCCTTCC CTC AG TCA
G CACCTCATG GTGTAGTCTTCTTG CATGTG ACTTATGTCCCTG CACAAGAAAAG AACTTCACAACTG
CTCCTG CCATTTGTC
ATG ATG G AAAAG CACACTTTCCTCGTG AAG GTGTCTTTGTTTCAAATG G CACACACTG
GTTTGTAACACAAAG G AATTTTTA
TG AACCACAAATCATTACTACACACAACACATTTGTGTCTG G TAACTG TG AT G TTG TAATAG
GAATTGTCAACAACACAGTT
TAT G ATCCTTTG C AACCTG AATTAG A CTCATTCAAG GAG G AG TTAG ATAAATATTTTAAG AAT
CATAC ATCAC CAG AT G TTG
ATTTAG GTGACATCTCTG G CATTAATG CTTCAG TTG TAAACATTCAAAAAG AAATTG AC CG C CT
CAATG AG G TTG C CAAG A
ATTTAAATGAATCTCTCATCG ATCTCCAAGAACTTG G AAAG TATG AG CAGTATATAAAATG G CCATG
GTACATTTG G CTAG
GTTTTATAG CTG G CTTGATTG CCATAGTAATG GTGACAATTATG CTTTG CTG TATG ACCAG TTG CT
GTAG TTGT CTCAAG G G
CTGTTGTTCTTGTG GATCCTG CTG CAAATTTGATG AAG AC G ACTCTG AG CCAGTG CT CAAAG G AG
TCAAATTACATTACAC
ATAAACGAACTTATG G ATTTG TTTATG A G AATCTTCACAATTGG AACTGTAACTTTGAAG CAA G GTG
AAATCAAG GATG CT
ACTC CTTC AG ATTTTG TTCG CG CTACTG CAACG ATAC CGATACAAG CCTCACTCCCTTTC G GATG
G CTTATTG TT G G CGTTG C
ACTT CTTG CTG TTTTTCAG AG CG CTTCCAAAATC ATAACC CTCAAAAAG AG ATG G CAACTAG
CACTCTCCAAG G GTGTTCAC
TTTGTTTG CAACTTG CTGTTGTTGTTTGTAACAGTTTACTCACACCTTTTG CTCGTTG CTG CT G G CCTTG
AAG CCCCTTTTCTC
TAT CTTTATG CTTTAGTCTACTTCTTG CAG AG TATAAACTTTGTAAG AATAATAATG AG G CMG
GCTTTG CTG G AAATG CC
GTTCCAAAAACCCATTACTTTATGATG CCAACTATTTTCTTTG CTG G
CATACTAATTGTTACGACTATTGTATACCTTACAATA
GTGTAACTTCTTCAATTGTCATTACTTCAG GTGATG G CAC AACAAG TCCTATTTCTG AACATG ACTACCAG
ATTG G TG GTTA
TACT G AAAAATG G GAATCTG G A G TAAAA G ACTG TG TTG TATTACA CAG TTACTT CACTT
CAG ACTATTA CCAG CTG TA CTCA
ACTCAATTG AG TA CAG AC ACTG GTGTTGAACATGTTACCTTCTTCATCTACAATAAAATTGTTG ATG AG
CCT G AAG A ACATG
TCCAAATTCACACAATCG ACG GTTCATCCG G AG TTGTTAATCCAG TAATG G AAC CAATTTATG AT G
AACC G ACG ACG ACTA
CTAG CGTG CCTTTGTAAG CA C AAG CT G ATG AG TAC G AACTTATGTACTCATTCGTTTCG GAAG
AG A CA G G TA C G TTAATAG
TTAATAG CGTACTTCTTTTTCTTG CTTTCGTG GTATTCTTG CTAGTTACACTAG CCATCCTTACTG CG
CTTCGATTGTGTG CGT
ACTG CTG CAATATTG TTAAC G TG A G T CTTG TAAAA CCTTCTTTTTAC GTTTACT CTC G TG
TTAAAAAT CTG AATTCTTCTAG A
G TT CCTG ATCTTCTG GTCTAAACG AACTAAATATTATATTAGTTTTTCTGTTTG GAACTTTAATTTTAG CC
ATG G CA G ATTCC
AACG G TACTATTA CC G TTG AAG AG CTTAAAAAG CTCCTTG AACAATG G AACCTAGTAATAG
GTTTCCTATTCCTTACATG GA
TTTGTCTTCTACAATTTG CCTATG CCAACAG GAATAG GTTTTTGTATATAATTAAGTTAATTTTCCTCTG G
CT G TTATG G CCA
GTAACTTTAG CTTGTTTTGTG CTTG CTG CT G TTTAC AG AATAAATTG G ATC ACC G GTG G
AATTG CTATCGCAATG G CTTGTC
TTG TAG G CTTG ATG TG G CTC AG CTACTTCATTG CTTCTTTCAGACTGTTTG CG CGTACG
CGTTCCATGTG G TCATT CAATC CA
G AAA CTAAC ATTCTTCTC AACGTG CCACTCCATG G CACTATTCTG ACCAG ACCG CTTCTAG
AAAGTGAACTCGTAATCG G AG
CTG TG AT CCTTC GTG GACATCTTCGTATTG CTG GACACCATCTAG G AC G CTG TG AC ATCAAG
GACCTG CCTAAAGAAATCA
CTGTTG CTACATCACGAACG CTTTCTTATTACAAATTG G G AG CTTCG CAG CGTGTAG CAG
GTGACTCAG GTTTTG CTG CAT
ACAGTCG CTACAG GATTG G CAACTATAAATTAAACAC AG ACCATTCCAG TAG CAGTGACAATATTG
CTTTG CTTGTACAGT
AAGTGACAACAGATG TTTCATCTCGTTGACTTTCAG GTTACTATAG CAG A G ATATTACTAATTATTATG AG
GACTTTTAAAG
TTTCCATTTG G AATCTTG ATTACATC ATAAAC CTCATAATTAAAAATTTATCTAAGTC ACTAA CTG AG
AATAAATATT CTCAA
TTAGATG AAG AG CAA CCAATG G AG ATT G ATTAAAC G AACATGAAAATTATTCTTTTCTTG G CA
CTG ATAACA CTC G CTACTT
GTG AG CTTTATCACTACCAAG AG T G TG TTAG AG GTACAACAGTACTTTTAAAAG AACCTTG CT
CTTCT G GAACATACG AG G
G CAATTCACCATTTCATCCTCTAG CT G ATAACAAATTTG CACTG ACTTG CTTTAG CACTCAATTTG
CTTTTG CTTG TCCT G AC
G GCGTAAAACACGTCTATCAGTTACGTG CCAG ATC AG TTTCACCTAAACTG TT CATCAG ACAAG AG G
AAG TT CAAG AACTT
TA CTCTC CAATTTTTCTTATTG TTG CG G CAATA G T G TTTATAA CA CTTT G CTT CA CA CT
CAAAA G AAAG A CA G AATG ATT G AA
CTTTCATTAATTGACTTCTATTTGTG CTTTTTAG CCTTTCTG CTATTCCTTGTTTTAATTATG
CTTATTATCTTTTG G TT CTCACT
TGAACTG CAAGATCATAATGAAACTTGTCACG CCTAAACG AA CAT G AAATTTCTTGTTTT CTTAG G AAT
CATC ACAACT G TA
G CT G CATTTCAC CAAG AATG TA G TTTACAG T CATG TA CTTAA CATCAA CCATAT G TAG TTG
ATG ACC C G TG TCCTATTCA CTT
CTATTCTAAATG GTATATTAG AG TAG G AG CTATAAAATCA G CACCTTTAATTGAATTGTG CG TG G
ATG AG G CT G G TT CTAA
ATCACCCATTCAGTG CAT C G ATATC G GTAATTATACAGTTTCCTGTTTACCTTTTACAATTAATTG CCAG
GAACCTAAATTG G
GTAGTCTTGTAGTG C GTTG TTCG TTCTATG AAG ACTTTTTAG AG TAT CATG ACGTTCGTG TTG
TTTTAG ATTT CATCTAAAC G
AACAAACTAAATG TCTCTAAATG G ACCCC AAAATC AG CGAAATG C ACC CC G CATTACGTTTG GTG
G ACCCTCAGATTCAAC
124
CA 03168783 2022- 8- 19
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PCT/IB2021/052858
TGGCAGTAACCAGAATGGAGAACGCAGTGGGGCGCGATCAAAACAACGTCGGCCCCAAGGTTTACCCAATAATACTGCG
T
CTTGGTTCACCGCTCTCACTCAACATGGCAAGGAAGACCTTAAATTCCCTCGAGGACAAGGCGTTCCAATTAACACCAA
TA
GCAGTCCAGATGACCAAATTGGCTACTACCGAAGAGCTACCAGACGAATTCGTGGTGGTGACGGTAAAATGAAAGATCT
C
AGTCCAAGATGGTATTTCTACTACCTAGGAACTGGGCCAGAAGCTGGACTTCCCTATGGTGCTAACAAAGACGGCATCA
TA
TGGGTTGCAACTGAGGGAGCCTTGAATACACCAAAAGATCACATTGGCACCCGCAATCCTGCTAACAATGCTGCAATCG
TG
CTACAACTTCCTCAAGGAACAACATTGCCAAAAGGCTICTACGCAGAAGGGAGCAGAGGCGGCAGTCAAGCCTCTTCTC
G
TTCCTCATCACGTAGTCGCAACAGTTCAAGAAATTCAACTCCAGGCAGCAGTAAACGAACTTCTCCTGCTAGAATGGCT
GG
CAATGGCGGTGATGCTGCTCTTGCTTTGCTGCTGCTTGACAGATTGAACCAGCTTGAGAGCAAAATGTTIGGTAAAGGC
CA
ACAACAACAAGGCCAAACTGTCACTAAGAAATCTGCTGCTGAGGCTTCTAAGAAGCCTCGGCAAAAACGTACTGCCACT
A
AAG CATACAATGTAACACAAG CTTTCG G CAG AC GTG G TCCAG AACAAACCCAAG G AAATTTTG G G
GACCAGGAACTAATC
AGACAAGGAACTGATTACAAACATTGGCCGCAAATTGCACAATTTGCCCCCAGCGCTTCAGCGTTCTTCGGAATGTCGC
GC
ATTGGCATGGAAGTCACACCTTCGGGAACGTGGTTGACCTACACAGGTGCCATCAAATTGGATGACAAAGATCCAAATT
TC
AAAGATCAAGTCATTTTGCTGAATAAGCATATTGACGCATACAAAACATTCCCACCAACAGAGCCTAAAAAGGACAAAA
AG
AAGAAGGCTGATGAAACTCAAGCCTTACCGCAGAGACAGAAGAAACAGCAAACTGTGACTCTTCTTCCTGCTGCAGATT
T
GGATGATTTCTCCAAACAATTGCAACAATCCATGAGCAGTGCTGACTCAACTCAGGCCTAAACTCATGCAGACCACACA
AG
GCAGATGGGCTATATAAACGTTTTCGCTTTTCCGTTTACGATATATAGTCTACTCTTGTGCAGAATGAATTCTCGTAAC
TACA
TAGCACAAGTAGATGTAGTTAACTTTAATCTCACATAGCAATCTTTAATCAGTGTGTAACATTAGGGAGGACTTGAAAG
AG
CCACCACATTTTCACCGAGGCCACGCGGAGTACGATCGAGTGTACAGTGAACAATGCTAGGGAGAGCTGCCTATATGGA
A
GAGCCCTAATGTGTAAAATTAATITTAGTAGTGCTATCCCCATGTGATTTTAATAGCTTCTTAGGAGAATGNNNNNNNN
N
NNNNNNNNNNNNNNNNNNNNNNNNNN
SEQ. ID NO: 23
> MIG457_gp02 001118545.1 surface glycoprotein, from UK_MIG457genome accession
MW422256
M FVFLVLLPLVSSQCVN LTTRTQLPPAYTNSFTRGVYYPDKVF RSSVLHSTQDLFL PF FS NVTW F
HAISGTNGTKR F D N PVLP F N
DGVYFASTE KSNIIRGW 1 FGTTLDSKTQSLLIVN NATNVVI KVCE FQFCN DPF LGVYH KN N KSW M
ESE F RVYSSAN NCTF EYVSQ
PFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPG
DSSSGWTA
GAAAYYVGYLQPRTF LLKYNE NGTITDAVDCA LD P LSETKCT LKSFTVE KG IYQTSN F
RVQPTESIVRFP NITN LC P FG EVFNATRF
ASVYAW N RKRISNCVADYSVLYNSASFSTFKCYGVSPTKLN D LCFT NVYA DS FVI RG D EV
RQIAPGQTG KIADYNYK LP DDFTGC
VIAWNSN N LDSKVGG NYNYLYRLF R KSN LK P F E RD ISTE IYQAGST PCNG VEG F NCYF P
LQSYG FQPTYG VG YQPYRVVVLSF EL
LHAPATVCG PKKSTN LVKN KCVN FN F NG LTGTGVLTESNKKF LP FQQFG RD 1 D DTT DAVR D
PQT LE 1 LD IT PCSFGGVSVITPGT
NTSNQVAVLYQGVNCTEVPVAI HADQLTPTW RVYSTGSNVFQTRAGCL 1 GA E HVN NSYECD 1 PIGAG
ICASYQTQTNSH RRAR
SVASQSI IAYTMSLGAENSVAYSN NSIA IPIN FTISVTTE 1 LPVSMTKTSVDCTMYICG DST ECSN L
LLQYGSF CTQL N RALTG !AVE
QDKNTQEVFAQVKQIYKTPPIKDFGG F N FSQI L P D PSK PSKRSF 1 EDLLF N KVTLADAG F 1
KQYG DC LG DIAARD LICAQKF NG LTV
LP P L LT DE M IAQYTSALLAGTITSGWTFGAGAALQI P FAM QMAYR F NG 1 GVTQNVLYE NQK
LIAN QF NSAI G KIQDSLSSTASAL
G KLQDVVNQNAQALNTLVKQLSSN FGAISSVLN DI LARLDKVEAEVQI DR LITG RLQSLQTYVTQQL1
RAA E 1 RASAN LAATKMS
ECVLGQSKRVDFCG KGYH LMSF PQSAPHGVVF LHVTYVPAQE K N FTTA PAI CH DG KA HFPR EGV
FVSNGTHW FVTC/RN FY E P
QIITTHNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAK
NLNESLID
LQE LG KYEQYI KW PWYIW LG FIAG LIAIVMVTI M LCCMTSCCSC LKGCCSCGSCC K F DE
DDSEPVLKGVKLHYT
SEQ ID NO: 24
>MW493681.1 Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-
2/hurnan/USA/NM DOH-
2021013232/2021, complete genome. [Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2)],
Californian B.1.427 lineage
AAG G TTTATACCTTCCCAG GTAACAAACCAACCAACTTTCG ATCTCTTGTAG ATCTGTTCTCTAAACG
AACTTTAAAATCTGT
GTGGCTGTCACTCGGCTGCATGCTTAGTGCACTCACGCAGTATAATTAATAACTAATTACTGTCGTTGACAGGACACGA
GT
AACTCGTCTATCTTCTGCAGGCTGCTTACGGTTTCGTCCGTGTTGCAGCCGATCATCAGCACATCTAGGTTTTGTCCGG
GTG
TGACCGAAAGGTAAGATGGAGAGCCTTGTCCCTGGTTTCAACGAGAAAACACACGTCCAACTCAGTTTGCCTGTTTTAC
AG
GTTCGCGACGTGCTCGTACGTGGCTTTGGAGACTCCGTGGAGGAGGTCTTATCAGAGGCACGTCAACATCTTAAAGATG
G
CACTTGTGGCTTAGTAGAAGTTGAAAAAGGCGTTTTGCCTCAACTTGAACAGCCCTATGTGTTCATCAAACGTTCGGAT
GC
TCGAACTGCACCTCATGGTCATGTTATGGTTGAGCTGGTAGCAGAACTCGAAGGCATTCAGTACGGTCGTAGTGGTGAG
A
CACTTGGTGTCCTTGTCCCTCATGTGGGCGAAATACCAGTGGCTTACCGCAAGGTTCTTCTTCGTAAGAACGGTAATAA
AG
GAGCTGGTGGCCATAGTTACGGCGCCGATCTAAAGTCATTTGACTTAGGCGACGAGCTTGGCACTGATCCTTATGAAGA
TT
TTCAAGAAAACTGGAACACTAAACATAGCAGTGGTGTTACCCGTGAACTCATGCGTGAGCTTAACGGAGGGGCATACAC
T
CGCTATGTCGATAACAACTTCTGTGGCCCTGATGGCTACCCTCTTGAGTGCATTAAAGACCTTCTAGCACGTGCTGGTA
AA
125
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G CTTCATG CACTTTGTCCGAACAACTG GACTTTATTG ACACTA AG AG G G GTGTATACTG CTGCCGTG
AA CATG AG CATG AA
ATTG CTTG GTACACG G AACGTTCTG AAAAG AG CTATGAATTG CAGACACCTTTTGAAATTAAATTG G
CAAAG AAATTT
G ACATCTTCAATG G G G AAT G TCC AAATTTTG TATTTCCCTTAAATTC CATAAT CAAG A CTATT
CAACC AAG G G TTG AAAAG A
AAAAG CTTG ATG G CTTTATG G G TA G AATT C G AT CTG T CTAT CCAG TTG CGTCACCAAATG
AATG CAACCAAATGTG CCTTTC
AACTCTCATGAAGTGTG ATCATTGTG GTG AAACTTCATG G CAG ACG G G CGATTTTGTTAAAG
CCACTTG CGAATTTTGTG G
CACT G AG AATTTG ACTAAAGAAG GTG CCACTACTTGTG GTTACTTACCCCAAAATG CTG
TTGTTAAAATTTATT G TCC AG CA
TGTCACAATTCAG AAG TAG G ACCTG AG CATAGTCTTG CCG AATACCATAATG AATCTG G CTTG
AAAACCATTCTTCGTAAG
G GTG GTCG CACTATTG CCTTTG GAG G CTGTGTGTTCTCTTATGTTG GTTG CCATAACAAG TG TG
CCTATTG G GTTCCACGTG
CTAG CG CTAACATAG GTTGTAACCATAC AG GTGTTGTTG G AG AAG GTTCCGAAG
GTCTTAATGACAACCTTCTTGAAATAC
TCCAAAAAG AG AAAG TCAA CATCAATATTGTTG GTG ACTTTAAACTTAATGAAG AG ATCG
CCATTATTTTG G CAT CTTTTTC
TG CTTCCACAAGTG CTTTTGTG G AAACTGTGAAAGGTTTG GATTATAAAG
CATTCAAACAAATTGTTGAATCCTGTG GTAAT
TTTAAAGTTACAAAAG GAAAAG CTAAAAAAG GTG CCTG G AATATTG G T G AACA G AAAT
CAATACTG AG TCCTCTTTAT G CA
TTTG CAT CAG AG G CTG CTCGTGTTGTACGATCAATTTTCTCCCG CACTCTTG AAA CTG
CTCAAAATTCTG TG C GTG TTTTA CA
GAAG G CCG CTATAACAATACTAG ATG GAATTTCACAGTATTCACTG AG ACT CATTG ATG CTATG
ATGTTCACATCTG ATTT
G GCTACTAACAATCTAGTTGTAATG G CCTAC ATTAC AG GTGGTGTTGTTCAGTTGACTTCG CAGTG G
CTAACTAACATCTTT
G GCACTGTTTATGAAAAACTCAAACCCGTCCTTGATTG G CTTG AAG AG AAGTTTAAG GAAG G TG TAG
AG TTTC TTAG AG AC
G GTTG G GAAATTGTTAAATTTATCTCAACCTGTG CTTGTG AAATTGTCG GTG G ACAAATTGTCACCTG
TG CAAAG GAAATT
AAG G AG AG TG TTCAG ACATTCTTTAAG CTTGTAAATAAATTTTTG G CTTTGTGTG
CTGACTCTATCATTATTG GTG GAG CTA
AACTTAAAG CCTTG AATTTAG GTGAAACATTTGTCACG CACTCAAAG G G ATTGTAC AG AAAG TG TG
TTAAATCCAG AG AAG
AAACTG G CCTACTCATG CCTCTAAAAG CCCCAAAAG AAATTATCTT CTTAG AG G G AG
AAACACTTCCCACAG AAGTG TTAA
CAG A G G AA GTTG TCTT G AAAACTG GTGATTTACAACCATTAG AACAACCTACTAGTGAAG
CTGTTGAAG CTCCATTG GTTG
G TA CACCAGTTTGTATTAACG G G CTTATGTTG CTCGAAATCAAAGACACAG AAAAGTACTGTGCCCTTG
CAC CTAATATG A
TG GTAACAAACAATACCTTCACACTCAAAG G CG GTG CAC CAACAAAG GTTACTTTTG GTG
ATGACACTGTGATAGAAGTG C
AAG G TTAC AAG AG TG TG AATATCACTTTTG AACTTGATG AAAG G ATTG ATAAAG TACTTAATG
AG AA G TG CT CTG C CTATA
CAG TTG AA CTC G GTACAG AAGTAAATG AG TTC G CCT G TG TTG T G G CAG ATG
CTGTCATAAAAACTTTG CAACCAGTATCTG
AATTACTTACACCA CT G G G CATTGATTTAG ATG A G TG G AG TATG G CTACATACTACTTATTTG
ATG AG TCT G GTG AG TTTAA
ATTG G CTTCAC ATATG TATT G TT CTTTTTACC CTCC AG ATG AG G ATG AA G AAG AAG
GTGATTGTG AAG AA G AAG AG TTTG A
G CC ATC AACT CAATATG AG TAT G G TACTG AA G ATG ATTACC AAG GTAAACCTTTG G
AATTTG GIG CCACTTCTG CTG CT CTT
CAAC CTG AA G AAG A G CAAG AAGAAG ATTG GTTAGATG ATGATAGTCAACAAACTGTTG G
TCAACAAG AC G G CAGTG AG G
ACAAT CAG AC AACTACTATT CAAACAATTG TTG AG G TT CAA CCT CAATTAG AG ATG G AACTTA
CACCAG TTG TT CAG ACTAT
TGAAGTG AATAGTTTTAGTG G TTATTTAAAACTTA CTG A CAATG TATAC ATTAAAAATG CAG AC
ATTG TG GAAGAAG CTAA
AAAG GTAAAACCAAC AG TG GTTGTTAATG CAG CCAATGTTTACCTTAAACATG G AG GAG GTGTTG
CAG G AG CCTTAAATA
AG G CTACTAACAATG CCATG CAAGTTGAATCTGATGATTACATAG CTACTAATG GACCACTTAAAGTG G
GTG G TAG TTG T
GTTTTAAG CG G ACACAATCTTG CTAAACACTGTCTTCATGTTGTCG G CCCAAATGTTAACAAAG GTG
AAGACATTCAACTTC
TTAA G AG T G CTTATG AAAATTTTAATC AG CAC G AAG TTCTA CTTG CACCATTATTATCAG CTG
GTATTTTTG GTG CTG AC CCT
ATACATTCTTTAAG AG TTTG T G TAG ATACTGTTCG CACAAATGTCTACTTAG CT G TCTTTG
ATAAAAATCTCTATG A CAAACT
TGTTTCAAG CTTTTTG G AAATG AAGAGTGAAAAG CAAGTTGAACAAAAG ATCG CTG AG ATTCCTAAAG
AG G AAGTTAAG C
CATTTATAA CTG AAAG TAAA CCTT CAG TT G AACA G AG AAAACAAG ATG ATAAG AA AAT CAAA
G CTT G TG TTG AA G AAG TT
ACAACAACTCTG GAAGAAACTAAGTTCCTCACAGAAAACTTGTTACTTTATATTGACATTAATG G
CAATCTTCATCCAGATT
CTG CCACT CTTG TTAG TG A CATTG ACATCACTTTCTTAAAG AAAG AT G CTCCATATATAGTG G GT
G ATG TTG TT CAAG AG G G
TGTTTTAACTG CTGTG G TT ATACCTACTAAAAAG G CTG GTG G C ACTA CTG AAAT G
CTAGCGAAAG CTTTG AG AAAAGTG CC
AACAG ACAATTATATAACCACTTACCCG G GTCAG G GTTTAAATG GTTACACTGTAG AG GAG G
CAAAGACAGTG CTTAAAA
AG T G TAAAAG TG CCTTTTAC ATTCTACCAT CTATTATCT CTAATG AG AAG CAAGAAATTCTTG G
AACTGITTCTTG G AATTTG
CG AG AAATG CTTG CACATG CAG AAG AAA CAC G CAAATTAATG CCTGTCTGTGTG G AAACTAAAG
CC ATAG TTTCAACTATA
CAG CGTAAATATAAG G G TATTAAAATAC AAG AG G GTGTG GTTGATTATG GTG CTAG
ATTTTACTTTTAC ACC AG TAAAAC A
ACTG TAG CGTCACTTATCAACACACTTAACGATCTAAATGAAACTCTTGTTACAATG CCACTTG G
CTATGTAACACATG G CT
TAAATTTG GAAGAAG CTG CT C G G TATAT G A G AT CTCT CAAAG T G C CA G CTAC AG
TTTCTG TTTCTTCAC CTG AT G CTGTTAC
AG CGTATAATG GTTATCTTACTTCTTCTTCTAAAACACCTG AAG AACATTTTATTG AAAC CAT CT CA
CTTG CTG GTTCCTATA
AAGATTG GTCCTATTCTG G A CAATCTACACAACTAG G TATAG AATTTCTTAAG A G AG G TG
ATAAAAG TG TATATTA CA CTA
GTAATCCTACCACATTCCACCTAGATG GTG AAGTTATCACCTTTG ACAATCTTAAG AC ACTT CTTT CTTT
G AG AG AAGTG AG
GACTATTAAG G T G TTTACAA CA G TAG ACAACATTAACCTCCAC AC G CAA G TTG TG G ACATG
TCAAT G AC ATATG GACAACA
GTTTG GTCCAACTTATTTG G ATG G AG CT G ATG TTA CTAAAATAAAACCTCATAATTCA CATG AAG
G TAAAACATTTTATG TT
TTA CCTAATG AT G ACACTCTAC G TG TT G AG G CTTTTG AG TACTACCAC ACAACT G ATCCTAG
TTTTCTG G G TAG GTACATGT
CAG CATTAAATCACACTAAAAAGTG G AAATACCCACAAGTTAATG GTTTAACTTCTATTAAATG G G CAG
ATAACAA CTG TT
ATCTTG CC ACTG CATT G TTAA CACTC CAACAAATAG AG TTG AAGTTTAATCCACCTG CTCTACAAG
ATG CTTATTACAG AG C
126
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T/IB2021/052858
AAG G G CTG GTG AAG CT G CTAACTTTTGTG CACTTATCTTAG C CTACTG TAATAAG ACAG TAG G
TG AG TTAG GTGATGTTAG
AG AAACAATG AG TTACTTG TTT CAACAT G CCAATTTAG ATTCTTG C AAAAG A G TCTTG AAC G
TG GTGTGTAAAACTTGTG G
ACAAC AG CAG ACAACCCTTAAG G GTGTAG AAG CTGTTATG TA CATG G G CAC ACTTT CTTATG
AACAATTTAAG AAAG GTGT
TCAG ATACCTTGTACGTGTG GTAAACAAG CTACAAAATATCTAG TA CAA CAG G AG TC AC
CTTTTGTTATG ATG TCAG C AC CA
C CT G CTC AG TAT G AACTTAAG CATG GTACATTTACTTGTGCTAGTG AG TAC ACTG G TAATTAC
C AG TG TG GT CACTATAAAC
ATATAACTTCTAAAGAAACTTTGTATTG CATAG AC G GTG CTTTACTTACAAAG TC CT CAG AATACAAAG
GTCCTATTACG GA
TG TTTTCTACAAAG AAAAC AG TTACACAA CAA C CATAAAAC CAGTTACTTATAAATTG GATG
GTGTTGTTTGTACAGAAATT
G AC C CTAAG TTG G ACAATTATTATAAGAAAG ACAATT CTTATTTCAC AG AG CAAC C AATTG
ATCTTG TAC CAAAC CAAC CAT
ATCCAAACG CAAG CTTCG ATAATTTTAAGTTTGTATGTG ATAATATCAAATTTG CTG
ATGATTTAAACCAGTTAACTG G TTA
TAAG AAACCTG CTTCAAG AG AG CTTAAAGTTACATTTTTCCCTG ACTTAAATG GTG ATGTG GTG G
CTATT G ATTATAAAC AC
TACA CAC C CTCTTTTAAG AAAG G AG CTAAATTGTTACATAAACCTATTGTTTG G CATGTTAACAATG
CAACTAATAAAG C CA
CGTATAAACCAAAT AC CTG GTGTATACGTTGTCTTTG GAG CACAAAACCAG TTG AAA CATC
AAATTCGTTTG ATG TACTG AA
G TC AG AG G AC G CG CAG G GAATG G ATAATCTTGTCTG C G AA G ATCTAAAAC CAG T CTCT
G AAG AAG TA G TG G AAAATCCTA
C CATACAG AAAG AC G TTCTT G AG TG TAATG T G AAAACTA C C G AAG TTGTAG GAG
ACATTATACTTAAACCAG CAAATAATA
G TTTAAAAATTAC AG AAG AG GTTG G C CACAC AG ATCTAATG G CT G CTTATG TAG
ACAATTCTAG TC TTACTATTAAG AAAC
CTAATGAATTATCTAGAGTATTAG GTTTG AAAACC CTTG CTACTCATG GTTTAG CTG CTGTTAATAG
TGTCCCTTG G G ATAC
TATAG CTAATTATG CTAAG C CTTTTCTTAAC AAAG TT G TTAG TAC AACTACTAACAT AG TTAC AC
G GTGTTTAAACCGTGTTT
G TA CTAATTATATG CCTTATTTCTTTACTTTATTG CTA CAATT G TG TACTTTTACTAG AA G
TACAAATTCTAG AATTAAA G CAT
CTATG CC G ACTA CTATAG CAAAG AATACTG TTAAG AG TG TCG GTAAATTTTG TCTAG AG G
CTTCATTTAATTATTTGAAGTC
AC CTAATTTTT CTAAACTG ATAAATATTATAATTT G GTTTTTACTATTAAGTGTTTG CCTAG
GTTCITTAATCTACTCAACCG C
TG CTTTAG GTGTTTTAATGTCTAATTTAG G CAT G CCTTCTTACTGTACTG G TTAC AG AG AAG G
CTATTTGAACTCTACTAATG
TCACTATTG CAACCTACTGTACTG G TTCTATAC CTT G TAG TG TTT G TCTTAG T G GTTTAG
ATTCTTTAG AC AC CTATC CTTCTT
TAG AAACTATACAAATTACCATTTCATCTTTTAAATG G G ATTTAACTG CTTTTG G CTTAGTTG CAG AG
TG GTTTTTG G CATAT
ATTCTTTTCACTAG GTTTTTCTATGTACTTG GATTG G CTG CAATCATG CAATTGTTTTTCAG CTATITTG
CA GTAC ATTTTATT
AG TAATTCTTG G CTTATGTG GTTAATAATTAATCTTGTACAAATG G C CC CG ATTTC AG CTATG
GTTAGAATGTACATCTTCT
TTG CATCATTTTATTATGTATG GAAAAGTTATGTG CATG TTG TAG ACG
GTTGTAATTCATCAACTTGTATGATGTGTTACAA
AC G TAATAG AG CAA CAAG AG TC G AATGTACAACTATTGTTAATG GTGTTAG AAG
GTCCTTTTATGTCTATG CTAATG G AG G
TAAAG G CTTTTG CAAACTACACAATTG GAATTGTGTTAATTGTGATACATTCTGTG CTG G TAG TAC
ATTTATTAG T G AT G AA
GTTG CG AG AG ACTTG TCACTACAGTTTAAAAG ACCAATAAATCCTACTG ACCAGTCTTCTTACATCGTTG
ATAG TGTTACAG
TGAAGAATG GTTCCATCCATCTTTACTTTG ATAAAG CTG GTCAAAAGACTTATGAAAG
ACATTCTCTCTCTCATTTTGTTAAC
TTAG ACAAC CTG AG AG CTAATAACACTAAAG GTTCATTG C CTATTAATG TTATAG TTTTTG AT G
GTAAATCAAAATGTG AAG
AATCATCTG CAAAATCAG CGTCTGTTTACTACAGTCAG CTTATGTGTCAACCTATACTGTTACTAGATCAG G
CATTAGTGTC
TGATGTTG GTGATAGTG CG GAAGTTG CAGTTAAAATGTTTG ATG CTTACG TTAATACGTTTTC AT CAA
CTTTT AACG TAC CA
ATG GAAAAACTCAAAACACTAGTTG CAACTG CA G AAG CT G AACTTG CAAAGAATGTGTCCTTAG AC
AATGT CTTATCTACT
TTTATTTCAG CAG CTCG G CAAG G GTTTGTTG ATTC AG ATG TAG
AAACTAAAGATGTTGTTGAATGTCTTAAATTGTCACATC
AATCTGACATAGAAGTTACTG G CGATAGTTGTAATAACTATATG CTCACCTATAACAAAGTTGAAAACATG
ACACCCCGTG
AC CTTG GTG CTTGTATTG ACTGTAGTG CG CGTCATATTAATG CG CAG GTAG
CAAAAAGTCACAACATTG CTTTG ATATG GA
AC G TTAAAG ATTT CATG TCATTG TCTG AA CAACTA C G AAAACAAATAC G TAG TG CTG
CTAAAAAGAATAACTTACCTTTTAA
G TT G ACAT G TG CAACTACTAG ACAAGTTGTTAATGTTGTAACAACAAAG ATAG CACTTAAG G GTG
GTAAAATTGTTAATAA
TTG G TT G AAG C AG TTAATTA AAG TTACACTTG TG TTC CTTTTTG TTG CT G CTATTTT
CTATTTAATAACAC CTG TT CATG T CAT
GTCTAAACATACTG ACTTTTCAAGTGAAATCATAG GATACAAG G CTATTG ATGGTG G TG TC ACTC G
TG A CATAG CATCTAC
AG ATACTT G TTTTG CT AACAAA CATG CTG ATTTT G AC AC ATG GTTTAG CCAG CGTG GTG G
TAG TTATACTAATG ACAAAG CT
TG CCCATTGATTG CTG CAGTCATAACAAG AG AAG TG G GTTTTGTCGTG CCTG GTTTG CCTG G
CACGATATTACG CACA ACT
AATG GTG ACTTTTTG CATTTCTTAC CTAG AG TTTTTAG T G CAGTTG GTAACATCTGTTAC ACAC C
ATCAAAACTTATAG A GTA
CACTG A CTTTG CAACATCAG CTTGTGTTTTG G CT G CT GAATGTACAATTTTTAAAG ATG CTTCTG
GTAAG C CA G TAC C ATAT
TGTTATG ATACCAATGTACTAG AAG GTTCTGTTG CTTATGAAAGTTTACG C C CTG AC ACAC G TTATG
TG CTCATG GATG G CT
CTATTATTCAATTTCCTAACACCTACCTTGAAG G TT CTG TTAG AG TG GTAACAACTITTGATTCTG AG
TACTG TAG G CA C G G
CA CTTG TG A AA G ATCA G AA G CTG GTG TTTG TG TAT CTA CTA G TG G TA G ATG G G
TA CTTAA CAAT G ATTATTA CA G ATCTTTA
CCAG G AG TTTT CTGTG GTGTAG ATG CTGTAAATTT ACTTA CTAATATG TTTACACCACTAATTC AAC
CT ATTG G TG CMG GA
CATATCAG CATCTATAG TAG CTG GTG GTATTG TAG CTATCG TAG TAACATG CCTTG
CCTACTATTTTATG AG GTTTAG AAG A
G CTTTTG GTG AATA CAG T CATG TAG TTG C CTTTAATACTTTACTATTC CTTATG TCATT CACT G
TACT CTG TTTAA CAC CAG TT
TACT CATT CTTAC CTG GTGTTTATTCTGTTATTTACTTGTACTTG
ACATITTATCTTACTAATGATGTTTCITTTTTAG CAC ATA
TTC AG TG GATG G TTATG TTCACA C CTTT AG TAC CTTTCTG GATAACAATTG
CTTATATCATTTGTATTTCCACAAAG CATTTCT
ATTG GTT CTTTACTAATTAC CTAAAG AG ACGTG TAG TCTTTAATG G TG TTTC CTTTAG TA
CTTTTG AAGAAG CTG CG CTGTG
CAC CTTTTTG TTAAATAAAG AAATG TATCTAAAGTT G C G TAG T G ATG TG CTATTAC CT CTTAC
G CAATATAATAG ATACTTA
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G CT CTTTATAATAAG TACAAG TATTTTAG T G GAG CAATG GATACAACTAG CTACAG A G AAG CTG
CTTGTTGTCATCTCG CA
AAG G CTCTCAATG ACTTC AG TAA CTCAG GTTCTG AT G TTCTTTACCAAC CAC
CACAAACCTCTATCACCTCAG CTGTTTTG CA
G AG TG GTTTTAGAAAAATG G CATTC CCATCTG G TAAAG TTG AG G GTTGTATG
GTACAAGTAACTTGTG GTACAACTACACT
TAACG GTCTTTG G CTTGATG AC G TAG TTTACTG T CCAAG ACATGTGATCTG CA C CTCTG AAG
AC ATG CTTAACCCTAATTAT
GAAG ATTTACTCATTCGTAAGTCTAATCATAATTTCTTG GTACAG G CT G G TAATG TT C AACT CA G
G GTTATTG G ACATTCTA
TG CAAAATTGTGTACTTAAG CTTAAG GTTG ATACAG CCAATCCTAAGACACCTAAGTATAAGTTTGTTCG
CATTCAACCAG G
ACAG ACTTTTTCAGTGTTAG CTTGTTACAATG GTTCACCATCTG GTGTTTACCAATGTG CTATG AG G
CCCAATTTCACTATTA
AG G GTTCATTCCTTAATG GTTCATGTG G TAG TG TT G GTTTTAACATAG ATTATG ACT G TG
TCTCTTTTTG TTACATG CAC CAT
ATG GAATTACCAACTG G A G TTC ATG CTG G CACAGACTTAG AAG GTAACTTTTATG G AC CTTTTG
TT G ACAG G CAAACAG CA
CAAG CAG CT G GTACG G ACACAACTATTACAGTTAATGTTTTAG CTTG GTTGTACG CTG CT G
TTATAAATG GAG AC AG GTG G
TTTCTCAATCGATTTACCACAACTCTTAATG ACTTTAACCTTGTG G CTATG AA G TACAATTAT G
AACCTCTAACACAAG AC CA
TG TTG AC ATACTAG G AC CTCTTTCT G CTCAAACTG GAATTG CC G TTTTAG ATATG T G TG
CTTCATTAAAAGAATTACTG CAA
AATG GTATGAATG GACGTACCATATTG G GTAGTG
CTTTATTAGAAGATGAATTTACACCTTTTGATGTTGTTAGACAATG CT
CAG GTGTTACTTTCCAAAGTG CA G T G AAAA G AACAATCAAG G GTACACACCACTG G TT G TTA
CTCAC AATTTTG ACTTCACT
TTTAGTTTTAGTCCAG AG TA CTCAATG GTCTTTGTTCTTTTTTTTGTATGAAAATG CCTTTTTACCTTTTG
CTATG G GTATTAT
TG CTATGTCTG CTTTTG CAATG AT G TTT G TCAAACATAA G CAT G
CATTTCTCTGITTGTTTTTGTTACCTICTCTTG CCACTG
TAG CTTATTTTAATATG GTCTATATG CCTG CTAGTTG G GTG ATG CGTATTATGACATG GTTG GATATG
GTTGATACTAGTTT
GTCTG GTTTTAAG CTAAAAG ACT G TG TTATG TATG CATCAG CTG TAG TG TTACTAATCCTTATG
ACAG C AAG AACTG TG TAT
G AT G ATG GTG CTAG G AG AG T G TG GACACTTATG
AATGTCTTGACACTCGTTTATAAAGTTTATTATG GTAATG CTTTAG AT
CAAG CCATTTCCATGTG G G CT CTTATAATCT CTG TTACTT CTAACTACTCAG G T G TA G
TTACAACTG T CATG TTTTTG G C CAA
AG G TATT G TTTTTATG T G TG TTG AG TATT G CC CTATTTTCTTCATAACTG G TAATACACTTC
AG TG TATAAT G CTAGTTTATT
GTTTCTTAG G CTATTTTTGTACTTGTTACTTTG G CCTCTTTTGTTTACTCAACCG CTACTTTAG ACTG ACT
CTTG GTGTTTATG
ATTACTTAGTTTCTACACAG G AG TTTAG ATATATG AATTCACAG G GACTACTCCCACCCAAGAATAG
CATAGATG CCTTCAA
ACT CAACATTAAATTG TTG G GTGTTG GTG G CAAACCTTGTAT CAAAG TAG CCACTG
TACAGTCTAAAATG TC AG ATG TAAA
GTG CACAT CAG TAG TCTTACT CTCAG TTTTG CAACAACT CAG AG TAG AATCAT CATCTAAATT G
TG G G CT CAATG TG T CCAG
TTACACAATGACATTCTCTTAG CTAAAG ATACTACTG AAG CCTTTG AAAAAATG
GTTTCACTACTTTCTGTTTTG CTTTC CAT
G CAG G GTG CTG TAG ACATAAA CAAG CTTTGTGAAGAAATG CTG GACAACAG G G CAACCTTACAAG
CTATAG CCTC AG AG T
TTAGTTCCCTTCCATCATATG C AG CTTTTG CTACTG CTCAAGAAG CTTATG AG CAG G CTGTTG
CTAATG G TGATTCTG AAGT
TGTTCTTAAAAAGTTG AAGAAGTCTTTGAATGTG G CTAAATCTG AATTTG ACC GTGATG CAG CCATG
CAACG TAAG TT G GA
AAAG ATG G CTG AT CAAG CTATG ACCCAAATGTATAAACAG G CTAG ATCT G AG G ACAA G AG G
G CAAAAGTTACTAGTG CTA
TG C AG ACAATG CTTTTCACTATG CTTAGAAAGTTG G ATAAT G AT G
CACTCAACAACATTATCAACAATG CAAG AG ATG G TT
GTGTTCCCTTG AACATAATACCTCTTACAAC AG C AG CCAAATTAATG G TT G TCATACC A G
ACTATAACACATATAAAAATA C
G TG TG AT G GTACAACATTTACTTATG CATC AG CATTGTG G GAAATCCAACAG G TTG TAG ATG
CAGATAGTAAAATTGTTCA
ACTTAGTGAAATTAGTATG G ACAATTCACCTAATTTAG CATG G CCTCTTATTGTAACAG CTTTAAG G G
CCAATTCTG CT G TC
AAATTACAG AATAAT G AG CTTAGTCCTGTTG C ACTA C G ACAG ATGTCTTGTG CTG CC G G TA
CTACA CAAACT G CTTG CACT
GATGACAATG CGTTAG CTTACTACAACACAACAAAG G GAG GTAG GTTTG TA CTTG
CACTGTTATCCGATTTACAG GATTTG
AAATG G G CTAGATTCCCTAAG AG TG AT G G AACTG G TA CTATCTATAC AG AACTG G AACCAC
CTTG TAG G TTTG TTAC AG AC
ACACCTAAAG GTCCTAAAGTGAAG TATTTATACTTTATTAAAG GATTAAACAACCTAAATAG AG G TAT G G
TA CTTG G TAG T
TTAG CTG CCACAGTACGTCTACAAG CTG GTAATG CAACAG AAGTG CCTG
CCAATTCAACTGTATTATCTTTCTGTG CTTTTG
CTG TAG ATG CTG CTAAAG CTTACAAAGATTATCTAG CTAGTG GGGG
ACAACCAATCACTAATTGTGTTAAG ATG TTG TG TA
CACACACTG G TACT G GTCAG G CAATAACAGTTACACCG GAAG CCAATATG G ATCAAG AATCCTTTG
GIG GTG C ATCG TG TT
G TCTG TA CTG CCGTTG CCACATAGATCATCCAAATCCTAAAG GATTTTGTGACTTAAAAG
GTAAGTATGTACAAATACCTAC
AACTTGTG CTAATG AC CCTG TG G GTTTTACACTTAAAAACACAGTCTGTACCGTCTG CG GTATGTG
GAAAG GTTATG G CTG
TAG TTGTG ATC AACTCC G CGAACCCATG CTTCAGTCAG CTG ATG CACAATCGTITTTAAACG G
GTTTG CG GTGTAAGTG CA
G CC CGTCTTACAC CGTG CG G CACAG G CACTAGTACTGATGTCGTATACAG GG CTTTTG AC AT
CTACAATG ATAAAG TAG CT
G GTTTTG CTAAATTCCTAAAAACTAATTGTTGTCG CTTCCAAG AAAAG G ACGAAG ATGACAATTTAATTG
ATTCTTACTTTG
TAG TTAAG AG AC ACACTTTCT CTAACTACCAA CATG AAG AAA CAATTTATAATTTACTTAAA G ATT
G TCC AG CT G TTG CTAA
A CATG ACTTCTTTAAGTTTAG AATAG ACG GTG ACATG G TACCACATATAT CAC G TCAAC GTCTTA
CTAAATACACAATG G CA
GACCTCGTCTATG CTTTAAG G CATTTTGATGAAG G TAATTG TG AC AC ATTAAAAG AAATACTTG T
CACATA CAATT G TT G TG
ATG ATGATTATTTCAATAAAAAG GACTG GTATG ATTTTG TAG AAAACCCAG ATATATTACG CGTATACG
CCAACTTAG GTG
AACGTGTACG CCAAG CTTTG TTAAAAAC AG TAC AATTCTGTG ATG CCATGCGAAATG CTG
GTATTGTTG GTG TACTGACAT
TAG ATAATCAAG ATCTCAATG GTAACTG GTATG ATTTCG GTGATTTCATACAAACCACG CCAG G TAG T
G G AG TTCCTG TTG
TAG ATTCTTATTATTCATTGTTAATG CCTATATTAACCTTG ACC AG G G CTTTAACTG C AG AG T
CACAT G TT G ACACTG ACTTA
ACAAAG CCTTACATTAAGTG G GATTTGTTAAAATATGACTTCACG GAAG AG AG G TTAAAACTCTTTG AC
C G TTATTTTAAAT
ATTG G G ATCAG ACATACCACCCAAATTGTGTTAACTGTTTG GATGACAG ATG CATTCTGCATTGTG
CAAACTTTAATGTTTT
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ATTCTCTACAGTGTTCCCACTTACAAGTTTTG G ACCACTAG T G AG AAAAATATTTG TTG ATG G TG TT
CCATTTG TAG TTTCAA
CTG G ATAC CACTT CAG A G AG CTAG GTG TTGTACATAATCAG G ATGTAAACTTACATAG
CTCTAGACTTAGTTTTAAG GAAT
TACTTG T G TAT G CTG CTG A CCCTG CTATG CAC G CTG CTTCTG GTAATCTATTACTAGATAAACG
CACTACGTG CTTTTCAG TA
G CTG CACTTACTAACAATGTTG CTTTTC AAA CTGTCAAACCCG
GTAATTTTAACAAAGACTTCTATGACTTTG CTGTGTCTAA
G GGTTTCTTTAAG G AAG GAAGTTCTGTTGAATTAAAACACTTCTTCTTTG CT CAG G ATG GTAATG CTG
CTATC AG CGATTAT
G ACTACTATC G TTATAATCTAC CAACAATG TG TG ATATCAG ACAA CTACTATTT G TAG
TTGAAGTTGTTG ATAAGTACTTTG
ATTGTTACGATG GTG G CT G TATTAATG CTAAC CAAGTCATC GTCAACAACCTAGACAAATCAG CTG
GTTTTCCATTTAATAA
ATG G G GTAAG G CTAG A CTTTATTAT G ATT CAATG AG TTATG AG G ATC AAG AT G
CACTTTTCG CATATACAAA AC G TAATG T
CATCCCTACTATAACTCAAATGAATCTTAAGTATG CCATTAGTG CAAAGAATAG AG CT C G CAC C GTA G
CTG GTGTCTCTATC
TG TAG TA CTATG AC CAATAG ACAG TTTC ATCAAAA ATTATTG AAAT CAATAG CCG CCACTAG AG
GAG CTACTGTAGTAATT
G GAACAAG CAAATTCTATG GTG GTTG G CAC AACATGTTAAAAACTG TTTATAGTG ATG TAG AAAACC
CTCACCTTATG G GT
TG G G ATTATCCTAAATG TG ATAG AG CCATG CCTAACATG CTTAGAATTATG G CCTCACTTG
TTCTTG CTC G CAAACATACAA
CGTGTTGTAG CTTGTCACACCGTTTCTATAG ATTAG CTAATG AG TG TG CT CAAG TATTG AGTG AA
ATG GTCATGTGTG G CG
G TT CACTATATG TTAAA CCAG GTG G AACCTCATCAG GAG ATG C CA CAACTG CTTATG
CTAATAGTGTTTTTAACATTTGTCA
AG CT G TC AC G G CCAATGTTAATG CACTTTTATCTACTGATG GTAACAAAATTG CC G ATAAG TATG
TC C G CAATTTACAACAC
AG ACTTTATG AG TG T CTCTATAG AAATAG AG ATGTTGACACAGACTTTGTGAATG AG TTTTAC G
CATATTTG CGTAAACATT
TCTCAATG ATGATACTCTCTG AC G ATG CT G TTG TG T G TTTCAATAG CAC TTAT G CATCTCAAG
GTCTAGTG G CTAG CAT AAA
GAACTTTAAGTCAGTTCTTTATTATCAAAACAATGTTTTTATGTCTGAAG CAAAATGTTG G ACT G AG A CT
G ACCTTACTAAA
G GACCTCATGAATTTTG CTCTCAACATACAATG CTAGTTAAACAG G G TG ATG ATTATG T G TAC
CTTCCTTAC C CAG AT CCAT
CAAG AATCCTAG G G G CC G G CTGTTTTG TAG ATG ATATCGTAAAAACAG ATG GTACACTTATG
ATTG AACG GTTCGTGTCTT
TAG CTATAGATG CTTACCCACTTACTAAACATCCTAATCAG G AG TATG CTG AT G TCTTTCATTTG
TACTTACAATACATAAG A
AAG CTACATGATG AG TTAACAG G ACACATGTTAGACATGTATTCTGTTATG
CTTACTAATGATAACACTTCAAG GTATTG G
GAACCTGAGTTTTATG AG G CTATGTACACACCG CATACAGTCTTACAG G CTGTTG G G G CTTG TGTT
CTTTG CAATTCAC AG A
CTTCATTAAGATGTG GTG CTTG CATAC G TAG ACC ATTCTTATG TTG TAAATG
CTGTTACGACCATGTCATATCAACATCACAT
AAATTAGTCTTGTCTGTTAATCCGTATGTTTG CAATG CTCTAG GTTGTGATGTCACAG ATGTG
ACTCAACTTTACTTAG GAG
G TATG AG CTATTATT G TAAATCACATAAACC ACCCATTAG TTTT CCATTG TG TG CTAATG G ACA
AG TITTTG GTTTATATAAA
AATACATGTGTTG GTAGCGATAATGTTACTGACTTTAATG CAATTG CAACATGTGACTG G ACAAATG CTG
GTG ATTACATTT
TAG CTAACAC CTG TACTG AAAG ACT C AAG CTTTTTG CAG CA G AAAC G CTCAAAG CTACTG A
G GAG ACATTTAAACTGTCTT
ATG GTATTG CTACTGTACGTG AAGTG CTGTCTG ACAG A G AATTACATCTTTCATG G G AAGTTG G
TAAACCTA G ACC ACCAC
TTAACCGAAATTATGTCTTTACTG GTTATCGTGTAACTAAAAACAGTAAAGTACAAATAG G AG AG TACA C
CTTTG AAAAAG
GTG ACTATG GTGATG CTGTTGTTTACCG AG GTACAACAACTTACAAATTAAATGTTG GTGATTATTTTGTG
CTGACATCACA
TACAGTAATG CCATTAAGTG CAC CTACA CTAG T G C CA C AAG AG CA CTATG TTAG AATTACTG
G CTTATACCCAACACTCAAT
ATCTCATATGAGTTTTCTAG CAATGTTG CAAATTATCAAAAG GTTGGTATG CAAAAGTATTCTACACTCCAG G
G ACC ACCTG
G TA CTG GTAAG AG TC ATTTTG CTATTG G CCTAG CT CTCTACTAC CCTT CTG CTC G
CATAGTGTATACAG CTG CTCTCATG CC
G CT G TTG AT G CACTATG T G AG AA G G CATTAAAATATTTG CCTATAG ATAAATG TAG TAG
AATTATACCTG CAC G TG CT C G T
G TA G AG T G TTTTG ATAAATT CAAAG TG AATTC AACATTAG
AACAGTATGTCTTTTGTACTGTAAATG CATTG CCTG AG AC G A
CAG CAGATATAGTTGTCTTTGATG AAATTTCAATG G C CACAAATTATG ATTTG AG TG TTG TC AATG
CCAGATTACGTG CTAA
G C A CTAT G TG TACATTG G CGACCCTG CT CAATTACCTG CACC AC G CA CATTG CTAACTAAG
G G CAC ACTAG AACCAGAATA
TTTCAATTCAGTGTGTAGACTTATG AAAACTATAG GTCCAG ACATGTTCCTCG G AA CTTGTC G G
CGTTGTCCTG CTGAAATT
GTTGACACTGTG AG TG CTTTG GTTTATGATAATAAG CTTAAAG CACATAAAG AC AAATCAG CTCAATG
CTTTAAAATGTTTT
ATAAG G GTGTTATCACG CATG ATGTTTCATCTG CAATTAACAG GCCACAAATAG G CGTG GTAAG AG
AATTCCTTACACG TA
ACCCTG CTTG G A G AAAAG CTG T CTTTATTT CACCTTATAATTCAC AG AATG CTG TAG
CCTCAAAG ATTTTG G G ACTA CC AAC
TCAAACTGTTGATTCATCACAG G G CT CAG AATATG ACTATGTCATATTCACTCAAACCACTGAAACAG
CTCACTCTTGTAAT
G TAAACAG ATTTAATG TT G CTATTAC CAG AG C AAAAG TA G G CATACTTTG
CATAATGTCTGATAG AG ACCTTTATG ACAAG
TTG CAATTTACAA G TCTTG AAATTC CA C G TA G GAATGTG G CAACTTTACAAG CT G AAAATG
TAA CAG G ACTCTTTAAAGATT
G TA G TAAG GTAATCACTG G GTTACATCCTACACAG G CAC CTACACAC CTCAG TG TTG ACA
CTAAATTCAAAACTG AAG G TT
TAT G TG TTG A CATAC CTG G CATACCTAAG G ACATG A CCTATAG AAG ACTCATCTCTATG AT G
G G TTTTAAAATG AATTAT CA
AGTTAATG GTTACCCTAACATGTTTATCACC CG CG AAG AA G CTATAAG ACATGTACGTG CATG GATTG
GCTTCG ATGT CG A
G GG GTG TCATG CTACTAG AG AAG CTGTTG GTACCAATTTACCTTTACAG CTAG GTTTTTCTACAG
GTGTTAACCTAGTTG CT
GTACCTAC AG GTTATGTTG ATACAC CTAATAATAC AG ATTTTT CCAG AGTTAG TG CTAAACCACCG
CCTG G AG AT CAATTTA
AACACCTCATACCACTTATGTACAAAG G A CTTCCTTG G AATG TAG TG C G TATAAAG ATT G
TACAAATG TTAA G TG A CACACT
TAAAAATCTCTCTGACAG AG TC G TATTTG TCTTATG G G CAC ATG G CTTTG AG TTG AC
ATCTATG AA G TATTTT G TG AAAATA
G GACCTG AG CG CACCTGTTGTCTATGTG ATAG ACGTG CCACATG CTTTTCCACTG CTT CAG AC
ACTTATG CCTGTTG G CATC
ATTCTATTG GATTTG ATTAC G TCTATAAT CC G TTTATG ATTG ATG TTCAACAATG G G
GTTTTACAG GTAACCTACAAAG CAA
CCATGATCTGTATTGTCAAGTCCATG GTAATG CAC ATG TAG CTA G TTG TG AT G CAATCATG ACTA
G GTGTCTAG CTGTCCAC
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G AG TG CTTTGTTAAG C GT G TTG ACTG GACTATTG AATATCCTATAATTG GTG ATGAACTGAAG
ATTAATG CG G CTTG TAG A
AAG GTTCAACACATG GTTGTTAAAG CTG CATTATTAG CAG ACAAATTC C CAG TT CTTCA C G A
CATTG G TAACCCTAAAG CTA
TTAAG TG TG TA C CTCAA G CTG ATG TA G AAT G G AA G TTCTATG ATG CA CAG C CTTG
TAG TG ACAAAG CTTATAAAATAGAAG
AATTATTCTATTCTTATG C CAC ACATT CTG A CAAATT CACAG ATG GTGTATG CCTATTTTG GAATTG
CAATGTCG ATAG ATAT
CCTG CTAATTCCATTG TTTG TAG ATTTG ACACTAG AG TG CTATCTAACCTTAACTTG CCTG GTTGTG
ATG GTG G CAGTTTGT
ATGTAAATAAACATG CATTC CAC ACAC C AG CTTTTG ATAAAAGTG
CTTTTGTTAATTTAAAACAATTACCATTTTTCTATTAC
TCT G ACAG TC CAT G TG AG TCT CATG G AAAAC AAG TA G TG T CA G ATATAG
ATTATGTACCACTAAAGTCTG CTA C G TG TATA
ACAC G TT G CAATTTAG GTG GTG CT G TCT G TAG ACATCAT G CTAATG AG TACAG
ATTGTATCTCGATG CTTATAACATG ATG
ATCTCAG CTG G CTTTAG CTTGTG G GTTTACAAACAATTTGATACTTATAACCTCTG GAACACTTTTACAAG
ACTTC AG AG TTT
AG AAAATG T G G CTTTTAATGTTGTAAATAAG G G ACACTTTG ATG G ACAACAG G G TG AAG TAC
C AG TTTCTATCATTAATAA
CACTGTTTACACAAAAGTTGATG GTGTTG ATG TAG AATTG TTTG AAAATAAAACAA CATTA C CTG
TTAAT G TAG CATTTG AG
CTTTG G G CTAAG CG CAACATTAAAC CAGTACCAG AG GTGAAAATACTCAATAATTTG G GTGTG
GACATTG CTG CTAATA CT
GTG ATCTG G G ACTACAAAAG AG ATG CTCCAG CACATATATCTACTATTG G TG TTTG TTCTATG AC
TG ACATAG C C AAG AAA
C CAA CTG AAAC G ATTTG T G CAC CACTC ACTG TCTTTTTT G ATG G TAG A G TTG ATG G
TCAA G TAG ACTTATTTAGAAATG CCC
GTAATG G TG TT CTTATTACAG AAG GTAGTGTTAAAG GTTTAC AAC CAT CTGTAG GTCCCAAACAAG
CTAGTCTTAATG GAG
TCACATTAATTG G AG AAG C C G TAAAAACA CAG TT CAATTATTATAAG AAAG TTG ATG G TG
TTG TC CAACAATTAC CTG AAA
CTTACTTTACTC AG AG TAG AAATTTA CAAG AATTTAAAC C C AG G AG T CAAATG G
AAATTGATTTCTTAGAATTAG CTATG GA
TGAATTCATTGAACG GTATAAATTAG AAG G CTATG CCTTCGAACATATCGTTTATG G AG ATTTTAG
TCATA G TCA G TTA G GT
G GTTTACATCTACTGATTG G ACTAG CTAAACGTTTTAAG G AAT CAC CTTTT G AATTAG AAG
ATTTTATT C CTAT G G AC AG TA
CAGTTAAAAACTATTTCATAACAG ATG CG CAAAC AG G TTCAT CTAAG TG T G TG T G TT CT G
TTATTG ATTTATTACTTG AT G A
TTTTG TT G AAATAATAAAATC C C AAG ATTTATCTG TA G TTT CTAAG GTTGTCAAAGTG
ACTATTGACTATACAG AAATTTCAT
TTATG CTTTG GTGTAAAGATG G CCATGTAGAAACATTTTACCCAAAATTACAATCTAGTCAAG CG TG G
CAACCG G GTGTTG
CTATG CCTAATCTTTACAAAATG CAAAG AATG CTATTAG AAAAG TGTG AC CTT CAAAATTATG GT
GATAGTG CAACATTACC
TAAAG G CATAATG ATGAATGTCG CAAAATATACTCAACTGTGTCAATATTTAAACACATTAACATTAG
CTGTACCCTATAAT
ATG A G AG TTATACATTTT G GTG CTG GTTCTGATAAAG G AG TTG C AC CAG GTACAG
CTGTTTTAAGACAGTG GTTG CCTACG
G GTACG CTG CTTG TC G ATT CAG AT CTTAATG ACTTTG TCTCTG ATG CAGATTCAACTTTGATTG
GTG ATTGTG CAACTG TAC
ATACAG CTAATAAATG G G ATCT CATTATTAG TG ATATG TAC G AC C CTAAG ACTAAAAATG
TTACAAAAG AAAATG A CTCTA
AAG AG G GTTTTTTCACTTACATTTGTG G GTTTATACAACAAAAG CTAG CT CTTG GAG G TTCC GTG
G CTATAAAGATAACAG
AACATTCTTGGAATG CTGATCTTTATAAG CTCATG G G ACACTTCG CATG GTG GACAG
CCTTTGTTACTAATGTGAATG CGTC
ATCATCTGAAG CATTTTTAATTG G ATGTAATTATCTTG G CAAA C CA C G CGAACAAATAG ATG
GTTATG TCATG CATG CAAAT
TACATATTTTG G AG G AATACAAATC CAATTCAG TTG T CTT C CTATT CTTTATTT G ACAT G AG
TAAATTTC C C CTTAAATTAAG
G G G TACT G CTGTTATGTCTTTAAAAGAAG GTCAAATCAATGATATGATTTTATCTCTTCTTAGTAAAG G
TAG A CTTATAATT
AG AG AAAACAACAG AG TTG TTATTT CTAG TG ATG TTCTTG TTAACAACTAAA CG AAC AATG
TTTG TTTTTCTT G TTTTATT G C
CACTAG TCTCTATTCAG TG TGTTAATCTTACAAC CAG AA CTCAATTACC CCCTG
CATACACTAATTCTTTCACACGTG GTG TT
TATTAC CCTG AC AAAG TTTTC AG ATC CTCAG TITTACATTCAACTCAG G ACTT G TT CTTAC OTT
CTITTC CAATG TTACTT G G
TTCCATGCTATACATGTCTCTG G G AC CAAT G G TACTAAG AG G TTTG ATAAC C CT G TC CTAC
CATTTAAT G ATG GTGTTTATTT
TG CTTCCACTG AG AAG TCTAA CATAATAAG AG G CT G GATTTTTGGTACTACTTTAG ATTC G AAG
A C C CAG TC C CTACTTATT
GTTAATAACG CTACTAATGTTGTTATTAAAGTCTGTGAATTTCAATTTTGTAATGATCCATTTTTG G
GTGTTTATTACCACAA
AAAC AACAAAA G TT G TAT G GAAAGTG AG TT CAG A G TTTATTCTA G TG CGAATAATTG
CACTTTTG A ATATG TCTCTC AG C CT
TTTCTTATG G A C CTTG AAG G AAAACAG G GTAATTTCAAAAATCTTAG G G
AATTTGTGTTTAAGAATATTGATG GTTATTTTA
AAATATATTCTAAG CACACG CCTATTAATTTAGTG C G TG AT CT C C CTCAG G GTTTTTCG G
CTTTAGAACCATTG G TAG ATTT
G CCAATAG GTATTAACATCACTAG G TTTC AAA CTTTACTT G CTTTACATAG AAG TTATTTG ACT C
CTG GTG ATTCTTCTTCAG
GTTG G AC AG CTG GTG CTG CAG CTTATTATGTG G GTTATCTTCAACCTAG
GACTTTTCTATTAAAATATAATG AAAATG GAAC
CATTACAG ATG CTGTAG ACTGTG CA CTTG ACCCT CTCT CAG AAACAAAG TG TACGTTG AAATCCTT
CACTG TAG AAAAAG G
AATCTATCAAACTT CTAACTTTA G AG T C CAAC CAACA G AATCTATTGTTAG
ATTTCCTAATATTACAAACTTGTG CCCTTTTG
GTG AAGTTTTTAACG C CAC C AG ATTTG CATCTGTTTATG CTTG G AACAG G AAG AG AAT CA G
CAACTGTGTTG CT G ATTATTC
TGTCCTATATAATTCCG CATCATTTTCCACTTTTAAGTGTTATG G A G TG TCTCCTACTAAATTAAATG
ATCTCTG CTTTACTAA
TGTCTATG CAG ATTCATTTG TAATTAG AG GTGATGAAGTCAG ACAAATCG CTCCAG G G CAAACTG G
AAAGATTG CTGATTA
TAATTATAAATTAC CAG AT G ATTTTAC A G G CT G CGTTATAG CTTG GAATTCTAACAATCTTG
ATTCTAAG GTTG GTG GTAAT
TATAATTACCG GTATAGATTGTTTAG GAAGTCTAATCTCAAACCTTTTG AG AG AG ATATTTCAA CTG
AAATCTATCAG G CCG
G TA G CACACCTTGTAATG G TG TT G AAG G TTTTAATTG TTACTTTC CTTTACAATCAT ATG G
TTTC C AAC C CA CTAAT G G TG TT
G GTTAC C AAC CATACAG A G TAG TAG TA CTTTCTTTTG AACTTC TACAT G CAC CAG
CAACTGTTTGTG G AC CTAAAAAG T CTA
CTAATTTG GTTAAAAACAAATGTGTCAATTTCAACTTCAATG GTTTAACAG G CA CAG GT GTT CTTACTG
AG TCTAACAAAAA
GTTTCTG C CTTTC CAA CAATTTG G C AG AG ACATTG CTG ACACTACTGATG CTG TC C G TG
ATC CAC AG ACA CTTG AG ATT CTT
G ACATTA CAC CATGTT CTTTTG GTG GTGTCAGTGTTATAACACCAG GAACAAATACTTCTAACCAG GTTG
CTGTTCTTTATC
130
CA 03168783 2022- 8- 19
WO 2021/176434 PC
T/IB2021/052858
AG G GTGTTAACTG CA CAG AAG TCCCTG TTG CTATTCATG CAGATCAACTTACTCCTACTTG G
CGTGTTTATTCTACAG GTTC
TAATGTTTTTCAAACACGTG CAG G CTGTTTAATAG G G G CTG AA CATGTCAACAA CTCATATG AG
TGTG ACATACCCATTG G
TG CAG GTATATG CG CTAG TTATC AG ACT CAG ACTAATT CTCCTCG G CG G G CACG TAG
TGTAG CTAGTCAATCCATCATTG C
CTACACTATGTCACTTG GTG C AG AAAATTCAG TTG CTTACTCTAATAACTCTATTG CCAT ACC CA C
AAATTTTACTATTAG TG
TTACCACAG AAATT CTACCAG TG TCTATG ACCAAG ACATCAG TAG ATTG TA CAATG TAC ATTTGTG
GTGATTCAACTG AATG
CAG CAATCTTTTGTTG CAATATG G CAGTTTTTGTACACAATTAAACCGTG CTTTAACTG GAATAG CT G
TTG AACAAG ACAAA
AACACCCAAG AAGTTTTTG CACAAGTCAAACAAATTTACAAAACACCACCAATTAAAG ATTTTG GTG
GTITTAATTTTTCAC
AAATATTAC CAG AT CCATC AAAACC AAG CAA G AG G TCATTTATT G AAG ATCTACTTTTCAAC
AAA G T G ACACTT G C AG ATG
CTG G CTTCATCAAACAATATG GTGATTG CCTTG GTG ATATTG CTG CTAG A G ACCTCATTTG TG
CACAAAAGTTTAACG G CCT
TACTGTTTTG CCACCTTTG CTCACAG ATGAAATG ATTG CTCAATACACTTCTG CACTGTTAG
CGGGTACAATCACTTCTG G TT
G GACCTTTG GTG CAG GTG CTG CATTACAAATACCATTTG CTATG CAAATG G CTTATAG GTTTAATG
GTATTG G AG TTACAC
AG AATG TT CTCTATG AG AACCAAAAATTG ATTG CCAACCAATTTAATAGTG CTATTG G C AAAATT
CAAG ACT CACTTTCTTC
CACAG CAAGTG CA CTTG GAAAACTTCAAGATGTG GTCAACCAAAATG CACAAG CTTTAAAC AC G
CTTGTTAAACAACTTAG
CTCCAATTTTG GTG CAATTTC AAGTGTTTTAAATG ATATCCTTTCACG TCTTGACAAAG TTG AG G
CTGAAGTG CAAATTG AT
AG G TTG AT CACAG G CAG A CTTCAAAG TTTG CAG ACATAT G TG A CTCAAC AATTAATTAG AG
CTG CAG AAATCA G AG CTT CT
G CTAATCTTG CT G CTACTAAAAT G TCA G AG TG TG TACTTG G ACAATCAAAAAG AG TTG
ATTTTT G TG GAAAG G G CTATCAT
CTTATG T CCTTC CCTC AG TCA G CACCTCATG G TG TAG T CTTC TTG CATGTG
ACTTATGTCCCTG CACAAGAAAAGAACTTCAC
AACTG CTCCTG C CATTTG T C ATG AT G GAAAAG CA CACTTTCCTC G TG AAG
GTGTCTTTGTTTCAAATG G CACACACTG GTTT
GTAACACAAAG GAATTTTTATG AACCACAAATCATTACTACAG ACAACACATTTGTGTCTG GTAACTGTG
ATGTTGTAATAG
GAATTGTCAACAACACAGTTTATGATCCTTTG CAACCTGAATTAG ACTCATT CAA G GAG G AG TTAG
ATAAATATTTTAAG AA
TCATACATCACCAG ATGTTGATTTAG G TG A CATCT CTG G CATTAATG
CTTCAGTTGTAAACATTCAAAAAGAAATTG ACC G C
CTC AATG AG G TT G CCAA G AATTTAAAT G AATCTCTCATC G AT CTCCAAG AACTTG G AAAG
TATG AG CAGTATATAAAATG G
CCATG GTACATTTG G CTAG GTTTTATAG CTG G CTTG ATTG CCATAGTAATG GT G ACAATTATG
CTTTG CTGTATG ACCAG TT
G CT G TAG TTG T CTCAA G G G CTG TT G TT CTTG TG GATCCTG CTG CAAATTTG AT G AA
G AC G ACT CTG AG CCAG TG CT CAAAG
G AG TC AAATTA CATTA CACATAAAC G AA CTTAT G G ATTTG TTTAT G AG AATCTT CACAATTG
G AACTG TAACTTTG AA G CAA
G GT G AAAT CAAG G ATG CTACTCCTTCAGATTTTGTTCG CG CTACTG CAACGATACCGATACAAG
CCTCACTCCCTTTCG GAT
G GCTTATTGTTG G C GTTG CACTTCTTG CTGTTTTTCATAG CG CTTCCAAAATCATAACCCTCAAAA AG
AG ATG G CAACT AG C
ACT CTC CAAG G GTGTTCACTTTGTTTG CAACTTG CTGTTGTTG TTTG TAAC AG TTTACTCACAC
CTTTTG CTCGTTG CTG CTG
G CCTTGAAG CCCCTTTTCTCTATCTTTATG CTTTAGTCTACTTCTTG CAG A G TATAAACTTTG TAAG
AATAATAATG AG G CTT
TG G CTTTG CTG G AAATG CC GTTCCAAAAACCCATTACTTTATG ATG CCAACTATTTTCTTTG CTG G
CATACT AATTG TTAC G A
CTATTGTATACCTTACAATAGTGTAACTTCTTCAATTGTCATTACTTCAG GTGATG G CACAAC AA G
TCCTATTT CTG AA CATG
ACTA CCAG ATTG GTG GTTATACTGAAAAATG G GAATCTG G AG TAAAAG ACTGTG TTG TATTA
CACAG TTACTTCACTTCAG
ACTATTACC AG CTG TACT CAACT CAATT G AGTACAG AC ACTG G TG TTG AAC AT G
TTACCTTCTT CATCTACAATAAAATT GTT
G AT G AG C CTG AAG AACATG TC CAAATT CACA CAATC G AC G G TT CATCC G G AG TTG
TTAATCC AG TAATG G AA C CAATTTAT
GATGAACCGACG ACGACTACTAG CGTG CCTTTG TAAG CACAAG CTG ATG AG TACG
AACTTATGTACTCATTCG TTTC G G AA
GAG ACAG GTACGTTAATAGTTAATAG CGTACTTCTTTTTCTTG CTTTCGTG GTATTCTTG
CTAGTTACACTAG CC ATCCTTAC
TG CG CTTCGATTGTGTG CGTACTG CTG CAATATTGTTAACGTG
AGTCTTGTAAAACCTTCTTTTTACGTTTACTCTCGTGTTA
AAAAT CTG AATTCTTCTA G AG TTCCTG ATCTTCTG GTCTAAACG AA CTAAATATTATATTAG TTTTTC
TG TTTG G AACTTTAAT
TTTAG CC ATG G TAG ATTCCAACG GTACTATTACCGTTG AAG AG CTTAAAAAG CTCCTTG AACAATG
G AA CCTAG TAATAG G
TTTCCTATTCCTTACATG GATTTGTCTTCTACAATTTG CCTATG CCAACAG G AATAG
GTTTTTGTATATAATTAAGTTAATTTT
TCTCTG G CTGTTATG G CCAGTAACTTTAG CTTGTTTTGTG CTG CTG CTG TTTAC AG AATAAATTG G
ATC ACC G GTG G AATT
G CTATCG CAATG G CTTGTCTTG TAG G CTTGATGTG G CTCAG CTACTTCATTG
CTTCTTTCAGACTGTTTG CG CGTACG CG TT
CCATGTG GTCATTCAATCCAG AAACTAACATTCTTCTCAACGTG CCACTCCATG G CACTATTCTG ACCAG
ACC G CTTCTAG A
AAGTGAACTCGTAATCG GAG CTGTG ATCCTTCGTG G AC ATCTTCGTATTG CTGG ACACCATCTAG GACG
CTGTGACATCAA
G GACCTG CCTAAAGAAATCACTGTTG CTACATCACGAACG CTTTCTTATTACAAATTGG G AG CTTCG C
AG CGTGTAG CAG G
TGACTCAG GTTTTG CTG CATACAGTCG CTACAG GATTG G CAACTATAAATTAAACACAG ACCATTCCAG
TAG CAGTG ACAA
TATTG CTTTG CTTG TACAG TAAGTGACAAC AG ATGITT CATCT CGTTG ACTTTCAG
GTTACTATAGCAG AG AT ATTACTAATT
ATTATG AG GACTTTTAAAGTTTCCATTTG GAATCTTG ATTACATCATAAACCT CATA
ATTAAAAATTTATCTAAGTCA CTAA C
TG A G AATAAATATT CTCAATTAG ATG AA G AG CAACCAATG GAG ATTG ATTAAAC G AA C ATG
AAAATTATTCTTTTCTTG G C
ACTG ATAACACTCG CTA CTTG TG AG CTTTATCAC TACC AAG AG TG TG TTAG AG G TACAA CAG
TA CTTTTAAAAG AACCTT G C
TCTTCTG G AACATAC G AG G G CAATTCACCATTTCATCCTCTAG CT G ATAA CAAATTTG CA CTG
ACTTG CTTTAG CACTCAATT
TG CTTTTG CTTG TC CTG AC G G CGTAAAACACGTCTATCAGTTACGTG CCAG ATC AG
TTTCACCTAAACTGTT CATCAG ACAA
GAG G AA G TTCAA G AACTTTACTCTCCAATTTTTCTTATTGTTG CG G CAATAG TGTTTATAACACTTTG
CTTCACACTCAAAAG
AAAG ACAGAATGATTGAACTTTCATTAATTGACTTCTATTTGTG CTTTTTAG CCTTTCTG
CTATTCCTTGTTTTAATTATGCTT
ATTATCTTTTG GTTCTCACTTGAACTG C AAG ATC ATAAT G AAACTTG T CAC G
CCTAAACGAACATGAAATTTCTTGTTTTCTT
131
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
AG G AATCATCACAACTGTAG CTG
CATTTCACCAAGAATGTAGTTTACAGTCATGTACTCAACATCAACCATATGTAGTTGAT
GACCCGTGTCCTATTCACTTCTATTCTAAATG GTATATTAG AGTAG GAG CTAGAAAATCAG
CACCTTTAATTGAATTGTG CG
TGGATGAGGCTGGTTCTAAATCACCCATTCAGTACATCGATATCGGTAATTATACAGTTTCCTGTTTACCTTTTACAAT
TAAT
TG CCAG G AACCTAAATTG G GTAGTCTTGTAGTG
CGTTGTTCGTTCTATGAAGACTTTTTAGAGTATCATGACGTTCGTGTTG
TTTTAGATTTCATCTAAACGAACAAACTATAATGTCTGATAATGGACCCCAAAATCAGCGAAATGCACCCCGCATTACG
TTT
GGTGGACCCTCAGATTCAACTGGCAGTAACCAGAATGGAGAACGCAGTGGGGCGCGATCAAAACAACGTCGGCCCCAAG
GTTTACCCAATAATACTG CGTCTTG GTTCACCG CTCTCACTCAACATG G CAAG G
AAGACCTTAAATTCCCTCG AG G ACAAG
G CGTTCCAATTAACACCAATAG CAGTCCAGATG ACCAAATTG G CTACTACCGAAGAG CTACCAG
ACGAATTCGTG GTG GT
GACG GTAAAATGAAAGATCTCAGTCCAAGATG GTATTTCTACTACCTAG G AACTG G G CCAG AAG CTG G
ACTTCCCTATG GT
G CTAACAAAG ACG G CATCATATG G GTTG CAACTGAG G GAG CCTTGAATACACCAAAAGATCACATTG
G CACCCGCAATCC
TG CTAACAATG CTG CAATCGTG CTACAACTTCCTCAAG GAACAACATTG CCAAAAG G CTTCTACG
CAGAAG G GAG CAGAG
GCGGCAGTCAAGCCTCTTCTCGTTCCTCATCACGTAGTCGCAACAGTTCAAGAAATTCAACTCCAGGCAGCAGTAGGGG
AA
TTTCTCCTGCTAGAATGGCTGGCAATGGCGGTGATG CTGCTCTTGCTTTGCTGCTG CTTG ACAG ATTG
AACCAG CTTG AGA
GCAAAATGTCTGGTAAAGGCCAACAACAACAAGGCCAAACTGTCACTAAGAAATCTGCTGCTGAGGCTTCTAAGAAGCC
T
CGGCAAAAACGTACTGCCACTAAAGCATACAATGTAACACAAGCTTTCGGCAGACGTGGTCCAGAACAAACCCAAGG
AAATTTTGGGGACCAGGAACTAATCAGACAAGGAACTGATTACAAACATTGGCCGCAAATTGCACAATTTGCCCCCAGC
G
CTTCAGCGTTCTTCGGAATGTCGCGCATTGGCATGGAAGTCACACCTTCGGGAACGTGGTTGACCTACACAGGTGCCAT
CA
AATTGGATGACAAAGATCCAAATTTCAAAGATCAAGICATTTTGCTGAATAAGCATATTGACGCATACAAAACATTTCC
ACC
AACAG AG CCTAAAAAG G ACAAAAAGAAGAAG G CTGATG AAACTCAAG CCTTACCG
CAGAGACAGAAGAAACAG CAAACT
GTG ACTCTTCTTCCTG CTG CAGATTTG G ATGATTTCTCCAAACAATTG CAACAATCCATG AG
CAGTGCTGACTCAACTCAG G
CCTAAACTCATG CAGACCACACAAG G CAG ATG G G CTATATAAACGTTTTCG
CTTTTCCGTTTACGATATATAGTCTACTCTT
GTGCAGAATGAATTCTCGTAACTACATAGCACAAGTAGATGTAGTTAACTTTAATCTCACATAGCAATCTTTAATCAGT
GTG
TAACATTAG G GAG GACTTGAAAG AG CCACCACATTTTCACCG AG G CCACG CG
GAGTACGATCGAGTGTACAGTG AACAAT
GCTAGGGAGAGCTGCCTATATGGAAGAGCCCTAATGTGTAAAATTAATTTTAGTAGTGCTATCC
SEQ ID NO: 25
>Q0V21856.1: S surface protein
M FVF LVLLP LVSI QCVN LTTRTQLP PAYTNSFTRGVYYP D KVF RSSVL HSTQD LF LP F FS
NVTWF HAI HVSGTNGTKRFDN PVLPF
N DGVYFASTE KSN I I RGWI FGTTLDSKTQSLLIVN NATNVVI KVCE FQFCN DPFLGVYYH KN N
KSCM ESE F RVYSSAN NCTF EYVS
QPF LM DLEG KQG N FKN LREFVFKN I DGYFKIYSKHTPI N LVRDLPQG FSALE PLVD LP IG I N
ITRFQTLLALH RSYLTPG DSSSGWT
AGAAAYYVGYLQP RTF LLKYN E NGTITDAVDCALDPLSETKCTLKSFTVEKG IYQTSNFRVQPTESIVRF PN
ITN LCP FG EVFNATR
FASVYAWN R KRISNCVADYSVLYNSASFSTFKCYGVSPTKLN D LC FTNVYADSFVI RG DEVRQIAPGQTG
KIADYNYKLPDDFTG
CVIAWNSN N L DS KVGG NYNYRYRLFRKSN LKP FERDISTE IYQAGSTPCNGVEG F NCYFP LQSYG
FQPTNGVGYQPYRVVVLSF
ELLHAPATVCG PKKSTN LVKN KCVN FN F NG LTGTGVLTESN KKF LP FQQFG
RDIADTTDAVRDPQTLEILDITPCSFGGVSVITPG
TNTSNQVAVLYQGVNCTEVPVAI HADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVN NSYECD I P I GAG
ICASYQTQTNSP RRAR
SVASQSII AYTMSLGAE NSVAYSN NSIAI PTN FTISVTTE I L PVSMTKTSVDCT MY ICG DSTECSN
L LLQYGSFCTQLN RALTG IAVE
QDKNTQEVFAQVKQIYKTPPIKDFGG F N FSQI L P D PSKPSKRSF I EDLLFN KVTLADAG F I KQYG
DC LG DIAARD ICAQKF NG LTV
LP PL LTDE M IAQYTSALLAGTITSGWTFGAGAALQI PFAM QMAYR F NG I GVTQNVLYE NQKLIAN
QF NSAI G KIQDSLSSTASAL
G KLQDVVNQNAQALNTLVKQLSSN FGAISSVLN DI LS RL DKVEAEVQI DRLITG RLQSLQTYVTQQLI
RAAE1RASAN LAATKMSE
CVLGQSKRVDFCG KGYH L MS F PQSAP HGVVF LHVTYVPAQEKN FTTAPAI CH DG KAH F PR EG
VFVSNGTHWFVTQR N FYE PQ
IITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKN
LNESLIDL
QELG KYEQYIKWPWYIWLG FIAG LIAIVMVTI M LCC MTSCCSCL KG CCSCGSCCKF DE
DDSEPVLKGVKLHYT
SEQ ID NO: 26
>MW306426.1 Severe acute respiratory syndrome coronavirus 2 isolate SARS-CoV-
2/hunnan/USA/CA-CZB-
12872/2020, complete genome. [Severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2)]. Californian
3.1.429 lineage
ACTTTCGATCTCTTGTAG ATCTGTTCTCTAAACGAACTTTAAAATCTGTGTG G CTGTCACTCG
GCTGCATGCTTAGTGCACTC
ACG CAGTATAATTAATAACTAATTACTGTCGTTGACAG GACACGAGTAACTCGTCTATCTTCTG CAG G CTG
CTTACG GTTTC
GTCCGTGTTG CAG CCGATCATCAG CACATCTAG GTTTTGTCCG G GTGTG ACCGAAAG GTAAGATG GAG
AG CCTTGTCCCT
G GTTTCAACGAG AAAACACACGTCCAACTCAGTTTG CCTGTTTTACAG GTTCG CGACGTG CTCGTACGTG G
CTTTG GAG AC
TCCGTG G AG GAG GTCTTATCAGAG G CACGTCAACATCTTAAAGATG G CACTTGTG G CTTAG
TAGAAGTTGAAAAAG G CGT
TTTG CCTCAACTTGAACAG CCCTATGTGTTCATCAAACGTTCG G ATG CTCGAACTG CACCTCATG
GTCATGTTATG GTTGAG
CTGGTAGCAGAACTCGAAGGCATTCAGTACGGTCGTAGTGGTGAGACACTTGGTGTCCTTGTCCCTCATGTGGGCGAAA
T
ACCAGTGGCTTACCGCAAGGTTCTTCTTCGTAAGAACGGTAATAAAGGAGCTGGTGGCCATAGTTACGGCG
CCGATCTAA
132
CA 03168783 2022- 8- 19
WO 2021/176434 PC
T/IB2021/052858
AGTCATTTGACTTAG G CGACG AG CTTG G CACTGATCCTTATGAAGATTTTCAAG AAAACTG G AA
CACTAAACATAG CAGTG
GTGTTACCCGTGAACTCATG CGTG AG CTTAACG GAG G G G CATACACTCG CTATGTCG ATAA CAA
CTTCTGTG G CCCTG ATG
G CTACCCTCTTG AG TG CATTAAAGACCTTCTAG CAC G TG CTG GTAAAG CTTCATG CACTTTG T CC
G AACAACT G GACTTTAT
TG ACACTAAG AG G G GTGTATACTG CTG CC GTG AACATG AG CATGAAATTG CTTG GTACACG
GAACGTTCTGAAAAG AG CT
ATG AATTG CAG AC ACCTTTTG AAATTAAATTG G CAAAGAAATTTGACATCTTCAATG G G G AATG
TCCAA ATTTTG TATTTCC
CTTAAATTCCATAATCAAG ACTATTCAACCAAG G GTTGAAAAG AAAAAG CTTG ATG G CTTTATG G
GTAGAATTCGATCTGT
CTATCCAGTTG CGTCACCAAATGAATG CAACCAAATGTG CCTTTCAACTCTCATGAAGTGTG ATCATTGTG
GTG AAACTTCA
TG G CAG AC GGGCG ATTTTG TTAAAG CCACTTG CGAATTTTGTG G CACTG AG AATTTG ACTAAAG
AAG GTGCCACTACTTGT
G GTTACTTACCCCAAAATG CTGTTGTTAAAATTTATTGTCCAG C ATG TC ACAATT CAG AA G TAG G
ACCT G AG CATAGTCTTG
CCG AATACCATAATGAATCTG G CTTG AAAACCATTCTTCGTAAG C GTG GTCG CA CTATTG CCTTTG
GAG G CTGTGTGTTCTC
TTATGTTG GTTG CCATAACAAGTGTG CCTATTG G GTTCCACGTG CTAG CG CTAACATAG GTTG
TAACCATACAG GTGTTG TT
G G AG AAG GTTCCGAAG G TCTTAATG AC AACCTTCTTG AAATACTCCAAAAAG AG
AAAGTCAACATCAATATTGTTG G TG AC
TTTAAACTTAATG AAG AG ATCG CCATTATTTTG GCATCTTTTTCTG CTTCCACAAGTG CTTTTGTG
GAAACTGTG AAAG GTTT
G GATTATAAAG CATTCAAACAAATTGTTGAATCCTGTG GTAATTTTAAAG TTACAAAAGG AAAAG
CTAAAAAAG GTG CCTG
GAATATTG GTG AACAG AAATCAATACTGAGTCCTCTTTATG CATTTG CATCAG AG G CTG CTCG T G
TT GTAC G ATC AATTTTC
TCCCG CACTCTTGAAACTG CTCAAAATTCTGTG CGTGTTTTACAGAAG G CCG CTATAACAATACTAGATG G
AATTTCACAGT
ATTCACTG AG ACT CATTG ATG CTATG ATG TT CACAT CTG ATTTG G
CTACTAACAATCTAGTTGTAATG G CCTACATTACAG G
TG G TG TTG TT CAG TT G ACTTC G C AG TG G CTAACTAACATCTTTG G
CACTGTTTATGAAAAACTCAAACCCGTCCTTGATTG G
CTT G AAG A G AAG TTTAA G GAAG G TG TAG AG TTT CTTAG AG AC G G TTG G G
AAATTGTTAAATTTATCTCAACCTGTG CTTGT
GAAATTGTCG GTG GACAAATTGTCACCTGTG CAAAGGAAATTAAG GAG AG TG TTCAG AC ATT
CTTTAAG CTTGTAAATAAA
TTTTTG G CTTTGTGTG CTGACTCTATCATTATTG GTG GAG CTAAACTTAAAG CCTTGAATTTAG GTG
AAACATTTGTTACG C
ACTCAAAG G GATTGTACAGAAAGTGTGTTAAATCCAG AG AAG AAACTG G CCTACTCATG CCTCTAAAAG
CCCCAAAAG AA
ATTATCTTCTTAG AG G G AG AAACACTTC CCACAG AAG TG TTAACAG AG G AAG TT G TCTTG
AAAACTG GTGATTTACAACCA
TTAGAACAACCTACTAGTGAAG CTGTTGAAG CTCCACTG GTTG GTACACCAGTTTGTATTAACG G G
CTTATGTTG CTC G AA
ATCAAAGACACAGAAAAGTACTGTG CCCTTG CACCTAATATGATG G TAACAAA CAATAC CTTC ACA CT
CAAAG G CG GTG CA
CCAACAAAG GTTACTTTTG GTG ATG A CACTG TG ATAG AAG TG CAAG GTTACAAG AG TG TG
AATATCACTTTT G AACTTG AT
GAAAG G ATT G ATAAAG TACTTAAT G AG AAG TG CT CTG C CTATA CAG TT G AACT CG G
TACAG AA GTAAAT G AG TTC G CCTGT
G TT G TG G CAGATG CT G TCATAAAAACTTTG CAACCAGTATCTGAATTACTTACACCACTG G
GCATTGATTTAG ATG AG TG G
AG TATG G CTACATACTACTTATTTG ATG AG TCTG GTG A G TTTAAATTG G CTTCA CATAT G
TATTG TT CTTTTTAC CCTCC AG A
TG A G G AT G AAG AA G AA G GTGATTGTGAAG AAG AAG AG TTT G AG C CATC AA
CTCAATATG AG TATG GTACTGAAG ATG AT
TACCAAG GTAAACCTTTG GAATTTG GTG CCACTTCTG CTG CT CTTCAAC CTG AAGAAG AG CAAG AA
G AA G ATTG G TTAG AT
G AT G ATAG TCAACAAACTG TTG G TCAACAAG AC G G CAG T G AG G A CAATC AG ACAA
CTACTATTCAAACAATT G TTG AG GT
TCAACCTCAATTAG AG ATG G AACTTACAC CAG TTG TT CAG ACTATT G AAG T G AATA G
TTTTAG T G GTTATTTAAAACTTACT
G AC AATG TATACATTAAAAATG CAG ACATTGTG G AAGAAG CTAAAAAG GTAAAACCAACAGTG G TT
G TTAATG CAG CCAA
TGTTTACCTTAAACATG GAG G AG G TG TT G CAG GAG CCTTAAATAAG G CTACTAACAATG CCATG
CAA G TT G AATCTG AT G A
TTACATAG CTACTAATG G ACCACTTAAAGTG G GTG G TAG TTG TG TTTTAAG CG GACACAATCTTG
CTAAACACTGTCTTCAT
GTTGTCG G CC CAAATGTTAACAAAG GTG AAG AC ATTC AA CTTCTTAAG AGTG
CTTATGAAAATTTTAATCAG CACG AAG TT
CTACTTG CACCATTATTATCAG CTG GTATTTTTG GTG CTG ACCCTATACATTCTTTAAG AG TTTGTG
TAG ATACTG TTC G CAC
AAATGTCTACTTAG CTGTCTTTGATAAAAATCTCTATG ACAAACTTGTTTCAAG CTTTTTG G AAAT G AAG
AG T G AAAA G CAA
GTTGAACAAAAGATCG CTG AG ATTCCTAAAG AG GAAGTTAAG CCATTTATAACTG AAAGTAAACCTT CAG
TTG AAC AG AG
AAAAC AAG AT G ATAAG AAAATCAAAG CTTG TG TT G AAG AAGTTACAACAACTCTG GAAG
AAACTAAG TT CCTC ACAG AAA
ACTT G TTACTTTATATTG AC ATTAAT G G CAATCTTCATCCAG ATTCTG CCACTCTTGTTAGTG ACATT
G AC AT CACTTTCTTAA
AG AAAG ATG CTCCATATATAGTG G GTG ATGTTGTTCAAG AG G GTGTTTTAACTG CT G TG
GTTATACCTACTAAAAAG G CTG
GTG G CACTACTG AAATG CTAG CGAAAG CTTTG AG AAAAGTG
CCAACAGACAATTATATAACCACTTACCCG G GTC AG G GT
TTAAATG G TTAC ACTG TAG A G GAG G CAAAG ACAGTG CTTAAAAAGTGTAAAAGTG
CCTTTTACATTCTACCATCTATTATCT
CTAATG AG AAG CAA G AAATTCTT G GAACTGTTTCTTG GAATTTG C G AG AAATG CTTG CAC AT
G CAG AAG AAA CAC G CAAA
TTAATG CCTGTCTGTGTG G AAACTAAAG CCATAG TTTCAACTATAC AG CGTAAATATAAG G
GTATTAAAATACAAG AG G GT
GTG G TT G ATTATG GTG CTA G ATTTTA CTTTTA CA C CA G TAAAA CAA CTG TA G C G TCA
CTTATC AA CACA CTTAA C G AT CTAA
ATG AAACTCTTGTTACAATG CC ACTT G G CTATGTAACACATG G CTTAAATTTG GAAG AAG CTG
CTCG GTATATG AG AT CTCT
CAAAGTG CCAG CTAC AG TTTCTG TTTCTTCACCTG ATG CTGTTACAG CGTATAATG G
TTATCTTACTTCTT CTTCTAAAAC AC
CTG AAGAACATTTTATTGAAACCATCTCACTTG CTG GTTCCTATAAAGATTG GTCCTATTCTG G AC
AATCTA CACAACTAG G
TATAG AATTTCTTAAG AG AG G TG ATAAAAG T G TATATTAC ACTAG TAATCCTACC ACATT
CCACCTAG AT G GTG AAGTTATC
ACCTTT G A CAAT CTTAA G ACACTTCTTTCTTTG AG AG AAG TG AG GACTATTAAG G TG
TTTACAACA G TAG ACAACATTAACC
TCCACACG CAAGTTGTG G ACATG TC AATG A CATAT G G AC AACAG TTTG G TCC AACTTATTT G
G AT G GAG CTGATGTTACTA
AAATAAAACCTCATAATTCACATG AAG GTAAAACATTTTATGTTTTACCTAATGATGACACTCTACGTGTTG AG
G CTTTTG A
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G TA CTAC C ACACAA CTG ATC CTAG TTTT CTG G G TAG GTACATGTCAG
CATTAAATCACACTAAAAAGTG G AAATACCCACA
AG TTAATG GTTTAACTTCTATTAAATG G G CAGATAACAACTGTTATCTTG C C ACT G CATTG TTAAC
A CTC C AACAAATAG AG
TTG AAG TTTAAT C CAC CTG CT CTACAA G ATG CTTATTACAG AG CAAG G G CTG G TG AA G
CTG CTAACTTTTGTG CACTTATCT
TAG CCTACTGTAATAAG ACAG TAG G T G AG TTAG GTG ATG TTAG A G AAACAATG AG TTACTT
G TTTCAACATG CCAATTTAG
ATTCTTG CAAAAG AG TCTTG AA C G TG GTGTGTAAAACTTGTG G AC AAC AG CAG
ACAACCCTTAAG G G TG TA G AA G CT G TT
ATGTACATG G G CACACTTTCTTATG AACAATTTAAG AAAG GTGTTCAG ATACCTTGTACGTGTG
GTAAACAAG CTACAAAA
TAT CTAG TACAACA G G AG TCAC CTTTT G TTATG AT G TCA G CAC C AC CTG CT CAG TATG
AACTTAAG CATG GTACATTTACTT
GTG CTAG TG AG TACACTG GTAATTACCAGTGTG
GTCACTATAAACATATAACTTCTAAAGAAACTTTGTATTG CATAGACG
GTG CTTTACTTACAAAGTCCTCAG AATACAAAG GTCCTATTACG G ATGTTTT CTAC AAAG AAAACAG
TTACACAAC AAC CAT
AAAACCAGTTACTTATAAATTG G AT G G TG TTG TTT G TAC AG AAATTG A C CCTAAG TT G G
ACAATTATTATAAG AAA G A CAA
TTCTTATTTCAC AG AG CAACCAATTG AT CTT G TAC CAAAC C AAC CATATC CAAAC G CAAG
CTTC G ATAATTTTAAG TTT G TA
TGTGATAATATCAAATTTG CT G ATG ATTTAAAC CAG TTAA CTG G TTATAAG AAA C CTG CTTC
AAG AG AG CTTAAAG TTAC AT
TTTTC C CT G ACTTAAATG GTGATGTG GTG G CTATTG ATTATAAAC ACTAC AC AC C CT
CTTTTAAG AAAG G AG CTAAATT G TT
ACATAAACCTATTGTTTG G CATGTTAACAATG CAACTAATAAAG C CAC G TATAAA C CAAATAC CTG
GTGTATACGTTGTCTT
TG G AG CA CAAAACCAGTTG AAAC ATCAAATTCG TTTG ATGTACTG AAGTCAG AG G ACG CG CAG
G GAATG G ATAATCTTG C
CTG CGAAG ATCTAAAACCAGTCTCTG AAGAAGTAGTG GAAAATCCTACCATACAG AAAGACGTTCTTG
AGTGTAATGTG A
AAACTACCG AAG TTG TAG G AG ACATTATA CTTAAAC CAG CAAATAATAGTTTAAAAATTACAG AAG
AG GTTG GCCACACA
G AT CTAAT G G CT G CTTATG TAG ACAATTCTAG TCTTACTATTAAG AAACCTAATG AATTATCTAG
AGTATTAG GTTTGAAAA
CCCTTG CTACTCATG GTTTAG CTG CTGTTAATAGTGTCCCTTG G G ATACTATAG CTAATTATGCTAAG
CCTITTCTTAACAAA
GTTGTTAGTACAACTACTAACATAGTTACACG GTG TTTAAACCG TG TTTG TACTAATTATATG
CCTTATTTCTTTACTTTATTG
CTAC AATTG TG TACTTTTACTAG AA G TACAAATTCTAG AATTAAAG CATCTATG C CGACTACTATAG
CAAAGAATACTGTTA
AG AG TGTCG GTAAATTTTGTCTAG AG G CTTCATTTAATTATTTGAAGTCACCTAATTTTTCTAAACTG
ATAAATATTATAATT
TG GTTTTTACTATTAAGTGTTTG CCTAG GTTCTTTAATCTACTCAACCG CT G CTTTAG
GTGTTTTAATGTCTAATTTAG G CAT
G C CTTCTTACTG TACT G GTTACAG AG AAG G CTATTTG AACTCTACTAATGTCACTATTG CAAC
CTACTG TA CTG GTTCTATAC
CTT G TAG TG TTTGT CTTAG TG G TTTAG ATT CTTTAG ACA C CTAT C CTT CTTTAG
AAACTATA C AAATTAC CATTTC AT CTTTTA
AATG G GATTTAACTG CTTTTG G CTTAGTTG CAG AG TG GTTTTTG G CATATATTCTTTTCACTAG G
TTTTTCTATG TA CTTG GA
TTG G CTG CAATCATG CAATTGTTTTTCAG CTATTTTG CAGTACATTTTATTAGTAATTCTTG G
CTTATGTG GTTAATAATTAAT
CTTGTACAAATG G CCCCG ATTTCAG CTATG GTTAG AATGTACATCTTCTTTG CATCATTTTATTATGTATG
GAAAAGTTATGT
G C AT G TT G TAG AC G G TTG TAATTC AT CAACTTG TATG AT G TG TTACAAAC G TAATA G
AG CAAC AAG AG TC G AATGTACAAC
TATTGTTAATG GTGTTAGAAG GTCCTTTTATGTCTATG CTAATG G AG GTAAAG G CTTTTG
CAAACTACACAATTG GAATTGT
GTTAATTGTGATACATTCTGTG CTG G TAG TACATTTATTAG TG ATGAAGTTG CG AG AG ACTTG
TCACT ACAG TTTAA AAG AC
CAATAAATCCTACTG AC CAG TCTT CITA CATC G TTG ATAG T G TTACAG TG AAG AATG
GTTCCATCCATCTTTACTTTGATAAA
G CT G G TC AAAAG A CTTAT G AAAG ACATT CTCTCTCTC ATTTT G TTAACTTA G ACAAC CTG
A G AG CTAATAACACTAAAG G TT
CATTG CCTATTAATGTTATAGTTTTTGATG GTAAATCAAAATGTGAAGAATCATCTG CAAAATCAG
CGTCTGTTTACTACAG
TCAG CTTATGTGTCAACCTATACTGTTACTAG ATCAG G CATTAG TGTCT G AT GTTG GTG ATAGTG CG
GAAGTTG CAGTTAA
AATGTTTGATG CTTACGTTAATACGTTTTCATCAACTTTTAACGTACCAATG G AAAAA CTCAAAACACTAG TT
G CAACTG CA
GAAG CTGAACTTG CAAAG AATGTGTCCTTAG AC AATG TCTTATCTACTTTTATTTCAG CAG CTCG G
CAAG G GTTTGTTG ATT
CAG ATG TAG AAACTAAAG ATG TTG TT G AAT G TCTTAAATTG T CACATC AATCT G AC ATAG
AAG TTACTG G CG ATA G TTG TA
ATAACTATATG CTC AC CTATAACAAAG TTG AAAACATG AC ACCCCG TG AC CTTG GTG CTTGTATTG
ACTGTAGTG CG CGTCA
TATTAATG CG CAG GTAG CAAAAAGTCACAACATTG CTTTGATATG
GAACGTTAAAGATTTCATGTCATTGTCTGAACAACTA
CG AAAACAAATAC G TAG TG CTG CTAAAAA G AATAACTTAC CTTTTAAG TTG AC ATG T G
CAACTACTA G A CAA GTT G TTAAT
GTTGTAACAACAAAG ATAG CACTTAAG G GTG GTAAAATTGTTAATAATTG GTTGAAG
CAGTTAATTAAAGTTACACTTGTG
TTCCTTTTTGTTG CT G CTATTTTCTATTTAATAACAC CTG TTCAT G TCATG TCTAAAC ATACTG
ACTTTTC AAG TG AAATCATA
G GATACAAG G CTATTG ATG GTG GTGTCACTCGTGACATAG CATCTACAGATACTTGTTTTG
CTAACAAACATG CTGATTTTG
ACACATG GTTTAG CCAG CGTG GTG G TAG TTATA CTAATG ACAAAG CTTG CCCATTGATTG CTG
CAGTCATAACAAG AG AAG
TG G GTTTTGTCGTG CCTG GTTTG CCTG G CACGATATTACG CAC AACTAATG GTGACTTTTTG CATTT
CTTAC CTAG AG TTTTT
AG T G CAGTTG G TAATAT CTG TTA CAC AC CATC AAAACTTATAG A G TAC ACTG ACTTTG
CAACATCAG CTTGTGTTTTG G CTG
CTG AAT G TA C AATTTTTAA A G ATG CTTCTG GTAAG C CA G TA C CATATTG TTAT G ATA C
CAATG TA CT A G AA G GTTCTGTTG C
TTATGAAAGTTTACG C C CTG A CACAC G TTAT G TG CTCATG G AT G G CT CTATTATT C
AATTT C CTAACACCTAC CTT G AAG G TT
CTGTTAG AG TG GTAACAACTTTTGATTCTG AG TACTG TAG G CACG G CACTT G TG AAA G AT
CAG AAG CTG G TG TTTG T G TAT
CTACTAGTG G TAG ATG G G TACTTAAC AATG ATTATTAC AG ATCTTTAC CAG G AG TITT CTG T
G G TG TAG ATG CT G TAAATTT
ACTTACTAATATG TTTAC AC CACTAATT CAAC CTATTG GTG CTTTG G AC ATATCA G C AT CTATA
G TAG CTG GTG G TATTG TA
G CTATCG TAG TAAC ATG CCTTG CCTACTATTTTATG AG GTTTAGAAG AG CTTTTG GTG AATAC AG
TC ATG TAG TTG CCTTTA
ATACTTTACTATTCCTTATGTCATTCACTGTACTCTGTTTAACACCAGTTTACTCATTCTTACCTG
GTGTTTATTCTGTTATTTA
CTT G TACTTG AC ATTTTATCTTACTAATG ATG TTTCTTTTTTA G CAC ATATT CAG T G G AT G G
TTATG TTCAC AC CTTTAG TAC C
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TTTCTG GATAACAATTG CTTATATCATTTG TATTTC CAC AAAG CATTTCTATTG GTT CTTT AG
TAATTAC CTAAAG AG ACG TG
TAG TCTTTAATG GTGTTTCCTTTAGTACTTTTGAAG AAG CT G CG CTGTG CAC CTTTTT G
TTAAATAAAG AAATGTATCTAAAG
HG C G TA G TG ATGTG CTATTACCTCTTACG CAATATAATAGATACTTAG CT CTTTATAATAAGTACAAG
TATTTTAG TG GAG
CAATG GATACAACTAG CTACAG AG AAG CTG CTTG TT G TCATCTC G CAAAG G CT CTCAAT G
ACTTCAG TAACTC AG GTTCTG
ATG TTCTTTAC CAAC CA C CACAAAC CTCTATC AC CT C AG CT GTTTT G CAG AG TG GTTTTAG
AAAAATG G CATTCCCATCTG GT
AAAG TTG AG G GTTGTATG GTACAAGTAACTTGTG G TAC AACTAC ACTT AAC G GTCTTTG G CTTG
AT G ACG TAG TTTACTG T
C CAA G ACAT G TG ATCTG CAC CT CTG AAG ACAT G CTTAAC C CTAATTATG AA G ATTTACTC
ATTC G TAAG TCTAATCATAATTT
CTTG G TAC AG G CTGGTAATGTTCAACTCAG G GTTATTGG ACATTCTATG CAAAATTGTGTACTTAAG
CTTAAG GTTGATACA
G C C AATC CTAAG AC AC CTAA G TATAAG TTTG TT C G CATTCAACCAG G A CAG
ACTTTTTCAG T G TTAG CTTGTTACAATG G TT
CACCATCTG GTGTTTACCAATGTG CTATG AG G CCCAATTTCACTATTAAG G GTTCATTCCTTAATG
GTTCATGTG GTAGTGT
TG GTTTTAACATAGATTATG ACTGTGTCTCTTTTTG TTACATG CA C CATATG GAATTACCAACTG G AG
TT CATG CTG G CACA
GACTTAGAAG GTAACTTTTATG G AC CTTTTGTTG ACAG G CAAACAG CA CAAG CAG CTG GTACG G
AC ACAACTATTACAG TT
AATGTTTTAG CTTG GTTGTACG CTG CTGTTATAAATG G AG AC AG GTG GTTTCTCAATCG
ATTTACCACAACTCTTAATG ACT
TTAACCTTGTG G CTATG AAG TACAATTATG AAC CTCTAACAC AAG AC C ATG TTG AC ATACTAG G
AC CT CTTTCTG CTCAAAC
TG G AATTG CCGTTTTAGATATGTGTG CTTCATTAAAAGAATTACTG CAAAATG GTATG AATGG AC G
TAC CATATTG G G TAG
TG CTTTATTAG AAGATG AATTTACACCTTTTGATGTTGTTAG ACAATG CTCAG GTGTTACTTTCCAAAGTG
CAGTG AAAAG A
ACAATCAAG G G TACA CAC CACTG GTTGTTACTCACAATTTTGACTTCACTTTTAGTTTTAGTCCAG AG
TACTCAATG GTCTTT
G TT CTTTTTTTTG TATG AAAATG CCTTTTTACCTTTTG CTATGG GTATTATTG CTATG TCTG CTTTTG
C AATG ATG TTTG TC AA
ACATAAG CAT G CATTTCTCTGTTTGTTTTTGTTACCTTCTCTTG C CA CTG TAG CTTATTTTAATATG
GTCTATATG CCTG CTAG
HG G GTGATG CGTATTATG ACATG GTTG GATATG GTTGATACTAG TTTGTCTGGTTTTAAG CTAAAAG
ACTGTG TTATG TAT
G C AT CAG CTG TAG TG TTACTAATC CTTAT G ACAG CAAG AA CTG TG TAT G ATG ATG GTG
CTAG GAG AG TG TG G ACACTTATG
AATGTCTTGACACTCGTTTATAAAGTTTATTATG GTAATG CTTTAG AT CAAG CCATTTCCATG TG G G
CTCTTATAATCTCTGT
TACTTCTAACTACTCAG GTGTAG TT ACAACTGTC ATG TTTTT G G C CAG AG GTATTG TTTTTATGTG
TG TTG AG TATTG CC CTA
TTTTCTT CATAA CTG G TAATAC ACTTC AG TG TATAAT G CTAGTTTATTGTTTCTTAG G
CTATTTTTGTACTTGTTACTTTG G CC
TCTTTTGTTTACTCAACCG CTACTTTAGACTGACTCTTG GTGTTTATGATTACTTAGTTTCTACACAG G AG
TTTAG ATATATG
AATTCACAG G GACTACTCCCACC CAAGAATAG CATAGATG CCTTCAAACTCAACATTAAATTGTTG G
GTGTTG GTG G CAAA
C CTTG TATCAAA G TAG C CACTG TA CAG TCTAAAAT G TCA G ATG TAAAG TG CA CATCA G
TAG TCTTACT CT CAG TTTTG CAAC
AACT CAG AG TAG AATCATCATCTAAATTGTG GG CTCAATGTGTCCAGTTACACAATGACATTCTCTTAG
CTAAAG AT ACTAC
TGAAG CCTTTG AAAAAATG GTTTCACTACTTTCTGTTTTG CTTTCCATG CAG G GTG CTG TA G AC
ATAAAC AA G CTTTG T G AA
GAAATG CT G GACAACAG G G CAACCTTACAAG CTATAG CTT CAG AG TTTAG TTC CCTTC
CATCATAT G CAG CTTTTG CTACTG
CTCAAGAAG CTTATG AG CAG G CTGTTG CTAATG GTGATTCTG AAGTTG TT CTTAAAAAG TTG AAG
AAGTCTTTGAATGTG G
CTAAATCTG AATTTG AC C G TG ATG CA G C C AT G CAACGTAAGTTG G AAAAG ATG G CTG
ATCAAG CTAT G ACC C AAATG TATA
AACAG G CTA G ATCTG AG GACAAG AG G G CAAAAGTTACTAGTG CTATG C AG ACAATG
CTTTTCACTATG CTTAGAAAG TTG
GATAATGATG CACTCAACAACATTATCAACAATG CAAG AG AT G G TTG TG TT C C CTTG AAC
ATAATAC CTCTTACAACAG CA
G CCAAACTAATG G TTG TCATAC CAG ACTATAAC ACATATAAAAATACG TG TG ATG
GTACAACATTTACTTATG CATC AG CAT
TGTG G G AAATCCAACAG G TTG TAG ATG CAG ATAGTAAAATTGTTCAACTTAGTG AAATTAGTATG G
ACAATT CAC CTAATT
TAG CATG G CCTCTTATTGTAACAG CTTTAAG G G CCAATTCTG CTGTCAAATTAC AG AATAATG AG
CTTAGTCCTGTTG CACT
ACGACAGATGTCTTGTG CTG CCG GTACTACACAAACTG CTTG CACTGATG ACAATG CGTTAG
CTTACTACAACACAACAAA
G GG AG G TAG GTTTGTACTTG CA CTG TTATC C G ATTTACA G GATTTGAAATG G G CTAG ATTC
C CTAA G AG TG ATG GAACTG
G TA CTG T CTATA CAG AA CTG G AAC CAC CTTG TAG G TTTG TTAC AG ACAC AC CTAAAG
GTCCTAAAGTG AAGTATTTATACTT
TATTAAAG G ATTAAACAAC C TAAATAG AG GTATG GTACTTG G TAG TTTAG CTG
CCACAGTACGTCTACAAG CT G GTAATG C
AACAG AAGTG C CT G CCAATTCAACTGTATTATCTTTCTGTG CTTTTG CTG TAG AT G CTG CTAAAG
CTTACAAAG ATTATCTA
G CTAGTG GGGGACAACCAATCACTAATTGTGTTAAGATGTTGTGTACACACACTG GTACTG GTCAG G
CAATAACAGTTACA
CCG GAAG CCAATATG G AT CAAG AATCCTTTG GTG GTG CATCG TG TTGTCTG TA CTG CCGTTG C
CAC ATAG ATCAT CCAAAT
CCTAAAG G ATTTTGTG ACTTAAAAG GTAAGTATGTACAAATACCTACAACTTGTG CTAATGACCCTGTG G
GTTTTACACTTA
AAAACACAGTCTGTACCGTCTG CG GTATGTG GAAAG GTTATG G CTGTAGTTGTGATCAACTCCG
CGAACCCATG CTTC AG T
CAG CTGATG CAC AATCG TTTTTAAACG G GTTTG CG GTGTAAGTG CAG CCCGTCTTACACCGTG CG
GCACAG G CACTAGTAC
TG ATG TC G TATA CA G G G CTTTTG A CAT CTA C AATG ATAAA G TA G CTG GTTTTG CTA
AATTC CTAAA AA CTA ATTG TTG TC G C
TTCCAAGAAAAG GACGAAG ATG ACAATTTAATTG ATTCTTACTTTG TAGTTAAG AG ACACACTTT CT
CTAACTAC CAA CATG
AAGAAACAATTTATAATTTACTTAAG GATTGTCCAG CTGTTG CTAAACATG ACTT CTTTAAG TTTAG
AATAG AC G GTGACAT
G GTAC CAC ATATATCAC G TCAAC GTCTTACTAAATACACAATG G CAG AC CTC G TCTATG
CTTTAAG G CATTTTGATG AAG GT
AATTGTG ACACATTAAA AG AAATACTTG TC AC ATA CAATTG TTG TG ATG AT G
ATTATTTCAATAAAAAG GACTG G TAT G ATT
TTG TAG AAAAC C CAG ATATATTAC G CGTATACG CCAACTTAG GTGAACGTG TACG CCAAG
CTTTGTTAAAAACAGTACAAT
TCTGTGATG CCATG CG AAATG CTG GTATTGTTG G TG TACT G ACATTAG ATAATCAA G ATCT
CAATG GTAACTG GTATG ATTT
CG GTGATTTCATACAAACCACG CCAGGTAGTG G AG TTC CTG TTGTAG ATTCTTATTATTCATTGTTAATG
CCTATATTAACC
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TTG ACCAG G G CTTTAACTG C AG AGTCACATGTTG ACACTGACTTAACAAAG CCTTACATTAAGTG G G
ATTTGTTAAAATAT
GACTTCACG GAAG AG AG GTTAAAACTCTTTG ACC G TTATTTTAAATATT G G G ATCAG
ACATACCACCCAAATTGTGTTAACT
GTTTG G ATG AC AG ATG CATTCTG CATTGTG
CAAACTTTAATGTTTTATTCTCTACAGTGTTCCCACTTACAAGTTTTG GACCA
CTAG TG AG AAAAATATTTGTTG ATG GTGTTCCATTTGTAGTTTCAACTG G ATACCACTTCAG AG AG
CTAG G TG TTG TA CATA
ATCAG G AT G TAAA CTTAC ATAG CTCTAGACTTAGTTTTAAG GAATTACTTGTGTATG CTG CTG ACC
CTG CTATG CAC G CTG C
TTCTG GTAATCTATTACTAGATAAACG CA CTAC G TG CTTTTC AG TAG CTG C A CTTACTAACAAT G
TTG CTTTTCAAACTG T CA
AACCCG GTAATTTTAACAAAGACTTCTATGACTTTG CTGTGTCTAAG G GTTTCTTTAAG GAAG
GAAGTTCTGTTGAATTAAA
ACACTTCTTCTTTG CT CAG GATG GTAATG CT G CTATCAG CGATTATG
ACTACTATCGTTATAATCTACCAACAATGTGTG ATA
TCAG ACAACTACTATTTG TAG TT G AAG TTG TTG ATAAG TACTTTG ATTG TTACGATG GTG G
CTGTATTAATG CTAACCAAGT
CATC GTCAACAACCTAG AC AAATCAG CTG GTTTTCCATTTAATAAATG G G GTAAG G
CTAGACTTTATTATG ATTCAATGAGT
TATG AG G ATCAAG ATG C A CTTTT C G
CATATACAAAACGTAATGTCATCCCTACTATAACTCAAATGAATCTTAAGTATGCCA
TTAGTG C AAAG AATAG AG CTCG CACC G TAG CTG G TG TCTCTAT CTG TAG TA CTATG
ACCAATAG AC AG TTTCATC AAAAAT
TATTGAAATCAATAG CCG CCACTAG AG G AG CTA CTG TAG TAATTG GAACAAG CAAATTCTATGGTG
G TTG G CACAACATGT
TAAAAACTGTTTATAGTG ATG TAG AAAACCCT CAC CTTATG G GTTG G G ATTATCCTAAATGTGATAG
AG CCATG CCTAACA
TG CTTAG AATTATG G CCTCACTTGTTCTTG CTCG CAAACATACAACGTG TTG TAG
CTTGTCACACCGTTTCTATAGATTAG CT
AATG AG TGTG CTC AAG TATTG AG TG AAATG GTCATGTGTG G CG GTTCACTATATGTTAAACCAG
GTG GAACCTCATCAG G
AG AT G CCACAACTG CTTATG CTAATAGTGTTTTTAACATTTGTCAAG CT G TC AC G G
CCAATGTTAATG CACTTTTATCTACTG
ATG GTAACAAAATTG CCG ATAAGTATGTCCG CAATTTACAACAC AG ACTTTATG AG TG TCTC TATAG
AAATAG AG ATGTTG
ACAC AG ACTTTG T G AAT G AG TTTTA C G CATATTTG C G TAAACATTTCTC AATG AT G ATA
CTCT CTG AC G ATG CTGTTGTGTG
TTTCAATAG CACTTATG CATCTCAAG GTCTAGTG G CTAG CATAAAG
AACTTTAAGTCAGTTCTTTATTATCAAAACAATGTTT
TTATGTCTGAAG CAAAATGTTG G ACTG AG A CTG ACCTTA CTAAAG GACCTCATG AATTTTG CTCTC
AA CATA CAATG CTAGT
TAAACAG G G TG ATG ATTATGTGTAC CTTC CTTAC CC AG ATCCATC AAG AATCCTAG G G G CCG
G CTG TTTTG TAG ATG ATAT
CGTAAAAACAGATG GTACACTTATGATTGAACG GTTCGTGTCTTTAG CTATAGATG
CTTACCCACTTACTAAACATCCTAAT
CAG G AG TATG CT G ATG TCTTTCATTTG TACTTACAATA CATAA G AAAG CTACATGATG AG
TTAAC AG G ACACATG TTAG AC
ATGTATTCTGTTATG CTTACTAATG ATAAC ACTT CAAG GTATTG G G AAC CTG A G TTTTATG AG G
CTATG TACAC AC C G CATA
CAGTCTTACAG G CTGTTG G G G CTTGTGTTCTTTG CAATTCACAG ACTT CATTAAG ATG TG GTG
CTTG C ATAC G TAG AC CATT
CTTATGTTGTAAATG CTG TTAC G AC CATG TCATATCAACATCACATAAATTAG TCTTG T CTG TTAAT
CC G TATG TTT G CAATG
CTCCAG G TTG T G ATG TCACA G ATG TG ACT CAACTTTACTTAG G AG GTATG AG
CTATTATTGTAAATCACATAAACCACCCAT
TAG TTTT CCATT G TG TG CTAATG GACAAGTTTTTG GTTTATATAAAAATACATGTGTTG G TA G
CGATAATGTTACTGACTTTA
ATG CAATTG CAAC ATG T G ACT G G AC AAATG CTG GTGATTACATTTTAG CTAACACCT G TACTG
AAAG ACT CAAG CTTTTTG C
AG CA G AAAC G CTCAAAG CTACTG A G GAG ACATTTAAA CT G TCTTATG GTATTG
CTACTGTACGTG AAGTG CT G TCTG ACAG
AG AATTACATCTTT CATG G G AA G TTG GTAAACCTAG ACCACCACTTAACCGAAATTATGTCTTTACTG
GTTATCGTGTAACT
AAAAAC AG TAAAG TAC AAATAG G AG AGTACACCTTTG AAAAAG GTGACTATG GTGATG CTG TTG
TTTACC G AG GTACAAC
AACTTACAAATTAAATGTTG GTG ATTATTTTGTG CTG AC ATCACATACAG TAATG CCATTAAGTG CAC
CTACACTAGTG C CA
CAAG AG CACTATGTTAG AATTACTG G CTTATACCCAAC ACTC AATAT CTCAT ATG AG TTTTCTAG
CAATGTTG CAAATTATC
AAAAG GTTG GTATG CAAAAGTATTCTACACTCCAG G GACCACCTG GTACTGGTAAGAGTCATTTTG
CTATTG G CCTAG CTC
TCTACTACCCTTCTG CTCG CATAGTGTATACAG CTTG CTCTCATG CC G CTG TT G ATG CACTATG T
G AG AAG G CATTAAAATA
TTTG CCTATAG ATAAAT G TAG TAG AATTATA CCTG C AC G T G CTC G TG TAG AG TG TTTTG
ATAAATT CAAAG T G AATT CAA CA
TTAGAACAGTATGTCTTTTGTACTGTAAATG CATTG CCTG AG AC G ACA G CAG ATATAG TTG TCTTTG
AT G AAATTTCAATG G
CCACAAATTATGATTTG AG TG TTG T CAATG CCAG ATTACGTG CTAAG CACTATGTG TACATTG G C
G ACC CTG CTCAATTACC
TG CACCACG CAC ATTG CTAACTAAG GG CACACTAG AA CCAG AATATTT CAATT CAG T G TG TAG
ACTTATG AAAACTATAG G
TCCAGACATGTTCCTCG G AA CTTGTCG G CGTTGTCCTG CTGAAATTGTTGACACTGTG AGTG CTTTG
GTTTATG ATAATAAG
CTTAAAG CA CATAAA G ACAAATCAG CTCAATG CTTTAAAATGTTTTATAAG G GTGTTATCACG CAT G
ATG TIT CATCT G CAA
TTAACAG G CCACAAATAG G CGTG GTAAG AG AATT CCTTACACGTAACCCTG CTT G GAG AAAAG
CTGTCTTTATTT CAC CTT
ATAATTCACAGAATG CTG TA G CC TCAAAG ATTTTG G G ACTACCAACTCAAACTGTTG ATTCATCACAG
G G CTCAGAATATG
ACTATG TC ATATT CACTC AAACCACTG AAA CAG CT CACTCTTG TAATG TAAACA G ATTTAATG
TTG CTATTACCAG A G CAAA
AG TAG G CATACTTTG C ATAATG T CT G ATAG AG ACCTTTATG ACAAGTTG CAATTTA CAA G
TCTT G AAATTCCAC G TAG GAAT
GTG G CAA CTTTA CA A G CT G AAAATG TAA CA G G A CTUTTAAA G ATTG TA G TAA G G
TAATCA CTG G G TTA CATCCT A CACA G
G C AC CTACA CACCTC AG TG TTG A CACTAAATTCAAAACTG AAG G TTTAT G TG TTG A C
ATACCTG G CATACCTAAG G ACATG
ACCTATAG AAGACTCATCTCTATGATG G GTTTTAAAATG AATTATCAAGTTAATG
GTTACCCTAACATGTTTATCACCCG CG
AAGAAG CTATAAG A CATG TAC G T G CAT G GATTG G CTTCG ATG T C G AG G G GTGTCATG
CTACTAG A G AAG CTGTTG GTACC
AATTTACCTTTAC AG CTAG G TTTTTCTAC AG G T G TTAACCTAG TT G CTGTACCTACAG G TTAT
G TTG AT ACACCTAATAATAC
AG ATTTTTCC AG AG TTAG TG CTAAACCACCG CCTG GAG
ATCAATTTAAACACCTCATACCACTTATGTACAAAG G ACTT CCT
TG G AATGTAGTG CGTATAAAG ATTG TA CAAATG TTAAGTG ACACACTTAAAAATCTCTCTGACAG AG
TCG TATTTGTCTTAT
G GG CACATG G CTTTG AG TTG ACAT CTATG AAGTATTTTGTGAAAATAG G ACCTG AG CG CAC
CTG TTG TCTATG TG ATAG AC
136
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GTG CCACATG CTTTTCCACTG CTT CAG AC ACTTATG CCTGTTG G CATCATTCTATTG G
ATTTGATTACGTCTATAATCCGTTT
ATG ATTG ATGTTCAACAATG G G GTTTTACAG GTAACCTACAAAG CAAC CATG AT CTG TATT G
TCAAG TC CATG GTAATG CA
CATG TAG CTAGTTGTG ATG C AATCAT G ACTA G G TG TCTA G CTG TC CAC G AG T G
CTTTGTTAAG C G TG TTG ACT G G ACTATT
GAATATCCTATAATTG G TG AT G AACT G AAG ATTAATG CG G CTTG TA G AAAG GTTCAACACATG
G TTGTTAAAG CTG CATTA
TTAG CAG AC AAATTC C CAG TTCTTC AC G ACATTG G TAAC C CTAAAG
CTATTAAGTGTGTACCTCAAG CTG AT G TAG A ATG G
AAG TTCTATG AT G CACAG C CTTG TA G TG A CAAAG CTTATAAAATA G AA G
AATTATTCTATTCTTATG CCACACATTCTG ACA
AATTCACAG ATG GTGTATG CCTATTTTG G AATTG CAATG TC G ATAG ATAT C CT G CTAATTCC
ATTG TTTG TAG ATTTG ACACT
AG AGTG CTATCTAACCTTAACTTG CCTG GTTGTGATG G TG G CAGTTTGTATGTAAATAAACATG CATTC
CAC AC ACCAG CTT
TTG ATAAAAGTG CTTTT G TTAATTTAAAACAATTAC C ATTTTTCTATTACT CTG A CAG TC CATG TG
AG TCTCATG GAAAACAA
GTAGTGTCAGATATAG ATTATGTACCACTAAAGTCTG CTACGTGTATAACACGTTGCAATTTAG GTG GTG
CTGTCTG TAG A
CATCATG CTAATG AG TACAG ATT G TATCTCG ATG CTTATAACATGATG ATCTC AG CTG G CTTTAG
CTTGTG G GTTTACAAAC
AATTTGATACTTATAACCTCTG G AAC ACTTTTACAA G ACTTCAG A G TTTAG AAAATG T G G
CTTTTAATGTTGTAAATAAG G G
ACACTTTG ATG G AC AACAG G
GTGAAGTACCAGTTTCTATCATTAATAACACTGTTTACACAAAAGTTGATGGTGTTG ATGT
AG AATTG TTTG AAAATAAAAC AACATTACCTGTTAATG TAG CATTTG AG CTTTG G G CTAAG CG
CAA CATTAAAC CAG TAC C
AG AG GTG AAAATA CT CAATAATTTG G GTGTG G AC ATTG CTG CTAATACTG TG ATCTG G G
ACTACAAAAG AG ATG CTCCAG
CACATATATCTACTATTG G TG TTTG TTCTATG ACTG AC ATAG C CAAG AAAC C AACTG AAA C G
ATTTG T G CAC C ACTCA CTG T
CTTTTTTGATG GTAG AG TTG ATG GTCAAG TAG ACTTATTTAG AAATG CC CGTAATG GTG
TTCTTATTAC AG AAG G TAGTG TT
AAAG G TTTACAAC CATCTG TAG GT C C CAAACAAG CTAGTCTTAATG G AG TCACATTAATT G GAG
AAG CCGTAAAAACACAG
TTCAATTATTATAAGAAAGTTG ATG G TG TTG TC CAACAATTAC CTG AAA CTTACTTTA CTCAG AG
TA G AAATTTACAAG AAT
TTAAACCCAG G AG T CAAATG GAAATTG ATTTCTTAGAATTAG CTATG GATGAATTCATTG AACG
GTATAAATTAGAAG G CT
ATG CCTTCGAACATATCGTTTATG G AG ATTTTAG TCATAGTCAG TTAG GTG GTTTACATCTACTGATTG
GACTAG CTAAACG
TTTTAAGG AATC AC CTTTTG AATTAG AAGATTTTATTCCTATG G
ACAGTACAGTTAAAAACTATTTCATAACAG ATG CG CAA
ACAG G TTC ATCTAAG TG TG T G TG TT CTG TTATT G ATTTATTA CTTG ATGATTTTGTTG
AAATAATAAAAT C C CAA G ATTTATC
TG TAG TTTCTAAG GTTGTCAAAGTGACTATTG ACTATACAG AAATTTCATTTATG CTTTG GTGTAAAGATG
G C C ATG TAG AA
ACATTTTACCCAAAATTACAATCTAGTCAAG CGTG G CAACCG G GTGTTG CTATG
CCTAATCTTTACAAAATG CAAAG AATG C
TATTAG AAAAG TG TG AC CTT CAAAATTATG GTGATAGTG CAACATTACCTAAAG G CATAATGATG
AATGTCGCAAAATATA
CTCAACTGTGTCAATATTTAAACACATTAACATTAG CTG TA C C CTATAATAT G AG A G
TTATACATTTTG GTG CTG G TTCT G AT
AAAG G AG TTG CACCAG GTACAG CTGTTTTAAGACAGTG GTTG CCTACG G GTACG CTG CTTGTCG
ATTCAG AT CTTAATG AC
TTTGTCTCTGATG CA G ATT C AACTTTG ATTG GTGATTGTG CAACTGTACATACAG CTAATAAATG G G
AT CTCATTATTAG TG
ATATG TACG ACC CTAAG ACTAAAAATG TTACAAAAG AAAATG ACTCTAAAG AG G GTTTTTT CA
CTTACATTTGT G G GTTTAT
ACAACAAAAG CTAG CT CTTG GAG GTTCCGTG G CTATAAAGATAACAG AACATTCTTG GAATG CTG
ATCTTTATAAG CT CAT
G GG ACACTTCG CATG GTG G ACAG CCTTTGTTACTAATGTGAATG CGTCATCATCTG AAG
CATTTTTAATTG GATGTAATTAT
CTTG G CAAAC CAC G C G AACAAATAG ATG GTTATGTCATG CAT G CAAATTACATATTTTGG AG
GAATACAAATCCAATTCAG
TTG TCTT C CTATTCTTTATTTG A CATG A G TAAATTTC C C CTTAAATTAAG G G GTACTG
CTGTTATGTCTTTAAAAG AAG GTCA
AATCAATGATATG ATTTTATCTCTTCTTAGTAAAG G TAG A CTTATAATTA G AG AAAACAAC AG AG
TTG TTATTT CTAG TG AT
GTTCTTGTTAACAACTAAACGAACAATGTTTGTTTTTCTTGTTTTATTG
CCACTAGTCTCTATTCAGTGTGTTAATCTTACAAC
CAG AACTCAATTAC C C C CT G CATACACTAATTCTTTCACACGTG G TG TTTATTA C C CT G A
CAAAG TTTTCA G ATC CTCAG TTT
TACATTCAACTCAG G ACTTG TT CTTAC CTTTCTTTTC C AATG TTACTTG G TTC CATG
CTATACATGTCTCTG G G AC CAATG CT
ACTAAG AG G TTT G ATAAC C CT G TC CTAC C ATTTAAT G ATG GTGTTTATTTTG CTTC C
ACTG A G AAG T CTAACATAATAA G AG
G CTG GATTTTTG GTACTACTTTAGATTCGAAG ACCCAGTCCCTACTTATTGTTAATAACG
CTACTAATGTTGTTATTAAAG TC
TGTGAATTTCAATTTTGTAATGATCCATTTTTG G GTGTTTATTACCACAAAAACAACAAAAGTTGTATG G
AAAGTG AG TTCA
G AG TTTATTCTA G TG CGAATAATTG C ACTTTTG AATATG TCTCT C AG C CTTTT CTTATG G A
C CTTG AAG G AAAAC AG G GTAA
TTTCAAAAATCTTAG G GAATTTGTGTTTAAGAATATTGATG GTTATTTTAAAATATATTCTAAG CACACG
CCTATTAATTTAG
TG CGTGATCTCCCTCAG G GTTTTTCG G CTTTAGAACCATTG GTAG ATTTG CCAATAG
GTATTAACATCACTAGGTTTCAAAC
TTTACTTG CTTTACATAGAAGTTATTTGACTCCTG GTGATTCTTCTTCAG GTG GACAG CTG GTG CTG CAG
CTTATTATGTG G
GTTATCTTCAACCTAG G ACTTTTCTATTAAAATATAATGAAAATG G AACCATTACAG ATG CTG TA G
ACTG TG CACTTG AC C C
TCTCTCAG AAACAAAG TGTACGTTG AAATC CTTCA CTG TAG AAAAAG G AATCTATCAAACTT
CTAACTTTAG AGTC CAAC CA
A CA G AATCTATTGTTAG ATTTCCTA ATATTACAAACTTGTG CCCTTTTG G TG AA G TTTTTAA C G
C CA C CA G ATTTG CATCTGT
TTATG CTTG G AACAG G AAG A G AATC AG CAA CTG T G TTG CTG
ATTATTCTGTCCTATATAATTCCG CAT CATTITC C ACTTTTA
AG T G TTATG G A G TG T CTC CTACTAAATTAAATG AT CTCTG CTTTACTAATGTCTATG
CAGATTCATTTGTAATTAG AG G T G AT
GAAGTCAG ACAAATCG CTCCAG G G CAAACTG GAAAGATTG CT G ATTATAATTATAAATTAC CA G
ATG ATTTTACAG G CT G C
GTTATAG CTTG GAATTCTAACAATCTTGATTCTAAG GTG GTG GTAATTATAATTACCG
GTATAGATTGTTTAG GAAGTCTA
ATCT CAAAC CTTTTG AG AG AG ATATTTCAACTG AAAT CTAT CAG G CCG G TAG
CACACCTTGTAATG GTGTTGAAG GTTTTAA
TTGTTACTTTCCTTTACAATCATATG GTTTCCAACCCACTAATG G TG TTG G TTAC C AAC CATACAG A
G TAG TAG T ACTTTCTT
TTG AACTTCTACATG CA C CAG CAACTGTTTGTG G AC CTAAAAAG TCTACTAATTT G
GTTAAAAACAAATGTGTCAATTTCAA
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CTTCAATG GTTTAACAG G CA CA G G TG TTCTTACT G AG T CTAACAAAAAG TTTCT G
CCTTTCCAACAATTTG G C AG AG ACATT
G CTGACACTACTG ATG CTGTCCGTG ATC CAC AG ACA CTTG AG ATT CTTG ACATTACAC CATG TT
CTTTTG GTG GTGTCAGTG
TTATAACACCAG GAACAAATACTTCTAACCAG GTTG CTG TTCTTTATC AG G GTGTTAACTG CACAG
AAGTCCCTGTTG CTAT
TCATG CAG ATCAACTTACTCCTACTTG G CGTGTTTATTCTAC AG GTTCTAATGTTTTTCAAACACGTG CAG
G CTGTTTAATAG
G GG CTG AACATGTCAACAACTCATATG AG TG TG ACATACCCATTG GTG CAG GTATATG CG
CTAGTTATCAG ACTCAG ACTA
ATTCTCCTCG GCGGG CACGTAG TG TAG CTAG TCAATC CAT CATTG CCTACACTATGTCACTTG GTG
CAG AAAATTCAGTTG C
TTACTCTAATAACTCTATTG C CATAC CCACAAATTTTACTATTAG TGTTACCACAG AAATTCTAC CAGTG
TCTATG ACCAAG A
CATC AG TA G ATT G TACA ATG TACATTTG T G GTG ATTCAACTG AATG C AG CAATCTTTTGTTG
CAATATG G C AG TTTTTG TAC
ACAATTAAACCGTG CTTTAACTG G AATAG CTGTTG AACAAG ACAAAAACACCCAAGAAGTTTTTG
CACAAGTCAAACAAAT
TTA CAAAACA C CAC C AATTAAAG ATTTTG GTG G TTTTAATTTTTC ACAAATATTA C CAG AT C C
AT CAAAAC CAAG CAAG AG G
TCATTTATTG AA G ATCTACTTTTCAA CAAAG TG ACA CTTG CAG AT G CTG G
CTTCATCAAACAATATG GTGATTG CCTTG GTG
ATATTG CT G CTAG AG A CCTCATTTG TG CA CAAAAG TTTAAC G G CCTTACTGTTTTG C CAC
CTTTG CTCACAG AT G AAAT G AT
TG CTCAATACACTTCTG CACTGTTAG CG G GTACAATCACTTCTG GTTG G AC CTTTG GTG CAG GTG
CTG CATTACAAATAC CA
TTTG CTATG CAAATG G CTTATAG GTTTAATG GTATTG G AG TTACA CAG AATG TT CTCTATG AG
AAC CA AAAATT G ATT G CCA
AC CAATTTAATAG CG CTATTG G CAAAATTCAAG ACTCACTTTCTTCCACAG CAAGTG CACTTG G
AAAACTTCAAG ATGTG GT
CAACCAAAATG CACAAG CTTTAAACACG CTTGTTAAACAACTTAG CTCCAATTTTG GTG CAATTTCAAG TG
TTTTAAATG AT
ATC CTTTC AC G T CTTG ACAAAGTTG AG G CTG AA G TG CAAATTGATAG G TT G ATC ACAG G
CAG ACTTCAAAG TTTG C AG ACA
TATG TG ACTCAAC AATTAATTAG A G CTG CAGAAATCAG AG CTTCTG CTAATCTTG CTG
CTACTAAAATG T CAG AG TGTG TAC
TTG GACAATCAAAAAG AG TTG ATTTTTG TG GAAAG G G CTATCATCTTATGTCCTTCCCTCAGTCAG
CAC CT CATG GTG TAG T
CTTCTTG CATGTGACTTATGTCCCTG CAC AAG AAAAG AACTTCAC AACTG CTC CT G
CCATTTGTCATGATG GAAAAG CACAC
TTTCCTCGTG AAG GTGTCTTTGTTTCAAATG G CACACACTG G TTT G TAA CAC AAA G
GAATTTTTATG AACCACAAATCATTA
CTAC AG ACAACACATTTG T G TCT G G TAACTG TG AT G TTG TAATA G
GAATTGTCAACAACACAGTTTATGATCCTTTG CAACC
TGAATTAG ACTCATTCAAG GAG G A G TTA G ATAAATATTTTAAG AATCATACATCAC CAG AT G TTG
ATTTAGGTGACATCTCT
G GCATTAATG CTTCAGTTGTAAACATTCAAAAAGAAATTG ACCG C CTCAATG AG GTTG
CCAAGAATTTAAAT G AAT CT CT C
ATCG ATCTCCAAG AACTTG G AAAG TAT G AG CAGTATATAAAATG G CCATG GTACATTTG G CTAG
GTTTTATAG CTG G CTTG
AUG CCATAGTAATG GTGACAATTATG CTTTG CT G TATG AC CAG TTG CTG TAG TT G TCT CAAG
G G CTGTTG TTCTIGTG GAT
CCTG CTG CAAATTTG ATG AAG ACG ACT CTG AG CCAGTG CT CAAAG
GAGTCAAATTACATTACACATAAACG AA CTTATG G A
TTTG TTTATG AG AATCTTCACAATTG GAACTGTAACTTTGAAG CAAG GTGAAATCAAG GATG CTACTC
CTT CAG ATTTT G TT
CG CG CTACTG CAACGATACCG ATACAAG CCTCACTCCCTTTCG G ATG G CTTATTGTTG G CGTTG C
ACTT CTTG CTGTTTTTCA
TAG CG CTTC CAAAATCATAAC C CT CAAAAA G AG AT G G CAACTAG C ACTCTC CAA G G G TG
TT CACTTTG TTT G C AACTT G CTG
TTGTTGTTTG TAACAGTTTACTCACACCTTTTG CTCGTTG CTGTTG G CCTTGAAG
CCCCTTTTCTCTATCTTTATG CTTTAGTC
TACTTCTTG CAG AG TATAAACTTTG TAAG AATAATAATG AG G CTTTG G CTTTG CTG GAAATG
CCGTTCCAAAAACCCATTAC
TTTATGATG CCAACTATTTTCTTTG CTG G CATACTAATTGTTACG
ACTATTGTATACCTTACAATAGTGTAACTTCTTCAATTG
TCATTACTTCAG GT G ATG G CA CAACAAG TC CTATTTCT G AACATG ACTAC CAG ATTG GTG G
TTATA CTG AA AAATG G GAAT
CTG G AG TAAAAG ACTG TG TT G TATTACAC AG TTACTT CACTT CAG ACTATTAC CAG
CTGTACTCAACTCAATTG AGTAC AG A
CACTG GTGTTG AACAT GTTACCTT CTTCATCTAC AATAAAATTG TTG ATG AG CCTG
AAGAACATGTCCAAATTCACACAATC
G AC G GTTCATCCG GAGTTGTTAATCCAGTAATGG AACCAATTTATG ATG AAC CG ACG ACG A
CTACTAG CG TG CCTTTGTAA
G CAC AAG CTGATG AG TAC G AACTTATG TACT CATTC GTTTCG G AAG AG ACAG
GTACGTTAATAGTTAATAG CGTACTTCTT
TTTCTTG CTTTCGTG GTATTCTTG CTAGTTACACTAG CCATCCTTACTG C G CTTCGATTGTGTG C
GTACTG CTG CAATATTG TT
AAC G TG AG TCTT G TAAAAC CTT CTTTTTAC G TTTACTCT C G TG TTAAAAATCTG AATT
CTTCTAG AG TTC CTG AT CTT CTG GTC
TAAACGAACTAAATATTATATTAGTTTTTCTGTTTG GAACTTTAATTTTAG CCATG G CAG ATTCCAACG G
TACTATTAC C G TT
GAAG AG CTTAAAAAG CTC CTTG AA CAAT G GAACCTAGTAATAG GTTTCCTATTCCTTACATG G
ATTTG T CTTCTACAATTTG
CCTATG CCAACAG GAATAG GTTTTTGTATATAATTAAGTTAATTTTTCTCTG G CT G TTATG G
CCAGTAACTTTAG CTTGTTTT
GTG CTTG CTG CTGTTTACAG AATAAATTG G ATCACCG GTG GAATTG CTATCG CAATG G CTTG
TCTTG TAG G CTTG ATGTG G
CTC AG CTACTTCATTG CTTCTTTCAG ACTG TTTG CG CGTACG CGTTCCATGTG GTCATT CAATC CAG
AAA CTAAC ATTCTTCT
CAACGTG CCACTCCATG G CACTATTCTGACCAG ACCG CTTCTAGAAAGTG AACTCGTAATCG GAG CTG
TG ATC CTTCGTG G
ACATCTTCGTATTG CT G GACACCATCTAG G AC G CT G TG ACATCAAG G A C CTG
CCTAAAGAAATCACTGTTG CTACAT CAC G
AACG CTTTCTTATTACAAATTG G GAG CTTCG CAG CGTG TAG CAG GTG A CTCAG GTTTTG CTG
CATACAGTCG CTACAG GAT
TG G CAACTATAAATTAAAC ACAG A C CATT C CA G TAG CA G TG A CAATATTG CTTTG CTTG
TACAGTAAGTGACAACAG ATGT
TTCATCTCGTTG ACTTTCAG GTTACTATAG CAG AG ATATTACTAATTATTATG AG
GACTTTTAAAGTTTCCATTTG GAATCTT
G ATTACAT CATAAA C CTC ATAATTAAAAATTTAT CTAAG TCACTAACT G AG A ATAAAT ATTCT
CAATTAG ATG AAG AG CAA C
CAATG GAG ATTG ATTAAAC G AA CATG AAAATTATTCTTTTCTTG G CACTG ATAACA CT C G
CTACTT GTG A G CTTTATC A CTA
C CAAG AGTGTG TTAG AG GTACAACAGTACTTTTAAAAGAACCTTG CTCTTCTG G AACATACG AG G G
CAATTC AC CATTTCA
TCCTCTAG CTGATAACAAATTTG CACTG ACTTG CTTTAG CACTCAATTTG CTTTTG CTTGTCCTGACG G
C GTAAAACACG T CT
ATCAGTTACGTG CCAG ATCAG TTTC AC CTAAACTG TTCATCAG ACAAG AG G AA G TTC AAG
AACTTTACTCTCCAATTTTTCTT
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ATTGTTGCGGCAATAGTGTTTATAACACTTTGCTTCACACTCAAAAGAAAGACAGAATGATTGAACTITCATTAATTGA
CTT
CTATTTGTGCTTTTTAGCCTTTCTGCTATTCCTTGTTTTAATTATGCTTATTATCTTTTGGTTCTCACTTGAACTGCAA
GATCAT
AATGAAACTTGTCACGCCTAAACTAACATGAAATTTCTTGTTTTCTTAGGAATCATCACAACTGTAGCTGCATTTCACC
AAG
AATGTAGTTTACAGTCATGTACTCAACATCAACCATATGTAGTTGATGACCCGTGTCCTATTCACTTCTATTCTAAATG
GTAT
ATTAGAGTAGGAGCTAGAAAATCAGCACCTTTAATTGAATTGTGCGTGGATGAGGCTGGTICTAAATCACCCATTCAGT
AC
ATCGATATCGGTAATTATACAGTTTCCTGTTTACCTTTTACAATTAATTGCCAGGAACCTAAATTGGGTAGTCTTGTAG
TGC
GTTGTTCGTTCTATGAAGACTTTTTAGAGTATCATGACGTTCGTGTTGTTTTAGATTICATCTAAACGAACAAACTATA
ATGT
CTGATAATGGACCCCAAAATCAGCGAAATGCACCCCGCATTACGTTTGGTGGACCCTCAGATTCAACTGGCAGTAACCA
GA
ATGGAGAACGCAGTGGGGCGCGATCAAAACAACGTCGGCCCCAAG GTTTACCCAATAATACTG CGTCTTG
GTTCACCG CT
CTCACTCAACATG G CAAG GAAG ACCTTAAATTCCCTCGAG GACAAG G CGTTCCAATTAACACCAATAG
CAGTCCAGATG AC
CAAATTGGCTACTACCGAAGAGCTACCAGACGAATTCGTGGTGGTGACGGTAAAATGAAAGATCTCAGTCCAAGATGGT
ATTTCTACTACCTAGGAACTGGGCCAGAAGCTGGACTTCCCTATGGTGCTAACAAAGACGGCATCATATGGGTTGCAAC
TG
AGGGAGCCTTGAATACACCAAAAGATCACATTGGCACCCGCAATCCTGCTAACAATGCTGCAATCGTGCTACAACTTCC
TC
AAGGAACAACATTGCCAAAAGGCTTCTACGCAGAAGGGAGCAGAGGCGGCAGTCAAGCCTCTTCTCGTTCCTCATCACG
T
AGTCGCAACAGTTCAAGAAATTCAACTCCAGGCAGCAGTAGGGGAATTICTCCTGCTAGAATGGCTGGCAATGGCGGTG
A
TGCTGCTCTTGCTTTGCTGCTGCTTGACAGATTGAACCAGCTTGAGAGCAAAATGTCTGGTAAAGGCCAACAACAACAA
GG
CCAAACTGTCACTAAG AAATCTG CTG CTG AG G CTTCTAAGAAG CCTCG G CAAAAACGTACTG
CCACTAAAG CATACAATGT
AACACAAGCTTTCGGCAGACGTGGTCCAGAACAAACCCAAGGAAATTTTGGGGACCAGGAACTAATCAGACAAGGAACT
GATTACAAACATTGGCCGCAAATTGCACAATTTGCCCCCAGCGCTTCAGCGTTCTTCGGAATGTCGCGCATTGGCATGG
AA
GTCACACCTTCGGGAACGTGGTTGACCTACACAGGTGCCATCAAATTGGATGACAAAGATCCAAATTTCAAAGATCAAG
TC
ATTTTGCTGAATAAGCATATTGACGCATACAAAACATTTCCACCAACAGAGCCTAAAAAGGACAAAAAGAAGAAGGCTG
A
TGAAACTCAAGCCTTACCGCAGAGACAGAAGAAACAGCAAACTGTGACTCTTCTTCCTGCTGCAGATTTGGATGATTIC
TC
CAAACAATTGCAACAATCCATGAGCAGTGCTGACTCAACTCAGGCCTAAACTCATGCAGACCACACAAGGCAGATGGGC
T
ATATAAACGTTTTCGCTTTTCCGTTTACGATATATAGTCTACTCTTGTGCAGAATGAATTCTCGTAACTACATAGCACA
AGTA
GATGTAGTTAACTTTAATCTCACATAGCAATCTTTAATCAGTGTGTAACATTAGGGAGGACTTGAAAGAGCCACCACAT
TTT
CACCGAGGCCACGCGGAGTACGATCGAGTGTACAGTGAACAATGCTAGGGAGAGCTGCCTATATGGAAGAGCCCTAATG
TGTAAAATTAATTTTAGTAGTGCTATCCCCATGTGATTTTAATAGC
SEQ ID NO: 27
> QP172086.1. S-protein surface glycoprotein
M FVF LVLLP LVSI QCVN LTTRTQLP PAYTNSFTRGVYYP D KVF RSSVLHSTQD LF LP F FS
NVTWF HAI HVSGTNGTKRFDNPVLPF
N DGVYFASTE KSN I I RGWI FGTTLDSKTQSLLIVN NATNVVI KVCE FQFCN DPFLGVYYH KN
NKSCM ESE F RVYSSAN NCTF EYVS
QPF LM DLEG KQG N FKN L RE FVF KN I DGYF KIYSKHTP I N LVRDLPQG FSAL E P LVDL
PI G I N ITRFQTLLALH RSYLTPG DSSSGWT
AGAAAYYVGYLQPRTFLLKYN E NGTITDAVDCALDPLSETKCTLKSFTVEKG IYQTSNFRVQPTESIVRF PN
ITN LCPFG EVFNATR
FASVYAWN R KR ISNCVADYSVLYNSASFSTF KCYGVS PTKLN DLCFTNVYADSFVIRG DEVRQIAPGQTG
KIADYNYKLPDDFTG
CVIAWNSN N LDSKVGG NY NYRY RL F R KSN LKPFERDISTE IYQAGSTPCNGVEG FNCYFPLQSYG F
QPTNG VG YQPYRVVVLSF
ELLHAPATVCG PKKSTN LVKNKCVN FN F NG LTGTG VLTESN KKF LP FQQFG
RDIADTTDAVRDPQTLE I LDITPCSFGGVSVITPG
TNTSNQVAVLYQGVNCTEVPVAI HADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVN NSYECD I PI GAG I
CASYQTQTNSP RRAR
SVASQS1lAYTMSLGAENSVAYSN NSIAI PIN FTISVTTE I L PVSMTKTSVDCTMYICG DSTECSN
LLLQYGSFCTQLN RA LTG IAVE
QDKNTQEVFAQVKQIYKTPPIKDFGG F N FSQI L PD PSKPSKRSF I EDLLFNKVTLADAG F I KQYG
DC LG DIAARD L ICAQKF NG LTV
LP P L LTD E M IAQYTSAL LAGTITSGWTFGAGAALQI P FAMQMAYRF NG I GVTQNVLYE
NQKLIANQFNSAIG KIQDSLSSTASAL
G KLQDVVNQNAQALNTLVKQLSSN FGAISSVLN DI LSRLDKVEAEVQIDRLITG RLQSLQTYVTQQLI RAAE
I RASANLAATKMSE
CVLGQSKRVDFCGKGYI-ILMSFPQSAPI-IGVVFLHVTYVPAQEKNFTTAPAICI-IDGKAI-IFPREGVFVSNGTI-
IWFVTQRNFYEPQ
IITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKN
LNESLIDL
QELG KYEQYI KWPWYIWLG FIAG LIAIVMVTI M LCC MTSCCSCL KG CCSCGSCCKF DE
DDSEPVLKGVKLHYT
SEQ ID NO: 28
>nucleocapsid phosphoprotein [Severe acute respiratory syndrome coronavirus 2]
(Accession No: QIA98561)
MSDNG PQNQRNAPRITFGG PSDSTGSNQNG ERSGARSKQRRPQG LPN NTASWFTALTQHG KE DLK F
PRGQGVP I NTNSS P
DDQI GYYRRATR RI RGG DG KM KDLSPRWYFYYLGTG PEAG LPYGANKDG I IWVATEGAL NTP KD H
IGTR N PAN NAAIVLQLP
QGTTLP KG FYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAG NG G DAALA LL L LD R LNQL
ESK M SG KGQQQQG
QTVTKKSAAEASKKPRQKRTATKAYNVTQAFG RRG PEQTQG N FG DQE L I
RQGTDYKHWPQIAQFAPSASAF FG MSRIG M EV
TPSGTWLTYTGAI KLDDKDPN FKDQVI LLNKH I DAYKTF
PPTEPKKDKKKKADETQALPQRQKKQQTVILLPAADLDDFSKQLQ
QSMSSADSTQA
139
CA 03168783 2022- 8- 19
WO 2021/176434
PCT/IB2021/052858
SEQ ID NO: 29
>membrane glycoprotein [Severe acute respiratory syndrome coronavirus 2]
(Accession No: 01A98557)
MADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYANRNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGG
IAIAMACL
VGLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRPLLESELVIGAVILRGHLRIAGHHLGRCDIKDLPK
EITVATSRT
LSYYKLGASQRVAGD SGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ
SEQ ID NO: 30
>TLR9 agonist oligo
AACGTTCGAG
SEQ ID NO: 31
>modified oligo with 2'-deoxy-7-deazaguanosine
TCG,AACG,TTCGi
wherein Gi is 2'-deoxy-7-deazaguanosine
SEQ ID NO: 32
>modified oligo with 2'-deoxy-7-deazaguanosine and glycerol
TCGiAACG,TTCG,XGiCTTGiCAAGiCT
wherein G1 is 2'-deoxy-7-deazaguanosine and X is glycerol
140
CA 03168783 2022- 8- 19
