Note: Descriptions are shown in the official language in which they were submitted.
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MUTATIONS RESPONSIBLE FOR ATTENUATION IN MEASLES VIRUS
OR HUMAN RESPIRATORY SYNCYTIAL VIRUS SUBGROUP B
Field Of The Invention
This invention relates to isolated,
recombinantly-generated, attenuated measles virus or
human respiratory syncytial virus subgroup B having
specified attenuating mutations. This invention was
made with Government support under a grant awarded by
the Public Health Service. The Government has certain
rights in the invention.
Background Of The Invention
Enveloped, negative-sense, single stranded
RNA viruses are uniquely organized and expressed. The
genomic RNA of negative-sense, single stranded viruses
serves two template functions in the context of a
nucleocapsid: as a template for the synthesis of
messenger RNAs (mRNAs) and as a template for the
synthesis of the antigenome (+) strand. Negative-
sense, single stranded RNA viruses encode and package
their own RNA dependent RNA Polymerase. Messenger RNAs
are only synthesized once the nucleocapsid has entered
the cytoplasm of the infected cell. Viral replication
occurs after synthesis of the mRNAs and requires the
continuous synthesis of viral proteins. The newly
synthesized antigenome (+) strand serves as the
template for generating further copies of the (-)
strand genomic RNA.
The polymerase complex actuates and achieves
transcription and replication by engaging the cis-
acting signals at the 3~ end of the genome, in
particular, the promoter region. Viral genes are then
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transcribed from the genome template unidirectionally
from its 3' to its 5' end. There is always less mRNA
made from the downstream genes (e. g., the polymerase
gene (L)) relative to their upstream neighbors (i.e.,
the nucleoprotein gene (N)). Therefore, there is always
a gradient of mRNA abundance according to the position
of the genes relative to the 3'-end of the genome.
Based on the revised reclassification in 1993
by the International Committee on the Taxonomy of
Viruses, an Order, designated Mononegavirales, has been
established. This Order contains three families of
enveloped viruses with single stranded, nonsegmented
RNA genomes of minus polarity (negative-sense). These
families are the Paramyxoviridae, Rhabdoviridae and
Filoviridae. The family Paramyxoviridae has been
further divided into two subfamilies, Paramyxovirinae
and Pneumovirinae. The subfamily Paramyxovirinae
contains three genera, Paramyxovirus, Rubulavirus and
Morbillivirus. The subfamily Pneumovirinae contains
the genus Pneumovirus.
The new classification is based upon
morphological criteria, the organization of the viral
genome, biological activities and the sequence
relatedness of the genes and gene products. The
morphological distinguishing feature among enveloped
viruses for the subfamily Paramyxovirinae is the size
and shape of the nucleocapsids (diameter l8mm, lmm in
length, pitch of 5.5 nm), which have a left-handed
helical symmetry. The biological criteria are: 1)
antigenic cross-reactivity between members of a genus,
and 2) the presence of neuraminidase activity in the
genera Paramyxovirus, Rubulavfrus and its absence in
genus Morbillivirus. In addition, variations in the
coding potential of the P gene are considered, as is
the presence of an extra gene (SIi) in Rubulaviruses.
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Pneumoviruses can be distinguished from
Paramyxovirinae morphologically because they contain
narrow nucleocapsids. In addition, pneumoviruses have
major differences in the number of protein-encoding
cistrons (10 in pneumoviruses versus 6 in
Paramyxovirinae) and an attachment protein (G) that is
very different from that of Paramyxovirinae. Although
the paramyxoviruses and pneumoviruses have six proteins
that appear to correspond in function (N, P, M, G/H/HN,
F and L), only the latter two proteins exhibit
significant sequence relatedness between the two
subfamilies. Several pneumoviral proteins lack
counterparts in most of the paramyxoviruses, namely the
nonstructural proteins NSl and NS2, the small
hydrophobic protein SH, and a second protein M2. Some
paramyxoviral proteins, namely C and V, lack
counterparts in pneumoviruses. However, the basic
genomic organization of pneumoviruses and
paramyxoviruses is the same. The same is true of
rhabdoviruses and filoviruses. Table 1 presents the
current taxonomical classification of these viruses,
together with examples of each genus.
Table 1
Classification of Nonsegmented, negative-sense, single
stranded RNA Viruses of the Order Mononegavirales
Family Paramyxoviridae
Subfamily Paramyxovirinae
Genus Paramyxovirus
Sendai virus (mouse parainfluenza virus
type 1)
Human parainfluenza virus (PIV) types 1
and 3
Bovine parainfluenza virus (BPV} type 3
Genus Rubulavirus
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Simian virus 5 (SV) (Canine
parainfluenza virus type 2)
Mumps virus
Newcastle disease virus (NDV) (avian
Paramyxovirus 1)
Human parainfluenza virus types 2, 4a
and 4b
Genus Morbillivirus
Measles virus (MV)
Dolphin Morbillivirus
Canine distemper virus (CDV)
Peste-des-petits-ruminants virus
Phocine distemper virus
Rinderpest virus
Subfamily Pneumovirinae
Genus Pneumovirus
Human respiratory syncytial virus (RSV)
Bovine respiratory syncytial virus
Pneumonia virus of mice
Turkey rhinotracheitis virus
Family Rhabdoviridae
Genus Lyssavirus
Rabies virus
Genus Vesiculovirus
Vesicular stomatitis virus
Genus Ephemerovirus
Bovine ephemeral fever virus
Family Filovirdae
Genus Filovirus
Marburg virus
For many of these viruses, no vaccines of any
kind are available. Thus, there is a need to develop
vaccines against such human and animal pathogens. Such
vaccines would have to elicit a protective immune
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response in the recipient. The qualitative and
quantitative features of such a favorable response are
extrapolated from those seen in survivors of natural
virus infection, who, in general, are protected from
reinfection by the same or highly related viruses for
some significant duration thereafter.
A variety of approaches can be considered in
seeking to develop such vaccines, including the use of:
(1) purified individual viral protein vaccines (subunit
vaccines); (2) inactivated whole virus preparations;
and (3) live, attenuated viruses.
Subunit vaccines have the desirable feature
of being pure, definable and relatively easily produced
in abundance by various means, including recombinant
DNA expression methods. To date, with the notable
exception of hepatitis B surface antigen, viral subunit
vaccines have generally only elicited short-lived
and/or inadequate immunity, particularly in naive
recipients.
Formalin inactivated whole virus preparations
of polio (IPV) and hepatitis A have proven safe and
efficacious. In contrast, immunization with similarly
inactivated whole viruses such as respiratory syncytial
virus and measles virus vaccines elicited unfavorable
immune responses and/or response profiles which
predisposed vaccinees to exaggerated or aberrant
disease when subsequently confronted with the natural
or ~~wild-type~~ virus.
Early attempts (1966) to vaccinate young
children used a parenterally administered formalin-
inactivated RSV vaccine. Unfortunately, several field
trials of this vaccine revealed serious adverse
reactions -- the development of a severe illness with
unusual features following subsequent natural infection
with RSV (Bibliography entries 1,2). It has been
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suggested that this formalinized RSV antigen elicited
an abnormal or unbalanced immune response profile,
predisposing the vaccinee to RSV disease (3,4).
Thereafter, live, attenuated RSV vaccine
candidates were generated by cold passage or chemical
mutagenesis. These RSV strains were found to have
reduced virulence in seropositive adults.
Unfortunately, they proved either over or under-
attenuated when given to seronegative infants; in some
cases, they also were found to lack genetic stability
(5,6). Another vaccination approach using parenteral
administration of live virus was ineffective and
efforts along this line were discontinued (7).
Notably, these live RSV vaccines were never associated
with disease enhancement as observed with the formalin-
inactivated RSV vaccine described above. Currently,
there are no RSV vaccines approved for administration
to humans, although clinical trials are now in progress
with cold-passaged, chemically mutagenized strains of
RSV designated A2 and B-1.
Appropriately attenuated live derivatives of
wild-type viruses offer a distinct advantage as vaccine
candidates. As live, replicating agents, they initiate
infection in recipients during which viral gene
products are expressed, processed and presented in the
context of the vaccinee~s specific I~iC class I and II
molecules, eliciting humoral and cell-mediated immune
responses, as well as the coordinate cytokine and
chemokine patterns, which parallel the protective
immune profile of survivors of natural infection.
This favorable immune response pattern is
contrasted with the delimited responses elicited by
inactivated or subunit vaccines, which typically are
largely restricted to the humoral immune surveillance
arm. Further, the immune response profile elicited by
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some formalin inactivated whole virus vaccines, e.g.,
measles and respiratory syncytial virus vaccines
developed in the 1960's, have not only failed to
provide sustained protection, but in fact have led to a
predisposition to aberrant, exaggerated, and even fatal
illness, when the vaccine recipient later confronted
the wild-type virus.
While live, attenuated viruses have highly
desirable characteristics as vaccine candidates, they
have proven to be difficult to develop. The crux of
the difficulty lies in the need to isolate a derivative
of the wild-type virus which has lost its disease-
producing potential (i.e., virulence), while retaining
sufficient replication competence to infect the
recipient and elicit the desired immune response
profile in adequate abundance.
Historically, this delicate balance between
virulence and attenuation has been achieved by serial
passage of a wild-type viral isolate through different
host tissues or cells under varying growth conditions
(such as temperature). This process presumably favors
the growth of viral variants (mutants), some of which
have the favorable characteristic of attenuation.
Occasionally, further attenuation is achieved through
chemical mutagenesis as well.
This propagation/passage scheme typically
leads to the emergence of virus derivatives which are
temperature sensitive, cold-adapted and/or altered in
their host range -- one or all of which are changes
from the wild-type, disease-causing viruses -- i.e.,
changes that may be associated with attenuation.
Several live virus vaccines, including those
for the prevention of measles and mumps (which are
paramyxoviruses), and for protection against polio and
rubella (which are positive strand RNA viruses), have
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been generated by this approach and provide the
mainstay of current childhood immunization regimens
throughout the world.
Nevertheless, this means for generating
attenuated live virus vaccine candidates is lengthy
and, at best, unpredictable, relying largely on the
selective outgrowth of those randomly occurring genomic
mutants with desirable attenuation characteristics.
The resulting viruses may have the desired phenotype in
vitro, and even appear to be attenuated in animal
models. However, all too often they remain either
under- or overattenuated in the human or animal boat
for whom they are intended as vaccine candidates.
Even as to current vaccines in use, there is
still a need for more efficacious vaccines. For
example, the current measles vaccines provide
reasonably good protection. However, recent measles
epidemics suggest deficiencies in the efficacy of
current vaccines. Despite maternal immunization, high
rates of acute measles infection have occurred in
children under age one, reflecting the vaccines'
inability to induce anti-measles antibody levels
comparable to those developed following wild-type
measles infection (8,9,10). As a result, vaccine-
immunized mothers are less able to provide their
infants with sufficient transplacentally-derived
passive antibodies to protect the newborns beyond the
first few months of life.
Acute measles infections in previously
immunized adolescents and young adults point 'to an
additional problem. These secondary vaccine failures
indicate limitations in the current vaccines' ability
to induce and maintain antiviral protection that is
both abundant and long-lived (11,12,13). Recently, yet
another potential problem was revealed. The
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hemagglutinin protein of wild-type measles isolated
over the past 15 years has shown a progressively
increasing distance from the vaccine strains (14).
This "antigenic drift" raises legitimate concerns that
the vaccine strains may not contain the ideal antigenic
repertoire needed to provide optimal protection. Thus,
there is a need for improved vaccines.
Rational vaccine design would be assisted by
a better understanding of these viruses, in particular,
by the identification of the virally encoded
determinants of virulence as well as those genomic
changes which are responsible for attenuation.
Previously, in U.S. provisional application
60/026,823 and International application
PCT/US97/16718, both of which are hereby incorporated
by reference, the generation and isolation of
recombinantly-generated, attenuated, nonsegmented,
negative-sense, single stranded RNA viruses of the
Order Mononegavirales having at least one attenuating
mutation in the 3' genomic promoter region and having
at least one attenuating mutation in the RNA polymerase
gene was disclosed. Identification of attenuating
changes in other regions of the genomes of these
viruses would further assist rational vaccine design.
Summary Of The Invention
Accordingly, it is an object of this
invention to identify additional regions of the genomes
of measles virus and human respiratory syncytial virus
subgroup B where mutations result in attenuation of
those viruses.
It is a further object of this invention to
produce recombinantly-generated viruses which
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incorporate such attenuating mutations in their
genomes.
It is still a further object of this
invention to formulate vaccines containing such
attenuated viruses.
These and other objects of the invention as
discussed below are achieved by the generation and
isolation of recombinantly-generated, attenuated,
measles virus or human respiratory syncytial virus
subgroup B having specified attenuating mutations.
In the case of measles virus, one or more
attenuating mutations are selected from the group
consisting of: (1) for the N gene, nucleotide changes
which produce changes in an amino acid selected from
the group consisting of residues 129 (glutamine
lysine), 148 (glutamic acid -~ glycine) and 479 (serine
threonine); (2) for the P gene, nucleotide changes
which produce changes in an amino acid selected from
the group consisting of residues 225 (glutamic acid ->
glycine), 275 (cysteine -~ tyrosine) and 439 (leucine
--~ proline); (3) for the C gene, nucleotide changes
which produce changes in an amino acid selected from
the group consisting of residues 73 (alanine -~
valine), 104 (methionine ~ threonine) and 134 (serine
-~ tyrosine); and (4) for the F gene-end signal (the
cis-acting transcription termination signal), the
change at nucleotide 7243 (T --~ C) , where these
nucleotides, as well as others delineated in this
application (unless stated otherwise), are presented in
positive strand, antigenomic, that is, message (coding)
sense.
In the case of human respiratory syncytial
virus subgroup B, there is an attenuating mutation in
the M gene-end signal (the cis-acting transcription
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termination signal) at nucleotide 4199 (T ~ C), where
these nucleotides are presented in positive strand,
antigenomic, that is, message (coding) sense.
In another embodiment of this invention,
S these attenuated measles or human respiratory syncytial
subgroup B viruses are used to prepare vaccines which
elicit a protective immune response against the wild-
type form of each virus.
In yet another embodiment of this invention,
an isolated, positive strand, antigenomic message sense
nucleic acid molecule (or an isolated, negative strand
genomic sense nucleic acid molecule) having the
complete viral nucleotide sequence (whether of wild-
type virus or virus attenuated by non-recombinant
means) is manipulated by introducing one or more of the
attenuating mutations described in this application to
generate an isolated, recombinantly-generated
attenuated measles or human respiratory syncytial
subgroup B virus. Each attenuated virus is then used
to prepare vaccines which elicit a protective immune
response against the wild-type form of each virus.
Brief Description Of The Fictures
Figure 1 depicts the passage history of the
Edmonston measles virus (15). The abbreviations have
the following meanings: HK - human kidney; HA - human
amnion; CE(am) - chick embryo; CEF - chick embryo
fibroblast; DK - dog kidney; WI-38 - human diploid
cells; SK - sheep kidney; * - plaque cloning. The
number following each abbreviation represents the
number of passages.
Figure 2 depicts a map of the measles virus
genome showing putative cis-acting regulatory elements
at and near the genome and antigenome termini. Top - a
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schematic map of the measles virus genome, beginning at
the 3' end with 52 nucleotides of leader sequence (1)
and ending at the 5' terminus with 37 nucleotides of
trailer sequence (t). Gene boundaries are denoted by
S vertical bars; below each gene is the number of
cistronic nucleotides. Bottom - an expanded schematic
view of the 3' extended genomic promoter regions of
genome and antigenome, showing the position and
sequence of the two highly conserved domains, A and B.
The intervening intergenic trinucleotide is denoted as
well. Nascent 5' RNAs encompassing the A' to B'
regions are presumed to contain the regulatory sequence
at which the N protein encapsidation initiates.
Figure 3 depicts a genetic map of the RSV
subgroup B wild-type strains designated 2H and 18537
(top portion), the intergenic sequences of those
strains (middle portion) and the 68 nucleotide overlap
between the M2 and L genes (bottom portion). The RSV
2B stain has six fewer nucleotides in the G gene,
encoding two fewer amino acid residues in the G
protein, as compared to the 18537 strain. The 2B
strain has 145 nucleotides in the 5' trailer region, as
compared to 149 nucleotides in the 18537 strain. The
28 strain has one more nucleotide in each of the NS-l,
NS-2 and N genes, and one fewer nucleotide in each of
the M and F genes, as compared to the 18537 strain.
Figure 4 depicts a Northern blot analysis of
poly (A)+ RNA isolated from Vero cells infected with
RSV subgroup A and B viruses. A 1.5 hour
autoradiograph of the blot is shown. Lanes 1-2 contain
RNA isolated from cells infected with RSV subgroup A
strains (lane 1, 3A; lane 2, A2). Lanes 3-7 contain
RNA isolated from cells infected with RSV subgroup B
strains: lane 3, B1; lane 4, 2B; lane 5, 2B33F; lane
6, 2B33F TS(+); lane 7, 18537. Monocistronic M gene
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and bicistronic M:SH gene transcripts are indicated by
arrows.
Figure 5 depicts a ribonuclease protection
assay of poly (A)+ RNA extracted from Vero cells
infected with RSV subgroup B wild-type 2B, mutant
2B33F, and 2B33F TS(+) revertant viruses to assess the
ratio of monocistronic M and SH mRNAs to bicistronic
M:SH transcripts for each virus. A 3 hour
autoradiograph of the gel is shown. Protected probe
fragments are indicated by arrows. Radiolabelled RNA
markers (M) were included as size standards: Lane l,
yeast RNA minus RNase; lane 2, yeast RNA plus RNase;
lane 3, 2B RNA plus RNase; lane 4, 2B33F RNA plus
RNase; lane 5, 2B33F TS+ RNA plus RNase; lane 6, yeast
RNA plus RNase; lane 7, yeast RNA minus RNase. RSV 2B-
specific probe was used in lanes 1-3 and 2B33F-specific
probe was used in lanes 4-7.
Figure 6 depicts a Northern blot analysis of
poly (A)+ RNA isolated from Vero cells infected with
RSV subgroup A and B viruses. A 1.5 hour
autoradiograph of the blot is shown. Lanes 1-2 contain
RNA isolated from cells infected with RSV subgroup A
strains (lane l, 3A; lane 2, A2). Lanes 3-7 contain
RNA isolated from cells infected with RSV subgroup B
strains (lane 3, B1; lane 4, 2B; lane 5, 2B33F; lane 6,
2B33F TS(+); lane 7, 18537). Monocistronic SH gene and
bicistronic M:SH gene transcripts are indicated by
arrows.
Detailed Descr~tion Of The Invention
Transcription and replication of negative-
sense, single stranded RNA viral genomes are achieved
through the enzymatic activity of a multimeric protein
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acting on the ribonucleoprotein core (nucleocapsid).
Naked genomic RNA cannot serve as a template. Instead,
these genomic sequences are recognized only when they
are entirely encapsidated by the N protein into the
nucleocapsid structure. It is only in that context
that the genomic and antigenomic terminal promoter
sequences are recognized to initiate the transcription
or replication pathways.
All paramyxoviruses require the two viral
proteins, L and P, for these polymerase pathways to
proceed. The pneumoviruses, including RSV, also
require the transcription elongation factor, M2, for
the transcriptional pathway to proceed efficiently.
Additional cofactors may also play a role, including
perhaps the virus-encoded NS1 and NS2 proteins, as well
as perhaps host-cell encoded proteins.
However, considerable evidence indicates that
it is the L protein which performs most, if not all,
the enzymatic processes associated with transcription
and replication, including initiation, and termination
of ribonucleotide polymerization, capping and
polyadenylation of mRNA transcripts, methylation and
perhaps specific phosphorylation of P proteins. The L
protein's central role in genomic transcription and
replication is supported by its large size, sensitivity
to mutations, and its catalytic level of abundance in
the transcriptionally active viral complex (16).
These considerations led to the proposal that
L proteins consist of a linear array of domains whose
concatenated structure integrates discrete functions
(17). Indeed, three such delimited, discrete elements
within the negative-sense virus L protein have been
identified based on their relatedness to defined
functional domains of other well-characterized
proteins. These include: (1) a putative RNA template
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recognition and/or phosphodiester bond formation
domain; (2) an RNA binding element; and (3) an ATP
binding domain. All prior studies of L proteins of
nonsegmented negative-sense, single stranded RNA
viruses have revealed these putative functional
elements (17) .
Without being bound by the following, it is
reasonable to presume that these non-protein coding,
promoter and other cis-acting genomic regulatory
domains are important determinants of the efficiency
with which transcription and replication by measles
virus (MV) and other viruses of the Order
Mononegavirales are actualized, in association with the
L protein, and that they may therefore be virulence
determinants for these viruses as well.
In summary, the invention is believed to
encompass a set of changes in several measles virus
genes and one cis-acting regulatory domain, and one
change in an RSV subgroup B cis-acting regulatory
domain, which result in attenuation of each virus while
retaining sufficient ability of the virus to replicate.
Therefore, as part of a rational vaccine design, such
mutations are introduced to provide the desired balance
of replication efficiency and immunogenicity: so that
the virus vaccine is no longer able to produce disease,
yet retains its capacity to infect the vaccinee~s
cells, to express sufficiently abundant gene products
to elicit the full spectrum and profile of desirable
immune responses, and to reproduce and disseminate
sufficiently to maximize the abundance of the immune
response elicited.
Animal studies have demonstrated a decrease
in viral replication sufficient to avoid illness but
adequate to elicit the desired immune response. This
likely represents a decrease in transcription, a
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decrease in gene expression of virally encoded
proteins, and/or a decrease in antisense templates and,
therefore, the production of fewer new genomes. The
resulting attenuated viruses are significantly less
S virulent than the wild-type.
The attenuating mutations described herein
may be introduced into viral strains by two methods:
(1) Conventional means such as chemical
mutagenesis during virus growth in cell cultures to
which a chemical mutagen has been added, selection of
virus that has been subjected to passage at suboptimal
temperature in order to select temperature sensitive
and/or cold adapted mutations, identification of mutant
virus that produce small plaques in cell culture, and
passage through heterologous hosts to select for host
range mutations. These viruses are then screened for
atteriuation of their biological activity in an animal
model. Attenuated viruses are subjected to nucleotide
sequencing of their coding and integenic regions to
locate the sites of attenuating mutations. Once this
has been done, method (2) is then carried out.
(2) A preferred means of introducing
attenuating mutations comprises making predetermined
mutations using site-directed mutagenesis. These
mutations are identified either by method (1) or by
reference to closely-related viruses whose attenuating
mutations are already known. One or more mutations as
defined herein are introduced into measles virus or RSV
subgroup 8 strains. Cumulative effects of different
combinations of coding and non-coding changes can also
be assessed.
The mutations to the N, P and/or C genes
and/or the F gene-end signal of measles virus, or to
the M gene-end signal of RSV subgroup B are introduced
by standard recombinant DNA methods into a DNA copy of
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the viral genome. This may be a wild-type or a
modified viral genome background (such as viruses
modified by method (1)), thereby generating a new
virus. Infectious clones or particles containing these
attenuating mutations are generated using the cDNA
"rescue" system, which has been applied to a variety of
viruses, including Sendai virus (18); measles virus
(19); respiratory syncytial virus (20); PIV-3 (21);
rabies (22); vesicular stomatitis virus (VSV) (15); and
rinderpest virus (23); these references are hereby
incorporated by reference. See, for measles virus
rescue, published International patent application WO
97/06270, designating the United States (24); for RSV
rescue, published International patent application WO
97/12032, designating the United States (25); these
applications are hereby incorporated by reference.
Briefly, all Mononegavirales rescue systems
can be summarized as follows: Each requires a cloned
DNA equivalent of the entire viral genome placed
between a suitable DNA-dependent RNA polymerase
promoter (e.g., the T7 RNA polymerase promoter) and a
self-cleaving ribozyme sequence (e. g., the hepatitis
delta ribozyme) which is inserted into a propagatable
bacterial plasmid. This transcription vector provides
the readily manipulable DNA template from which the RNA
polymerase (e. g., T7 RNA polymerase) can faithfully
transcribe a single-stranded RNA copy of the viral
antigenome (or genome) with the precise, or nearly
precise, 5' and 3' termini. The orientation of the
viral genomic DNA copy and the flanking promoter and
ribozyme sequences determine whether antigenome or
genome RNA equivalents are transcribed. Also required
for rescue of new virus progeny are the virus-specific
traps-acting proteins needed to encapsidate the naked,
single-stranded viral antigenome or genome RNA
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transcripts into functional nucleocapsid templates:
the viral nucleocapsid (N or NP) protein, the
polymerise-associated phosphoprotein (P) and the
polymerise (L) protein. These proteins comprise the
active viral RNA-dependent RNA polymerise which must
engage this nucleocapsid template to achieve
transcription and replication.
The traps-acting proteins required for
measles virus rescue are the encapsidating protein N,
and the polymerise complex proteins, P and L. For RSV,
the virus-specific traps-acting proteins include N, P
and L, plus an additional protein, M2, the RSV-encoded
transcription elongation factor.
Typically, these viral traps-acting proteins
are generated from one or more plasmid expression
vectors encoding the required proteins, although some
or all of the required traps-acting proteins may be
produced within mammalian cells engineered to contain
and express these virus-specific genes and gene
products as stable transformants.
The typical (although not necessarily
exclusive) circumstances for rescue include an
appropriate mammalian cell milieu in which T7
polymerise is present to drive transcription of the
antigenomic (or genomic) single-stranded RNA from the
viral genomic cDNA-containing transcription vector.
Either cotranscriptionally or shortly thereafter, this
viral antigenome (or genome) RNA transcript is
encapsidated into functional templates by the
nucleocapsid protein and engaged by the required
polymerise components produced concurrently from co-
transfected expression plasmids encoding the required
virus-specific traps-acting proteins. These events and
processes lead to the prerequisite transcription of
viral mRNAs, the replication and amplification of new
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genomes and, thereby, the production of novel viral
progeny, i.e., rescue.
For the rescue of rabies, VSV and Sendai, T7
polymerise is provided by recombinant vaccinia virus
S VTF7-3. This system, however, requires that the
rescued virus be separated from the vaccinia virus by
physical or biochemical means or by repeated passaging
in cells or tissues that are not a good host for
poxvirus. For MV cDNA rescue, this requirement is
avoided by creating a cell line that expresses T7
polymerise, as well as viral N and P proteins. Rescue
is achieved by transfecting the genome expression
vector and the L gene expression vector into the helper
cell line. Advantages of the host-range mutant of the
vaccinia virus, MVA-T7, which expresses the T7 RNA
polymerise, but produces little or no infectious
progeny in mammalian cells, are exploited to rescue
RSV, Rinderpest virus and MV. After simultaneous
expression of the necessary encapsidating proteins,
synthetic full length antigenomic viral RNA are
encapsidated, replicated and transcribed by viral
polymerise proteins and replicated genomes are packaged
into infectious virions. In addition to such
antigenomes, genome analogs have now been successfully
rescued for Sendai and PIV-3 (21,26).
The rescue system thus provides a composition
which comprises a transcription vector comprising an
isolated nucleic acid molecule encoding a genome or
antigenome of a nonsegmented, negative-sense, single
stranded RNA virus of the Order Mononegavirales having
(a) for measles virus, at least one attenuating
mutation in the N, P or C genes or the F gene-end
signal; and (b) for RSV subgroup 8, at least one
attenuating mutation in the M gene-end signal, together
with at least one expression vector which comprises at
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least one isolated nucleic acid molecule encoding the
traps-acting proteins necessary for encapsidation,
transcription and replication (e.g., N, P and L for
measles virus; N, P, L and M2 for RSV). Host cells are
then transformed or transfected with the at least two
expression vectors just described. The host cells are
cultured under conditions which permit the co-
expression of these vectors so as to produce the
infectious attenuated virus.
The rescued infectious virus is then tested
for its desired phenotype (temperature sensitivity,
cold adaptation, plaque morphology, and transcription
and replication attenuation), first by in vitro means.
The mutations in the N, P or C genes or the F gene-end
IS signal of measles virus and in the M gene-end signal of
RSV subgroup B are also tested using the minireplicon
system where the required traps-acting encapsidation
and polymerase activities are provided by wild-type or
vaccine helper viruses, or by plasmids expressing the
N, P and different L genes harboring gene-specific
attenuating mutations (19,27,83).
If the attenuated phenotype of the rescued
virus is present, challenge experiments are conducted
with an appropriate animal model. Non-human primates
provide the preferred animal model for the pathogenesis
of human disease. These primates are first immunized
with the attenuated, recombinantly-generated virus,
then challenged with the wild-type form of the virus.
Monkeys are infected by various routes, including but
not limited to intranasal, intratracheal or
subcutaneous routes of inoculation (28).
Experimentally infected rhesus and cynomolgus macaques
have also served as animal models for studies of
vaccine-induced protection against measles (29). For
evaluating attenuation levels of RSV mutants, the
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cotton rat or mouse models may also be used (30,31).
Protection is measured by such criteria as disease
signs and symptoms, survival, virus shedding and
antibody titers. If the desired criteria are met, the
attenuated, recombinantly-generated virus is considered
a viable vaccine candidate for testing in humans. The
"rescued" virus is considered to be "recombinantly-
generated", as are the progeny and later generations of
the virus, which also incorporate the attenuating
mutations.
Even if a "rescued" virus is underattenuated
or overattenuated relative to optimum levels for
vaccine use, this is information which is valuable for
developing such optimum strains.
Optimally, a codon containing an attenuating
point mutation may be stabilized by introducing a
second or a second plus a third mutation in the codon
without changing the amino acid encoded by the codon
bearing only the attenuating point mutation.
Infectious virus clones containing the attenuating and
stabilizing mutations are also generated using the eDNA
"rescue" system described above.
In one embodiment of the invention, measles
virus mutations are assessed, because sequence data are
now available as described herein for the disease-
causing wild-type virus and for the disease-preventing
vaccines which have a demonstrated history of efficacy.
Measles virus was first isolated in tissue
culture in 1954 (32) from an infected patient named
David Edmonston. This Edmonston strain of measles
became the progenitor for many live-attenuated measles
vaccines including Moraten, which is the current
vaccine in the United States (AttenuvaxTM; Merck Sharp &
Dohme, West Point, PA) and was licensed in 1968 and has
proven to be efficacious.
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Aggressive immunization programs instituted
in the mid to late 1960s resulted in the precipitous
drop in reported measles cases from near 700,000 in
1965 to 1500 in 1983. In parallel, other vaccine
strains were also developed from the Edmonston strain
(see Fig. 1), Schwarz (Institut Merieux, Lyon, France),
Zagreb (Zagreb, Yugoslavia) and AIK-C (Japan). These
other vaccines have also proven to be efficacious and
have been used extensively. An early, reactogenic,
underattenuated vaccine strain (RubeovaxT"": Merck Sharp
& Dohme; this may be the same as the Edmonston H
strain) produced measles-like illness in children and
its use thus was discontinued. It, however, was
further attenuated successfully to produce the Moraten
vaccine strain (see Fig. 1) (33). Live measles virus
vaccine provides a success story of the development of
an efficacious vaccine and provides a model for
understanding the molecular mechanisms of viral vaccine
attenuation among nonsegmented, negative-sense, single
stranded RNA viruses.
Because of its significance as a major cause
of human morbidity and mortality, measles virus (MV)
has been quite extensively studied. MV is a large,
relatively spherical, enveloped particle composed of
two compartments, a lipoprotein membrane and a
ribonucleoprotein particle core, each having distinct
biological functions (34). The virion envelope is a
host cell-derived plasma membrane modified by three
virus-specified proteins: The hemagglutinin (H;
approximately 80 kilodaltons (kD)) and fusion (F1,Z;
approximately 60 kD) glycoproteins project on the
virion surface and confer host cell attachment and
entry capacities to the viral particle (16).
Antibodies to H and/or F are considered protective
since they neutralize the virus' ability to initiate
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infection (35,36,37). The matrix (M; approximately 37
kD) protein is the amphipathic protein lining the
membrane's inner surface, which is thought to
orchestrate virion morphogenesis and thus consummate
virus reproduction (38). The virion core contains the
15,894 nucleotide long genomic RNA upon which template
activity is conferred by its intimate association with
approximately 2600 molecules of the approximately 60 kD
nucleocapsid (N) protein (39,40,41). Loosely
associated with this approximately one micron long
helical ribonucleoprotein particle are enzymatic levels
of the viral RNA dependent RNA polymerase (L;
approximately 240 kD) which in concert with the
polymerase cofactor (P; approximately 70 kD), and
perhaps yet other virus-specified as well as
host-encoded proteins, transcribes and replicates the
MV genome sequences (42).
Prior to International application
PCT/US97/16718, the entire nucleotide sequences (only
for the Edmonston 8 laboratory strain and the AIR-C
vaccine strain), coding potential, and organization of
the MV genome had been reported (34). The six virion
structural proteins are encoded by six contiguous,
non-overlapping genies which are arrayed as follows:
3'-N-P-M-F-H-L-5'. Two additional MV gene products of
as yet uncertain function have also been identified.
These two nonstructural proteins, known as C
(approximately 20 kD) and V (approximately 45 kD), are
both encoded by the P gene, the former by a second
reading frame within the P mRNA; the latter by a
cotranscriptionally edited P gene-derived mRNA which
encodes a hybrid protein having the amino terminal
sequences of P and a new zinc finger-like cysteine-rich
carboxy terminal domain (16).
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In addition to the sequences encoding the
virus-specified proteins, the MV genome contains
distinctive non-protein coding domains resembling those
directing the transcriptional and replicative pathways
of related viruses (16,43). These regulatory signals
lie at the 3' and 5' ends of the MV genome and in short
internal regions spanning each intercistronic boundary.
The former encode the putative promoter and/or
regulatory sequence elements directing genomic
transcription, genome and antigenome encapsidation, and
replication. The latter signal transcription
termination and polyadenylation of each monocistronic
viral mRNA and then reinitiation of transcription of
the next gene. In general, the MV polymerase complex
appears to respond to these signals much as the
RNA-dependent RNA polymerases of other non-segmented
negative strand RNA viruses (16,43,44,45).
Transcription initiates at or near the 3' end
of the MV genome and then proceeds in a 5' direction
producing monocistronic mRNAs (41,43,46). As the
polymerase traverses the MV genomic template, it
encounters putative stop/start signals which, in 3' to
5' order, are: a semi-conserved transcription
termination/polyadenylation signal (A/G U/C UA A/U NN
A,, where N may be any of the four bases) at which each
monocistronic RNA is completed; a non-transcribed
intergenic trinucleotide punctuation mark (CUU; except
at the H:L boundary where it is CGU); and a
semiconserved start signal for transcription initiation
of the next gene (AGG A/G NN C/A A A/G G A/U, where N
may be any of the four bases) (46,47). Since some
polymerase complexes fail to reinitiate, the abundance
of each MV mRNA diminishes in parallel with the
distance of the encoding gene from the genomic 3' end.
This mRNA gradient directly corresponds to the relative
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abundance of each virus-specified protein. This
indicates that MV protein expression is ultimately
controlled at the transcriptional level (45).
The 3' and 5' MV genomic termini contain
non-protein coding sequences with distinct parallels to
the leader and trailer RNA encoding regions of VSV
(43). Nucleotides 1-55 define the region between the
genomic 3' terminus and the beginning of the N gene,
while 37 additional nucleotides can be found between
the end of the L gene and the 5' terminus of the
genome. However, unlike VSV, or even the
paramyxoviruses Sendai and NDV, MV does not transcribe
these terminal regions into short, unmodified (+) or
(-) sense leader RNAs (48,49,50). Instead, leader
readthrough transcripts, including full-length
polyadenylated leader:N, leader:N:P, leader:N:P:M, and
of course full-length antigenome MV RNAs are
transcribed (49,50). Thus, the short leader
transcript, the key operational element determining the
switch from transcription to replication of the VSV
single-stranded, negative polarity genome (51,52,53),
seems absent in MV. This leads to consideration and
exploration of alternative models for this crucial
reproductive event (43).
Measles virus, as well as all other
Mononegavirales except the rhabdoviruses, appears to
have extended its terminal regulatory domains beyond
the confines of leader and trailer encoding sequences
(43). For measles, these regions encompass the 107 3'
genomic nucleotides (the "3' genomic promoter region",
also referred to as the "extended promoter", which
comprises 52 nucleotides encoding the leader region,
followed by three intergenic nucleotides, and 52
nucleotides encoding the 5' untranslated region of N
mRNA) and the 109 5' end nucleotides (69 encoding the
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3' untranslated region of L mRNA, the intergenic
trinucleotide and 37 nucleotides encoding the trailer).
Within these 3' terminal approximately 100 nucleotides
of both the genome and antigenome are two short regions
of shared nucleotide sequence: 14 of 16 nucleotides at
the absolute 3' ends of the genome and antigenome are
identical. Internal to those termini, an additional
region of 12 nucleotides of absolute sequence identity
have bean located. Their position at and near the
sites at which the transcription of the MV genome must
initiate and replication of the antigenome must begin,
suggests that these short unique sequence domains
encompass an extended promoter region.
These discrete sequence elements may dictate
alternative sites of transcription initiation -- the
internal domain mandating transcription initiation at
the N gene start site, and the 3' terminal domain
directing antigenome production (43,49,54). In
addition to their regulatory role as cis-acting
determinants of transcription and replication, these 3'
extended genomic and antigenomic promoter regions
encode the nascent 5' ends of antigenome and genome
RNAs, respectively. Within these nascent RNAs reside
as yet unidentified signals for N protein nucleation,
another key regulatory element required for
nucleocapsid template formation and consequently for
amplification of transcription and replication. Figure
2 schematically shows the location and sequence of
these highly conserved, putative cis-acting regulatory
domains.
Terminal non-protein coding regions similar
in location, size and spacing are present in the -
genomes of other members of the genus Paramyxoviridae,
though only 8-11 of their absolute terminal nucleotides
are shared by MV (43,55). The genomic terminii of the
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Morbillivirus canine distemper virus (CDV) displays a
greater degree of homology with its MV relative: 73~
of the nucleotides of the leader and trailer sequences
of these two viruses are identical, including 16 of 18
at the absolute 3' termini and 17 of 18 at their 5'
ends (56). No accessory internal CDV genomic domain-
sharing homology to that of the MV extended promoter
has been found. However, there is a 20 nucleotide long
stretch lying between CDV genomic nucleotides 85 and
104 and 15,587 and 15,606 in which 15 of the 20
nucleotides are complementary (Gene Bank accession
number AF 14953). This indicates that CDV, like MV
contains an additional region within its non-coding 3'
genomic and antigenomic ends that may provide important
cis-acting promoter and/or regulatory signals (56).
Additionally, the precise length of the 3'-
leader region (55 nucleotides) is identical among
several members of the Family Paramyxoviridae (MV, CDV,
PIV-3, HPV-3, SV and NDV). Further evidence for the
importance of these extended, non-protein coding
regions comes from analyses of a large number of
distinct copy-back Defective Interfering genomes (DIs)
recently cloned from subacute sclerosing
panencephalitis (SSPE) brain tissue. No DI with a stem
shorter than the 95 5' terminal genomic nucleotides was
found. This indicates that the minimal signals needed
for My DI RNA replication and encapsidation extend well
beyond the 37 nucleotide long trailer sequence to
encompass the additional internal putative regulatory
domain ( 57 ) .
In all Paramyxoviruses, the cis-acting
signals required for essential viral functions,
including replication, transcription and encapsidation
are contained in the non-coding genomic termini. The
obligatory traps-acting elements for functionality are
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contained in the N, P and L genes. Mutations in any of
these regions may result in alteration of vital
functions, including attenuation of viral
transcription/replication efficiency.
S The attenuation potential in the cis-acting
sequence elements and in the tracts-acting protein genes
has been demonstrated in several viral systems by
sequence analysis of their genomes (58,59).
The measles embodiment of this invention
involved an analysis of the nucleotide sequences of the
progenitor Edmonston wild-type MV isolate, together
with available measles vaccine strains derived from
this isolate (see Figure 1). Independent other wild-
type isolates were examined for comparative purposes as
well. In particular, the emphasis was on regions other
than the 3' genomic promoter region and the L gene;
those regions were the focus of International
application PCT/US97/16718.
The nucleotide sequences (in positive strand,
antigenomic, message sense) of four wild-type and five
vaccine measles strains are set forth as follows with
reference to the appropriate SEQ ID NOS. contained
herein:
Virus Nucleotide Seguence
Wild-Tune
Edmonston SEQ ID NO:1
1977 SEQ ID N0:2
1983 SEQ ID N0:3
Montefiore SEQ ID N0:4
Vaccine
RubeovaxT" SEQ ID N0:5
Moraten SEQ ID N0:6
Zagreb SEQ ID N0:7
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AIR-C SEQ ID N0:8
Each measles virus genome listed above is
15,894 nucleotides in length. Translation of the N
gene starts with the codon at nucleotides 108-110; the
translation stop codon is at nucleotides 1683-1685.
The translated N protein is 525 amino acids long.
Translation of the P gene starts with the codon at
nucleotides 1807-1809; the translation stop codon is at
nucleotides 3328-3330. The translated P protein is 506
amino acids long. Translation of the C gene starts
with the codon at nucleotides 1829-1831; the
translation stop codon is at nucleotides 2387-2389.
The translated C protein is 189 amino acids long.
Translation of the F gene starts with the codon at
nucleotides 5449-5451; the translation stop codon is at
nucleotides 7108-7110. The translated F protein is 553
amino acids long. The F gene stop/polyadenylation
signal includes an eleven nucleotide gene-and signal at
nucleotides 7237-7247, followed by an intergenic region
at nucleotides 7248-7250 and the H gene-start signal at
nucleotides 7251-7260.
Note that nucleotide 2499 of 1983 wild-type
measles virus is indicated as "G" in SEQ ID N0:3. In
fact, the base is actually a mixture of "G" and ~C".
Also note that nucleotide 2143 of RubeovaxT"" vaccine
virus is indicated as "T" in SEQ ID N0:5. In nine
clones sequenced, this base was "T" in seven and "C" in
two; thus, this base can be "T" or nC".
In addition, the Schwarz vaccine virus genome
is identical to that of the Moraten vaccine virus
genome (SEQ ID N0:6).
An analysis of the coding and noncoding
(intercistronic) regions of the MV genome was carried
out. Nucleotide and amino acid differences
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distinguishing the N, P and C gene and protein
sequences, and nucleotide differences distinguishing
the F gene-end signal in the F/H intercistronic region
of the Edmonston wild-type isolate, vaccine strains and
other independently~isolated wild-type viruses were
compared and aligned (see Tables 3-5 in Example 1
below) .
As shown in Table 3, there are five
nucleotide changes in the N genes of MV vaccine strains
compared to the progenitor Edmonston wild-type isolate.
Two of these changes, at nucleotides 275 and 623, were
conservative changes which did not result in changes to
the amino acid sequence. Three changes, at nucleotides
492, 550 and 1542, resulted in changes to the amino
acid sequence of certain of the vaccine strains: (1)
a change from a "C" to an "A" at nucleotide 492
resulted in a mutation from glutamine to lysine at
amino acid 129 for the AIR-C vaccine strain; (2) a
change from an "A" to a "G" at nucleotide 550 resulted
in a mutation from glutamic acid to glycine at amino
acid 148 for the Moraten and Schwarz vaccine strains;
and (3) a change from a "T" to an "A" at nucleotide
1542 resulted in a mutation from serine to threonine at
amino acid 479 for the Rubeovax~", Moraten and Schwarz
vaccine strains. Because none of these three mutations
were present in any of the later wild-type isolates,
these three N gene mutations are potentially
attenuating in the vaccine strains.
Without being bound by theory, the
attenuating phenotype of these three N gene mutations
may be based upon the following discussion. The N
protein must serve a number of functions in the measles
virus life cycle. It must be able to interact with the
viral genomic RNA and other copies of N to form the
nucleocapsid complex in which the MV genome is always
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found. It interacts with the polymerise complex to
allow transcription and replication. It has also been
found to interact with the P protein separate from the
replication complex. All of these functions could be
points at which mutations might result in attentuation
by affecting replicational efficiency of the virus.
Based on the deletion analysis of Bankamp et
al. (60), the changes observed in the Edmonston vaccine
lineage fall into areas that affect the functionality
of the N protein as outlined below:
(1) Changes at amino acid 129 (glutamine to
lysine in AIK-C) and amino acid 148 (glutamic acid to
glycine in Moraten and Schwarz) both fall into a region
necessary for the interaction of N and P proteins in
solution. This interaction helps to keep the N protein
from aggregating in a non-nucleocapsid specific manner.
The P protein is also thought to serve as a chaperone,
delivering N protein to the replicating genome for use
in encapsidation. In Sendai virus, the first 400 amino
acids comprise a domain that is also involved in the
ability to encapsidate RNA, suggesting that at least
some part of this region interacts with the RNA.
(2) The change at amino acid 479 (serine to
threonine in RubeovaxT'", Moraten, and Schwarz) falls
within an area, that when deleted results in the
formation of unstructured aggregates; this suggests it
is an area of N:N interaction. This carboxy-terminal
region of the N protein has also been shown in Sendai
virus to interact with the P protein when assembled in
nucleocapsids. In addition, the sequence from amino
acid 400 to the carboxy-terminus (amino acid 525) shows
a noticably higher level of variation among wild-type
MV N proteins compared to the rest of the protein.
As shown in Table 4, there are three
nucleotide change in the P gene and three nucleotide
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changes in the C gene of MV vaccine strains compared to
the progenitor Edmonston wild-type isolate. The first
change in the P gene, from "A" to "G" at nucleotide
2480, resulted in a mutation from glutamic acid to
glycine at amino acid 225 for all vaccine strains;
however, this change was not present in any of the
later wild-type isolates. This unique mutation in the
P protein is in one of the less conserved Morbillivirus
amino acids: It is glutamic acid in both the wild-type
and vaccine strains of the rinderpest virus, and
cysteine in the canine distemper and phocine distemper
virus strains (58). However, because this unique
mutation is common to all the MV vaccine strains
examined, but was not present in the later wild-type
isolates, a.t is viewed as a potentially attenuating
mutation.
The P and V mRNAs share the same start codon
and the first 231 amino acids of the P and V proteins
are identical. The V mRNA has an extra "G" between
nucleotides 2498 and 2499 of the P mRNA. Editing takes
place during transcription when an extra non-template-
directed "G" residue is inserted between nucleotides
2498 and 2499, causing a shift in the reading frame,
whereby the carboxy-terminal 276 amino acids of the P
protein are replaced with a 68 amino acid cysteine-rich
carboxy-terminus of the V protein. However, the
mutation encoding amino acid 225 is located before the
extra "G", so that mutation is potentially attenuating
for both the P and the V proteins. At the present
time, the function of the V protein is not known.
The second change in the P gene, from "G" to
"A" at nucleotide 2630, resulted in a mutation from
cysteine to tyrosine at amino acid 275. The third
change in the P gene, from "T" to "C" at nucleotide
3122, resulted in a mutation from leucine to proline at
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amino acid 439. These two mutations were unique to the
AIK-C vaccine strain -- they were not present in the
other vaccine strains or in any of the wild-type
isolates -- and, therefore, they are viewed as
potentially attenuating.
The first change in the C gene, from "C" to
"T" at nucleotide 2046, resulted in a mutation from
alanine to valine at amino acid 73 for all later wild-
type isolates, as well as for all vaccine strains.
Because of the presence of this mutation in the vaccine
strains, but not in the progenitor wild-type strain,
this mutation is viewed as potentially attenuating.
The next change in the C gene, from "T" to
"C" at nucleotide 2139, resulted in a mutation from
methionine to threonine at amino acid 104 for the
RubeovaxTM, Moraten and Schwarz vaccine strains.
Because this mutation was not present in any of the
later wild-type isolates, this C gene mutation is
potentially attenuating in the vaccine strains.
The third change in the C gene, from "C" to
"A" at nucleotide 2229, resulted in a mutation from
serine to tyrosine at amino acid 134. This mutation
was unique to the AIK-C vaccine strain -- it is not
present in the other vaccine strains or in any of the
other wild-type strains -- and, therefore, it is viewed
as potentially attenuating.
The regions comprising the cis-acting
elements which control transcription initiation and
termination for each MV gene were found to be highly
conserved among all measles viruses examined. With one
exception, the sequences of the gene-start and gene-end
signals were identical for all the viruses analyzed.
However, as shown in Table 5, there was one
mutation in the F gene-end signal which spans
nucleotides 7237-7247 (a.n antigenomic, message sense)
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in two of the vaccine strains -- Moraten and Schwarz --
compared to the progenitor wild-type MV isolate, other
derivative vaccine strains and other wild-type
isolates: At nucleotide position 7243, Moraten and
Schwarz had a "A", whereas the wild-type isolates and
the other vaccine strains had a "T".
This F gene-end signal mutation is thought to
affect the efficiency of transcription termination,
which in turn could affect the levels of F gene
expression, as well as downstream H gene expression.
Decreases in F and H gene expression potentially are
partially responsible for attenuation of the Moraten
and Schwarz vaccine strains. This is consistent with
the suggestion that a decrease in MV F gene expression
may be a factor in attenuation (61). The importance of
mutations in gene-start and gene-end signals was
exemplified by the observation that a change in the RSV
M2 gene-start signal had a profound attenuating effect
on the virus and was associated with the is phenotype
of the virus ( 62 ) .
Based on Table 3 and the foregoing
discussion, the key attenuating sites for the MV N
protein are as follows: amino acid residues 129
(glutamine ~ lysine), 148 (glutamic acid ~ glycine)
and 479 (aerine -~ threonine). Based on Table 4 and
the foregoing discussion, the key attenuating sites for
the P and C proteins are as follows: amino acid
residues 225 (glutamic acid -> glycine), 275 (cysteine
-~ tyrosine) and 439 (leucine ~ proline) for the P
protein and amino acid residues 73 (alanine ~ valine),
104 (methionine ~ threonine) and 134 (serine ~
tyrosine) for the C protein.
It is understood that the nucleotide changes
responsible for these amino acid changes are not
limited to those set forth in Tables 3 and 4 of Example
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1 below; all changes in nucleotides which result in
codons which are translated into these amino acids are
within the scope of this invention.
In addition, based on Table 5 and the
foregoing discussion, the key attenuating mutation for
the F gene-end signal is nucleotide 7243 (T -> C) (in
antigenomic, message sense).
In a further emobodiment of this invention,
the measles virus phenotype is further attenuated by
combining one or more of the above-referenced N, P or C
gene or F gene-end signal mutations with one or more of
each of the coordinate 3' genomic promoter region and L
gene mutations described in International application
PCT/US97/16718, which are as follows: for the MV 3'
genomic promoter region, the mutations are nucleotide
26 (A --~ T) , nucleotide 42 (A -~ T or A ~ C) and
nucleotide 96 (G -~ A) (in antigenomic, message sense),
while for the L protein the mutations are amino acid
residues 331 (isoleucine ~ threonine), 1409 (alanine
--~ threonine), 1624 (threonine ~ alanine), 1649
(arginine ~ methionine), 1717 (aspartic acid -
alanine), 1936 (histidine -> tyrosine), 2074
(glutamine ~ arginine) and 2114 (arginine -> lysine).
Again, it is understood that all changes in nucleotides
which result in codons which are translated into these
amino acids are within the scope of this invention.
Human respiratory syncytial virus (RSV) is
another nonsegmented, negative-sense, single stranded
enveloped RNA virus. RSV belongs to the Subfamily
Pneumovirinae and the genus Pneumovirus (see Table 1).
Two major subgroups of human RSV, designated
A and B, have been identified based on reactivities of
the F and G surface glycoproteins with monoclonal
antibodies (63). More recently, the A and B lineages
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of RSV strains have been confirmed by sequence analysis
(64,65). Bovine, ovine, and caprine strains of this
virus have also been isolated. The host specificity of
the virus is most clearly associated with the G
attachment protein, which is highly divergent between
the human and the bovine/ovine strains (66,67), and may
be influenced, at least in part, by receptor binding.
RSV is the primary cause of serious viral
pneumonia and bronchiolitis in infants and young
children. Serious disease, i.e., lower respiratory
tract disease (LRD), is most prevalent in infants less
than six months of age. It moat commonly occurs in the
nonimmune infant's first exposure to RSV. RSV
additionally is associated with asthma and
hyperreactive airways and it is a significant cause of
mortality in high risk" children with bronchopulmonary
dysplasia and congenital heart disease (CHD). It is
also one of the common viral respiratory infections
predisposing to otitis media in children. In adults,
RSV generally presents as uncomplicated upper
respiratory illness; however, in the elderly it rivals
influenza as a predisposing factor in the development
of serious LRD, particularly bacterial bronchitis and
pneumonia. Disease is always confined to the
respiratory tract, except in the severely
immunocompromised, where dissemination to other organs
can occur. Virus is spread to others by fomites
contaminated with virus-containing respiratory
secretions, and infection initiates through the nasal,
oral, or conjunctival mucosa.
RSV disease is seasonal and virus is usually
isolated only in the winter months, e.g., from November
to April in northern latitudes. The virus is
ubiquitous, and over 90~ of children have been infected
at least once by 2 years of age. Multiple strains
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cocirculate. There is no direct evidence of antigenic
drift (such as that seen with influenza A viruses), but
sequence studies demonstrating accumulation of amino
acid changes in the hypervariable regions of the G
protein and SH proteins suggest that immune pressure
may drive virus evolution.
In mouse and cotton rat models, both the F
and G proteins of RSV elicit neutralizing antibodies
and immunization with these proteins alone provides
longterm protection against reinfection (68,69).
In humans, complete immunity to RSV does not
develop and reinfections occur throughout life (70,71);
however, there is evidence that immune factors will
protect against severe disease. A decrease in severity
of disease is associated with two or more prior
infections and there is evidence that children infected
with one of the two major RSV subgroups may be somewhat
protected against reinfection with the homologous
subgroup (72), observations which suggest that a live
attenuated virus vaccine may provide protection
sufficient to prevent serious morbidity and mortality.
Infection with RSV elicits both antibody and cell
mediated immunity. Serum neutralizing antibody to the
F and G proteins has been associated, in some studies,
with protection from LRD, although reduction in upper
respiratory disease (URD) has not been demonstrated.
High levels of serum antibody in infants is associated
with protection against LRD, and adminstration of
intravenous immunoglobulin with high RSV neutralizing
antibody titers has been shown to protect against
severe disease in high risk children (71,73,74). The
role of local immunity, and nasal antibody in
particular, is being investigated.
The RSV virion consists of a
ribonucleoprotein core contained within a lipoprotein
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envelope. The virions of pneumoviruses are similar in
size and shape to those of all other paramyxoviruses.
then visualized by negative staining and electron
microscopy, virions are irregular in shape and range in
diameter from 150-300 nm (75). The nucleocapsid of
this virus is a symmetrical helix similar to that of
other paramyxoviruses, except that the helical diameter
is 12-15 nm rather than l8nm. The envelope consists of
a lipid bilayer that is derived from the host membrane
and contains virally coded transmembrane surface
glycoproteins. The viral glycoproteins mediate
attachment and penetration and are organized separately
into virion spikes. All members of the paramyxovirus
subfamily have hemagglutinating activity, but this
function is not a defining feature for pneumoviruses,
being absent in RSV but present in Pneumovirus of mice
(PVM) (76). Neuraminidase activity is present in
members of the genera Paramyxovirus, Rubulavirus, and
is absent in Morbillivirus and Pneumovirus (76).
RSV possesses two subgroups, designated A and
B. The Wild-type RSV (strain 2B) genome is a single
strand of negative-sense RNA of 15,218 nucleotides (SEQ
ID N0:9) that are transcribed into ten major subgenomic
mRNAs which encode eleven gene products. Each of the
ten mRNAs encodes a major polypeptide chain: Three are
transmembrane surface proteins (G, F and SH); three are
the proteins associated with genomic RNA to form the
viral nucleocapsid (N, P and L); two are nonstructural
proteins (NSl and NS2) which accumulate in the infected
cells but are also present in the virion in trace
amounts and may play a role in regulating transcription
and replication; one is the nonglycosylated virion
matrix protein (M); and the last is M2, another
nonglycosylated protein recently shown to be an RSV-
specified transcription elongation factor (see Figure
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3) (another gene product is also encoded by the M2
gene). These ten viral proteins account for nearly all
of the viral coding capacity.
The viral genome is encapsidated with the
major nucleocapsid protein (N), and is associated with
the phosphoprotein (P), and the large (L) polymerase
protein. These three proteins have been shown to be
necessary and sufficient for directing RNA replication
of eDNA encoded RSV minigenomes (77). Further studies
have shown that for transcription to proceed with full
processing, the M2 protein (ORF 1) is required (75).
When the M2 protean is missing, truncated transcripts
predominate, and rescue of the full length genome does
not occur (75) .
Hoth the M (matrix protein) and the M2
proteins are internal virion-associated proteins that
are not present in the nucleocapsid structure. By
analogy with other nonsegmented negative-stranded RNA
viruses, the M protein is thought to render the
nucleocapsid transcriptionally inactive before
packaging and to mediate its association with the viral
envelope. The NSl and NS2 proteins have only been
detected in very small amounts in purified virions, and
at this time are considered non-structural. Their
functions are uncertain, though they may be regulators
of transcription and replication. Three transmembrane
surface glycoproteins are present in virions: G, F, and
SH. G and F (fusion) are envelope glycoproteins that
are known to mediate attachment and penetration of the
virus into the host cell. In addition, these
glycoproteins represent major independent immunogens
(78). The function of the SH protein is unknown,
although a recent report has implicated its involvement
in the fusion function of the virus (79).
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As discussed below, the genomes of two wild-
type RSV subgroup H strains (2B and 18537) were
sequenced in their entirety, as described in
International application PCT/US9716718 (see SEQ ID
NOS:9 and 10). Genomic RNA is neither capped nor
polyadenylated (80). In both the virion and
intracellularly, genomic RNA is tightly associated with
the N protein.
The 3' end of the genomic RNA consists of a
44-nucleotide extragenic leader region that is presumed
to contain the major viral promoter (Fig. 3). The 3'
genomic promoter region is followed by ten viral genes
in the order 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5' (Fig. 3).
The L gene is followed by a 145-149 nucleotide
extragenic trailer region (see Figure 3). Each gene
begins with a conserved nine-nucleotide gene start
signal 3'-GGGGCAAAU (except for the ten-nucleotide gene
start signal of the L gene, which is 3'-GGGACAAAAU; and
the gene start signal of the SH gene for 2B and 18537,
Which is 3'-GGGGUAAAU; differences underlined). For
each gene, transcription begins at the first nucleotide
of the signal. Each gene terminates with a semi-
conserved 12-14 nucleotide gene end (3'-A G U/G U/A
ANNN U/A A3_5) (where N can be any of the four bases)
that directs transcription termination and
polyadenylation (Fig. 3). The first nine genes are
non-overlapping and are separated by intergenic regions
that range in size from 3 to 56 nucleotides for RSV B
strains (Fig. 3). The intergenic regions do not
contain any conserved motifs or any obvious features of
secondary structure and have been shown to have no
influence on the preceding and succeeding gene
expression in a minreplicon system (Fig. 3). The last
two RSV genes overlap by 68 nucleotides (Fig. 3). The
gene-start signal of the L gene is located inside of,
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rather than after, the M2 gene. This 68 nucleotide
overlap sequence encodes the last 68 nucleotides of the
M2 mRNA (exclusive of the Poly-A tail), as well as the
first 68 nucleotides of the L mRNA.
Ten different species of subgenomic
polyadenylated mRNAs and a number of polycistronic
polyadenylated read-through transcripts are the
products of genomic transcription (75).
Transcriptional mapping studies using UV light mediated
genomic inactivation showed that RSV genes are
transcribed in their 3' to 5' order from a single
promoter near the 3' end (81). Thus, RSV synthesis
appears to follow the single entry, sequential
transcription model proposed for all Mononegavirales
(16,82). According to this model, the polymerase (L)
contacts genomic RNA in the nucleocapsid form at the 3'
genomic promoter region and begins transcription at the
first nucleotide. RSV mRNAs are co-linear copies of
the genes, with no evidence of mRNA editing or
splicing.
Sequence analysis of intracellular RSV mRNAs
showed that synthesis of each transcript begins at the
first nucleotide of the gene start signal (75). The 5'
end of the mRNAs are capped with the structure
m7G(5')ppp(5')G~ (where the underlined G is the first
template nucleotide of the mRNA) and the mRNAs are
polyadenylated at their 3' ends (83). Both of these
modifications are thought to be made co-
transcriptionally by the viral polymerase. Three
regions of the RSV 3' genomic promoter have been found
to be important as cis acting elements (84). These
regions are the first ten nucleotides (presumably
acting as a promoter), nucleotides 21-25, and the gene
start signal located at nucleotides 45-53 (84). Unlike
other Paramyxovirinae, such as measles, Sendai and PIV-
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3, the remainder of the leader and non-coding region of
NS1 gene of RSV was found to be highly tolerant of
insertions, deletions and substitutions (84).
Additionally, by saturation mutagenesis
(wherein each base is replaced independently by each of
the other three bases and compared for translation and
replication efficiencies) within the first 12
nucleotides of the 3' genomic promoter region, a U-
tract located at nucleotides 6-10 was shown to be quite
intolerant of substitutions (84). In contrast, the
first five nucleotides were relatively tolerant of a
number of substitutions and two of them at position
four were up-regulatory mutations, resulting in a four-
to 20-fold increase in RSV-CAT RNA replication and
transcription. Using a bi-cistronic minireplicon
system, gene-start and gene-end motifs were shown to be
signals for mRNA synthesis and appear to be self-
contained and largely independent of the nature of
adjoining sequence (85).
The L gene start signal lies 68 nucleotides
upstream of the M2 gene-end signal, resulting in gene
overlap (Fig. 3) (75). The presence of the M2 gene-end
signal within the L gene results in a high frequency of
premature termination of L gene transcripts. Full
length L mRNA is much less abundant and is made when
the polymerase fails to recognize the M2 gene-end
motif. This results in much lower transcription of L
mRNA. The gene overlap seems incompatible with a model
of linear sequential transcription. It is not known
whether the polymerase that exits the M2 gene jumps
backward to the L gene-start signal or whether there is
a second, internal promoter for L gene transcription
(75). It is also possible that the L gene is
accessible by a small fraction of polymerases that fail
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to start transcription at the M2 gene-start signal and
slide down the M2 gene to the L gene-start signal.
The relative abundance of each RSV mRNA
decreases with the distance of its gene from the
promoter, presumably due to polymerise fall-off during
sequential transcription (81). Gene overlap is a
second mechanism that reduces the synthesis of full
length L mRNA. Also, certain mRNAs have features that
might reduce the efficiency of translation. The
initiation codon for SIi mRNA is in a suboptimal Kozak
sequence context, while the G ORF begins at the second
methionyl codon in the mRNA.
RSV RNA replication is thought (75) to follow
the model proposed from studies with vesicular
stomatitis virus and Sendai virus (16,82). This
involves a switch from the stop-start mode of mRNA
synthesis to an antiterminator read-through, the latter
resulting in synthesis of positive sense replication-
intermediate (RI) RNA that is an exact complementary
copy of genomic RNA. This serves in turn as the
template for the synthesis of progeny genomes. The
mechanism involved in the switch to the antiterminator
mode is proposed to involve cotranscriptional
encapsidation of the nascent RNA by N protein (16,82).
RNA replication in RSV like other nonsegmented
negative-strand RNA viruses is dependent on ongoing
protein synthesis (86). Predicted RI RNA has been
detected for the standard virus as well as RSV-CAT
minigenome (75,86). RI RNA was 10-20 fold less
abundant intracellularly than was the progeny genome
both for the standard and the minigenome system.
The RSV subgroup B embodiment of this
invention involved an analysis of the nucleotide
sequences of various wild-type, vaccine and revertant
RSV strains. In particular, the emphasis was on
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regions other than the 3' genomic promoter region and
the L gene; those regions ware the focus of
International application PCT/US97/16718.
The nucleotide sequences (in positive strand,
antigenomic, message sense) of various wild-type,
vaccine and revertant RSV subgroup B strains are set
forth as follows with reference to the appropriate SEQ
ID NOS. contained herein:
Virus Nucleotide Seauence Genome
Wild-Tyke Lend
2H SEQ ID N0:9 15218
18537 SEQ ID NO:10 15229
Vaccine
2B33F SEQ ID N0:11 15219
2B20L SEQ ID N0:12 15219
Revertant
2B33F TS(+) SEQ ID N0:13 15219
2B20L TS(+) SEQ ID N0:14 15219
Translation of the M gene starts with the
codon at nucleotides 3262-3264; the translation stop
codon is at nucleotides 4030-4032. The translated M
protein is 256 amino acids long. The M gene
stop/polyadenylation signal includes a twelve
nucleotide gene-end signal at nucleotides 4196-4207,
followed by an intergenic region at nucleotides 4208-
4216 and the SH gene-start signal at nucleotides 4217-
4225.
An analysis of the coding and noncoding
(intercistronic) regions of the RSV subgroup B genome
was carried out. Nucleotide and amino acid differences
distinguishing the SH gene and protein sequences, and
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nucleotide differences distinguishing the M gene-end
signal in the M/SH intercistronic region of various
wild-type, vaccine and revertant RSV strains were
carried out (see Tables 6, 7 and 9 in Example 2 below).
The regions comprising the cis-acting
elements which control transcription termination for
each gene were found to be highly conserved among all
RSV subgroup B viruses examined. With one exception,
the sequences of the gene-start and gene-end signals
were identical for all the viruses analyzed. The third
nucleotide of the M gene-end signal of the wild-type
2B, vaccine 2B33F and revertant 2B33F TS(+) strains was
a G, while the third nucleotide of all other RSV
subgroup B gene-end signals was a T.
More importantly, as shown in Table 7, there
was one mutation in the M gene-end signal which spans
nucleotides 4196-4207 in the wild-type 2B virus (in
antigenomic, message sense) and spans nucleotides 4197-
4208 in the 2B33F vaccine strain and the 2B33F TS(+)
revertant strain: At nucleotide position 4199, wild-
type 2B virus had a "T", whereas the 2B33F and 2B33F
TS(+) strains had a "C" in the corresponding nucleotide
position 4200 (these strains have an extra nucleotide
in their 3' genomic promoter regions). This mutation
was not present in any of the 18537 wild-type strain,
the 2B20L vaccine strain or its TS(+) revertant strain.
As shown in Table 11 and Figures 4-6, the
sequence of the M gene-end signal impacts SH gene
expression. The RSV subgroup B 2B33F mutant and its
TS(+) revertant have this unique nucleotide at this
fourth position of the M gene-end signal (at nucleotide
4200 in the mutant and revertant) that is not found in
their 2B parental strain (at nucleotide 4199) or in any
of the other RSV subgroup B or A viruses analyzed.
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As shown by Northern blot analyses (Figures 4
and 6) and a ribonuclease protection assay (Figure 5)
which are discussed in Example 2 below, the wild-type
2B strain produced a slight excess of bicistronic M:SH
over monocistronic M transcripts. In contrast the
2B33F mutant and its 2B33F TS(+) revertant produced
practically no monocistronic M and SH transcripts;
instead, the bulk of their transcription products were
bicistronic and higher molecular weight read-through
transcripts. These bicistronic and read-through
transcripts are likely to be constrained in their
ability to translate the SH gene product. Thus, the
strains containing this mutation have down-regulated SH
expression compared to the 2B parental strain, and have
essentially stopped producing the SH protein. This
shift to the predominance of bicistronic transcription
products and the concomitant down-regulation of the
downstream gene product, SH, provides evidence that the
mutation in the M gene-end signal contributes to the
attenuation phenotype of these two strains.
Therefore, based on Tables 6-11, Figures 4-6
and the foregoing discussion, the key attenuating
mutation for the M gene-end signal is nucleotide 4199
(T ~ C) (in antigenomic, message sense).
It is interesting to note that the SH gene of
the 2B33F mutant is blistered with nucleotide changes
(biased hypermutation) compared to that of the 2B
parent (see Table 6), some of which would result in
amino acid substitutions in the SH protein. One change
at nucleotide 4498 of 2B33F converts the predicted SH
translation stop codon to glutamine. This results in a
predicted length for the 2B33F SH protein that is
substantially longer than that of the 2B parent.
In a further embodiment of this invention,
the RSV subgroup B phenotype is further attenuated by
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combining the above-referenced M gene-end signal
mutation with one or more of each of the coordinate 3'
genomic promoter region and L gene mutations described
in International application PCT/US97/16718, which are
as follows: for the RSV subgroup 8 3' genomic promoter
region, the mutations are nucleotide 4 (C -~ G), and
the insertion of an additional A in the stretch of A's
at nucleotides 6-11 (in antigenomic message sense),
while for the L protein the mutations are amino acid
residues 353 (arginine -~ lysine), 451 (lysine
arginine), 1229 (aspartic acid -~ asparagine), 2029
(threonine ~ isoleucine) and 2050 (asparagine
aspartic acid). Again, it is understood that all
changes in nucleotides which result in codons which are
translated into these amino acids are within the scope
of this invention.
When the 3' genomic promoter region is
modified by the insertion of an additional A in the
stretch of A's at nucleotides 6-11, it is understood
that the attenuating mutation in the M gene-end signal
will be at nucleotide 4200, rather than nucleotide
4199.
The attenuated viruses of this invention
exhibit a substantial reduction of virulence compared
to wild-type viruses which infect human and animal
hosts. The extent of attenuation is such that symptoms
of infection will not arise in most immunized
individuals, but the virus will retain sufficient
replication competence to be infectious in and elicit
the desired immune response profile in the vaccinee.
The attenuated viruses of this invention may
be used to formulate a vaccine. To do so, the
attenuated virus is adjusted to an appropriate
concentration and formulated with any suitable vaccine
adjuvant, diluent or carrier. Physiologically
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acceptable media may be used as carriers. These
include, but are not limited to: an appropriate
isotonic medium, phosphate buffered saline and the
like. Suitable adjuvants include, but are not limited
to MPLT"" (3-O-deacylated monophosphoryl lipid A; RIBI
ImmunoChem Research, Inc., Hamilton, MT) and IL-12
(Genetics Institute, Cambridge, MA).
In one embodiment of this invention, the
formulation including the attenuated virus is intended
for use as a vaccine. The attenuated virus may be mixed
with cryoprotective additives or stabilizers such as
proteins (e. g., albumin, gelatin), sugars (e. g.,
sucrose, lactose, sorbitol), amino acids (e. g., sodium
glutamate), saline, or other protective agents. This
mixture is maintained in a liquid state, or is then
dessicated or lyophilized for transport and storage and
mixed with water immediately prior to administration.
Formulations comprising the attenuated
viruses of this invention are useful to immunize a
human or animal subject to induce protection against
infection by the wild-type counterpart of the
attenuated virus. Thus, this invention further
provides a method of immunizing a subject to induce
protection against infection by an RNA virus of the
Order Mononegavirales by administering to the subject
an effective immunizing amount of a vaccine formulation
incorporating an attenuated version of that virus as
described hereinabove.
A sufficient amount of the vaccine in an
appropriate number of doses must be administered to the
subject to elicit an immune response. Persons skilled
in the art will readily be able to determine such
amounts and dosages. Administration may be by any
conventional effective form, such as intranasally,
parenterally, orally, or topically applied to any
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mucosal surface such as intranasal, oral, eye, lung,
vaginal or rectal surface, such as by an aerosol spray.
The preferred means of administration is by intranasal
administration.
In connection with International application
PCT/US97/16718, samples of the Moraten measles virus
vaccine strain were deposited by Applicants on August
21, 1997 with the American Type Culture Collection,
12301 Parklawn Drive, Rockville, Maryland 20852,
U.S.A., under the provisions of the Budapest Treaty for
the Deposit of Microorganisms for the Purposes of
Patent Procedures ("Budapest Treaty") and have been
assigned ATCC accession number VR2587, and samples of
the 2H wild-type RSV virus were deposited by Applicants
on August 21, 1997 with the American Type Culture
Collection, 12301 Parklawn Drive, Rockville, Maryland
20852, U.S.A., under the provisions of the Budapest
Treaty and have been assigned ATCC accession number
VR2586.
Given these two deposited strains and the
sequence information for these and other strains
provided herein, one can use site-directed mutagenesis
and rescue techniques described above to introduce
mutations (or restore a wild-type genotype) of all the
strains described herein, as well as taking these
strains and making additional mutations from the panel
of mutations set forth in Tables 3-11 below.
In order that this invention may be better
understood, the following examples are set forth. The
examples are for the purpose of illustration only and
are not to be construed as limiting the scope of the
invention.
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Examples
Standard molecular biology techniques are
utilized according to the protocols described in
Sambrook et al. (87).
Example 1
Measles
Moraten MV vaccine virus was grown once,
directly from the AttenuvaxT"" vaccine vial (Lot #0716B) ,
the Schwarz vaccine virus was grown once (Lot
96G04/M179 G41D), while the Zagreb and RubeovaxT""
vaccine viruses were each grown twice in the Vero cells
before RNAs were made for sequence analysis. MV
wildtype isolate Montefiore (57) was passed 5-6 times
in Vero cells before extraction of RNA materials and
similarly, MV wildtype isolates 1977, 1983 (14) were
grown 5-7 times before extracting materials for
analysis. Edmonston wild-type isolate received from
Dr. J. Beeler (CBER) (see Fig. 1) was the original
Edmonston isolate already passaged seven times in human
kidney cells and three times in Vero cells before
receipt and further passaged once in Vero cells before
using for sequence analysis.
RNA was prepared by infecting Vero cells at a
multiplicity of infection (m.o.i.) of 0.1 to 1.0 and
allowed to reach maximum cytopathology before being
harvested. Total RNA from measles virus-infected cells
was extracted using Trizol"" reagent (Gibco-BRL).
The total RNA isolated from Vero cell passage
material was amplified by the Reverse Transcriptase-PCR
(Perkin-Elmer/Cetus) procedure using measles (Edmonston
B strain (19)) specific primer pairs spanning the 3'
and 5' promoter regions and the L gene of the viral
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genome. Table 2 presents these primer sequences. The
primers of SEQ ID NOS:15-34, 54, 57 and 58 are in
antigenomic message sense. The primers of SEQ ID
NOS:35-53, 55, 56 and 59 are in genomic negative-sense.
Table 2
Primers for PCR and Sequencing MV L Genes
and Genomic Termini
so4~CATATCACTCACTCTGGGATGGAG9o~o (SEQ ID N0:15)
93~iTCAGAACATCAAGCACCGCC939o (SEQ ID N0:16)
9~41ACAGTCAAGACTGAGATGAG9.,so (SEQ ID N0:17)
ioooiAAGAGTCAGATACATGTGGAloozo (SEQ ID N0:18)
1o3s1ACATGAATCAGCCTAAAGTClo3~o (SEQ ID N0:19)
ios~aCCGAAAGAGTTCCTGCGTTACGACClos9a (SEQ ID N0:20)
iioesCAGTCCACACAAGTACCAGGliioz (SEQ ID N0:21)
ii4siGTCAGAAGCTGTGGACCATCli4ao (SEQ ID N0:22)
iie4iAATATTGCTACAACAATGGClieso ( SEQ ID NO
:
2
3
)
izissACTCTTCATTCCTAGACTGGlzzis (SEQ ID N0:24)
izs4zGTCCAATTATGACTATGAAClzssi ( SEQ ID NO
:
2
5
)
izesiAGAACAGACATGAAGCTTGClzsfo ( SEQ ID NO : 2 6 )
iszszCCAACAAGGAATGCTTCTAGlszsi (SEQ ID N0:27)
isssiACAGCACTATCTATGATTGACCTGGI3s~s (SEQ ID N0:28)
13s3oGCAACATGGTTTACACATGC139~s (SEQ ID N0:29)
i4zeoAGATTGAGAGTTGATCCAGGI4zss (SEQ ID N0:30)
i4sz9AGGAGATACTTAAACTAAGC14s4e (SEQ ID N0:31)
i4seiTAAGCTTATGCCTTTCAGCGlsooo (SEQ ID N0:32)
1s33~TTAACGGACCTAAGCTGTGCls3ss (SEQ ID N0:33)
15s~1GAAACAGATTATTATGACGGlss9o ( SEQ ID NO
:
34
)
szsoCGGGCTATCTAGGTGAACTTCAGG9zs~ (SEQ ID N0:35)
ssooATTTGGATATGGAATATGAG94ei (SEQ ID N0:36)
984oACTCAACTGAACTACCAGTG98zi ( SEQ ID NO
:
3
7
)
ioiaiAAGAACATCATGTATTTCAGloisz ( SEQ ID NO
:
3
8
)
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iosasTTATCAACGCACTGCTCATGlosso ( ID NO :
SEQ 3 9
)
iosisATTTTCAGCAATCACTTGGCATGCCloess (SEQ ID N0:40)
iiaaoGCCTCTGTGCAAACAAGCTGllasi ( ID NO :
SEQ 41 )
iisaeTCTCTAGTTACTCTAGCAGCiisis (SEQ ID N0:42)
iaoioAGGTCGTTGTTTGTGAGGAGlissi ( ID NO :
SEQ 43 )
ia3siTCGTCCTCTTCTTTACTGTClz3~a (SEQ ID N0:44)
iasesCCGTCCTCGAGCTAGCCTCGI2s.,o (SEQ ID N0:45)
isosaCTCCTCCAGGCTCACATTGGlaosa (SEQ ID N0:46)
i3aaoGGGTTGGTACATAGCTCTGCissol (SEQ ID N0:47)
13~s~CACCCATCTGATATTTCCCTGATGG13.,43 (SEQ ID N0:48)
i4ossTGGTTGACAGTACAAATCTGl9oeo (SEQ ID N0:49)
masoCTGAAATGGGAAGATTGTGCI4,~m (SEQ ID N0:50)
me2oAGCAATCTACACTGCCTACCl~eo1 ( ID NO :
SEQ 51 )
isieoTCACAGATGATTCAATTATClsisi (SEQ ID N0:52)
isssoGATCCTAGATATAAGTTCTClssii (SEQ ID N0:53)
lACCAAACAAAGTTGGGTAAGGal (SEQ ID N0:54)
GGGGGATCCIOOATCCCTAATCCTGCTCTTGTCCC~e (SEQ ID N0:55)
aooGATTCCTCTGATGGCTCCAClei (SEQ ID N0:56)
ls~zITAACAGTCAAGGAGACCAAAGls~41 (SEQ ID N0:57)
GGGAAGCTTlseoiAACCCTAATCCTGCCCTAGGTGGlsaa3( ID NO :
SEQ 5 8
)
isas4ACCAGACAAAGCTGGGAATAGAlsa~3 (SEQ ID N0:59)
Overlapping PCR fragments of the
complete
viral genome were directly sequenced without
cloning to
achieve the consensus sequence, by the dideoxy
terminator cycle sequencing method using
both strands
(ABI PRISM 377 sequencer and ABI PRISM sequencing
Kit).
To determine the sequence at the absolute
termini, a
ligation procedure described previously used
was (56).
The nucleotide sequences were determined for
regions other than the genomic promoter region and the
L gene of the progenitor Edmonston wild-type MV
isolate, for the available vaccine strains derived from
this isolate, as well as for other wild-type strains.
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Significant nucleotide (in antigenomic, message sense)
and amino acid differences were then compared and
aligned as set forth in Tables 3-5 (differences are in
italics):
Table 3
Differences in MV N Nucleotides and Amino Acids
Between Edmonston Wild-Type and Vaccine Strains
Nucleotide 275 492 550 623 1542
Edmonston w-t GTC CAA GAG GCC TCG
Mutation GTG AAA GGG GCT ACG
Amino Acid 56 229 148 172 479
Edmonston w-t V Q E A S
RubeovaxTM vac. V Q E A T
Moraten vac. V Q G A T
Schwarz vac. V Q G A T
Zagreb vac. V Q E A S
AIK-C vac. V K E A S
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Table 4
Differences in MV P and C Nucleotides and Amino Acids
Between Wild-Type and Vaccine Strains
Gene C C C P* P P
Nucleotide 2046 2139 2229 2480 2630 3122
Edmonston w-t GCC ATG TCT GAG TGT CTA
Mutation GTC ACG TAT GGG TAT CCA
Amino Acid 73 104 134 225 275 439
Edmonston w-t A M S E C L
1977 w-t V M S E C L
1983 w-t V M S E C L
Montefiore w-t V M S E C L
Rubeovax'"" V T S G C L
vac .
Moraten vac. V T S G C L
Schwarz vac. V T S G C L
Zagreb vac. V M S G C L
AIK-C vac. V M Y G Y P
* Identical change in V protein
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Table 5
Differences in MV F Gene-End Signal Between
Edmonston Wild-Type and Vaccine Strains
Nucleotides 7237-7247
Edmonston w-t G T T A A T T A A A
A
RubeovaxTM vac G T T A A T T A A A
. A
Moraten vac . G T T A A T C A A A
A
Schwarz vac . G T T A A T C A A A
A
Zagreb vac . , T T A A T T A A A
G A
AIR-C vac . G T T A A T T A A A
A
T
7243
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Example 2
RSV Subgroup B
The temperature-sensitive (ts) phenotype is
strongly associated with attenuation in vivo; in
addition, some non-is mutations may also be
attenuating. Identification of is and non-is
attenuating mutations was achieved by sequence analysis
and evaluation of ts, cold-adapted (ca), and in vivo
growth phenotypes of RSV mutants and revertants.
The genomes of the following three RSV 2B
strains have been completely sequenced: The 2B wild-
type parent, a is and ca derivative thereof designated
2833F and one ts(+) revertant designated 2B33F TS(+).
The 2833F strain is described in U.S. Serial No.
08/059,444 (88), which is hereby incorporated by
reference. After identifying regions where mutations
in 2B33F are located, nine additional isolates of 2B33F
"revertants" obtained following in vitro paesaging at
39°C and in vivo passaging in African green monkeys or
chimpanzees have been sequenced in those previously-
identified mutant regions. The ts, ca, and attenuation
phenotypes of many of these revertants have now been
characterized and assessed. Correlations between is
phenotype, virus attenuation and sequence changes have
been identified.
A summary of results is presented in Tables
6-11.
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Table 6
Sequence comparison between RSV 2B and 2B33F strains
Nucl. ~ Nucleotide changes
pos t
Gene/ 3' end RSV 2B RSV RSV 2B33F Amino acid
region of vRNA 2B33F TS(+), 5a changes
revertant
Genomic 4 C G G non-coding
promoter6 - extra extra A non-coding
A
M 4175 T C C non-coding
4199 T C C non-coding
SH 4329 T C C Phe-Leu (10)
4409 T C C none Ile (36)
4420 T C C Ile-Thr (40)
4442 T C C none His (4?)
4454 T C C none Cys (51)
4484 T C C none Tyr (61)
4497 T C C Stop-Gln (66)
4505 T C C none Ser (68)
4525 T C C Ile-Thr (75)
4526 T C C Ile-Thr (75)
4542 T C C Stop-Gln (81)
4561 T C C Leu-Pro (87)
4575 T C C Trp-Arg (92)
4 5 9 T C C none Thr ( 9
8 9 )
L 9559 G A A Arg-Lys (353)
9853* A G A Lys-Arg (451)*
12186 G A A Asp-Asn (1229)
14587 C T T Thr-Ile (2029)
15071 A G G non-coding
t For 2B33F and 2B33F TS{+), nucl. pos. numbers
are one larger than for 2B for M, SH & L genes
* At pos. 9853, the Lys-Arg change has reverted
back to Lys in the 2B33F TS(+) strain
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Table 7
Differences in M Gene-End Signal Between
RSV 2B and 2B33F strains
Nucleotide Nucleotide
Numbers Sequence
2B 4196-4207 A G G T A A A T A A A A
2B33F 4197-4208 A G G C A A A T A A A A
2B33F TS(+) 4197-4208 A G G C A A A T A A A A
T
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ro
ro
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w o, .
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x ~ ._ .. ..
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b . ~ . .r .
m w
m O \ O \ N I
ro \
ro
If1 M ~ i ~
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d
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a ~
A V~ l(1 . V~ w A d~ f!
N V~ d~ d~
V~
H ~ ao N . . ,n ao o, o \ N \
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ei e-1 v-I N N y -1
v-i rl ~ v O
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M V
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ro m
x
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m m
x ~
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a ~ v ~ ~, M ..
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m
0
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ro a~
to m '
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o m ro m ro m a m v m o
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m m m m m m ~~-I
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'CJ d1 W O M
(JI
ro rl
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ro ro
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ro ro ~ ro ,~ ro H
ro ~ 3
N ~ N ~ N ~k N ~k N ~k f"I
Pr L1~ ri ri (~
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Table 9
2B33F Revertants
is In vjtro AGM Chime
(+)
5a 4a 3b pp2 pp4 pp6 pp7 lA 3A 5A
base no.t
M
4176,4200 S S S S S S S S S S
SH
14 bases* S S S S S S S S S S
L
9560 s s s s s s s s s s
9854 28 2B 2B S S S S 28 2B 2B
12187 S s s s S s s S ~s s
14588 S S S S S S S S S S
15072 S S S S S S S S S S
Phenotype
is 2B 2B 2B r r S S 2B 28 2B
ca S S S 2B S 28 S ND ND ND
Attenuatedr r r (r) (r) S S ND r r
t These 2B33F revertant base nos. are one larger than for 2B for M,
SH and L genes
* bases 4330,4410,4421,4443,4455,4485,4498,4506,4526,4527,4543,
4562,4576,4599
S = same base as 2B33P'
28 = reversion to 2B base or complete reversion in phenotype
r = moderate reversion in phenotype
(r) = slight reversion is phenotype
ND = not done
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Table 10
RSV 2B, is and Revertant Strains: Phenotype Summary
Virus IsolateSource In In Vivo
Vitro
Phenotype Attenuation
is Cotton
ca AGM
Rat
RSV 2H Wild-type Parent Strain- - - -
RSV 2833F ca, is mutant isolated++++ ++ ++++ +++
from 2B, cold-passaged
x 33
RSV 2B33F 2833F spinner passage- ++ ++ +
- 5a
TS (+) plaque picked at 39C
i
RSV 2B33F
- 4a 2B33F spinner passage- ++ ++ ND I
TS(+) plaque picked at 39C
RSV 2833F 2833F spinner passage- ++ ++ ND
- 3b
TS(+) plaque picked at 39C
AGM pp2 2833F-infected AGM + - +++ ND
A2,
d7 nasal wash plaque
picked at 32C
AGM pp4 2833F-infected AGM + ++ +++ ND
A2,
d7 nasal wash plaque
picked at 32C
AGM pp6 2B33F-infected AGM ++++ - ++++ ND
A4,
d12 nasal wash plaque I
picked at 32C ii
I
AGM pp7 2B33F-infQCted AGM ++++ ++ ++++ ND I
A4,
dl2 nasal wash plaque
picked at 32C
Chimp pplA 2B33F-infected chimp -
#1552, d4 tracheal
lavage. plaque picked
at 32C
Chimp pp3A 2833F-infected chimp - ~ ++ ND
#1560, d6 tracheal
lavage, plaque picked
at 32C
Chimp ppSA 2833F-infected chimp - ~ ++ ND
#1563, d10 tracheal
lavage. plaque picked
at 32C
aru = noz cone
- = wild-type phenotype, i.e., not temperature sensitive, not cold
adapted, not attenuated
+ to ++++ = increasing levels of temperature sensitivity, cold-
adaptation or attenuation
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Northern blot analysis of poly (A)+ RNA
isolated from RSV-infected Vero cells was performed
using a mixture of 32P-labelled riboprobes specific for
the M gene of RSV subgroup A and B viruses to determine
the effect of the M gene-end signal sequences on M gene
transcription. The negative sense hybridization probes
were T7 RNA polymerase transcripts synthesized .in vitro
from PCR products containing the T7 promoter sequence.
As shown in Figure 4, Northern blot analysis using M
gene probes depicted abundant monocistronic M gene
transcripts for RSV subgroup A viruses, whereas
bicistronic M:SH transcripts were predominant for
subgroup B viruses. Bicistronic M:SH transcripts are
likely to be constrained in their ability to translate
the SH gene and thus represent a potential means for
controlling viral SH gene expression. The 2B33F mutant
(lane 5) and 2B33F TS(+) revertant (lane 6) strains
produced practically no monocistronic M transcripts;
the bulk of their transcription products were
bicistronic and higher molecular weight read-through
transcripts. Thus, these two strains have essentially
stopped producing the SH protein.
In contrast, the wild-type subgroup B strains
2B, B1 and 18537 produced a slight excess of
bicistronic over monocistronic mRNAs (lanes 3, 4, 7).
The subgroup A 3A virus showed comparable levels of
monocistronic and bicistronic products (lane 1). At
the other extreme from what was observed for the 28
mutant strains was the M gene transcription pattern of
the A2 virus (lane 2). For this strain, monocistronic
M transcripts were produced in abundance, while read-
through transcription was minimal.
Northern blot results were confirmed by a
ribonuclease protection assay which was performed on
the same poly (A)+ RNA that was used for the Northern
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blot, in order to assess the ratio of monocistronic M
and SH mRNAs to bicistronic M:SH for each RSV subgroup
B virus. Riboprobes were used which were negative
sense virus-specific '2P-labelled transcripts of 284
nucleotides in length (B viruses) that spanned the M:SH
gene junction. The full-length probe should be
protected from RNase digestion predominantly by
bicistronic M:SH transcripts. Monocistronic M and SH
transcripts are expected to protect approximately 165
and 110 nucleotide probe fragments, respectively, from
RNase digestion.
In an assay for 2B, 2B33F, and 2B33F TS(+)
viral RNA shown in Figure 5, viral RNA or control yeast
RNA was hybridized with 5 X 10' cpm of probe;
thereafter, the hybridized RNA was then digested with
RNase Tl (diluted 1:100), precipitated with ethanol,
and the protected probe fragments were separated on a
denaturing 6~ polyacrylamide gel.
Results of this ribonuclease protection assay
are depicted in Figure 5. In this assay, the signal
intensity of the protected probe fragment corresponding
to bicistronic M:SH relative to that of monocistronic M
for each virus was in agreement with the results
obtained by Northern blotting with the M gene probes,
that is, greater monocistronic signal for 2B and
practically no monocistronic signal for 2B33F and 2B33F
TS (+) (Fig. 5) .
To evaluate the influence of the M gene-end
signal on expression of the downstream SH gene,
Northern blot analysis of poly (A)+ RNA of the RSV
viruses was performed using negative sense 32P-labelled
riboprobes specific for the SH gene of an RSV subgroup
A and B strain to appraise the influence of the M GE
signal on expression of the downstream SH gene (see
Figure 6). The pattern of SH gene transcripts produced
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by each virus, that is, the level of monocistronic SH
to bicistronic M:SH, was comparable to that observed
for the M gene transcription products. Those RSV
viruses that were inefficient in terminating M gene
transcription at the M geae-end signal were also
compromised in the synthesis of monocistronic SH
transcripts. The 2B33F mutant and its TS(+) revertant
synthesized practically no monocistronic product, but
accumulated abundant M:SH transcripts. The wild-type
3A, 2H, B1 and 18537 viruses accumulated comparable
levels of both transcription products, while the A2
strain produced monocistronic SH mRNA as the most
abundant product of SH gene transcription. The
transcripts identified by Northern blot analysis were
quantitated by phosphorimager analysis and a relative
ratio of monocistronic SH to bicistronic M:SH was
determined for each virus. As shown in Table 11, the
ratios ranged from 0.23 to 11.1, with the lowest values
observed for the RSV subgroup B strains containing the
mutation at the fourth nucleotide (T ~ C) of the M
gene-end signal:
Table 11
Ratio of Monocistronic SH to Bicistronic M:SH
Transcripts in RSV Subgroup A and B Strains
Virus SH M:SH
2B 1.4
2H33F 0.23
2B33F TS(+) 0.29
B1 1.0
18537 0.76
A2 11.1
3A 2 . 2
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Several significant observations can be drawn
from these data: As shown in Table 6, there are
relatively few sequence changes identified in the
mutant strain: RSV 2B33F differs from parental RSV 2B
by two changes at the 3' genomic promoter region, two
changes at the non-coding 5'-end of the M gene,
including one in the M gene-end signal, and four coding
changes plus one non-coding (poly(A) motif) change in
the RNA dependent RNA polymerase coding L gene. In
addition, 14 changes mapped to the SH gene alone.
An attenuating mutation can be identified in
the M gene-end signal of the attenuated virus strain
2B33F: The shift from a slight excess of bicistronic
over monocistronic mRNAs in the wild-type 2B strain to
the predominance of bicistronic transcription products
in the 2B33F vaccine strain and the 2B33F TS(+)
revertant strain provides evidence that the mutation in
the M gene-end signal contributes to the attenuation
phenotype of these latter two viral strains.
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CA 02323927 2000-09-25
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SEQUENCE LISTING
<110> American Cyanamid Company
<120> Mutations Responsible for Attenuation in Measles Virus
or Human Respiratory Syncytial Virus Subgroup B
<130> 33428-00/PCT
<140>
<141>
<150> 60/079466
<151> 1998-03-26
<160> 59
<170> PatentIn Ver. 2.0
<210> 1
<211> 15894
<212> DNA
<213> Measles virus
<400> I
accaaacaaa gttgggtaag gatagatcaa tcaatgatca tattctagtg cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagactt ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaattag tagtgatcaa tccaggttcg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gcccaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
gaaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaac ctttaccagc 1020
aaatggggga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtaaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
agatcagtag agcggttgga cccagacaag cccaagtatc atttctacac ggtgatcaaa I38o
1
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WO 99/49017 PCT/US99/06225
gtgagaatga gctaccgaga ttggggggca aggaagatag gagggtcaaa cagagtcgag 1440
gagaagccag ggagagctac agagaaaccg ggcccagcag agcaagtgat gcgagagctg 1500
cccatcttcc aaccggcaca cccctagaca ttgacactgc atcggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgcttaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctatagtgta caatgacaga aatcttctag 1680
actaggtgcg agaggccgag gaccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccatca accatccact cccacgattg 1800
gagccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc acctgcaggg aagagaaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggccagg gacctggaga gagcgatgac gacgctgaaa ctttgggaat ccccccaaga 2100
aatctccagg catcaagcac tgggttacag tgttattatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc cccggacccc 2460
ggtagggcca gcacttccga gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca atgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc caactagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacccacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttatg tacatgtttc 3600
tgctgggggt tgttgagggc agcgatcccc tagggcctcc aatcgggcga gcatttgggt 3660
ccctgccctt aggtgttggc agatccacag caaagcccga agaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctcgatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgataggc cctgggaaga tcatcgacaa tacagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca agatgagcaa gactctccat gcacaactcg 4260
2
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ggttcaagaa gaccttatgt tacccgctga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa aacgaccccc ctcacaatga cagccagaag 4500
gcccggacaa aaaagccccc tccgaaagac tccacggacc aagcgagagg ccagccagca 4560
gccgacggca agcgcgaaca ccaggcggcc ccagcacaga acagccctga cacaaggcca 4620
ccaccagcca ccccaatctg catcctcctc gtgggacccc cgaggaccaa cccccaaggc 4680
tgcccccgat ccaaaccacc aaccgcatcc ccaccacccc cgggaaagaa acccccagca 4740
attggaaggc ccctccccct cttcctcaac acaagaactc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc tccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggccca 4920
cggcgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggttc 4980
ccccggtgcc cacaggcagg gacaccaacc cccgaacaga cccagcaccc aaccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagaaccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
accccagccc cgatccggcg gggagccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctcctccttt tctcgaaggg accaaaagat caatccacca cacccgacga cactcaactc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccagacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagctta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagac 6180
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tccaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtagtcgagg tgaacggcgt gaccatccaa gtcgggagca ggaggtatcc agacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacggga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
3
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cacaagtctc ctcttcgtca tcaagcaacc accgcaccca gcatcaagcc cacctgaaat 7200
tatctccggc ttccctctgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag tcattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctgtttg tcatgtctct gagcttgatc gggttgctag ccattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttaga cttgtattta agtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtatggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaaaggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actatcttga 8100
gcaaccagtc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt cacggggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccttatca acggatgatc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cgaacagatg acaagttgcg 8400
aatggagaca tgcttccaac aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttgatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc aacctcttca ctgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaggccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatcgcag 9120
atagggctgc tagtgaacca atcacatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg ggaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcttaagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc cagtggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacatttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac tattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
4
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aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ctctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgatg tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgtgag agcagcaaaa gggtttatag ggttccctca agtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggattg ccctcatttt tccagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
ataaagtccc caatgatcaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatctata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccctac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg atattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa attctgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcctcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaaggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgctg gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagct ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
ctaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcgagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gctcatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttctcttgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttat gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc agaggctagg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggatttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggaag 14580
acggcttgtt cttgggtgag ggatcgggtt ctatgttgat cacttataag gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc~ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 14820
tcaatttcat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttgcc taacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctca ttatagagaa gtgaaccttg 15060
tataccctag atacagcaac ttcatatcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtga 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tttgggggca cattcttctt tactccggga acagaaagtt gataaataag tttatccaga 15600
atctcaagtc cggctatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
6
CA 02323927 2000-09-25
WO 99/49017 PCT/US99J06225
actaattggt tgaactccgg aaccctaatc ctgccctagg tggttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 2
<211> 15894
<212> DNA
<213> Measles virus
<400> 2
accaaacaaa gttgggtaag gatagatcaa tcaatgatca tattctagta cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttc 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatcccggga gattcctcaa 240
ttaccactcg atctagactt ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatatttt tcacatgatg atccaagtag tagtgatcaa tccaggttcg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gctcaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
ggaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaat ctttaccagc 1020
aaatggggga aactgcacca tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttacttcga tccagcatat ttcagactag 1200
ggcaagagat ggtgaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaagatgca aggcttgttt cagagatcgc aatgcatact acagaggaca 1320
ggatcagtag agcggttgga cccagacaat cccaagtgtc attcctacac ggtgatcaaa 1380
atgaaaatga gctaccgaga tgggggggta aggaagatat gagggtcaaa cagagtcggg 1440
gagaagccag agagagctac agagaaacca ggcccagcag agcaagtgac gcgagagcta 1500
cccatcctcc aaccgacaca cccttagaca ttgacactgc atcggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgctcaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctagagtgta caatgacaga gatcttctag 1680
actaggtgca agaggccgag gaccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccacca accatccact cccacgattg 1800
gggccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc gcctgcaagg aagagaaggc aagcagtccg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gatctggaga gagcgatgac gacgctgaaa ctttgggaat cccctcagga 2100
aatctccagg catcaagcac tgggttacag tgttattatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
7
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccaaa gcttaggaaa actctcaatg ttcccccgcc cccggaccct 2460
ggtagggcca gcacttccga gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgtactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ttattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatcaccaa gctagaatca 2820
ctgctgttat tgaaggggga agttgagtca atcaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccttggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggctgaa gttctcaaga aacccgttgc cagccgacaa 3060
atccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttccgga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgacatc aaaggagcca acgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc tagctaatac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacccacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca gaaaagatga atgttttatg tacatgtttc 3600
tgctgggggt tgttgaggac agcgatctcc tagggcctcc aatcgggcga gcatttgggt 3660
ctctgccctt aggtgttggc agatccacag caaaacccga agaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcatacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctggatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcagataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgattggc catgggaaga tcatcgacaa tgcagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa aagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
ggttcaagaa gaccctatgt tacccactga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgttatca taaatgatga ccaaggatta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa gacgaccctc ctcacaatga cagccagaag 4500
gcccggaaaa aaaggccccc tccgaaagac tccacagacc aaatgagagg ccagccagca 4560
gctgacggca agcacgaaca ccaggcggcc ccagcacaga acagccctga cataaggcca 4620
ccaccagcca tcccaatctg catcctcctc gtaggacccc cgaggaccaa cccccaaggt 4680
tgccccccac ccaaaccacc aaccgcatcc ctaccacccc cgggaaagaa acccccagca 4740
actggaagag cccttcccct ttccctcaac acaagaactc cacaaccgaa ccacacaagc 4800
gaccgaggtg acccaaccgc aggcacccga ctccctagac agatcctctc cccctggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggccca 4920
cggcgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg cacaccaacc cccgaacaga cccagcaccc agccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cgacaaccaa accagaaccc agaccaccct 5160
gggccaccag ttcccagact cggccatcac cccgcagaaa ggaaaggcca caacctgcgc 5220
8
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
accccagccc cgatccggcg ggcagccacc caaccctaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctcttcctct tctcgaaggg actaaaagat caatccacca catccgacga cactcaactc 5400
cccgtcccta aaggagacac cgggaatccc ggaattaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccgttt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcag gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgagg gcaagtctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccctagctta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct cggaggagat 6180
atcaataagg tgttagaaaa gctcggatat agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct acccgacgct gtccgagatc aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tatacgactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tccaccaagt cctgtgctcg tacactcgta tctgggtctt ttgggaaccg gttcattttg 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtagtcgagg tgaacggcgt gaccatccaa gtcgggagca ggaggtatcc agacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttgtcg agcactagca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacagga 7080
acatcgaaat cctatgtaag gtcgctctga tcctctacaa ctcttggaac acaaatgtcc 7140
cacaagtctc ctcttcgtca tcaagcaacc accgcatcca gcatcaagcc cacctgaaat 7200
tatctccggc tcccctttgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag ttatcaacag agaacacctt atgattgata gaccttatgt 7380
tttgctggct gttctgttcg tcatgtttct gagcttgatc gggttgctag caattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa ttgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaaccc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttgga cttgtattta agtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtacggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaagggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actattttga 8100
9
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
gcaaccagtc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt cacgggggag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagctttcag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt,8280
ccccttctca acggatgacc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctat cccgacaaca agaacagatg acaagttgcg 8400
aatggagaca tgcttccagc aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggagtcttgt ctgttgatct 8520
gagtctaaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaagtccaa ccacaacaat gagtattggc tgactatccc 8640
gccaatgaag aacctagccc taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc aacctcttca ctgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgatcct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaagccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag gggatcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatagcag 9120
atagggctgc cagtgaacca atcacatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccccg aagttcacct agatagcccg atagttacca 9300
acaagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaac tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg gaaattcgct gtactctaaa gtcagtaata 9600
aggttttcca atgcttgagg gacactaatt cacggcttgg tctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc caatggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
taacatttga gctggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ctgctatgac cattgatgct agatatacag agcttctagg aagagtcaga tacatgtgga 10020
aattgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacggtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcacgag ttagttgaag ctctagatta cattttcata actgatgaca 10260
tacacctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ctcaggtgaa ggattaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgcttcatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgacccc cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgata tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
atttgactaa ggcactccac actctggctg tctcaggagt ccctaaagat ctcaaagaaa 11040
gtcacagagg ggggccagtc ctaaaaacct actcccgaag cccagcccac acaaatacca 11100
ggaacgtgag ggcagcaaaa gggtttatag ggttccctca gataattcgg caggaccaag 11160
acactaatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacaactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggatta ccctcatttt ttcagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
gcaaagtccc caatgaccaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatttata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcatta gtgcaagggg acaatcagac catagctgta acaaaaaggg 11580
tacccagcac atggccttac aaccttaaga aatgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg acattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtttatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcag attctgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccaggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcatcactga tgcctgaaga gaccctccat caagtaatga 12180
cacagcaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctaa 12300
tccacagtcc aaacccaatg ttaaagggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc agcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgcta gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattaaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagcc ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
caaggcaaag ggctaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcacatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcaagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgctccta gggttgggcg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc caatgataga tcatcccagg atacccagct 13380
ctcgcaagct agagctgagg gcagagctgt gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtag 13500
aatttgttac atggtccaca ccccaactat atcacattct agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gcttatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
11
CA 02323927 2000-09-25
WO 99/49017 PC'TNS99/06225
ggcactgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagtttaca tttcttttgt gtgaaagtga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttgt gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc ggaggctagg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atcttcggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggatttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca atacaagcaa gcacaatctt cccatttctg 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggaag 14580
acggcttatt cttgggtgag ggatcgggtt ctatgttgat cacttataag gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tctctgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaggt gctctttaac gggaggcccg aagtcacatg ggtaggcagt gtagattgct 14820
tcaattacat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttacc taacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctca ttatagagaa gtgaaccttg 15060
tataccccag atacagcaac ttcatatcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtgc 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaaa ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaggaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctagaatc actcgcaaat 15540
tttgggggca cattcttctt tactccggga acagaaagtt gataaataag tttatccaga 15600
atctcaagtc cggttatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaag gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
actaattggt tgaactccgg aaccctaatc ctgccccagg tggttaggca ttatttgtaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 3
<211> 15894
<212> DNA
<213> Measles virus
<400> 3
accaaacaaa gttgggtaag gatagatcaa tcaatgatca tattctagta cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagacta ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttgtttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag catcaggctg ttagaggttg 420
12
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaagtag tagtgatcaa tccaggtccg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccattcta gcccaaattt gggtcttgct cgcgaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga attcagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag aggacacccg 840
ggaacaaacc aaggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatccta actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaat ctttaccagc 1020
aaatgggaga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccccctg ctctggagct atgccatggg agtaggggtg gaacttgaaa 1140
actccatggg aggtttgaac tttggtcgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtgaggagg tcagctggga aagtcagttc cacattagca tctgaactcg 1260
gtatcactgc tgaggatgca aggcttgttt cagagattgc aatgcacact actgaggaca 1320
ggaccagtag agcggttgga cccagacaag cccaagtgtc atttctacac ggtgatcaaa 1380
gtgagaatga gctaccagga ttggggggca aggaagatag gagggtcaaa cagagtcggg 1440
gagaagccag ggagagctac agagaaaccg ggtctagcag agcaagcgat gcgagagctg 1500
cccatcttcc aaccagcgca cccctagaca ttgacactgc atcggagtca ggccaagatc 1560
cgcaggacag tcgacggtca gctgacgccc tgctcaggct gcaagccatg gcaggaatct 1620
tggaagaaca aggctcagac acggacaccc ctagggtgta caatgacaga gatcttctag 1680
actaggtgcg agaggccgag gaccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagccaacca accatccact cctacgactg 1800
gggccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc gtcgaggaag ccatggcagc atggtcacaa 1920
atatcagaca acccaggaca ggaccgaacc acccgcaagg aagaggaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcagtgc acctcgcatc 2040
tgcggtcagg gatctggaga gagcgatgac aacgctgaaa ctttgggaat cccctcaaga 2100
aatctccagg catcaagcac tgggttacag tgttatcatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga cgatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatct 2400
agaggcaaca acttcccgaa gcttgggaaa actctcaatg ttcctccgcc cccgaacccc 2460
ggtagggcca gcacttccga gacacccatt aaaaagggga cagacgcgag attagcctca 2520
tttggagcgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gtggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ttattatgat gatgagctgt tctccgatgt ccaagacatc 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaaaaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaactcaatc ccgacctgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcaa 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggcccc 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca acgatcttgc caagttccac 3300
13
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caacctcatg 3360
ccaatcgacc taattagtac agcctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacctacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttacg tacatgtttc 3600
tgctgggggt tgttgaggac agcgatcccc tagggcctcc aatcgggcga gcatttgggt 3660
ccctgccctt aggtgttggt agatccacag caaaacccga agaactcctc aaagaggcca 3720
ctgagcttga catagtcgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctggatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct agaattcaga tcggtcaatg cagtggcttt caacctgctg gtgaccctta 4020
ggattgacaa agcgattggc cctgggaaga tcatcgataa tgcagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgctg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
ggttcaaaaa gaccttatgt tacccactga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcccc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc~aatacccgaa aacgaccccc ctcataatga cagccagaag 4500
gcccggacaa aaaagccccc tccaaaagac tccacggacc aagtgagagg ccagccagca 4560
gctgacggca agcgtgaaca ccaggcggcc tgggcacaga acagccccga cacaaggcaa 4620
ccaccagcca tcccaatctg cgtcctcctc gtgggacccc cgaggaccaa cccccaaggt 4680
cgcccccgac ccagaccacc aaccgcatcc ccacagcccc cgggaaagag acccccagca 4740
actggaaggc ccctccccct ttccctcaac gcaagaactc cacaaccgaa ccgcacaagc 4800
gatcgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc cccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccgac agaacccaga ccccggccca 4920
cggcgccgcg cccccacctc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg cacaccaacc ctcgaacaga cccagcaccc agccatcgac 5040
aattcaagac ggggggcccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca caggaaccga accagaatcc agaccaccct 5160
gggccaccag ttcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
acccctgccc tgatccggtg ggcggccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaagggccc ccgaaccgca aaagacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctccccctct tctcgaaggg accaaaagat caatccacca cacccgacga cactcaattc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtagggat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgctg gagttgtcct ggcgggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ttgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctagggctca aattgctcag atactataca gaaatcctgt cactatttgg ccccagctta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagat 6180
14
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtactc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagaaggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tccaccaagt cctgtgctcg tacacttgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga atctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaggaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtggtcgagg tgaacggcgt gaccatccaa gtcgggagca ggcggtatcc ggacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtttacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacagga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
cacaagtctc ctcttcgtca tcaagcaacc accgcatcca gcatcgagcc cacctgaaat 7200
tgtctccgga ttccctctgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag acaaccccca 7320
tcctagggga agtaggatag ttattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctattcg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cataagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
gatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcaccgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gaactcatga atgcattggt gaactcaact ctactggagg ccagggtaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttgga cttgtattta aatcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtacggggga acttacctag tggaaaagcc 7980
taatctgagc agtaaagggt cagagttgtc acaactgagc atgcaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actattttga 8100
gcaaccagtc agtaatgatt tcagcaactg catggtggct ttgggggagc tcaaattcgc 8160
agccctttgt cacagggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccctatca acggatgatc cagtgataga caggctctac ctctcatctc acagaggcgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cggacagatg acaagttgcg 8400
aatggagaca tgcttccagc aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttaatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcagga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc tacctcttca ctgttccaat taaggaagca ggcgaggact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctatgat acttccagag ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaagccg ctcattttct tacttttatc cttttaggtt 8940
gcctataagg ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggatata tcactcactc 9060
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tgggatggtg ggcatgggag tcagctgcac agtcactcgg gaagatggaa ccaaccgcag 9120
atagggctgc cagtgaacca atcacatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agctatcctg gagtatgctc gagtccctca cgcatacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccgacccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
caaggaagat ccgtgagctc ctcaaaaagg gaaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcctgagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaaatt attaacttgg gagtttacat gcacagctcc caatggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac cagtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacgtttga actggtcttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac cattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
aactgataga tggtttcttc cctgcactcg ggaatccaac ttaccaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ccctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatattct gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca cccctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaaaggaa ctgggtcacg gaggcttgta aatgttttcc 10740
ttaatgattc gagctttgac ccatatgaca tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aattatttta aggacaatgg gatggccaag gacgagcacg 10980
atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaaccc actcccgaag cccagtccac acaagtacca 11100
agaacgtgag agcagcaaaa gggtttatag gattccctca tgtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaggctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttattt gcacaaaggc 11280
taaatgagat ttacggatta ccctcatttt tccagtggct gcataagagg cttgaaacct 11340
ctgtcctcta tgtaagtgac cctcattgcc cccctgacct tgacgcccat gtcccgttat 11400
gcaaagtccc caatgaccaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatttata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccttac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg acataggcca tcacctcaag gcaaatgaga 11700
caattgtctc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa atcctgatct 11940
16
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgatct cttaataagg atggcactgt tgcccgctcc tatcgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc tcatcactaa tgcctgaaga gacccttcat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgcgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaagggt tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgcta gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caatttagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggctagagcc ctaagaagcc 12660
atatgtgggc aaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gccatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttat ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
caaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtaccactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcaagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaggg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagcttagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gcttatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcagcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcttc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttacaca 13920
caactgtgtg caacatgatt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttcttctgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa tatccaggca aaacacttgt gtgttctagc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctacgac ctgtagagaa atgtgcagtt ctaaccgatc 14160
atatcaaggc agaggctagg ttatctccag cagggtcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcatttttg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggatttcaga cctccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggtaatct cgccaattat gaaatccacg ctttccgcag aatcgggtta aactcatccg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggaag 14580
acggcttgtt cttgggtgag gggtcgggtt ctatgttgat cacttataag gagatactaa 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggtc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 14820
17
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tcaatttcat agtcagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttacc taacaaagat actatagaga agctagagga attagcagcc atcttatcga 14940
tggctctgct ccttggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctta ttatagagaa gtgaaccttg 15060
tctaccctag atacagcaac ttcatatcta ctgaatctta tttagtcatg acagatctca 15120
aagctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtgc 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg gtatcaaccc tattctgaag aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaaa ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaactct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccatg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tttgggggca tattcttctt tactccggga acagaaagtt gataaatcgg tttatccaga 15600
atctcaagtc cggttacctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ctaagtcaga gaaacagatt attatgacgg ggggtttaaa acgtgagtgg gtttttaagg 15720
taacaatcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
attaattggt tggactccgg gaccctaatc ctgccctagg tagttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 4
<211> 15894
<212> DNA
<213> Measles virus
<400> 4
accaaacaaa gttgggtaag gatagatcaa tcaatgatca tattctagta cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
tgaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aattcctgga gattcctcaa 240
ttaccactcg atccagacta ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag catcaggctg ttagaggttg 420
ttcagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaagcag tagtgatcaa tccaggtccg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agatcctgag ggattcaaca 600
tgattctggg taccattcta gcccagatct gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc tttacgccga ttcatggtgg ctctaatcct ggatatcaag aggacacccg 840
ggaacaaacc taggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcttg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaat ctttaccagc 1020
aaatgggaga aactgcaccc tacatggtaa tcctagagaa ctcaattcag aacaagttca 1080
gcgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggtcgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtgaggagg tcagctggaa aggtcagttc cacattggca tccgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
ggatcagtag agcggtcgga cccagacaag cccaagtatc atttctacac ggtgatcaaa 1380
18
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
gtgagaatga gctaccagga ttggggggca aggaagacag gagggtcaaa cagagtcggg 1440
gagaagccag.ggagagctac agagaaaccg agtccagcag agcaagtgat gcgagagctg 1500
cccatcctcc aaccagcatg cccctagaca ttgacactgc atcggagtca ggccaagatc 1560
cgcaggacag tcgaaggtca gctgacgctc tgctcaggct gcaagccatg gcaggaatct 1620
tggaagaaca aggctcagac acggacaccc ctagggtata caatgacaga gatcttctag 1680
attaggtgcg agaggccgag gaccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagccaacca accatccact cccacgactg 1800
gagccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc gtcgaggaag ccatggcagc atggtcagaa 1920
atatcagaca atccaggaca ggaccgagcc gcctgcaagg aagaggaggc aggcagttcg 1980
ggtctcagca aaccatgctt ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gatctggaga aagcgatgac gacgctgaaa ctttgggaat cccctcaaga 2100
aatctccagg catcaagcac tgggttacag tgttatcatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga cgatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgaa actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc cccgaacccc 2460
agtagggcca gcacttccga gacacccatt aaaaagggga cagacgcgag attggcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac cgtcagggcc agatgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctccgatgt ccaagacatc 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ttgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga ttgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaactcaatc ccgacctgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga agcccgttgc cagccgacaa 3060
ctccagggaa tgactaatgg acggaccagt tccagaggac agctgctgaa ggaatttcaa 3120
ctaaagccga tcgggaaaaa ggtgagctca gccgtcgggt ttgtccctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctgt tgactctcct tgatgatatc aaaggagcca acgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc taattagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcctaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacctacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggtgata ggaaggatga atgctttatg tacatgtttc 3600
tgctgggggt tgttgaggac agagatcccc tagggcctcc aatcgggcga gcattcgggt 3660
ccctgccctt aggtgttggt agatccacag caaaacccga ggaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaaccctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaatgcaaa ccaagtgtgc aatgcggtta atctaatacc gctggacacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccca 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgcta gtgaccctca 4020
ggattgacaa ggcgattggc cctgggaaga tcatcgacaa tgcagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
19
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ggttcaagaa gaccttatgt tacccactga tggatatcaa tgaagacctt aatcggttac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatacccgaa aacgaccccc ctcataatga cagccagaag 4500
gcccggacaa aaaagccccc tccaaaagac ttcacggacc aagcgagagg ccagccagca 4560
gccgacagca agtgtggaca ccaggcggcc caagcacaga acagccccga cacaaggcca 4620
ccaccagcca tcccaatccg cgtcctcctc gtaggacccc cgaggaccaa cccccaaggt 4680
cgctccggac acagaccacc agccgcatcc ccacagccct cgggaaagga acccccagca 4740
actggaaggc cccttccccc ctcccccaac gcaagaaccc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agaccctccc tccccggcat 4860
actaaacaaa acttagggcc aaggaacaca cacacccgac agaacccaga ccccggcccg 4920
cggcaccgcg cccccacccc ccgaaaacca gagggagccc ccaaccaatc ccgccgcccc 4980
ccccggtgcc cacaggtagg cacaccaacc cccgaacaga cccagcaccc agccaccgac 5040
aatccaagac ggggggcccc ccccaaaaaa aggcccecag gggccgacag ccagcatcgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagagccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgaaaaaa ggaaaggcca caacccgcgc 5220
accccaggcc cgatccggcg ggaagccacc caacccgaac cagcacccaa gagcgatccc 5280
tgggggaccc ccaaaccgca aaagacatca gtatcccacc gcctctccaa gtcccccggt 5340
ctcctcctct tctcgaaggg accaaaagat caatccacca catccgacga cactcaattc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaatgtctt tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtagggat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattgg tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gaaattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagttgtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcaagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca ggcaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctagggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagctta 6120
cgggacccca tatctgcgga gatatccatc caggctttga gctatgcgct tgggggagat 6180
atcaataagg tattagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca atataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tccaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatcctct gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtggtcgagg tgaacggtgt gaccatccaa gtcgggagca ggaggtatcc ggacgcggtg 6780
tacctgcaca gaattgacct cggtcctccc atatcattgg agaagttgga cgtagggaca 6840
aatctgggga atgcaattgc taagctggag gatgccaagg aattgctgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtttacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gggaacaagt tggtatgtca agaccaggcc taaagcctga tcttacaggg 7080
acatcaaaat cctatgtaag gtcgctctga tcccctacaa ctcttgaaac acagatttcc 7140
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
cacaagtctc ctctccgtca tcaagcaacc accgcatcca gcatcaaggc cacccgaaat 7200
tgtctccggc ttccctctgg ccgaacgata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac accgagaccg aataaatgcc ttctacaaag acaaccccca 7320
tcctaaggga agtaggatag ttattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctattcg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cattagactc catcgggcag ccatctacac cgcagagatc cataagagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
gatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aaaattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gaactcatga atgcattggt gaactcaact ctactggagg ccagggcaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttgga cttgtattta agtcgaggtt acaatgtgtc 7920
atctatagtc accatgacat cccagggaat gtacggggga acttacctag tgggaaagcc 7980
taatctgagc agtaaagggt cagagttgtc acaactgagc atgcaccgag tgtttgaagt 8040
aggggttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actattttga 8100
gcaaccagtc agtaatgatt tcagcaactg catggtggct ttgggggagc tcaggttcgc 8160
agccctctgt cacagggaag attctgtcac ggttccctat caggggtcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccctatca acggatgatc cagtgataga taggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cggacagatg acaagttgcg 8400
aatggagaca tgcttccagc aggcgtgtaa gggtaaaaac caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttaatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcagga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaaaccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc aacctcttca ctgttccaat caaggaagca ggcgaggact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtaattct 8820
acctggtcag gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tatgtttaca gcccaggccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccaa tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ttcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcactcgg gaagatggaa ccaatcgcag 9120
atagggctgc cagtgaaccg atcacatgat gtcactcaga caccaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggtttccc gtcatggact 9240
cgctatctgt caaccagatc ttgtaccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agctatcctg gagtatgctc gagtccctca cgcttacagc cttgaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attctccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
caaggaagat ccgtgagctc ctaaaaaagg gaaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcctgagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaaatt attaacttgg gagtttacat gcacagctcc caatggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagc 9840
tgttaatctc tcgtgacctt gttgctataa tcagtaagga gtctcaacat gtatattacc 9900
tgacgtttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac cattgatgct aggtatgcag aacttctagg aagagtcaga tacatgtgga 10020
21
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagctatgc 10080
tggagccact ttcacttgct tacctgcaac tgagggacat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ccttagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gtcaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaagggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca cccctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggagatcat 10560
ttgctggagt gagatttggc tgttttatgc ctcttagcct ggacagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgatcct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgata tgataatgta tgtcgtaagt ggagcctacc 10800
tccatgaccc tgagttcaat ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt cgctaaaatg acttacaaaa tgagggcatg ccaagtgatc gctgaaaatc 10920
taatctcaaa cgggattggc aagtatttta aggacaatgg gatggccaag gatgagcacg 10980
atttgactaa ggcactccac actctggctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgttaa agcagaaaaa gggtttgtag gattccctca tgtaattcgg cagaatcaag 11160
acactgatca tccggagaat atagaaacct acgagacagt cagcgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttattt gcacagaggc 11280
taaatgagat ttacggatta ccctcatttt ttcagtggct gcataagagg cttgaaacct 11340
ctgtcctcta tgtaagtgat cctcattgcc cccccgacct tgacgcccat gtcccgttat 11400
gcaaagtccc caatgaccaa atcttcatca agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctacttata cctggctgct tatgagagcg 11520
gggtaaggat tgcctcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccttac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg acattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc attgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta tcttgcatat tccctgaacg tcctaaaagt gatacagcaa attttgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccgagatgt agtcataccc ctcctcacaa 12000
acaacgatct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaacatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcatcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgcgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctaa 12300
tccatagtcc aaacccaatg ttaaaagggt tattccatga tgacagtaaa gaagaggacg 12360
agagactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgcta gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caatttagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggctagagcc ctaagaagcc 12660
atatgtgggc aagactagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
22
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tgaagcttgc cttcgtaaga gccccaagta gatccttgcg atctgccgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
caaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcgactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtcag agtggcaagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa agttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag atactggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacattct agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gcttatagag ccaagattat 13680
tcaccatcta cttgggccag tgtgcagcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcttc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta ccttgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttcttttgt gtgaaagcga tgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttgt gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accgattcga ggtctaaggc cggtagagaa atgtgcagtt ctaaccgatc 14160
atatcaaggc agaggctagg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccgtcg aggatctatc aaacagataa 14280
gattgagagt tgatccagga ttcatttttg atgccctcgc tgaggtaaat gtcagtcagc 14340
caaaggtcgg cagcaacaac atctcaaata tgagcatcaa ggatttcaga cctccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggtagtct tgccaattat gaaatccatg ctttccgcag aatcgggtta aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggaag 14580
acggcttgtt cttgggtgag gggtcgggtt ctatgttgat cacttataag gagatactaa 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaggt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt atagattgct 14820
tcaatttcat agtcagtaat atccctacct ctagtgtggg atttatccat tcagatatag 14880
agaccttacc caacaaagat actatagaga agttagagga attggcagcc atcttatcga 14940
tggctctact ccttggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagctatg tagggtctca ttatagagaa gtgaaccttg 15060
tctaccctag gtacagcaac ttcatatcta ctgaatctta tttagttatg acagatctca 15120
aagctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtgc 15180
ggacttcacc tggacttata ggtcacatcc tatctatcaa gcaactaagc tgcatacaag 15240
caattgtggg aggcgcagtt agtagaggtg atatcaaccc tattctgaaa aaacttacac 15300
ctatagagca ggtgctgatc agttgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattaatcca ccatgatgtt gcctcagggc aagatggatt gcttaactct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agtaggcaac gagaacttgt atctaggatc actcgcaaat 15540
tttgggggca tattcttctt tactccggga acagaaagtt gataaatcgg tttatccaga 15600
atctcaagtc cggttatcta atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttaaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagcgct ctgattaagg 15780
23
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
attaattggt tgaactccgg aaccctaatc ctaccctagg tagttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 5
<211> 15894
<212> DNA
<213> Measles virus
<400> 5
accaaacaaa gttgggtaag gatagttcaa tcaatgatca tcttctagtg cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagactt ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaattag tagtgatcaa tccaggttcg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gcccaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tggttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
gaaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaac ctttaccagc 1020
aaatggggga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtaaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
agatcagtag agcggttgga cccagacaag cccaagtatc atttctacac ggtgatcaaa 1380
gtgagaatga gctaccgaga ttggggggca aggaagatag gagggtcaaa cagagtcgag 1440
gagaagccag ggagagctac agagaaaccg ggcccagcag agcaagtgat gcgagagctg 1500
cccatcttcc aaccggcaca cccctagaca ttgacactgc aacggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgcttaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctatagtgta caatgacaga aatcttctag 1680
actaggtgcg agaggccgag ggccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccatca accatccact cccacgattg 1800
gagccaatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc acctgcaggg aagagaaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gacctggaga gagcgatgac gacgctgaaa ctttgggaat ccccccaaga 2100
aatctccagg catcaagcac tgggttacag tgttattacg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
24
CA 02323927 2000-09-25
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gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc cccggacccc 2460
ggtagggcca gcacttccgg gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca atgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc caactagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagacct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacccacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttatg tacatgtttc 3600
tgctgggggt tgttgaggac agcgattccc tagggcctcc aatcgggcga gcatttgggt 3660
ccctgccctt aggtgttggc agatccacag caaagcccga aaaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctcgatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgataggc cctgggaaga tcatcgacaa tacagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
ggttcaagaa gaccttatgt tacccgctga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa aacgaccccc ctcacaatga cagccagaag 4500
gcccggacaa aaaagccccc tccgaaagac tccacggacc aagcgagagg ccagccagca 4560
gccgacggca agcgcgaaca ccaggcggcc ccagcacaga acagccccga cacaaggcca 4620
ccaccagcca ccccaatctg catcctcctc gtgggacccc cgaggaccaa cccccaaggc 4680
tgcccccgat ccaaaccacc aaccgcatcc ccaccacccc cgggaaagaa acccccagca 4740
attggaaggc ccctccccct cttcctcaac acaagaactc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc tccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggccca 4920
cggcgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg gacaccaacc cccgaacaga cccagcaccc aaccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagaaccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
accccagccc cgatccggcg gggagccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacacca gtatcccaca gcctctccaa gtcccccggt 5340
ctcctcctct tctcgaaggg accaaaagat caatccacca cacccgacga cactcaactc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagttta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagac 6180
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcggaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tacaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtagtcgagg tgaacggcgt gatcatccaa gtcgggagca ggaggtatcc agacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacggga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
cacaagtctc ctcttcgtca tcaagcaacc accgcaccca gcatcaagcc cacctgaaat 7200
tatctccggc ttccctctgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag tcattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctgtttg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttaga cttgtattta ggtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtatggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaaaggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actatcttga 8100
26
CA 02323927 2000-09-25
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gcaaccagtc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt cacggggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccttatca acggatgatc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cgaacagatg acaagttgcg 8400
aatggagaca tgcttccaac aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttgatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc tacctcttca ctgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaagccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatcgcag 9120
atagggctgc tagtgaacca atcacatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg ggaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcttaagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc cagtggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacatttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac tattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ctctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgatg tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
27
CA 02323927 2000-09-25
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atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgtgag agcagcaaaa gggtttatag ggttccctca agtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggattg ccctcatttt tccagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
ataaagtccc caatgatcaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatctata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccctac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg atattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa attctgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcctcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaaggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgctg gataccacaa 12480
aaggcttgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattgaca ggaagaaagc 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagct ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
ctaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcgagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gctcatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
28
CA 02323927 2000-09-25
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ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttctcttgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttat gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc agaggctatg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggctttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggagg 14580
acggcttgtt cttgggtgag ggatcgggtt ctatgttgat cacttataag gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 14820
tcaatttcat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttgcc tgacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctca ttatagagaa gtgaaccttg 15060
tataccctag atacagcaac ttcatctcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtga 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tctgggggca cattcttctt tactccggga acagaaagtt gataaataag tttatccaga 15600
atctcaagtc cggctatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
actaattggt tgaactccgg aaccctaatc ctgccctagg tggttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 6
<211> 15894
<212> DNA
<213> Measles virus
<400> 6
accaaacaaa gttgggtaag gatagttcaa tcaatgatca tcttctagtg cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagactt ctggaccggt tggtgaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
29
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaattag tagtgatcaa tccaggttcg 540
gatggttcgg gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gcccaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
gaaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaac ctttaccagc 1020
aaatggggga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtaaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
agatcagtag agcggttgga cccagacaag cccaagtatc atttctacac ggtgatcaaa 1380
gtgagaatga gctaccgaga ttggggggca aggaagatag gagggtcaaa cagagtcgag 1440
gagaagccag ggagagctac agagaaaccg ggcccagcag agcaagtgat gcgagagctg 1500
cccatcttcc aaccggcaca cccctagaca ttgacactgc aacggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgcttaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctatagtgta caatgacaga aatcttctag 1680
actaggtgcg agaggccgag ggccagaaca acatccgcct accatccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccatca accatccact cccacgattg 1800
gagccaatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc acctgcaggg aagagaaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gacctggaga gagcgatgac gacgctgaaa ctttgggaat ccccccaaga 2100
aatctccagg catcaagcac tgggttacag tgttattacg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc cccggacccc 2460
ggtagggcca gcacttccgg gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca atgatcttgc caagttccac 3300
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc caactagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag gtccacaatg acagagacct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caacccacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttatg tacatgtttc 3600
tgctgggggt tgttgaggac agcgattccc tagggcctcc aatcgggcga gcatttgggt 3660
tcctgccctt aggtgttggc agatccacag caaagcccga aaaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctcgatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgataggc cctgggaaga tcatcgacaa tacagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
ggttcaagaa gaccttatgt tacccgctga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa aacgaccccc ctcacaatga cagccagaag 4500
gcccggacaa aaaagccccc tccgaaagac tccacggacc aagcgagagg ccagccagca 4560
gccgacggca agcgcgaaca ccaggcggcc ccagcacaga acagccctga cacaaggcca 4620
ccaccagcca ccccaatctg catcctcctc gtgggacccc cgaggaccaa cccccaaggc 4680
tgcccccgat ccaaaccacc aaccgcatcc ccaccacccc cgggaaagaa acccccagca 4740
attggaaggc ccctccccct cttcctcaac acaagaactc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc tccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggtcca 4920
cggtgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg gacaccaacc cccgaacaga cccagcaccc aaccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagaaccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
accccagccc cgatccggcg gggagccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctcctcctct tctcgaaggg accaaaagat caatccacca cacccgacga cactcaactc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gagacaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 606C
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagttta 612C
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagac 618C
31
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcggaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tacaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtagtcgagg tgaacggcgt gaccatccaa gtcgggagca ggaggtatcc agacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacggga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
cacaagtctc ctcttcgtca tcaagcaacc accgcaccca gcatcaagcc cacctgaaat 7200
tatctccggc ttccctctgg ccgaacaata tcggtagtta atcaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag tcattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctgtttg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
aatctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttaga cttgtattta ggtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtatggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaaaggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actatcttga 8100
gcaaccagtc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt cacggggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccttatca acggatgatc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cgaacagatg acaagttgcg 8400
aatggagaca tgcttccaac aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttgatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc tacctcttca ctgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaagccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
32
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatcgcag 9120
atagggctgc tagtgaacca atcacatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg ggaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcttaagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc cagtggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacatttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac tattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaactgaag ctctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgatg tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgtgag agcagcaaaa gggtttatag ggttccctca agtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggattg ccctcatttt tccagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
ataaagtccc caatgatcaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatctata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccctac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg atattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa attctgatct 11940
33
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcctcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaaggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgctg gataccacaa 12480
aaggcttgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagct ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
ctaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcgagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagatgca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gctcatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttctcttgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttat gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc agaggctatg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggctttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggagg 14580
acggcttgtt cttgggtgag ggatcgggtt ctatgttgat cacttataaa gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 1482C
34
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tcaatttcat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttgcc tgacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctca ttatagagaa gtgaaccttg 15060
tataccctag atacagcaac ttcatctcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtga 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tctgggggca cattcttctt tactccggga acaaaaagtt gataaataag tttatccaga 15600
atctcaagtc cggctatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
actaattggt tgaactccgg aaccctaatc ctgccctagg tggttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 7
<211> 15894
<212> DNA
<213> Measles virus
<400> 7
accaaacaaa gttgggtaag gatagttcaa tcaatgatca ttttctagtg cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattaaggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagactt ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga ccaatacttt tcacatgatg atccaattag tagtgatcaa tccaggttcg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gctcaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
gaaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaac ctttaccagc 1020
aaatggggga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtaaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
agatcagtag agcggttgga cccagacaag cccaagtatc atttctacac ggtgatcaaa 1380
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
gtgagaatga gctaccgaga ttggggggca aggaagatag gagggtcaaa cagagtcgag 1440
gagaagccag ggagagctac agagaaaccg ggcccagcag agcaagtgat gcgagagctg 1500
cccatcttcc aaccggcaca cccctagaca ttgacactgc atcggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgcttaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctatagtgta caatgacaga aatcttctag 1680
actaggtgcg agaggccgag ggccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccatca accatccact cccacgattg 1800
gagccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc acctgcaggg aagagaaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gacctggaga gagcgatgac gacgctgaaa ctttgggaat ccccccaaga 2100
aatctccagg catcaagcac tgggttacag tgttattatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctct caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc tccggacccc 2460
ggtagggcca gcacttccgg gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagtg tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ctaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca atgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc caactagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggttgat cgctccgata caacccacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttatg tacatgtttc 3600
tgctgggggt tgttgaggac agcgatcccc tagggcctcc aatcgggcga gcatttgggt 3660
ccctgccctt aggtgttggc aaatccacag caaagcccga aaaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc agtgcggtta atctgatacc gctcgatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgataggc cctgggaaga tcatcgacaa tacagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
36
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ggttcaagaa gaccttatgt tacccgctga tagatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa aacgaccccc ctcacaatga cagccagaag 4500
gcccggacaa aaaagccccc tccgaaagac tccacggacc aagcgagagg ccagccagca 4560
gccgacggca agcgcgaaca ccaggcggcc ccagcacaga acagccctga tacaaggcca 4620
ccaccagcca ccccaatctg catcctcctc gtgggacccc cgaggaccaa cccccaaggc 4680
tgcccccgat ccaaaccacc aaccgcatcc ccaccacccc cgggaaagaa acccccagca 4740
attggaaggc ccctccccct cttcctcaac acaagaactc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc tccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggccca 4920
cggcgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg gacaccaacc cccgaacaga cccagcaccc aaccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagaaccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
accccagccc cgatccggcg gggagccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctcctcccct tctcgaaggg accaaaagat caatccacca cacccgacga cactcaactc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagctta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagac 6180
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tccaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga tcactgcccg 6720
gtagtcgagg tgaacggcgt gaccatccaa gtcgggagca ggaggtatcc agatgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atatcattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcactagca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacggga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
37
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
cacaagtctc ctcttcgtca tcaagcaacc accgcaccca gcatcaagcc cacctgaaat 7200
tatctccggc ttccctctgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag tcattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctgtttg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcg,ctgt ccctgttaga cttgtattta ggtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtatggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaaaggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actatcttga 8100
gcaaccagcc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt cacggggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
ccccttatca acggatgatc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cgaacagatg acaagttgcg 8400
aatggagaca tgcttccaac aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttgatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
gccaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc tacctcttca atgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaggccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatcgcag 9120
atagggctgc tagtgaacca atctcatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg ggaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcttaagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc cagtggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacatttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac tattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
38
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ctctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgatg tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgtgag agcagcaaaa gggtttatag ggttccctca agtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggattg ccctcatttt tccagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
ataaagtccc caatgatcaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatctata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccctac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg atattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa attctgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcctcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaaggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgctg gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagct ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
39
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
ctaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcgagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagataca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gctcatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttctcttgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttat gtgttctggc agatttgtac tgtcaaccag 14100
ggacctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc agaggctagg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggctttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggagg 14580
acggcttgtt cttgggtgag ggatcgggtt ctatgttgat cacttataag gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 14820
tcaatttcat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttgcc taacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtccca ttatagagaa gtgaaccttg 15060
tataccctag atacagcaac ttcatatcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtga 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accaaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tttgggggca cattcttctt tactccggga acagaaagtt gataaataag tttatccaga 15600
atctcaagtc cggctatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
actaattggt tgaactccgg aaccctaatc ctgccctagg tggttaggca ttatttgcaa 15840
tagattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 8
<211> 15894
<212> DNA
<213> Measles virus
<400> 8
accaaacaaa gttgggtaag gatagttcaa tcaatgatca tcttctagtg cacttaggat 60
tcaagatcct attatcaggg acaagagcag gattagggat atccgagatg gccacacttt 120
taaggagctt agcattgttc aaaagaaaca aggacaaacc acccattaca tcaggatccg 180
gtggagccat cagaggaatc aaacacatta ttatagtacc aatccctgga gattcctcaa 240
ttaccactcg atccagactt ctggaccggt tggtcaggtt aattggaaac ccggatgtga 300
gcgggcccaa actaacaggg gcactaatag gtatattatc cttatttgtg gagtctccag 360
gtcaattgat tcagaggatc accgatgacc ctgacgttag cataaggctg ttagaggttg 420
tccagagtga ccagtcacaa tctggcctta ccttcgcatc aagaggtacc aacatggagg 480
atgaggcgga caaatacttt tcacatgatg atccaattag tagtgatcaa tccaggttcg 540
gatggttcga gaacaaggaa atctcagata ttgaagtgca agaccctgag ggattcaaca 600
tgattctggg taccatccta gcccaaattt gggtcttgct cgcaaaggcg gttacggccc 660
cagacacggc agctgattcg gagctaagaa ggtggataaa gtacacccaa caaagaaggg 720
tagttggtga atttagattg gagagaaaat ggttggatgt ggtgaggaac aggattgccg 780
aggacctctc cttacgccga ttcatggtcg ctctaatcct ggatatcaag agaacacccg 840
gaaacaaacc caggattgct gaaatgatat gtgacattga tacatatatc gtagaggcag 900
gattagccag ttttatcctg actattaagt ttgggataga aactatgtat cctgctcttg 960
gactgcatga atttgctggt gagttatcca cacttgagtc cttgatgaac ctttaccagc 1020
aaatggggga aactgcaccc tacatggtaa tcctggagaa ctcaattcag aacaagttca 1080
gtgcaggatc ataccctctg ctctggagct atgccatggg agtaggagtg gaacttgaaa 1140
actccatggg aggtttgaac tttggccgat cttactttga tccagcatat tttagattag 1200
ggcaagagat ggtaaggagg tcagctggaa aggtcagttc cacattggca tctgaactcg 1260
gtatcactgc cgaggatgca aggcttgttt cagagattgc aatgcatact actgaggaca 1320
agatcagtag agcggttgga cccagacaag cccaagtatc atttctacac ggtgatcaaa 1380
gtgagaatga gctaccgaga ttggggggca aggaagatag gagggtcaaa cagagtcgag 1440
gagaagccag ggagagctac agagaaaccg ggcccagcag agcaagtgat gcgagagctg 1500
cccatcttcc aaccggcaca cccctagaca ttgacactgc atcggagtcc agccaagatc 1560
cgcaggacag tcgaaggtca gctgacgccc tgcttaggct gcaagccatg gcaggaatct 1620
cggaagaaca aggctcagac acggacaccc ctatagtgta caatgacaga aatcttctag 1680
actaggtgcg agaggccgag gaccagaaca acatccgcct accctccatc attgttataa 1740
aaaacttagg aaccaggtcc acacagccgc cagcccatca accatccact cccacgattg 1800
gagccgatgg cagaagagca ggcacgccat gtcaaaaacg gactggaatg catccgggct 1860
ctcaaggccg agcccatcgg ctcactggcc atcgaggaag ctatggcagc atggtcagaa 1920
atatcagaca acccaggaca ggagcgagcc acctgcaggg aagagaaggc aggcagttcg 1980
ggtctcagca aaccatgcct ctcagcaatt ggatcaactg aaggcggtgc acctcgcatc 2040
cgcggtcagg gacctggaga gagcgatgac gacgctgaaa ctttgggaat ccccccaaga 2100
aatctccagg catcaagcac tgggttacag tgttattatg tttatgatca cagcggtgaa 2160
gcggttaagg gaatccaaga tgctgactct atcatggttc aatcaggcct tgatggtgat 2220
agcaccctat caggaggaga caatgaatct gaaaacagcg atgtggatat tggcgaacct 2280
gataccgagg gatatgctat cactgaccgg ggatctgctc ccatctctat ggggttcagg 2340
41
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400
agaggcaaca actttccgaa gcttgggaaa actctcaatg ttcctccgcc cccggacccc 2460
ggtagggcca gcacttccgg gacacccatt aaaaagggca cagacgcgag attagcctca 2520
tttggaacgg agatcgcgtc tttattgaca ggtggtgcaa cccaatgtgc tcgaaagtca 2580
ccctcggaac catcagggcc aggtgcacct gcggggaatg tccccgagta tgtgagcaat 2640
gccgcactga tacaggagtg gacacccgaa tctggtacca caatctcccc gagatcccag 2700
aataatgaag aagggggaga ctattatgat gatgagctgt tctctgatgt ccaagatatt 2760
aaaacagcct tggccaaaat acacgaggat aatcagaaga taatctccaa gctagaatca 2820
ctgctgttat tgaagggaga agttgagtca attaagaagc agatcaacag gcaaaatatc 2880
agcatatcca ccctggaagg acacctctca agcatcatga tcgccattcc tggacttggg 2940
aaggatccca acgaccccac tgcagatgtc gaaatcaatc ccgacttgaa acccatcata 3000
ggcagagatt caggccgagc actggccgaa gttctcaaga aacccgttgc cagccgacaa 3060
ctccaaggaa tgacaaatgg acggaccagt tccagaggac agctgctgaa ggaatttcag 3120
ccaaagccga tcgggaaaaa gatgagctca gccgtcgggt ttgttcctga caccggccct 3180
gcatcacgca gtgtaatccg ctccattata aaatccagcc ggctagagga ggatcggaag 3240
cgttacctga tgactctcct tgatgatatc aaaggagcca atgatcttgc caagttccac 3300
cagatgctga tgaagataat aatgaagtag ctacagctca acttacctgc caaccccatg 3360
ccagtcgacc caactagtac aacctaaatc cattataaaa aacttaggag caaagtgatt 3420
gcctcccaag ttccacaatg acagagatct acgacttcga caagtcggca tgggacatca 3480
aagggtcgat cgctccgata caaccgacca cctacagtga tggcaggctg gtgccccagg 3540
tcagagtcat agatcctggt ctaggcgaca ggaaggatga atgctttatg tacatgtctc 3600
tgctgggggt tgttgaggac agcgatcccc tagggcctcc aatcgggcga gcatttgggt 3660
ccctgccctt aggtgttggc agatccacag caaagcccga aaaactcctc aaagaggcca 3720
ctgagcttga catagttgtt agacgtacag cagggctcaa tgaaaaactg gtgttctaca 3780
acaacacccc actaactctc ctcacacctt ggagaaaggt cctaacaaca gggagtgtct 3840
tcaacgcaaa ccaagtgtgc aatgcggtta atctgatacc gctcgatacc ccgcagaggt 3900
tccgtgttgt ttatatgagc atcacccgtc tttcggataa cgggtattac accgttccta 3960
gaagaatgct ggaattcaga tcggtcaatg cagtggcctt caacctgctg gtgaccctta 4020
ggattgacaa ggcgataggc cctgggaaga tcatcgacaa tacagagcaa cttcctgagg 4080
caacatttat ggtccacatc gggaacttca ggagaaagaa gagtgaagtc tactctgccg 4140
attattgcaa aatgaaaatc gaaaagatgg gcctggtttt tgcacttggt gggatagggg 4200
gcaccagtct tcacattaga agcacaggca aaatgagcaa gactctccat gcacaactcg 4260
ggttcaagaa gaccttatgt tacccgctga tggatatcaa tgaagacctt aatcgattac 4320
tctggaggag cagatgcaag atagtaagaa tccaggcagt tttgcagcca tcagttcctc 4380
aagaattccg catttacgac gacgtgatca taaatgatga ccaaggacta ttcaaagttc 4440
tgtagaccgt agtgcccagc aatgcccgaa aacgaccccc ctcacaatga cagccagaag 4500
gcccggacaa aaaagccccc tccgaaagac tccactgacc aagcgagagg ccagccagca 4560
gccgacggca agcacgaaca ccaggcggcc ccagcacaga acagccctga tacaaggcca 4620
ccaccagcca ccccaatctg catcctcctc gtgggacccc cgaggaccaa cccccaaggc 4680
tgcccccgat ccaaaccacc aaccgcatcc ccaccacccc cgggaaagaa acccccagca 4740
attggaaggc ccctccccct cttcctcaac acaagaactc cacaaccgaa ccgcacaagc 4800
gaccgaggtg acccaaccgc aggcatccga ctccctagac agatcctctc tccccggcaa 4860
actaaacaaa acttagggcc aaggaacata cacacccaac agaacccaga ccccggccca 4920
cggcgccgcg cccccaaccc ccgacaacca gagggagccc ccaaccaatc ccgccggctc 4980
ccccggtgcc cacaggcagg gacaccaacc cccgaacaga cccagcacct aaccatcgac 5040
aatccaagac gggggggccc ccccaaaaaa aggcccccag gggccgacag ccagcaccgc 5100
gaggaagccc acccacccca cacacgacca cggcaaccaa accagaaccc agaccaccct 5160
gggccaccag ctcccagact cggccatcac cccgcagaaa ggaaaggcca caacccgcgc 5220
42
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
accccagccc cgatccggcg gggagccacc caacccgaac cagcacccaa gagcgatccc 5280
cgaaggaccc ccgaaccgca aaggacatca gtatcccaca gcctctccaa gtcccccggt 5340
ctcctcctct tctcgaaggg accaaaagat caatccacca cacccgacga cactcaactc 5400
cccaccccta aaggagacac cgggaatccc agaatcaaga ctcatccaat gtccatcatg 5460
ggtctcaagg tgaacgtctc tgccatattc atggcagtac tgttaactct ccaaacaccc 5520
accggtcaaa tccattgggg caatctctct aagatagggg tggtaggaat aggaagtgca 5580
agctacaaag ttatgactcg ttccagccat caatcattag tcataaaatt aatgcccaat 5640
ataactctcc tcaataactg cacgagggta gagattgcag aatacaggag actactgaga 5700
acagttttgg aaccaattag agatgcactt aatgcaatga cccagaatat aagaccggtt 5760
cagagtgtag cttcaagtag gagacacaag agatttgcgg gagtagtcct ggcaggtgcg 5820
gccctaggcg ttgccacagc tgctcagata acagccggca ttgcacttca ccagtccatg 5880
ctgaactctc aagccatcga caatctgaga gcgagcctgg aaactactaa tcaggcaatt 5940
gaggcaatca gacaagcagg gcaggagatg atattggctg ttcagggtgt ccaagactac 6000
atcaataatg agctgatacc gtctatgaac caactatctt gtgatttaat cggccagaag 6060
ctcgggctca aattgctcag atactataca gaaatcctgt cattatttgg ccccagctta 6120
cgggacccca tatctgcgga gatatctatc caggctttga gctatgcgct tggaggagac 6180
atcaataagg tgttagaaaa gctcggatac agtggaggtg atttactggg catcttagag 6240
agcagaggaa taaaggcccg gataactcac gtcgacacag agtcctactt cattgtcctc 6300
agtatagcct atccgacgct gtccgagatt aagggggtga ttgtccaccg gctagagggg 6360
gtctcgtaca acataggctc tcaagagtgg tataccactg tgcccaagta tgttgcaacc 6420
caagggtacc ttatctcgaa ttttgatgag tcatcgtgta ctttcatgcc agaggggact 6480
gtgtgcagcc aaaatgcctt gtacccgatg agtcctctgc tccaagaatg cctccggggg 6540
tacaccaagt cctgtgctcg tacactcgta tccgggtctt ttgggaaccg gttcatttta 6600
tcacaaggga acctaatagc caattgtgca tcaatccttt gcaagtgtta cacaacagga 6660
acgatcatta atcaagaccc tgacaagatc ctaacataca ttgctgccga taactgcccg 6720
gtagtcgagg tgaacggcgt gaccatccaa gtcgggagca ggaggtatcc agacgctgtg 6780
tacttgcaca gaattgacct cggtcctccc atattattgg agaggttgga cgtagggaca 6840
aatctgggga atgcaattgc taagttggag gatgccaagg aattgttgga gtcatcggac 6900
cagatattga ggagtatgaa aggtttatcg agcacttgca tagtctacat cctgattgca 6960
gtgtgtcttg gagggttgat agggatcccc gctttaatat gttgctgcag ggggcgttgt 7020
aacaaaaagg gagaacaagt tggtatgtca agaccaggcc taaagcctga tcttacggga 7080
acatcaaaat cctatgtaag gtcgctctga tcctctacaa ctcttgaaac acaaatgtcc 7140
cacaagtctc ctcttcgtca tcaagcaacc accgcaccca gcatcaagcc cacctgaaat 7200
tatctccggc ttccctctgg ccgaacaata tcggtagtta attaaaactt agggtgcaag 7260
atcatccaca atgtcaccac aacgagaccg gataaatgcc ttctacaaag ataaccccca 7320
tcccaaggga agtaggatag tcattaacag agaacatctt atgattgata gaccttatgt 7380
tttgctggct gttctgtttg tcatgtttct gagcttgatc gggttgctag ccattgcagg 7440
cattagactt catcgggcag ccatctacac cgcagagatc cataaaagcc tcagcaccaa 7500
tctagatgta actaactcaa tcgagcatca ggtcaaggac gtgctgacac cactcttcaa 7560
aatcatcggt gatgaagtgg gcctgaggac acctcagaga ttcactgacc tagtgaaatt 7620
catctctgac aagattaaat tccttaatcc ggatagggag tacgacttca gagatctcac 7680
ttggtgtatc aacccgccag agagaatcaa attggattat gatcaatact gtgcagatgt 7740
ggctgctgaa gagctcatga atgcattggt gaactcaact ctactggaga ccagaacaac 7800
caatcagttc ctagctgtct caaagggaaa ctgctcaggg cccactacaa tcagaggtca 7860
attctcaaac atgtcgctgt ccctgttaga cttgtattta ggtcgaggtt acaatgtgtc 7920
atctatagtc actatgacat cccagggaat gtatggggga acttacctag tggaaaagcc 7980
taatctgagc agcaaaaggt cagagttgtc acaactgagc atgtaccgag tgtttgaagt 8040
aggtgttatc agaaatccgg gtttgggggc tccggtgttc catatgacaa actatcttga 8100
43
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
gcaaccagtc agtaatgatc tcagcaactg tatggtggct ttgggggagc tcaaactcgc 8160
agccctttgt caccgggaag attctatcac aattccctat cagggatcag ggaaaggtgt 8220
cagcttccag ctcgtcaagc taggtgtctg gaaatcccca accgacatgc aatcctgggt 8280
caccttatca acggatgatc cagtgataga caggctttac ctctcatctc acagaggtgt 8340
tatcgctgac aatcaagcaa aatgggctgt cccgacaaca cgaacagatg acaagttgcg 8400
aatggagaca tgcttccaac aggcgtgtaa gggtaaaatc caagcactct gcgagaatcc 8460
cgagtgggca ccattgaagg ataacaggat tccttcatac ggggtcttgt ctgttgatct 8520
gagtctgaca gttgagctta aaatcaaaat tgcttcggga ttcgggccat tgatcacaca 8580
cggttcaggg atggacctat acaaatccaa ccacaacaat gtgtattggc tgactatccc 8640
accaatgaag aacctagcct taggtgtaat caacacattg gagtggatac cgagattcaa 8700
ggttagtccc tacctcttca atgtcccaat taaggaagca ggcgaagact gccatgcccc 8760
aacataccta cctgcggagg tggatggtga tgtcaaactc agttccaatc tggtgattct 8820
acctggtcaa gatctccaat atgttttggc aacctacgat acttccaggg ttgaacatgc 8880
tgtggtttat tacgtttaca gcccaagccg ctcattttct tacttttatc cttttaggtt 8940
gcctataaag ggggtcccca tcgaattaca agtggaatgc ttcacatggg accaaaaact 9000
ctggtgccgt cacttctgtg tgcttgcgga ctcagaatct ggtggacata tcactcactc 9060
tgggatggtg ggcatgggag tcagctgcac agtcacccgg gaagatggaa ccaatcgcag 9120
atagggctgc tagtgaacta atctcatgat gtcacccaga catcaggcat acccactagt 9180
gtgaaataga catcagaatt aagaaaaacg tagggtccaa gtggttcccc gttatggact 9240
cgctatctgt caaccagatc ttataccctg aagttcacct agatagcccg atagttacca 9300
ataagatagt agccatcctg gagtatgctc gagtccctca cgcttacagc ctggaggacc 9360
ctacactgtg tcagaacatc aagcaccgcc taaaaaacgg attttccaac caaatgatta 9420
taaacaatgt ggaagttggg aatgtcatca agtccaagct taggagttat ccggcccact 9480
ctcatattcc atatccaaat tgtaatcagg atttatttaa catagaagac aaagagtcaa 9540
cgaggaagat ccgtgaactc ctcaaaaagg ggaattcgct gtactccaaa gtcagtgata 9600
aggttttcca atgcttaagg gacactaact cacggcttgg cctaggctcc gaattgaggg 9660
aggacatcaa ggagaaagtt attaacttgg gagtttacat gcacagctcc cagtggtttg 9720
agccctttct gttttggttt acagtcaaga ctgagatgag gtcagtgatt aaatcacaaa 9780
cccatacttg ccataggagg agacacacac ctgtattctt cactggtagt tcagttgagt 9840
tgctaatctc tcgtgacctt gttgctataa tcagtaaaga gtctcaacat gtatattacc 9900
tgacatttga actggttttg atgtattgtg atgtcataga ggggaggtta atgacagaga 9960
ccgctatgac tattgatgct aggtatacag agcttctagg aagagtcaga tacatgtgga 10020
aactgataga tggtttcttc cctgcactcg ggaatccaac ttatcaaatt gtagccatgc 10080
tggagcctct ttcacttgct tacctgcagc tgagggatat aacagtagaa ctcagaggtg 10140
ctttccttaa ccactgcttt actgaaatac atgatgttct tgaccaaaac gggttttctg 10200
atgaaggtac ttatcatgag ttaattgaag ctctagatta cattttcata actgatgaca 10260
tacatctgac aggggagatt ttctcatttt tcagaagttt cggccacccc agacttgaag 10320
cagtaacggc tgctgaaaat gttaggaaat acatgaatca gcctaaagtc attgtgtatg 10380
agactctgat gaaaggtcat gccatatttt gtggaatcat aatcaacggc tatcgtgaca 10440
ggcacggagg cagttggcca ccgctgaccc tccccctgca tgctgcagac acaatccgga 10500
atgctcaagc ttcaggtgaa gggttaacac atgagcagtg cgttgataac tggaaatctt 10560
ttgctggagt gaaatttggc tgctttatgc ctcttagcct ggatagtgat ctgacaatgt 10620
acctaaagga caaggcactt gctgctctcc aaagggaatg ggattcagtt tacccgaaag 10680
agttcctgcg ttacgaccct cccaagggaa ccgggtcacg gaggcttgta gatgttttcc 10740
ttaatgattc gagctttgac ccatatgatg tgataatgta tgttgtaagt ggagcttacc 10800
tccatgaccc tgagttcaac ctgtcttaca gcctgaaaga aaaggagatc aaggaaacag 10860
gtagactttt tgctaaaatg acttacaaaa tgagggcatg ccaagtgatt gctgaaaatc 10920
taatctcaaa cgggattggc aaatatttta aggacaatgg gatggccaag gatgagcacg 10980
44
CA 02323927 2000-09-25
WO 99149017 PCT/US99/06225
atttgactaa ggcactccac actctagctg tctcaggagt ccccaaagat ctcaaagaaa 11040
gtcacagggg ggggccagtc ttaaaaacct actcccgaag cccagtccac acaagtacca 11100
ggaacgtgag agcagcaaaa gggtttatag ggttccctca agtaattcgg caggaccaag 11160
acactgatca tccggagaat atggaagctt acgagacagt cagtgcattt atcacgactg 11220
atctcaagaa gtactgcctt aattggagat atgagaccat cagcttgttt gcacagaggc 11280
taaatgagat ttacggattg ccctcatttt tccagtggct gcataagagg cttgagacct 11340
ctgtcctgta tgtaagtgac cctcattgcc cccccgacct tgacgcccat atcccgttat 11400
ataaagtccc caatgatcaa atcttcatta agtaccctat gggaggtata gaagggtatt 11460
gtcagaagct gtggaccatc agcaccattc cctatctata cctggctgct tatgagagcg 11520
gagtaaggat tgcttcgtta gtgcaagggg acaatcagac catagccgta acaaaaaggg 11580
tacccagcac atggccctac aaccttaaga aacgggaagc tgctagagta actagagatt 11640
actttgtaat tcttaggcaa aggctacatg atattggcca tcacctcaag gcaaatgaga 11700
caattgtttc atcacatttt tttgtctatt caaaaggaat atattatgat gggctacttg 11760
tgtcccaatc actcaagagc atcgcaagat gtgtattctg gtcagagact atagttgatg 11820
aaacaagggc agcatgcagt aatattgcta caacaatggc taaaagcatc gagagaggtt 11880
atgaccgtta ccttgcatat tccctgaacg tcctaaaagt gatacagcaa attctgatct 11940
ctcttggctt cacaatcaat tcaaccatga cccgggatgt agtcataccc ctcctcacaa 12000
acaacgacct cttaataagg atggcactgt tgcccgctcc tattgggggg atgaattatc 12060
tgaatatgag caggctgttt gtcagaaaca tcggtgatcc agtaacatca tcaattgctg 12120
atctcaagag aatgattctc gcctcactaa tgcctgaaga gaccctccat caagtaatga 12180
cacaacaacc gggggactct tcattcctag actgggctag cgacccttac tcagcaaatc 12240
ttgtatgtgt ccagagcatc actagactcc tcaagaacat aactgcaagg tttgtcctga 12300
tccatagtcc aaacccaatg ttaaaaggat tattccatga tgacagtaaa gaagaggacg 12360
agggactggc ggcattcctc atggacaggc atattatagt acctagggca gctcatgaaa 12420
tcctggatca tagtgtcaca ggggcaagag agtctattgc aggcatgctg gataccacaa 12480
aaggcctgat tcgagccagc atgaggaagg gggggttaac ctctcgagtg ataaccagat 12540
tgtccaatta tgactatgaa caattcagag cagggatggt gctattgaca ggaagaaaga 12600
gaaatgtcct cattgacaaa gagtcatgtt cagtgcagct ggcgagagct ctaagaagcc 12660
atatgtgggc gaggctagct cgaggacggc ctatttacgg ccttgaggtc cctgatgtac 12720
tagaatctat gcgaggccac cttattcggc gtcatgagac atgtgtcatc tgcgagtgtg 12780
gatcagtcaa ctacggatgg ttttttgtcc cctcgggttg ccaactggat gatattgaca 12840
aggaaacatc atccttgaga gtcccatata ttggttctac cactgatgag agaacagaca 12900
tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960
cagtgtactc atgggcttac ggtgatgatg atagctcttg gaacgaagcc tggttgttgg 13020
ctaggcaaag ggccaatgtg agcctggagg agctaagggt gatcactccc atctcaactt 13080
cgactaattt agcgcatagg ttgagggatc gtagcactca agtgaaatac tcaggtacat 13140
cccttgtccg agtggcgagg tataccacaa tctccaacga caatctctca tttgtcatat 13200
cagataagaa ggttgatact aactttatat accaacaagg aatgcttcta gggttgggtg 13260
ttttagaaac attgtttcga ctcgagaaag ataccggatc atctaacacg gtattacatc 13320
ttcacgtcga aacagattgt tgcgtgatcc cgatgataga tcatcccagg atacccagct 13380
cccgcaagct agagctgagg gcagagctat gtaccaaccc attgatatat gataatgcac 13440
ctttaattga cagagataca acaaggctat acacccagag ccataggagg caccttgtgg 13500
aatttgttac atggtccaca ccccaactat atcacatttt agctaagtcc acagcactat 13560
ctatgattga cctggtaaca aaatttgaga aggaccatat gaatgaaatt tcagctctca 13620
taggggatga cgatatcaat agtttcataa ctgagtttct gctcatagag ccaagattat 13680
tcactatcta cttgggccag tgtgcggcca tcaattgggc atttgatgta cattatcata 13740
gaccatcagg gaaatatcag atgggtgagc tgttgtcatc gttcctttct agaatgagca 13800
aaggagtgtt taaggtgctt gtcaatgctc taagccaccc aaagatctac aagaaattct 13860
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ggcattgtgg tattatagag cctatccatg gtccttcact tgatgctcaa aacttgcaca 13920
caactgtgtg caacatggtt tacacatgct atatgaccta cctcgacctg ttgttgaatg 13980
aagagttaga agagttcaca tttctcttgt gtgaaagcga cgaggatgta gtaccggaca 14040
gattcgacaa catccaggca aaacacttat gtgttctggc agatttgtac tgtcaaccag 14100
gggcctgccc accaattcga ggtctaagac cggtagagaa atgtgcagtt ctaaccgacc 14160
atatcaaggc agaggctagg ttatctccag caggatcttc gtggaacata aatccaatta 14220
ttgtagacca ttactcatgc tctctgactt atctccggcg aggatcgatc aaacagataa 14280
gattgagagt tgatccagga ttcattttcg acgccctcgc tgaggtaaat gtcagtcagc 14340
caaagatcgg cagcaacaac atctcaaata tgagcatcaa ggctttcaga cccccacacg 14400
atgatgttgc aaaattgctc aaagatatca acacaagcaa gcacaatctt cccatttcag 14460
ggggcaatct cgccaattat gaaatccatg ctttccgcag aatcgggttg aactcatctg 14520
cttgctacaa agctgttgag atatcaacat taattaggag atgccttgag ccaggggagg 14580
acggcttgtt cttgggtgag ggatcgggtt ctatgttgat cacttataag gagatactta 14640
aactaaacaa gtgcttctat aatagtgggg tttccgccaa ttctagatct ggtcaaaggg 14700
aattagcacc ctatccctcc gaagttggcc ttgtcgaaca cagaatggga gtaggtaata 14760
ttgtcaaagt gctctttaac gggaggcccg aagtcacgtg ggtaggcagt gtagattgct 14820
tcaatttcat agttagtaat atccctacct ctagtgtggg gtttatccat tcagatatag 14880
agaccttgcc taacaaagat actatagaga agctagagga attggcagcc atcttatcga 14940
tggctctgct cctgggcaaa ataggatcaa tactggtgat taagcttatg cctttcagcg 15000
gggattttgt tcagggattt ataagttatg tagggtctta ttatagagaa gtgaaccttg 15060
tataccctag atacagcaac ttcatatcta ctgaatctta tttggttatg acagatctca 15120
aggctaaccg gctaatgaat cctgaaaaga ttaagcagca gataattgaa tcatctgtga 15180
ggacttcacc tggacttata ggtcacatcc tatccattaa gcaactaagc tgcatacaag 15240
caattgtggg agacgcagtt agtagaggtg atatcaatcc tactctgaaa aaacttacac 15300
ctatagagca ggtgctgatc aattgcgggt tggcaattaa cggacctaag ctgtgcaaag 15360
aattgatcca ccatgatgtt gcctcagggc aagatggatt gcttaattct atactcatcc 15420
tctacaggga gttggcaaga ttcaaagaca accgaagaag tcaacaaggg atgttccacg 15480
cttaccccgt attggtaagt agcaggcaac gagaacttat atctaggatc acccgcaaat 15540
tttgggggca cattcttctt tactccggga acagaaagtt gataaataag tttatccaga 15600
atctcaagtc cggctatctg atactagact tacaccagaa tatcttcgtt aagaatctat 15660
ccaagtcaga gaaacagatt attatgacgg ggggtttgaa acgtgagtgg gtttttaagg 15720
taacagtcaa ggagaccaaa gaatggtata agttagtcgg atacagtgcc ctgattaagg 15780
actaattgat tgaactccgg aaccctaatc ctgccctagg tggttaggca ttatttgcaa 15840
tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894
<210> 9
<211> 15218
<212> DNA
<213> respiratory syncytial virus
<400> 9
acgcgaaaaa atgcgtacta caaacttgca cattcgaaaa aaatggggca aataagaact 60
tgataagtgc tatttaagtc taaccttttc aatcagaaat ggggtgcaat tcactgagca 120
tgataaaggt tagattacaa aatttatttg acaatgacga agtagcattg ttaaaaataa 180
catgttatac tgataaatta attcttctga ccaatgcatt agccaaagca gcaatacata 240
caattaaatt aaacggcata gtttttatac atgttataac aagcagtgaa gtgtgccctg 300
ataacaatat tgtagtgaaa tctaacttta caacaatgcc aatactacaa aatggaggat 360
acatatggga attgattgag ttgacacact gctctcaatt aaacggttta atggatgata 420
46
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
attgtgaaat caaattttct aaaagactaa gtgactcagt aatgactaat tatatgaatc 480
aaatatctga cttacttggg cttgatctca attcatgaat tatgtttagt ctaattcaat 540
agacatgtgt ttattaccat tttagttaat ataaaaactc atcaaaggga aatggggcaa 600
ataaactcac ctaatcaatc aaaccatgag cactacaaat gacaacacta ctatgcaaag 660
attgatgatc acagacatga gacccctgtc aatggattca ataataacat ctcttaccaa 720
agaaatcatc acacacaaat tcatatactt gataaacaat gaatgtattg taagaaaact 780
tgatgaaaga caagctacat ttacattctt agtcaattat gagatgaagc tactgcacaa 840
agtagggagt accaaataca aaaaatacac tgaatataat acaaaatatg gcactttccc 900
catgcctata tttatcaatc acggcgggtt tctagaatgt attggcatta agcctacaaa 960
acacactcct ataatataca aatatgacct caacccgtga attccaacaa aaaaaccaac 1020
ccaaccaaac caaactattc ctcaaacaac agtgctcaat agttaagaag gagctaatcc 1080
attttagtaa ttaaaaataa aagtaaagcc aataacataa attggggcaa atacaaagat 1140
ggctcttagc aaagtcaagt tgaatgatac attaaataag gatcagctgc tgtcatccag 1200
caaatacact attcaacgta gtacaggaga taatattgac actcccaatt atgatgtgca 1260
aaaacaccta aacaaactat gtggtatgct attaatcact gaagatgcaa atcataaatt 1320
cacaggatta ataggtatgt tatatgctat gtccaggtta ggaagggaag acactataaa 1380
gatacttaaa gatgctggat atcatgttaa agctaatgga gtagatataa caacatatcg 1440
tcaagatata aatggaaagg aaatgaaatt cgaagtatta acattatcaa gcttgacatc 1500
agaaatacaa gtcaatattg agatagaatc tagaaagtcc tacaaaaaaa tgctaaaaga 1560
gatgggagaa gtggctccag aatataggca tgattctcca gactgtggga tgataatact 1620
gtgtatagct gcacttgtga taaccaaatt agcagcagga gacagatcag gtcttacagc 1680
agtaattagg agggcaaaca atgtcttaaa aaacgaaata aaacgataca agggcctcat 1740
accaaaggat atagctaaca gtttttatga agtgtttgaa aaacaccctc atcttataga 1800
tgttttcgtg cactttggca ttgcacaatc atccacaaga gggggtagta gagttgaagg 1860
aatctttgca ggattgttta tgaatgccta tggttcaggg caagtaatgc taagatgggg 1920
agttttagcc aaatctgtaa aaaatatcat gctaggacat gctagtgtcc aggcagaaat 1980
ggagcaagtt gtggaagtct atgagtatgc acagaagttg ggaggagaag ctggattcta 2040
ccatatattg aacaatccaa aagcatcatt gctgtcatta actcaatttc ccaacttctc 2100
aagtgtggtc ctaggcaatg cagcaggtct aggcataatg ggagagtata gaggtacacc 2160
aagaaaccag gatctttatg atgcagctaa agcatatgca gagcaactca aagaaaatgg 2220
agtaataaac tacagtgtat tagacttaac agcagaagaa ttggaagcca taaagcatca 2280
actcaacccc aaagaagatg atgtagagct ttaagttaac aaaaaatacg gggcaaataa 2340
gtcaacatgg agaagtttgc acctgaattt catggagaag atgcaaataa caaagctacc 2400
aaattcctag aatcaataaa gggcaagttc gcatcatcca aagatcctaa gaagaaagat 2460
agcataatat ctgttaactc aatagatata gaagtaacta aagagagccc gataacatct 2520
ggcaccaaca tcatcaatcc aacaagtgaa gccgacagta ccccagaaac aaaagccaac 2580
tacccaagaa aacccctagt aagcttcaaa gaagatctca ccccaagtga caaccctttt 2640
tctaagttgt acaaggaaac aatagaaaca tttgataaca atgaagaaga atctagctac 2700
tcatatgaag agataaatga tcaaacaaat gacaacatta cagcaagact agatagaatt 2760
gatgaaaaat taagtgaaat attaggaatg ctccatacat tagtagttgc aagtgcagga 2820
cccacttcag ctcgcgatgg aataagagat gctatggttg gtctaagaga agagatgata 2880
gaaaaaataa gagcggaagc attaatgacc aatgataggt tagaggctat ggcaagactt 2940
aggaatgagg aaagcgaaaa aatggcaaaa gacacctcag atgaagtgtc tcttaatcca 3000
acttccaaaa aattgagtga cttgttggaa gacaacgata gtgacaatga tctatcactt 3060
gatgattttt gatcagcgat caactcactc agcaatcaac aacatcaata aaacagacat 3120
caatccattg aatcaactgc cagaccgaac aaacaaacgt ccatcagtag aaccaccaac 3180
caatcaatca accaattgat caatcagcaa cccgacaaaa ttaacaatat agtaacaaaa 3240
aaagaacaag atggggcaaa tatggaaaca tacgtgaaca agcttcacga aggctccaca 3300
47
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
tacacagcag ctgttcagta caatgttcta gaaaaagatg atgatcctgc atcactaaca 3360
atatgggtgc ctatgttcca gtcatctgtg ccagcagact tgctcataaa agaacttgca 3420
agcatcaata tactagtgaa gcagatctct acgcccaaag gaccttcact acgagtcacg 3480
attaactcaa gaagtgctgt gctggctcaa atgcctagta atttcatcat aagcgcaaat 3540
gtatcattag atgaaagaag caaattagca tatgatgtaa ctacaccttg tgaaatcaaa 3600
gcatgcagtc taacatgctt aaaagtaaaa agtatgttaa ctacagtcaa agatcttacc 3660
atgaagacat tcaaccccac tcatgagatc attgctctat gtgaatttga aaatattatg 3720
acatcaaaaa gagtaataat accaacctat ctaagatcaa ttagtgtcaa gaacaaggat 3780
ctgaactcac tagaaaatat agcaaccacc gaattcaaaa atgctatcac caatgcaaaa 3840
attattcctt atgcaggatt agtgttagtt atcacagtta ctgacaataa aggagcattc 3900
aaatatatca aaccacagag tcaatttata gtagatcttg gtgcctacct agaaaaagag 3960
agcatatatt atgtgactac taattggaag catacagcta cacgtttttc aatcaaacca 4020
ctagaggatt aaacttaatt atcaacactg aatgacaggt ccacatatat cctcaaacta 4080
cacactatat ccaaacatca taaacatcta cactacacac ttcatcacac aaaccaatcc 4140
cactcaaaat ccaaaatcac taccagccac tatctgctag acctagagtg cgaataggta 4200
aataaaacca aaatatgggg taaatagaca ttagttagag ttcaatcaat cttaacaacc 4260
atttataccg ccaattcaac acatatacta taaatcttaa aatgggaaat acatccatca 4320
caatagaatt cacaagcaaa ttttggccct attttacact aatacatatg atcttaactc 4380
taatcttttt actaattata atcactatta tgattgcaat actaaataag ctaagtgaac 4440
ataaagcatt ctgtaacaaa actcttgaac taggacagat gtatcaaatc aacacataga 4500
gttctaccat tatgctgtgt caaattataa tcctgtatat ataaacaaac aaatccaatc 4560
ttctcacaga gtcatggtgt cgcaaaacca cgctaactat catggtagca tagagtagtt 4620
atttaaaaat taacataatg atgaattgtt agtatgagat caaaaacaac attggggcaa 4680
atgcaaccat gtccaaacac aagaatcaac gcactgccag gactctagaa aagacctggg 4740
atactcttaa tcatctaatt gtaatatcct cttgtttata cagattaaat ttaaaatcta 4800
tagcacaaat agcactatca gttttggcaa tgataatctc aacctctctc ataattgcag 4860
ccataatatt catcatctct gccaatcaca aagttacact aacaacggtc acagttcaaa 4920
caataaaaaa ccacactgaa aaaaacatca ccacctaccc tactcaagtc tcaccagaaa 4980
gggttagttc atccaagcaa cccacaacca catcaccaat ccacacaagt tcagctacaa 5040
catcacccaa tacaaaatca gaaacacacc atacaacagc acaaaccaaa ggcagaacca 5100
ccacttcaac acagaccaac aagccaagca caaaaccacg tccaaaaaat ccaccaaaaa 5160
aagatgatta ccattttgaa gtgttcaact tcgttccctg cagtatatgt ggcaacaatc 5220
aactttgcaa atccatctgc aaaacaatac caagcaacaa accaaagaag aaaccaacca 5280
tcaaacccac aaacaaacca accaccaaaa ccacaaacaa aagagaccca aaaacaccag 5340
ccaaaacgac gaaaaaagaa actaccacca acccaacaaa aaaactaacc ctcaagacca 5400
cagaaagaga caccagcacc tcacaatcca ctgcactcga cacaaccaca ttaaaacaca 5460
cagtccaaca gcaatccctc ctctcaacca cccccgaaaa cacacccaac tccacacaaa 5520
cacccacagc atccgagccc tccacaccaa actccaccca aaaaacccag ccacatgctt 5580
agttattcaa aaactacatc ttagcagaga accgtgatct atcaagcaag aacgaaatta 5640
aacctggggc aaataaccat ggagttgatg atccacaagt caagtgcaat cttcctaact 5700
cttgctatta atgcattgta cctcacctca agtcagaaca taactgagga gttttaccaa 5760
tcgacatgta gtgcagttag cagaggttat tttagtgctt taagaacagg ttggtatact 5820
agtgtcataa caatagaatt aagtaatata aaagaaacca aatgcaatgg aactgacact 5880
aaagtaaaac ttatgaaaca agaattagat aagtataaga atgcagtaac agaattacag 5940
ctacttatgc aaaacacacc agctgtcaac aaccgggcca gaagagaagc accacagtat 6000
atgaactaca caatcaatac cactaaaaac ctaaatgtat caataagcaa gaagaggaaa 6060
cgaagatttc taggcttctt gttaggtgtg ggatctgcaa tagcaagtgg tatagctgta 6120
tcaaaagttc tacaccttga aggagaagtg aacaagatca aaaatgcttt gttgtctaca 6180
48
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aacaaagctg tagtcagttt atcaaatggg gtcagtgttt taaccagcaa agtgttagat 6240
ctcaagaatt acataaataa ccaattatta cccatagtaa atcaacagag ctgtcgcatc 6300
tccaacattg aaacagttat agaattccag cagaagaaca gcagattgtt ggaaatcacc 6360
agagaattta gtgtcaatgc aggtgtaaca acacctttaa gcacttacat gttgacaaac 6420
agtgagttac tatcattaat caatgatatg cctataacaa atgatcagaa aaaattaatg 6480
tcaagcaatg ttcagatagt aaggcaacaa agttattcca tcatgtctat aataaaggaa 6540
gaagtccttg catatgttgt acagctgcct atctatggtg taatagatac accttgctgg 6600
aaattgcaca catcgcctct atgcactacc aacatcaaag aaggatcaaa tatttgttta 6660
acaaggactg atagaggatg gtattgtgat aatgcaggat cagtatcctt ctttccacag 6720
gctgacactt gtaaagtaca gtccaatcga gtattttgtg acactatgaa cagtttgaca 6780
ttaccaagtg aagtcagcct ttgtaacact gacatattca attccaagta tgactgcaaa 6840
attatgacat caaaaacaga cataagcagc tcagtaatta cttctcttgg agctatagtg 6900
tcatgctatg gtaaaactaa atgcactgca tccaacaaaa atcgtgggat tataaagaca 6960
ttttctaatg gttgtgacta tgtgtcaaac aaaggagtag atactgtgtc agtgggcaac 7020
actttatact atgtaaacaa gctggaaggc aagaaccttt atgtaaaagg ggaacctata 7080
ataaattact atgaccctct agtgtttcct tctgatgagt ttgatgcatc aatatctcaa 7140
gtcaatgaaa aaatcaatca aagtttagct tttattcgta gatctgatga attactacat 7200
aatgtaaata ctggcaaatc tactacaaat attatgataa ctacaattat tatagtaatc 7260
attgtagtat tgttatcatt aatagctatt ggtttactgt tgtattgtaa agccaaaaac 7320
acaccagtta cactaagcaa agaccaacta agtggaatca ataatattgc attcagcaaa 7380
tagacaaaaa accacctgat catgtttcaa caacaatctg ctgaccacca atcccaaatc 7440
aacttacaac aaatatttca acatcacagt acaggctgaa tcatttcctc acatcatgct 7500
acccacataa ctaagctaga tccttaactt atagttacat aaaaacctca agtatcacaa 7560
tcaaccacta aatcaacaca tcattcacaa aattaacagc tggggcaaat atgtcgcgaa 7620
gaaatccttg taaatttgag attagaggtc attgcttgaa tggtagaaga tgtcactaca 7680
gtcataatta ctttgaatgg cctcctcatg cattactagt gaggcaaaac ttcatgttaa 7740
acaagatact caagtcaatg gacaaaagca tagacacttt gtctgaaata agtggagctg 7800
ctgaactgga tagaacagaa gaatatgctc ttggtatagt tggagtgcta gagagttaca 7860
taggatctat aaacaacata acaaaacaat cagcatgtgt tgctatgagt aaacttctta 7920
ttgagatcaa tagtgatgac attaaaaagc ttagagataa tgaagaaccc aattcaccta 7980
agataagagt gtacaatact gttatatcat acattgagag caatagaaaa aacaacaagc 8040
aaaccatcca tctgctcaag agactaccag cagacgtgct gaagaagaca ataaagaaca 8100
cattagatat ccacaaaagc ataaccataa gcaatccaaa agagtcaact gtgaatgatc 8160
aaaatgacca aaccaaaaat aatgatatta ccggataaat atccttgtag tatatcatcc 8220
atattgatct caagtgaaag catggttgct acattcaatc ataaaaacat attacaattt 8280
aaccataact atttggataa ccaccagcgt ttattaaatc atatatttga tgaaattcat 8340
tggacaccta aaaacttatt agatgccact caacaatttc tccaacatct taacatccct 8400
gaagatatat atacagtata tatattagtg tcataatgct tgaccataac gactctatgt 8460
catccaacca taaaactatt ttgataaggt tatgggacaa aatggatccc attattaatg 8520
gaaactctgc taatgtgtat ctaactgata gttatttaaa aggtgttatc tctttttcag 8580
agtgtaatgc tttagggagt tatcttttta acggccctta tcttaaaaat gattacacca 8640
acttaattag tagacaaagc ccactactag agcatatgaa tcttaaaaaa ctaactataa 8700
cacagtcatt aatatctaga tatcataaag gtgaactgaa attagaagaa ccaacttatt 8760
tccagtcatt acttatgaca tataaaagta tgtcctcgtc tgaacaaatt gctacaacta 8820
acttacttaa aaaaataata cgaagagcca tagaaataag tgatgtaaag gtgtacgcca 8880
tcttgaataa actaggatta aaggaaaagg acagagttaa gcccaacaat aattcaggtg 8940
atgaaaactc agtacttaca accataatta aagatgatat actttcggct gtggaaaaca 9000
atcaatcata tacaaattca gacaaaagtc actcagtaaa tcaaaatatc actatcaaaa 9060
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caacactctt gaaaaaattg atgtgttcaa tgcaacatcc tccatcatgg ttaatacact 9120
ggttcaattt atatacaaaa ttaaataaca tattaacaca atatcgatca aatgaggtaa 9180
aaagtcatgg gtttatatta atagataatc aaactttaag tggttttcag tttattttaa 9240
atcaatatgg ttgtatcgtt tatcataaag gactcaaaaa aatcacaact actacttaca 9300
atcaattttt gacatggaaa gacatcagcc ttagcagatt aaatgtttgc ttaattactt 9360
ggataagtaa ttgtttaaat acattaaaca aaagcttagg gctgagatgt ggattcaata 9420
atgttgtgtt atcacaatta tttctttatg gagattgtat actgaaatta tttcataatg 9480
aaggcttcta cataataaaa gaagtagagg gatttattat gtctttaatt ctaaacataa 9540
cagaagaaga tcaatttagg aaacgatttt ataatagcat gctaaataac atcacagatg 9600
cagctattaa ggctcaaaag gacctactat caagagtatg tcacacttta ttagacaaga 9660
cagtgtctga taatatcata aatggtaaat ggataatcct attaagtaaa tttcttaaat 9720
tgattaagct tgcaggtgat aataatctca ataacttgag tgagctatat tttctcttca 9780
gaatctttgg acatccaatg gtcgatgaaa gacaagcaat ggattctgta agaattaact 9840
gtaatgaaac taagttctac ttattaagta gtctaagtac attaagaggt gctttcattt 9900
atagaatcat aaaagggttt gtaaatacct acaacagatg gcccacctta aggaatgcta 9960
ttgtcctacc tctaagatgg ttaaactact ataaacttaa tacttatcca tctctacttg 10020
aaatcacaga aaatgatttg attattttat caggattgcg gttctatcgt gagtttcatc 10080
tgcctaaaaa agtggatctt gaaatgataa taaatgacaa agccatttca cctccaaaag 10140
atctaatatg gactagtttt cctagaaatt acatgccatc acatatacaa aattatatag 10200
aacatgaaaa gttgaagttc tctgaaagcg acagatcgag aagagtacta gagtattact 10260
tgagagataa taaattcaat gaatgcgatc tatacaattg tgtagtcaat caaagctatc 10320
tcaacaactc taatcacgtg gtatcactaa ctggtaaaga aagagagctc agtgtaggta 10380
gaatgtttgc tatgcaacca ggtatgttta ggcaaatcca aatcttagca gagaaaatga 10440
tagctgaaaa tattttacaa ttcttccctg agagtttgac aagatatggt gatctagagc 10500
ttcaaaagat attagaatta aaagcaggaa taagcaacaa gtcaaatcgt tataatgata 10560
actacaacaa ttatatcagt aaatgttcta tcattacaga tcttagcaaa ttcaatcagg 10620
catttagata tgaaacatca tgtatctgca gtgatgtatt agatgaactg catggagtac 10680
aatctctgtt ctcttggttg catttaacaa tacctcttgt cacaataata tgtacatata 10740
gacatgcacc tcctttcata aaggatcatg ttgttaatct taatgaggtt gatgaacaaa 10800
gtggattata cagatatcat atgggtggta ttgagggctg gtgtcaaaaa ctgtggacca 10860
ttgaagctat atcattatta gatctaatat ctctcaaagg gaaattctct atcacagctc 10920
tgataaatgg tgataatcag tcaattgata taagcaaacc agttagactt atagagggtc 10980
agacccatgc acaagcagat tatttgttag cattaaatag ccttaaattg ttatataaag 11040
agtatgcagg tataggccat aagcttaagg gaacagagac ctatatatcc cgagatatgc 11100
agttcatgag caaaacaatc cagcacaatg gagtgtacta tccagccagt atcaaaaaag 11160
tcctgagagt aggtccatgg ataaacacga tacttgatga ttttaaagtt agtttagaat 11220
ctataggcag cttaacacag gagttagaat acagaggaga aagcttatta tgcagtttaa 11280
tatttaggaa catttggtta tacaatcaaa ttgctttgca actccgaaat catgcattat 11340
gtaacaataa gctatattta gatatattga aagtattaaa acacttaaaa acttttttta 11400
atcttgatag cattgatatg gctttatcat tgtatatgaa tttgcctatg ctgtttggtg 11460
gtggtgatcc taatttgtta tatcgaagct tttataggag aactccagac ttccttacag 11520
aagctatagt acattcagtg tttgtgttga gctattatac tggtcacgat ttacaagata 11580
agctccagga tcttccagat gatagactga acaaattctt gacatgtgtc atcacatttg 11640
ataaaaatcc caatgccgag tttgtaacat tgatgaggga tccacaggct ttagggtctg 11700
aaaggcaagc taaaattact agtgagatta atagattagc agtaacagaa gtcttaagta 11760
tagccccaaa caaaatattt tctaaaagtg cacaacatta tactaccact gagattgatc 11820
taaatgacat tatgcaaaat atagaaccaa cttaccctca tggattaaga gttgtttatg 11880
aaagtttacc tttttataaa gcagaaaaaa tagttaatct tatatcagga acaaaatcca 11940
CA 02323927 2000-09-25
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taactaatat acttgaaaaa acatcagcaa tagatacaac tgatattaat agggctactg 12000
atatgatgag gaaaaatata actttactta taaggatact tccactagat tgtaacaaag 12060
acaaaagaga gttattaagt ttagaaaatc ttagtataac tgaattaagc aagtatgtaa 12120
gagaaagatc ttggtcatta tccaatatag taggagtaac atcgccaagt attatgttca 12180
caatggacat taaatataca actagcacta tagccagtgg tataataata gaaaaatata 12240
atgttaatag tttaactcgt ggtgaaagag gacccaccaa gccatgggta ggctcatcca 12300
cgcaggagaa aaaaacaatg ccagtgtaca acagacaagt tttaaccaaa aagcaaagag 12360
accaaataga tttattagca aaattagact gggtatatgc atccatagac aacaaagatg 12420
aattcatgga agaactgagt actggaacac ttggactgtc atatgaaaaa gccaaaaagt 12480
tgtttccaca atatctaagt gtcaattatt tacaccgttt aacagtcagt agtagaccat 12540
gtgaattccc tgcatcaata ccagcttata gaacaacaaa ttatcatttt gatactagtc 12600
ctatcaatca tgtattaaca gaaaagtatg gagatgaaga tatcgacatt gtgtttcaaa 12660
attgcataag ttttggtctt agcctgatgt cggttgtgga acaattcaca aacatatgtc 12720
ctaatagaat tattctcata ccgaagctga atgagataca tttgatgaaa cctcctatat 12780
ttacaggaga tgttgatatc atcaagttga agcaagtgat acaaaagcag cacatgttcc 12840
taccagataa aataagttta acccaatatg tagaattatt cttaagtaac aaagcactta 12900
aatctggatc tcacatcaac tctaatttaa tattagtaca taaaatgtct gattattttc 12960
ataatgctta tattttaagt actaatttag ctggacattg gattctgatt attcaactta 13020
tgaaagattc aaaaggtatt tttgaaaaag attggggaga ggggtacata actgatcata 13080
tgttcattaa tttgaatgtt ttctttaatg cttataagac ttatttgcta tgttttcata 13140
aaggttatgg taaagcaaaa ttagaatgtg atatgaacac ttcagatctt ctttgtgttt 13200
tggagttaat agacagtagc tactggaaat ctatgtctaa agttttccta gaacaaaaag 13260
tcataaaata catagtcaat caagacacaa gtttgcgtag aataaaaggc tgtcacagtt 13320
ttaagttgtg gtttttaaaa cgccttaata atgctaaatt taccgtatgc ccttgggttg 13380
ttaacataga ttatcaccca acacacatga aagctatatt atcttacata gatttagtta 13440
gaatggggtt aataaatgta gataaattaa ccattaaaaa taaaaacaaa ttcaatgatg 13500
aattttacac atcaaatctc ttttacatta gttataactt ttcagacaac actcatttgc 13560
taacaaaaca aataagaatt gctaattcag aattagaaga taattataac aaactatatc 13620
acccaacccc agaaacttta gaaaatatgt cattaattcc tgttaaaagt aataatagta 13680
acaaacctaa attttgtata agtggaaata ccgaatctat gatgatgtca acattctcta 13740
gtaaaatgca tattaaatct tccactgtta ccacaagatt caattatagc aaacaagact 13800
tgtacaattt atttccaatt gttgtgatag acaagattat agatcattca ggtaatacag 13860
caaaatctaa ccaactttac accaccactt cacatcagac atctttagta aggaatagtg 13920
catcacttta ttgcatgctt ccttggcatc atgtcaatag atttaacttt gtatttagtt 13980
ccacaggatg caagatcagt atagagtata ttttaaaaga tcttaagatt aaggacccca 14040
gttgtatagc attcataggt gaaggagctg gtaacttatt attacgtacg gtagtagaac 14100
ttcatccaga cataagatac atttacagaa gtttaaaaga ttgcaatgat catagtttac 14160
ctattgaatt tctaaggtta tacaacgggc atataaacat agattatggt gagaatttaa 14220
ccattcctgc tacagatgca actaataaca ttcattggtc ttatttacat ataaaatttg 14280
cagaacctat tagcatcttt gtctgcgatg ctgaattacc tgttacagcc aattggagta 14340
aaattataat tgaatggagt aagcatgtaa gaaagtgcaa gtactgttct tctgtaaata 14400
gatgcatttt aattgcaaaa tatcatgctc aagatgacat tgatttcaaa ttagataaca 14460
ttactatatt aaaaacttac gtgtgcctag gtagcaagtt aaaaggatct gaagtttact 14520
taatccttac aataggccct gcaaatatac ttcctgtttt tgatgttgta caaaatgcta 14580
aattgacact ttcaagaact aaaaatttca ttatgcctaa aaaaactgac aaggaatcta 14640
tcgatgcaaa tattaaaagc ttaatacctt tcctttgtta ccctataaca aaaaaaggaa 14700
ttaagacttc attgtcaaaa ttgaagagtg tagttaatgg agatatatta tcatattcta 14760
tagctggacg taatgaagta ttcagcaaca agcttataaa ccacaagcat atgaatatcc 14820
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taaaatggct agatcatgtt ttaaatttta gatcagctga acttaattac aatcatttat 14880
acatgataga gtccacatat ccttacttaa gtgaattgtt aaatagttta acaaccaatg 14940
agctcaagaa gctgattaaa ataacaggta gtgtgctata caaccttccc aacgaacagt 15000
agtttaaaat atcattaaca agtttggtca aatttagatg ctaacacatc attatattat 15060
agttattaaa aaatatacaa acttttcaat aatttagcat attgattcca aaattatcat 15120
tttagtctta aggggttaaa taaaagtcta aaactaacaa ttatacatgt gcattcacaa 15180
cacaacgaga cattagtttt tgacactttt tttctcgt 15218
<210> 10
<211> 15229
<212> DNA
<213> respiratory syncytial virus
<400> 10
acgcgaaaaa atgcgtacta caaacttgca cattcggaaa aaatggggca aataagaatt 60
tgataagtgc tatttaaatc taaccttttc aatcagaaat ggggtgcaat tcactgagca 120
tgataaaggt tagattacaa aatttatttg acaatgacga agtagcattg ttaaaaataa 180
catgttatac tgacaaatta attcttctga ccaatgcatt agccaaagca gtaatacata 240
caattaaatt aaacggcata gtttttatac atgttataac aagcagtgaa gtgtgccctg 300
acaacaatat tgtagtgaaa tctaacttta caacaatgcc aatattacaa aacggaggat 360
acatatggga attgattgag ttgacacact gctctcaatc aaatggtcta atggatgata 420
attgtgaaat caaattttct aaaagactaa gtgactcagt aatgactaat tatatgaatc 480
aaatatctga tttacttggg cttgatctca attcatgaat tatgtttagt ctaatttaat 540
agacatgtgt ttatcaccat tttagttaat ataaaacctc atcaaaggga aatggggcaa 600
ataaactcac ctaatcagtc aaaccatgag cactacaaat gacaacacta ctatgcaaag 660
attgatgatc acagacatga gacccctgtc gatggaatca ataataacat ctctcaccaa 720
agaaatcata acacacaaat tcatatactt gataaacaat gaatgtattg taagaaaact 780
tgatgaaaga caagctacat ttacattctt agtcaattat gagatgaagc tattgcacaa 840
agtagggagt accaaataca agaaatacac tgaatataat acaaaatatg gcactttccc 900
catgcctata tttatcaatc atgacgggtt tctagaatgt attggcatta agcctacaaa 960
acacactcct ataatataca aatatgacct caacccgtaa attccaacaa aaaactaacc 1020
catccaaact aagctattcc tcaaacaaca gtgctcaaca gttaagaagg agctaatcca 1080
ttttagtaat taaaaataaa ggcagagcca ataacataaa ttggggcaaa tacaaagatg 1140
gctcttagca aagtcaagtt aaatgataca ttaaataagg atcagctgct gtcatccagc 1200
aaatacacta ttcaacgtag tacaggagat aatattgaca ctcccaatta tgatgtgcaa 1260
aaacacctaa acaaactatg tggtatgcta ttaatcactg aagatgcaaa tcataaattc 1320
acaggattaa taggtatgtt atatgctatg tccaggttag gaagggaaga cactataaag 1380
atacttaaag atgctggata tcatgttaaa gctaatggag tagatataac aacatatcgt 1440
caagatataa acggaaagga aatgaaattc gaagtattaa cattatcaag cttgacatca 1500
gaaatacaag tcaatattga gatagaatct agaaagtcct acaaaaaaat gctaaaagag 1560
atgggagaag tggctccaga atataggcat gattctccag actgtgggat gataatactg 1620
tgtatagctg cacttgtaat aaccaagtta gcagcaggag atagatcagg tcttacagca 1680
gtaattagga gggcaaacaa tgtcttaaaa aacgaaataa aacgctacaa gggcctcata 1740
ccaaaggata tagctaacag tttttatgaa gtgtttgaaa aacaccctca tcttatagat 1800
gtttttgtgc actttggcat tgcacaatca tccacaagag ggggtagtag agttgaagga 1860
atctttgcag gattatttat gaatgcctat ggttcagggc aagtaatgct aagatgggga 1920
gttctagcca aatctgtaaa aaatatcatg ctaggacatg ctagtgtcca ggcagaaatg 1980
gaacaagttg tggaagttta tgagtatgca cagaagttgg gaggagaagc tggat.tctac 2040
52
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catatattga acaatccaaa agcatcattg ctgtcattaa ctcaatttcc taacttctca 2100
agtgtggtcc taggcaatgc agcaggtcta ggcataatgg gagagtatag aggtacacca 2160
agaaaccaag atctatatga tgcagccaaa gcatatgcag agcaactcaa agaaaatgga 2220
gtaataaact acagtgtatt agacttaaca gcagaagaat tggaagccat aaagcatcaa 2280
ctcaacccca aagaagatga tgtagagctt taagttaaca aaaaatacgg ggcaaataag 2340
tcaacatgga gaagtttgca cctgaatttc atggagaaga tgcaaacaac aaagctacca 2400
aattcctaga atcaataaag ggcaagtttg catcatccaa agatcctaag aagaaagata 2460
gcataatatc tgttaactca atagatatag aagtaactaa agagagcccg ataacatctg 2520
gcaccaacat catcaatcca ataagtgaag ctgatagtac cccagaagct aaagccaact 2580
acccaagaaa acccctagta agcttcaaag aagatctcac cccaagtgac aacccctttt 2640
ctaagttgta caaagaaaca atagaaacat ttgataacaa tgaagaagaa tctagctact 2700
catatgaaga aataaatgat caaacaaatg acaacattac agcaagacta gatagaattg 2760
atgaaaaatt aagtgaaata ttaggaatgc tccatacatt agtagttgca agtgcaggac 2820
ccacctcagc tcgcgatgga ataagagatg ctatggttgg tctaagagaa gaaatgatag 2880
aaaaaataag agcggaagca ttaatgacca atgataggtt agaggctatg gcaagactta 2940
ggaatgagga aagcgaaaaa atggcaaaag acacctcaga tgaagtgtct cttaatccaa 3000
cttccaaaaa attgagtaat ttgttggaag acaacgatag tgacaatgat ctatcacttg 3060
atgatttttg atcagtgatc aactcactca gcaatcaaca acatcaatga aacagacatc 3120
aatccattga atcaactgcc agactgaaca cacaaacgtc catcagcaga actaccaacc 3180
aatcaatcaa ccaattgatc aatcagcgac ctaacaaaat taacaatata gtaacaaaaa 3240
aagaacaaga tggggcaaat atggaaacat acgtgaacaa gcttcacgag ggctccacat 3300
acacagcagc tgttcagtac aatgttctag aaaaagatga tgatcctgca tcactaacaa 3360
tatgggtgcc tatgttccag tcatctgtgc cagcagactt gctcataaaa gaacttgcaa 3420
gcatcaacat actagtgaag cagatctcca cgcccaaagg accttcacta cgagtcacga 3480
ttaactcaag aagtgctgtg ctggcacaaa tgcctagtag ttttatcata agtgcaaatg 3540
tatcattaga tgaaagaagc aaattagcat atgatgtaac tacaccttgt gaaatcaaag 3600
catgcagtct aacatgctta aaagtaaaaa gtatgttaac tacagtcaaa gatcttacca 3660
tgaaaacatt caatcccact catgagatta ttgctctatg tgaatttgaa aatattatga 3720
catcaaaaag agtaataata ccaacctatc taagatcaat tagtgtcaaa aacaaggacc 3780
tgaactcact agaaaatata gcaaccaccg aattcaaaaa tgctatcacc aatgcgaaaa 3840
ttattcccta tgcaggatta gtattagtta tcacagttac tgacaataaa ggagcattca 3900
aatatatcaa gccacagagt caatttatag tagatcttgg ggcctaccta gaaaaagaga 3960
gcatatatta tgtgactaca aattggaagc atacagctac acgtttttca atcaaaccac 4020
tagaggatta aacttaatta tcaacactaa atgacaggtc cacatatatc ttcaaactat 4080
acattatatc caaacatcat gagcatttac actacacact tttaccatat aaatcaatct 4140
catttaaaat ccaaaattac ttccagctat catctgttag acctagagtg cgaataggta 4200
aataaaacca aaatatgggg taaatagaca ttagttagag ttcaatcaat ctcaacaacc 4260
atttataccg ccaattcagt acatatacta taaatctcaa aatgggaaat acatccatca 4320
caatagaatt cacaagcaaa ttttggcctt attttacact aatacatatg atcttaactc 4380
taatctcttt actaattata atcactatta tgattgcaat actaaataag ctaagtgaac 4440
ataaaacatt ctgcaacaaa actcttgaac taggacagat gtatcaaatc aacacatagt 4500
gttctaccat tatgctgtgt caaattataa tcttgtatat ataaacaaac aaatccaatc 4560
ttctcacaga gtcatggtgg cgcaaaacca cgccaaccat catgatagca tagagtagtt 4620
atttaaaaat taacataatg atgaattatt ggtatgagat caggaacaac attggggcaa 4680
atgcagccat gtccaagcac aagaatcggc gcactgccgg gactctagaa aggacctggg 4740
atactcttaa tcatctaatt gtaatatcct cttgtttata cagattaaat ttaaaatcta 4800
tagcacaaat agcactgtca gttttggcaa tgataatctc aacctctctc ataattgcag 4860
ccataatatt catcatctct gccaatcaca aagttacact aacaacggtt acagttcaaa 4920
53
CA 02323927 2000-09-25
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caataaaaaa ccacactgaa aaaaacatct ccacctacct tactcaagtc ccaccagaaa 4980
gggtcaactc atccaaacaa cccacaacca catcaccaat ccacacaaat tcagccacaa 5040
tatcaccaaa tacaaaatca gaaacacacc atacaacagc acaaaccaaa ggcagaatca 5100
ccacttcaac acagaccaac aagccaagca caaaatcacg ttcaaaaaat ccaccaaaaa 5160
aaccaaaaga tgattaccat tttgaagtgt tcaattttgt tccctgtagt atatgtggta 5220
ataatcaact ctgcaaatcc atctgcaaaa caataccaag caacaaacca aagaaaaaac 5280
caaccatcaa acccacaaac aaaccaacca ccaaaaccac aaacaaaaga gaccccaaaa 5340
caccagccaa aatgccaaaa aaagaaatca tcaccaaccc agcaaaaaaa ccaaccctca 5400
agaccacaga aagagacacc agcatttcac aatccaccgt gctcgacaca atcactccaa 5460
aatacacaat ccaacagcaa tccctccact caaccacctc cgaaaacaca cccagctcca 5520
cacaaatacc cacagcatcc gagccctcca cattaaatcc taattaaaaa acctagtcac 5580
atgcttagtt attcaaaaac tacatcttag cagagaaccg tgatctatca agcaagaaca 5640
aaattaaacc tggggcaaat aaccatggag ttgctgatcc acaggtcaag tgcaatcttc 5700
ctaactcttg ctgttaatgc attgtacctc acctcaagtc agaacataac tgaggagttt 5760
taccaatcga catgtagtgc agttagcaga ggttatttta gtgctttaag aacaggttgg 5820
tataccagtg tcataacaat agaattaagt aatataaaag aaaccaaatg caatggaact 5880
gacactaaag taaaacttat aaaacaagaa ttagataagt ataagaatgc agtaacagaa 5940
ttacagctac ttatgcaaaa cacgccagct gccaacaacc gggccagaag agaagcacca 6000
cagtacatga actacacaat caataccaca aaaaacctaa atgtatcaat~aagcaagaaa 6060
aggaaacgaa gatttctggg cttcttgtta ggtgtaggat ctgcaatagc aagtggtata 6120
gctgtatcca aagttttaca ccttgaagga gaagtgaaca aaatcaaaaa tgctttgttg 6180
tctacaaaca aagctgtagt cagtctatca aatggggtca gtgttttaac cagcaaagtg 6240
ttagatctca agaattacat aaataaccga atattaccca tagtaaatca acagagctgt 6300
cgcatctcca acattgaaac agttatagaa ttccagcaga agaatagcag attgttggaa 6360
atcaccagag aatttagtgt taatgcaggt gtaacaacac ctttaagcac ttacatgtta 6420
acaaacagtg agttactatc attgatcaat gatatgccta taacaaatga ccagaaaaaa 6480
ttaatgtcaa gcaatgttca gatagtaagg caacaaagtt attctatcat gtctataata 6540
aaggaagaag tccttgcata tgttgtacag ctacctatct atggtgtaat agatacacct 6600
tgctggaaat tacacacatc acctctatgc accaccaaca tcaaagaagg atcaaatatt 6660
tgtttaacaa ggactgatag aggatggtat tgtgataatg caggatcagt atccttcttc 6720
ccacaggctg atacttgcaa agtacagtcc aatcgagtat tttgtgacac tatgaacagt 6780
ttaacattac caagtgaagt cagcctttgt aacactgaca tattcaattc caagtatgac 6840
tgcaaaatta tgacatcaaa aacagacata agcagctcag taattacttc tcttggagct 6900
atagtgtcat gctatggaaa aactaaatgc actgcatcca ataaaaatcg tgggattata 6960
aagacatttt ctaatggttg tgactatgtg tcaaacaaag gagtagatac tgtgtcagtg 7020
ggcaacactt tatactatgt aaacaagctg gaaggcaaaa acctttatgt aaaaggggaa 7080
cctataataa attactatga tcctctagtg tttccttctg atgagtttga tgcatcaata 7140
tctcaagtca atgaaaaaat caatcaaagt ttagctttta ttcgtagatc tgatgaatta 7200
ctacataatg taaatactgg caaatctact acaaatatta tgataactac aattattata 7260
gtaatcattg tagtattgtt atcattaata gctattggtt tactgttgta ttgcaaagcc 7320
aaaaacacac cagttacact aagcaaagac caactaagtg gaatcaataa tattgcattc 7380
agcaaataga caaaaaacta cttaatcatg tttcaacaac aatctgctga ccaccaatcc 7440
caaatcaact taacaacaaa tatttcaaca tcatagcaca ggctgaatca tttcctcata 7500
tcatgctacc tacacaacta agctagatct tcaactcata gttacataaa aaccccaagt 7560
atcacaatca aacactaaat cgacacatca ttcacaaaat taacaactgg ggcaaatatg 7620
tcgcgaagaa atccttgtaa atttgagatt agaggtcatt gcttgaatgg tagaagatgt 7680
cactacagtc ataattattt tgaatggcct cctcatgcat tactagtgag gcaaaacttc 7740
atgttaaaca agatacttaa gtcaatggac aaaagcatag acactttgtc ggaaataagt 7800
54
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ggagctgctg aactggatag aacagaagaa tatgctcttg gtatagttgg agtgctagag 7860
agttacatag gatcaataaa caacataaca aaacaatcag catgtgttgc tatgagtaaa 7920
cttcttattg agatcaacag tgatgacatt aaaaaactga gagataacga agaacccaat 7980
tcgcctaaga taagagtgta caatactgtt atatcataca ttgagagcaa tagaaaaaac 8040
aacaagcaaa ccatccatct gctcaaaaga ctaccagcag acgtgctgaa gaagacaata 8100
aagaacacat tagatatcca caaaagcata accataagca actcaaaaga gtcaaccgtg 8160
aatgatcaaa atgaccaaac caaaaataat gatattaccg gataaatatc cttgtagtat 8220
atcatccata ttgatttcaa gtgaaagcat gattgctaca ttcaatcata aaaacatatt 8280
acaatttaac cataaccatt tggataacca ccagtgttta ttaaatcata tatttgatga 8340
aattcattgg acacctaaaa acttattaga tgccactcaa caatttctcc aacatcttaa 8400
catccctgaa gatatatata cagtatatat attagtgtca taatgcttga ccataacaat 8460
tttatatcat tcaaccataa aacaacctta ataaggttat gggacaaaat ggatcccatt 8520
attaatggaa actctgccaa tgtgtatcta actgatagtt atctaaaagg tgttatctct 8580
ttttcagaat gtaatgcttt agggagttac ctttttaacg gcccctatct taaaaatgat 8640
tacaccaact taattagtag acaaagccca ctactagagc atatgaatct aaaaaaacta 8700
actataacac agtcattaat atctagatat cataaaggtg aactgaagtt agaagaacca 8760
acttatttcc agtcattact tatgacatat aaaagtatgt cctcgtctga acaaattgct 8820
acaactaatt tacttaaaaa aataatacga agagctatag aaataagtga tgtaaaggtg 8880
tacgccatct tgaataaact gggactaaag gaaaaggaca gagttaagcc caacaataat 8940
tcaggtgatg aaaactcagt tcttacaacc ataatcaaag atgatatact ttcagctgtg 9000
gaaaacaatc aatcatatac aaattcagac aaaaatcatt cagtaaatca aaatatcact 9060
atcaaaacaa cactcttgaa aaaattgatg tgttcaatgc aacatcctcc atcatggtta 9120
atacactggt tcaatttata tacaaaatta aataacatat taacacaata tcgatcaaat 9180
gaggtaaaaa gtcatgggtt tatattaata gataatcaaa ctttaagtga ttttcagttt 9240
attttaaatc aatatggttg tatcgtttat cataaaggac tcaaaaaaat cacaactact 9300
acttacaatc aatttttgac atggaaagac atcagcctta gcagattaaa tgtttgctta 9360
attacttgga taagtaattg tttaaataca ttaaataaaa gcttagggct gagatgtgga 9420
ttcaataatg ttgtgttatc acaactattt ctttatggag attgtatact gaaattattc 9480
cataatgaag gcttctacat aataaaagaa gtagagggat ttattatgtc tttaattcta 9540
aacataacag aagaagatca atttaggaaa cgattttata atagcatgct aaataacatc 9600
acagatgcag ctattaaggc tcaaaaaaac ctactatcaa gagtatgtca cactttatta 9660
gacaagacag tgtctgataa tatcataaat ggtaaatgga taatcctatt aagtaaattt 9720
cttaaattga ttaagcttgc aggtgataat aatctcaata acttgagtga gctttatttt 9780
ctcttcagaa tctttggaca tccaatggtc gatgaaagac aagcaatgga tgctgtaaga 9840
attaactgta atgaaaccaa gttctactta ttaagtaatc taagtacgtt aagaggtgct 9900
ttcatttata gaatcataaa ggggtttgta aatacctaca acagatggcc cactttaagg 9960
aatgctattg ttctacctct aagatggttg aactattata aacttaatac ttatccatct 10020
ctacttgaaa tcacagagaa agatttgatt attttatcag gattgcggtt ctatcgtgag 10080
tttcatctgc ctaaaaaagt ggatcttgaa atgataataa atgacaaagc catttcacct 10140
ccaaaagatt taatatggac tagttttcct agaaattaca tgccatcaca tatacaaaat 10200
tatatagaac atgaaaagtt gaagttctct gaaagtgaca gatcaagaag agtactagag 10260
tattacttga gagataataa attcaatgaa tgcgatctat acaattgtgt ggtcaatcaa 10320
agctatctca acaactctaa ccatgtggta tcactaactg gtaaagaaag agagctcagt 10380
gtaggtagaa tgtttgctat gcaaccaggt atgtttaggc aaattcaaat cttagcagag 10440
aaaatgatag ccgaaaatat tttacaattc ttccctgaga gtttgacaag atatggtgat 10500
ctagagcttc aaaagatatt agaattaaaa gcaggaataa gcaacaagtc aaatcgttat 10560
aatgataact acaacaatta tatcagtaaa tgttctatca ttacagacct tagcaaattc 10620
aatcaagcat ttagatatga aacatcatgt atctgcagtg atgtattaga tgaactgcat 10680
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
ggagtacaat ctctgttctc ttggttgcat ttaacaatac ctcttgtcac aataatatgt 10740
acatatagac atgcacctcc ttttataaag gatcatgttg ttaatcttaa taaagttgat 10800
gaacaaagtg gattatacag atatcatatg ggtggtattg aaggctggtg tcaaaaactg 10860
tggaccattg aagctatatc attattagat ctaatatctc tcaaagggaa attctctatc 10920
acagctctaa taaatggtga taatcagtca attgatataa gtaaaccagt tagacttata 10980
gagggtcaga cccatgctca agcagattat ttgttagcat taaatagcct taaattgcta 11040
tataaagagt atgcgggcat aggccacaag ctcaagggaa cagagaccta tatatcccga 11100
gatatgcaat tcatgagcaa aacaatccag cacaatggag tgtactatcc agccagtatc 11160
aaaaaagtcc tgagagtagg tccatggata aatacaatac ttgatgattt taaagttagt 11220
ttagaatcta taggtagctt aacacaggag ttagaatata gaggagagag cttattatgc 11280
agtttaatat ttaggaacat ttggttatac aatcaaattg ctttgcaact ccgaaatcat 11340
gcattatgtc acaataagct atatttagat atattgaaag tattaaaaca cttaaaaact 11400
ttttttaatc ttgatagtat tgatatggct ttaacattgt atatgaattt gcctatgctg 11460
tttggtggtg gtgatcctaa tttgttatat cgaagctttt ataggagaac tccagacttc 11520
cttacagaag ctatagtaca ttcagtgttt gtgttgagct attatactgg tcacgattta 11580
caagataagc tccaggatct tccagatgat agactgaaca aattcttgac atgtatcatc 11640
acgtttgata aaaatcccaa tgccgagttt gtaacattga tgagagatcc acaggcttta 11700
gggtctgaaa ggcaagcaaa aattactagt gagattaata gattagcagt gacagaagtc 11760
ttaagtatag ctccaaacaa aatattttct aaaagtgcac aacattatac taccactgag 11820
attgatctaa atgatattat gcaaaatata gaaccaactt accctcatgg attaagagtt 11880
gtttatgaaa gtttaccttt ttataaagca gaaaaaatag ttaatcttat atcaggaaca 11940
aaatccataa ctaatatact tgaaaaaaca tcagcaatag attcaactga tattaatagg 12000
gctactgata tgatgaggaa aaatataact ttacttataa ggatacttcc actagattgt 12060
aacaaagaca aaagagagtt attaagttta gaaaatctta gtataactga attaagcaag 12120
tatgtaagag aaagatcttg gtcgttatcc aatatagtag gagtaacatc gccaagtatt 12180
atgttcacaa tggacattaa atatacaact agcactatag ccagtggtat aattatagaa 12240
aaatataatg ttaatagttt aactcgtggt gaaagaggac ctactaagcc atgggtaggt 12300
tcatctacgc aggagaaaaa aacaatgcca gtgtacaata gacaagtttt aaccaaaaag 12360
caaagagacc aaatagattt attagcaaaa ttagactggg tatatgcatc catagacaac 12420
aaagatgaat tcatggaaga actgagtact ggaacacttg gactgtcata tgagaaagcc 12480
aaaaaattgt ttccacaata tctaagtgtc aattatttac accgcttaac agtcagtagt 12540
agaccatgtg aattccctgc atcaatacca gcttatagaa caacaaatta tcatttcgat 12600
actagtccta tcaaccatgt attaacagaa aagtatggag atgaagatat cgacattgtg 12660
tttcaaaatt gcataagttt tggtcttagc ttaatgtcgg ttgtggaaca attcacaaac 12720
atatgtccta atagaattat tctcataccg aagctgaatg agatacattt gatgaaacct 12780
cctatattta caggagatgt tgatatcatc aagttgaagc aagtgataca aaaacagcac 12840
atgttcctac cagataaaat aagtttaacc caatatgtag aattattcct aagtaacaaa 12900
gcacttaaat ctggatctca catcaactct aatttaatat tagtacataa aatgtctgat 12960
tattttcata atgcttatat tttaagtact aatttagctg gacattggat tctgattatt 13020
caacttatga aggattcaaa aggtattttt gaaaaagatt ggggagaggg gtatataact 13080
gatcatatgt tcattaattt gaatgttttc tttaatgctt ataagactta tttgctatgt 13140
tttcataaag gttatggtaa agcaaaatta gaatgtgata tgaacacttc agatcttctt 13200
tgtgttttgg agctaataga cagtagctac tggaaatcta tgtctaaagt tttcctagaa 13260
caaaaagtca taaaatacat aatcaatcaa gacacaagtt tgcatagaat aaaaggttgt 13320
catagtttta agttatggtt tttaaaacgc cttaataatg ctaaatttac cgtatgccct 13380
tgggttgtta acatagatta tcacccaaca cacatgaaag ctatattatc ttacatagat 13440
ttagttagaa tggggttaat aaatgtagat aaattaacca ttaaaaataa aaataaattc 13500
aatgatgaat tttacacatc aaatctcttt tacattagtt ataacttttc agataacact 13560
56
CA 02323927 2000-09-25
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catttgctaa caaaacaaat aagaattgct aattcagaat tagaaaataa ttataacaaa 13620
ctatatcacc caaccccaga aactttagaa aatatgtcat taattcctgt caaaagtaat 13680
aatagtaata aacctaaatt tggtataagt ggaaataccg aatctatgat gacgtcaaca 13740
ttctccaata aaacgcatat taaatcttcc gctgttatta caagattcaa ttatagtaaa 13800
caagacttgt acaatttatt tccaattgtc gtgatagaca ggattataga tcattcaggt 13860
aatacagcaa aatctaacca actctacact accacttcac atcagacatc tttagtaagg 13920
aatagtgcat cactttattg catgcttcct tggcatcatg tcaatagatt taactttgta 13980
tttagttcca caggatgcaa gatcagtata gagtatattt taaaagatct taagattaaa 14040
gaccccagtt gtatagcatt cataggtgaa ggagctggta acttattatt acgtacagta 14100
gtagaacttc atccagacat aagatacatt tacagaagtt taaaagattg caatgatcat 14160
agtttaccta ttgaatttct aaggttatac aacgggcata taaacataga ttatggtgag 14220
aatttaacca ttcctgctac agatgcaact aataacattc attggtctta tttacatata 14280
aaatttgcag aacctattag catttttgtc tgcgatgctg aattacctgt tacagccaat 14340
tggagtaaaa ttataattga atggagtaag catgtaagaa agtgcaagta ctgttcctct 14400
gtaaatagat gcattttaat tgcaaaatat catgcccaag atgatattga tttcaaatta 14460
gataacatta ctatattaaa aacttacgtg tgcctaggta gcaagttaaa aggatctgaa 14520
gtttacttag tccttacaat aggccctgca aatatacttc ctgtttttaa tgttgtgcaa 14580
aatgctaaat tgattctttc aaggactaaa aatttcatta tgcctaaaaa aactgacaaa 14640
gaatctatcg atgcaaatat taaaagctta atacctttcc tttgttaccc tataacaaaa 14700
aaaggaatta agacttcatt gtcaaaattg aagagtgtag ttagtggaga tatattatca 14760
tattctatag ctggacgtaa tgaagtattc agcaacaagc ttataaacca caagcatatg 14820
aatatcctaa aatggctaga tcatgtttta aactttagat cagctgaact taattacaat 14880
catttatata tgatagagtc cacatatcct tacttaagtg aattgttaaa cagtttaaca 14940
accaatgagc tcaagaagct gattaaaata acaggtagtg tactatacaa ccttcccaac 15000
gaacagtaac ttaaaacatc attaacaagt ttgatcaaat ttagatgcta acacatcata 15060
atattatagt tattaaaaaa tatatatgca aacttttcaa taatttagca tattgattcc 15120
aaagttatca ttttggtctt aaggggttga ataaaaatct aaaactaaca attatacatg 15180
tgcatttaca acacaacgag acattagttt ttgacacttt ttttctcgt 15229
<210> 11
<211> 15219
<212> DNA
<213> respiratory syncytial virus
<400> 11
acgggaaaaa aatgcgtact acaaacttgc acattcgaaa aaaatggggc aaataagaac 60
ttgataagtg ctatttaagt ctaacctttt caatcagaaa tggggtgcaa ttcactgagc 120
atgataaagg ttagattaca aaatttattt gacaatgacg aagtagcatt gttaaaaata 180
acatgttata ctgataaatt aattcttctg accaatgcat tagccaaagc agcaatacat 240
acaattaaat taaacggcat agtttttata catgttataa caagcagtga agtgtgccct 300
gataacaata ttgtagtgaa atctaacttt acaacaatgc caatactaca aaatggagga 360
tacatatggg aattgattga gttgacacac tgctctcaat taaacggttt aatggatgat 420
aattgtgaaa tcaaattttc taaaagacta agtgactcag taatgactaa ttatatgaat 480
caaatatctg acttacttgg gcttgatctc aattcatgaa ttatgtttag tctaattcaa 540
tagacatgtg tttattacca ttttagttaa tataaaaact catcaaaggg aaatggggca 600
aataaactca cctaatcaat caaaccatga gcactacaaa tgacaacact actatgcaaa 660
gattgatgat cacagacatg agacccctgt caatggattc aataataaca tctcttacca 720
aagaaatcat cacacacaaa ttcatatact tgataaacaa tgaatgtatt gtaagaaaac 780
57
CA 02323927 2000-09-25
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ttgatgaaag acaagctaca tttacattct tagtcaatta tgagatgaag ctactgcaca 840
aagtagggag taccaaatac aaaaaataca ctgaatataa tacaaaatat ggcactttcc 900
ccatgcctat atttatcaat cacggcgggt ttctagaatg tattggcatt aagcctacaa 960
aacacactcc tataatatac aaatatgacc tcaacccgtg aattccaaca aaaaaaccaa 1020
cccaaccaaa ccaaactatt cctcaaacaa cagtgctcaa tagttaagaa ggagctaatc 1080
cattttagta attaaaaata aaagtaaagc caataacata aattggggca aatacaaaga 1140
tggctcttag caaagtcaag ttgaatgata cattaaataa ggatcagctg ctgtcatcca 1200
gcaaatacac tattcaacgt agtacaggag ataatattga cactcccaat tatgatgtgc 1260
aaaaacacct aaacaaacta tgtggtatgc tattaatcac tgaagatgca aatcataaat 1320
tcacaggatt aataggtatg ttatatgcta tgtccaggtt aggaagggaa gacactataa 1380
agatacttaa agatgctgga tatcatgtta aagctaatgg agtagatata acaacatatc 1440
gtcaagatat aaatggaaag gaaatgaaat tcgaagtatt aacattatca agcttgacat 1500
cagaaataca agtcaatatt gagatagaat ctagaaagtc ctacaaaaaa atgctaaaag 1560
agatgggaga agtggctcca gaatataggc atgattctcc agactgtggg atgataatac 1620
tgtgtatagc tgcacttgtg ataaccaaat tagcagcagg agacagatca ggtcttacag 1680
cagtaattag gagggcaaac aatgtcttaa aaaacgaaat aaaacgatac aagggcctca 1740
taccaaagga tatagctaac agtttttatg aagtgtttga aaaacaccct catcttatag 1800
atgttttcgt gcactttggc attgcacaat catccacaag agggggtagt agagttgaag 1860
gaatctttgc aggattgttt atgaatgcct atggttcagg gcaagtaatg ctaagatggg 1920
gagttttagc caaatctgta aaaaatatca tgctaggaca tgctagtgtc caggcagaaa 1980
tggagcaagt tgtggaagtc tatgagtatg cacagaagtt gggaggagaa gctggattct 2040
accatatatt gaacaatcca aaagcatcat tgctgtcatt aactcaattt cccaacttct 2100
caagtgtggt cctaggcaat gcagcaggtc taggcataat gggagagtat agaggtacac 2160
caagaaacca ggatctttat gatgcagcta aagcatatgc agagcaactc aaagaaaatg 2220
gagtaataaa ctacagtgta ttagacttaa cagcagaaga attggaagcc ataaagcatc 2280
aactcaaccc caaagaagat gatgtagagc tttaagttaa caaaaaatac ggggcaaata 2340
agtcaacatg gagaagtttg cacctgaatt tcatggagaa gatgcaaata acaaagctac 2400
caaattccta gaatcaataa agggcaagtt cgcatcatcc aaagatccta agaagaaaga 2460
tagcataata tctgttaact caatagatat agaagtaact aaagagagcc cgataacatc 2520
tggcaccaac atcatcaatc caacaagtga agccgacagt accccagaaa caaaagccaa 2580
ctacccaaga aaacccctag taagcttcaa agaagatctc accccaagtg acaacccttt 2640
ttctaagttg tacaaggaaa caatagaaac atttgataac aatgaagaag aatctagcta 2700
ctcatatgaa gagataaatg atcaaacaaa tgacaacatt acagcaagac tagatagaat 2760
tgatgaaaaa ttaagtgaaa tattaggaat gctccataca ttagtagttg caagtgcagg 2820
acccacttca gctcgcgatg gaataagaga tgctatggtt ggtctaagag aagagatgat 2880
agaaaaaata agagcggaag cattaatgac caatgatagg ttagaggcta tggcaagact 2940
taggaatgag gaaagcgaaa aaatggcaaa agacacctca gatgaagtgt ctcttaatcc 3000
aacttccaaa aaattgagtg acttgttgga agacaacgat agtgacaatg atctatcact 3060
tgatgatttt tgatcagcga tcaactcact cagcaatcaa caacatcaat aaaacagaca 3120
tcaatccatt gaatcaactg ccagaccgaa caaacaaacg tccatcagta gaaccaccaa 3180
ccaatcaatc aaccaattga tcaatcagca acccgacaaa attaacaata tagtaacaaa 3240
aaaagaacaa gatggggcaa atatggaaac atacgtgaac aagcttcacg aaggctccac 3300
atacacagca gctgttcagt acaatgttct agaaaaagat gatgatcctg catcactaac 3360
aatatgggtg cctatgttcc agtcatctgt gccagcagac ttgctcataa aagaacttgc 3420
aagcatcaat atactagtga agcagatctc tacgcccaaa ggaccttcac tacgagtcac 3480
gattaactca agaagtgctg tgctggctca aatgcctagt aatttcatca taagcgcaaa 3540
tgtatcatta gatgaaagaa gcaaattagc atatgatgta actacacctt gtgaaatcaa 3600
agcatgcagt ctaacatgct taaaagtaaa aagtatgtta actacagtca aagatcttac 3660
58
CA 02323927 2000-09-25
WO 99/49017 PCT/US99106225
catgaagaca ttcaacccca ctcatgagat cattgctcta tgtgaatttg aaaatattat 3720
gacatcaaaa agagtaataa taccaaccta tctaagatca attagtgtca agaacaagga 3780
tctgaactca ctagaaaata tagcaaccac cgaattcaaa aatgctatca ccaatgcaaa 3840
aattattcct tatgcaggat tagtgttagt tatcacagtt actgacaata aaggagcatt 3900
caaatatatc aaaccacaga gtcaatttat agtagatctt ggtgcctacc tagaaaaaga 3960
gagcatatat tatgtgacta ctaattggaa gcatacagct acacgttttt caatcaaacc 4020
actagaggat taaacttaat tatcaacact gaatgacagg tccacatata tcctcaaact 4080
acacactata tccaaacatc ataaacatct acactacaca cttcatcaca caaaccaatc 4140
ccactcaaaa tccaaaatca ctaccagcca ctatccgcta gacctagagt gcgaataggc 4200
aaataaaacc aaaatatggg gtaaatagac attagttaga gttcaatcaa tcttaacaac 4260
catttatacc gccaattcaa cacatatact ataaatctta aaatgggaaa tacatccatc 4320
acaatagaac tcacaagcaa attttggccc tattttacac taatacatat gatcttaact 4380
ctaatctttt tactaattat aatcactatc atgattgcaa cactaaataa gctaagtgaa 4440
cacaaagcat tctgcaacaa aactcttgaa ctaggacaga tgtaccaaat caacacacag 4500
agttccacca ttatgctgtg tcaaaccata atcctgtata tacaaacaaa caaatccaat 4560
cctctcacag agtcacggtg tcgcaaaacc acgctaacca tcatggtagc atagagtagt 4620
tatttaaaaa ttaacataat gatgaattgt tagtatgaga tcaaaaacaa cattggggca 4680
aatgcaacca tgtccaaaca caagaatcaa cgcactgcca ggactctaga aaagacctgg 4740
gatactctta atcatctaat tgtaatatcc tcttgtttat acagattaaa tttaaaatct 4800
atagcacaaa tagcactatc agttttggca atgataatct caacctctct cataattgca 4860
gccataatat tcatcatctc tgccaatcac aaagttacac taacaacggt cacagttcaa 4920
acaataaaaa accacactga aaaaaacatc accacctacc ctactcaagt ctcaccagaa 4980
agggttagtt catccaagca acccacaacc acatcaccaa tccacacaag ttcagctaca 5040
acatcaccca atacaaaatc agaaacacac catacaacag cacaaaccaa aggcagaacc 5100
accacttcaa cacagaccaa caagccaagc acaaaaccac gtccaaaaaa tccaccaaaa 5160
aaagatgatt accattttga agtgttcaac ttcgttccct gcagtatatg tggcaacaat 5220
caactttgca aatccatctg caaaacaata ccaagcaaca aaccaaagaa gaaaccaacc 5280
atcaaaccca caaacaaacc aaccaccaaa accacaaaca aaagagaccc aaaaacacca 5340
gccaaaacga cgaaaaaaga aactaccacc aacccaacaa aaaaactaac cctcaagacc 5400
acagaaagag acaccagcac ctcacaatcc actgcactcg acacaaccac attaaaacac 5460
acagtccaac agcaatccct cctctcaacc acccccgaaa acacacccaa ctccacacaa 5520
acacccacag catccgagcc ctccacacca aactccaccc aaaaaaccca gccacatgct 5580
tagttattca aaaactacat cttagcagag aaccgtgatc tatcaagcaa gaacgaaatt 5640
aaacctgggg caaataacca tggagttgat gatccacaag tcaagtgcaa tcttcctaac 5700
tcttgctatt aatgcattgt acctcacctc aagtcagaac ataactgagg agttttacca 5760
atcgacatgt agtgcagtta gcagaggtta ttttagtgct ttaagaacag gttggtatac 5820
tagtgtcata acaatagaat taagtaatat aaaagaaacc aaatgcaatg gaactgacac 5880
taaagtaaaa cttatgaaac aagaattaga taagtataag aatgcagtaa cagaattaca 5940
gctacttatg caaaacacac cagctgtcaa caaccgggcc agaagagaag caccacagta 6000
tatgaactac acaatcaata ccactaaaaa cctaaatgta tcaataagca agaagaggaa 6060
acgaagattt ctaggcttct tgttaggtgt gggatctgca atagcaagtg gtatagctgt 6120
atcaaaagtt ctacaccttg aaggagaagt gaacaagatc aaaaatgctt tgttgtctac 6180
aaacaaagct gtagtcagtt tatcaaatgg ggtcagtgtt ttaaccagca aagtgttaga 6240
tctcaagaat tacataaata accaattatt acccatagta aatcaacaga gctgtcgcat 6300
ctccaacatt gaaacagtta tagaattcca gcagaagaac agcagattgt tggaaatcac 6360
cagagaattt agtgtcaatg caggtgtaac aacaccttta agcacttaca tgttgacaaa 6420
cagtgagtta ctatcattaa tcaatgatat gcctataaca aatgatcaga aaaaattaat 6480
gtcaagcaat gttcagatag taaggcaaca aagttattcc atcatgtcta taataaagga 6540
59
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agaagtcctt gcatatgttg tacagctgcc tatctatggt gtaatagata caccttgctg 6600
gaaattgcac acatcgcctc tatgcactac caacatcaaa gaaggatcaa atatttgttt 6660
aacaaggact gatagaggat ggtattgtga taatgcagga tcagtatcct tctttccaca 6720
ggctgacact tgtaaagtac agtccaatcg agtattttgt gacactatga acagtttgac 6780
attaccaagt gaagtcagcc tttgtaacac tgacatattc aattccaagt atgactgcaa 6840
aattatgaca tcaaaaacag acataagcag ctcagtaatt acttctcttg gagctatagt 6900
gtcatgctat ggtaaaacta aatgcactgc atccaacaaa aatcgtggga ttataaagac 6960
attttctaat ggttgtgact atgtgtcaaa caaaggagta gatactgtgt cagtgggcaa 7020
cactttatac tatgtaaaca agctggaagg caagaacctt tatgtaaaag gggaacctat 7080
aataaattac tatgaccctc tagtgtttcc ttctgatgag tttgatgcat caatatctca 7140
agtcaatgaa aaaatcaatc aaagtttagc ttttattcgt agatctgatg aattactaca 7200
taatgtaaat actggcaaat ctactacaaa tattatgata actacaatta ttatagtaat 7260
cattgtagta ttgttatcat taatagctat tggtttactg ttgtattgta aagccaaaaa 7320
cacaccagtt acactaagca aagaccaact aagtggaatc aataatattg cattcagcaa 7380
atagacaaaa aaccacctga tcatgtttca acaacaatct gctgaccacc aatcccaaat 7440
caacttacaa caaatatttc aacatcacag tacaggctga atcatttcct cacatcatgc 7500
tacccacata actaagctag atccttaact tatagttaca taaaaacctc aagtatcaca 7560
atcaaccact aaatcaacac atcattcaca aaattaacag ctggggcaaa tatgtcgcga 7620
agaaatcctt gtaaatttga gattagaggt cattgcttga atggtagaag atgtcactac 7680
agtcataatt actttgaatg gcctcctcat gcattactag tgaggcaaaa cttcatgtta 7740
aacaagatac tcaagtcaat ggacaaaagc atagacactt tgtctgaaat aagtggagct 7800
gctgaactgg atagaacaga agaatatgct cttggtatag ttggagtgct agagagttac 7860
ataggatcta taaacaacat aacaaaacaa tcagcatgtg ttgctatgag taaacttctt 7920
attgagatca atagtgatga cattaaaaag cttagagata atgaagaacc caattcacct 7980
aagataagag tgtacaatac tgttatatca tacattgaga gcaatagaaa aaacaacaag 8040
caaaccatcc atctgctcaa gagactacca gcagacgtgc tgaagaagac aataaagaac 8100
acattagata tccacaaaag cataaccata agcaatccaa aagagtcaac tgtgaatgat 8160
caaaatgacc aaaccaaaaa taatgatatt accggataaa tatccttgta gtatatcatc 8220
catattgatc tcaagtgaaa gcatggttgc tacattcaat cataaaaaca tattacaatt 8280
taaccataac tatttggata accaccagcg tttattaaat catatatttg atgaaattca 8340
ttggacacct aaaaacttat tagatgccac tcaacaattt ctccaacatc ttaacatccc 8400
tgaagatata tatacagtat atatattagt gtcataatgc ttgaccataa cgactctatg 8460
tcatccaacc ataaaactat tttgataagg ttatgggaca aaatggatcc cattattaat 8520
ggaaactctg ctaatgtgta tctaactgat agttatttaa aaggtgttat ctctttttca 8580
gagtgtaatg ctttagggag ttatcttttt aacggccctt atcttaaaaa tgattacacc 8640
aacttaatta gtagacaaag cccactacta gagcatatga atcttaaaaa actaactata 8700
acacagtcat taatatctag atatcataaa ggtgaactga aattagaaga accaacttat 8760
ttccagtcat tacttatgac atataaaagt atgtcctcgt ctgaacaaat tgctacaact 8820
aacttactta aaaaaataat acgaagagcc atagaaataa gtgatgtaaa ggtgtacgcc 8880
atcttgaata aactaggatt aaaggaaaag gacagagtta agcccaacaa taattcaggt 8940
gatgaaaact cagtacttac aaccataatt aaagatgata tactttcggc tgtggaaaac 9000
aatcaatcat atacaaattc agacaaaagt cactcagtaa atcaaaatat cactatcaaa 9060
acaacactct tgaaaaaatt gatgtgttca atgcaacatc ctccatcatg gttaatacac 9120
tggttcaatt tatatacaaa attaaataac atattaacac aatatcgatc aaatgaggta 9180
aaaagtcatg ggtttatatt aatagataat caaactttaa gtggttttca gtttatttta 9240
aatcaatatg gttgtatcgt ttatcataaa ggactcaaaa aaatcacaac tactacttac 9300
aatcaatttt tgacatggaa agacatcagc cttagcagat taaatgtttg cttaattact 9360
tggataagta attgtttaaa tacattaaac aaaagcttag ggctgagatg tggattcaat 9420
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
aatgttgtgt tatcacaatt atttctttat ggagattgta tactgaaatt atttcataat 9480
gaaggcttct acataataaa agaagtagag ggatttatta tgtctttaat tctaaacata 9540
acagaagaag atcaatttaa gaaacgattt tataatagca tgctaaataa catcacagat 9600
gcagctatta aggctcaaaa ggacctacta tcaagagtat gtcacacttt attagacaag 9660
acagtgtctg ataatatcat aaatggtaaa tggataatcc tattaagtaa atttcttaaa 9720
ttgattaagc ttgcaggtga taataatctc aataacttga gtgagctata ttttctcttc 9780
agaatctttg gacatccaat ggtcgatgaa agacaagcaa tggattctgt aagaattaac 9840
tgtaatgaaa ctaggttcta cttattaagt agtctaagta cattaagagg tgctttcatt 9900
tatagaatca taaaagggtt tgtaaatacc tacaacagat ggcccacctt aaggaatgct 9960
attgtcctac ctctaagatg gttaaactac tataaactta atacttatcc atctctactt 10020
gaaatcacag aaaatgattt gattatttta tcaggattgc ggttctatcg tgagtttcat 10080
ctgcctaaaa aagtggatct tgaaatgata ataaatgaca aagccatttc acctccaaaa 10140
gatctaatat ggactagttt tcctagaaat tacatgccat cacatataca aaattatata 10200
gaacatgaaa agttgaagtt ctctgaaagc gacagatcga gaagagtact agagtattac 10260
ttgagagata ataaattcaa tgaatgcgat ctatacaatt gtgtagtcaa tcaaagctat 10320
ctcaacaact ctaatcacgt ggtatcacta actggtaaag aaagagagct cagtgtaggt 10380
agaatgtttg ctatgcaacc aggtatgttt aggcaaatcc aaatcttagc agagaaaatg 10440
atagctgaaa atattttaca attcttccct gagagtttga caagatatgg tgatctagag 10500
cttcaaaaga tattagaatt aaaagcagga ataagcaaca agtcaaatcg ttataatgat 10560
aactacaaca attatatcag taaatgttct atcattacag atcttagcaa attcaatcag 10620
gcatttagat atgaaacatc atgtatctgc agtgatgtat tagatgaact gcatggagta 10680
caatctctgt tctcttggtt gcatttaaca atacctcttg tcacaataat atgtacatat 10740
agacatgcac ctcctttcat aaaggatcat gttgttaatc ttaatgaggt tgatgaacaa 10800
agtggattat acagatatca tatgggtggt attgagggct ggtgtcaaaa actgtggacc 10860
attgaagcta tatcattatt agatctaata tctctcaaag ggaaattctc tatcacagct 10920
ctgataaatg gtgataatca gtcaattgat ataagcaaac cagttagact tatagagggt 10980
cagacccatg cacaagcaga ttatttgtta gcattaaata gccttaaatt gttatataaa 11040
gagtatgcag gtataggcca taagcttaag ggaacagaga cctatatatc ccgagatatg 11100
cagttcatga gcaaaacaat ccagcacaat ggagtgtact atccagccag tatcaaaaaa 11160
gtcctgagag taggtccatg gataaacacg atacttgatg attttaaagt tagtttagaa 11220
tctataggca gcttaacaca ggagttagaa tacagaggag aaagcttatt atgcagttta 11280
atatttagga acatttggtt atacaatcaa attgctttgc aactccgaaa tcatgcatta 11340
tgtaacaata agctatattt agatatattg aaagtattaa aacacttaaa aacttttttt 11400
aatcttgata gcattgatat ggctttatca ttgtatatga atttgcctat gctgtttggt 11460
ggtggtgatc ctaatttgtt atatcgaagc ttttatagga gaactccaga cttccttaca 11520
gaagctatag tacattcagt gtttgtgttg agctattata ctggtcacga tttacaagat 11580
aagctccagg atcttccaga tgatagactg aacaaattct tgacatgtgt catcacattt 11640
gataaaaatc ccaatgccga gtttgtaaca ttgatgaggg atccacaggc tttagggtct 11700
gaaaggcaag ctaaaattac tagtgagatt aatagattag cagtaacaga agtcttaagt 11760
atagccccaa acaaaatatt ttctaaaagt gcacaacatt atactaccac tgagattgat 11820
ctaaatgaca ttatgcaaaa tatagaacca acttaccctc atggattaag agttgtttat 11880
gaaagtttac ctttttataa agcagaaaaa atagttaatc ttatatcagg aacaaaatcc 11940
ataactaata tacttgaaaa aacatcagca atagatacaa ctgatattaa tagggctact 12000
gatatgatga ggaaaaatat aactttactt ataaggatac ttccactaga ttgtaacaaa 12060
gacaaaagag agttattaag tttagaaaat cttagtataa ctgaattaag caagtatgta 12120
agagaaagat cttggtcatt atccaatata gtaggagtaa catcgccaag tattatgttc 12180
acaatgaaca ttaaatatac aactagcact atagccagtg gtataataat agaaaaatat 12240
aatgttaata gtttaactcg tggtgaaaga ggacccacca agccatgggt aggctcatcc 12300
61
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acgcaggaga aaaaaacaat gccagtgtac aacagacaag ttttaaccaa aaagcaaaga 12360
gaccaaatag atttattagc aaaattagac tgggtatatg catccataga caacaaagat 12420
gaattcatgg aagaactgag tactggaaca cttggactgt catatgaaaa agccaaaaag 12480
ttgtttccac aatatctaag tgtcaattat ttacaccgtt taacagtcag tagtagacca 12540
tgtgaattcc ctgcatcaat accagcttat agaacaacaa attatcattt tgatactagt 12600
cctatcaatc atgtattaac agaaaagtat ggagatgaag atatcgacat tgtgtttcaa 12660
aattgcataa gttttggtct tagcctgatg tcggttgtgg aacaattcac aaacatatgt 12720
cctaatagaa ttattctcat accgaagctg aatgagatac atttgatgaa acctcctata 12780
tttacaggag atgttgatat catcaagttg aagcaagtga tacaaaagca gcacatgttc 12840
ctaccagata aaataagttt aacccaatat gtagaattat tcttaagtaa caaagcactt 12900
aaatctggat ctcacatcaa ctctaattta atattagtac ataaaatgtc tgattatttt 12960
cataatgctt atattttaag tactaattta gctggacatt ggattctgat tattcaactt 13020
atgaaagatt caaaaggtat ttttgaaaaa gattggggag aggggtacat aactgatcat 13080
atgttcatta atttgaatgt tttctttaat gcttataaga cttatttgct atgttttcat 13140
aaaggttatg gtaaagcaaa attagaatgt gatatgaaca cttcagatct tctttgtgtt 13200
ttggagttaa tagacagtag ctactggaaa tctatgtcta aagttttcct agaacaaaaa 13260
gtcataaaat acatagtcaa tcaagacaca agtttgcgta gaataaaagg ctgtcacagt 13320
tttaagttgt ggtttttaaa acgccttaat aatgctaaat ttaccgtatg cccttgggtt 13380
gttaacatag attatcaccc aacacacatg aaagctatat tatcttacat agatttagtt 13440
agaatggggt taataaatgt agataaatta accattaaaa ataaaaacaa attcaatgat 13500
gaattttaca catcaaatct cttttacatt agttataact tttcagacaa cactcatttg 13560
ctaacaaaac aaataagaat tgctaattca gaattagaag ataattataa caaactatat 13620
cacccaaccc cagaaacttt agaaaatatg tcattaattc ctgttaaaag taataatagt 13680
aacaaaccta aattttgtat aagtggaaat accgaatcta tgatgatgtc aacattctct 13740
agtaaaatgc atattaaatc ttccactgtt accacaagat tcaattatag caaacaagac 13800
ttgtacaatt tatttccaat tgttgtgata gacaagatta tagatcattc aggtaataca 13860
gcaaaatcta accaacttta caccaccact tcacatcaga catctttagt aaggaatagt 13920
gcatcacttt attgcatgct tccttggcat catgtcaata gatttaactt tgtatttagt 13980
tccacaggat gcaagatcag tatagagtat attttaaaag atcttaagat taaggacccc 14040
agttgtatag cattcatagg tgaaggagct ggtaacttat tattacgtac ggtagtagaa 14100
cttcatccag acataagata catttacaga agtttaaaag attgcaatga tcatagttta 14160
cctattgaat ttctaaggtt atacaacggg catataaaca tagattatgg tgagaattta 14220
accattcctg ctacagatgc aactaataac attcattggt cttatttaca tataaaattt 14280
gcagaaccta ttagcatctt tgtctgcgat gctgaattac ctgttacagc caattggagt 14340
aaaattataa ttgaatggag taagcatgta agaaagtgca agtactgttc ttctgtaaat 14400
agatgcattt taattgcaaa atatcatgct caagatgaca ttgatttcaa attagataac 14460
attactatat taaaaactta cgtgtgccta ggtagcaagt taaaaggatc tgaagtttac 14520
ttaatcctta caataggccc tgcaaatata cttcctgttt ttgatgttgt acaaaatgct 14580
aaattgatac tttcaagaac taaaaatttc attatgccta aaaaaactga caaggaatct 14640
atcgatgcaa atattaaaag cttaatacct ttcctttgtt accctataac aaaaaaagga 14700
attaagactt cattgtcaaa attgaagagt gtagttaatg gagatatatt atcatattct 14760
atagctggac gtaatgaagt attcagcaac aagcttataa accacaagca tatgaatatc 14820
ctaaaatggc tagatcatgt tttaaatttt agatcagctg aacttaatta caatcattta 14880
tacatgatag agtccacata tccttactta agtgaattgt taaatagttt aacaaccaat 14940
gagctcaaga agctgattaa aataacaggt agtgtgctat acaaccttcc caacgaacag 15000
tagtttaaaa tatcattaac aagtttggtc aaatttagat gctaacacat cattatatta 15060
tagttattaa agaatataca aacttttcaa taatttagca tattgattcc aaaattatca 15120
ttttagtctt aaggggttaa ataaaagtct aaaactaaca attatacatg tgcattcaca 15180
62
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acacaacgag acattagttt ttgacacttt ttttctcgt 15219
<210> 12
<211> 15219
<212> DNA
<213> respiratory syncytial virus
<400> 12
acgggaaaaa aatgcgtact acaaacttgc acattcgaaa aaaatggggc aaataagaac 60
ttgataagtg ctatttaagt ctaacctttt caatcagaaa tggggtgcaa ttcactgagc 120
atgataaagg ttagattaca aaatttattt gacaatgacg aagtagcatt gttaaaaata 180
acatgttata ctgataaatt aattcttctg accaatgcat tagccaaagc agcaatacat 240
acaattaaat taaacggcat agtttttata catgttataa caagcagtga agtgtgccct 300
gataacaata ttgtagtgaa atctaacttt acaacaatgc caatactaca aaatggagga 360
tacatatggg aattgattga gttgacacac tgctctcaat taaacggttt aatggatgat 420
aattgtgaaa tcaaattttc taaaagacta agtgactcag taatgactaa ttatatgaat 480
caaatatctg acttacttgg gcttgatctc aattcatgaa ttatgtttag tctaattcaa 540
tagacatgtg tttattacca ttttagttaa tataaaaact catcaaaggg aaatggggca 600
aataaactca cctaatcaat caaaccatga gcactacaaa tgacaacact actatgcaaa 660
gattgatgat cacagacatg agacccctgt caatggattc aataataaca tctcttacca 720
aagaaatcat cacacacaaa ttcatatact tgataaacaa tgaatgtatt gtaagaaaac 780
ttgatgaaag acaagctaca tttacattct tagtcaatta tgagatgaag ctactgcaca 840
aagtagggag taccaaatac aaaaaataca ctgaatataa tacaaaatat ggcactttcc 900
ccatgcctat atttatcaat cacggcgggt ttctagaatg tattggcatt aagcctacaa 960
aacacactcc tataatatac aaatatgacc tcaacccgtg aattccaaca aaaaaaccaa 1020
cccaaccaaa ccaaactatt cctcaaacaa cagtgctcaa tagttaagaa ggagctaatc 1080
cattttagta attaaaaata aaagtaaagc caataacata aattggggca aatacaaaga 1140
tggctcttag caaagtcaag ttgaatgata cattaaataa ggatcagctg ctgtcatcca 1200
gcaaatacac tattcaacgt agtacaggag ataatattga cactcccaat tatgatgtgc 1260
aaaaacacct aaacaaacta tgtggtatgc tattaatcac tgaagatgca aatcataaat 1320
tcacaggatt aataggtatg ttatatgcta tgtccaggtt aggaagggaa gacactataa 1380
agatacttaa agatgctgga tatcatgtta aagctaatgg agtagatata acaacatatc 1440
gtcaagatat aaatggaaag gaaatgaaat tcgaagtatt aacattatca agcttgacat 1500
cagaaataca agtcaatatt gagatagaat ctagaaagtc ctacaaaaaa atgctaaaag 1560
agatgggaga agtggctcca gaatataggc atgattctcc agactgtggg atgataatac 1620
tgtgtatagc tgcacttgtg ataaccaaat tagcagcagg agacagatca ggtcttacag 1680
cagtaattag gagggcaaac aatgtcttaa aaaacgaaat aaaacgatac aagggcctca 1740
taccaaagga tatagctaac agtttttatg aagtgtttga aaaacaccct catcttatag 1800
atgttttcgt gcactttggc attgcacaat catccacaag agggggtagt agagttgaag 1860
gaatctttgc aggattgttt atgaatgcct atggttcagg gcaagtaatg ctaagatggg 1920
gagttttagc caaatctgta aaaaatatca tgctaggaca tgctagtgtc caggcagaaa 1980
tggagcaagt tgtggaagtc tatgagtatg cacagaagtt gggaggagaa gctggattct 2040
accatatatt gaacaatcca aaagcatcat tgctgtcatt aactcaattt cccaacttct 2100
caagtgtggt cctaggcaat gcagcaggtc taggcataat gggagagtat agaggtacac 2160
caagaaacca ggatctttat gatgcagcta aagcatatgc agagcaactc aaagaaaatg 2220
gagtaataaa ctacagtgta ttagacttaa cagcagaaga attggaagcc ataaagcatc 2280
aactcaaccc caaagaagat gatgtagagc tttaagttaa caaaaaatac ggggcaaata 2340
agtcaacatg gagaagtttg cacctgaatt tcatggagaa gatgcaaata acaaagctac 2400
63
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caaattccta gaatcaataa agggcaagtt cgcatcatcc aaagatccta agaagaaaga 2460
tagcataata tctgttaact caatagatat agaagtaact aaagagagcc cgataacatc 2520
tggcaccaac atcatcaatc caacaagtga agccgacagt accccagaaa caaaagccaa 2580
ctacccaaga aaacccctag taagcttcaa agaagatctc accccaagtg acaacccttt 2640
ttctaagttg tacaaggaaa caatagaaac atttgataac aatgaagaag aatctagcta 2700
ctcatatgaa gagataaatg atcaaacaaa tgacaacatt acagcaagac tagatagaat 2760
tgatgaaaaa ttaagtgaaa tattaggaat gctccataca ttagtagttg caagtgcagg 2820
acccacttca gctcgcgatg gaataagaga tgctatggtt ggtctaagag aagagatgat 2880
agaaaaaata agagcggaag cattaatgac caatgatagg ttagaggcta tggcaagact 2940
taggaatgag gaaagcgaaa aaatggcaaa agacacctca gatgaagtgt ctcttaatcc 3000
aacttccaaa aaattgagtg acttgttgga agacaacgat agtgacaatg atctatcact 3060
tgatgatttt tgatcagcga tcaactcact cagcaatcaa caacatcaat aaaacagaca 3120
tcaatccatt gaatcaactg ccagaccgaa caaacaaacg tccatcagta gaaccaccaa 3180
ccaatcaatc aaccaattga tcaatcagca acccgacaaa attaacaata tagtaacaaa 3240
aaaagaacaa gatggggcaa atatggaaac atacgtgaac aagcttcacg aaggctccac 3300
atacacagca gctgttcagt acaatgttct agaaaaagat gatgatcctg catcactaac 3360
aatatgggtg cctatgttcc agtcatctgt gccagcagac ttgctcataa aagaacttgc 3420
aagcatcaat atactagtga agcagatctc tacgcccaaa ggaccttcac tacgagtcac 3480
gattaactca agaagtgctg tgctggctca aatgcctagt aatttcatca taagcgcaaa 3540
tgtatcatta gatgaaagaa gcaaattagc atatgatgta actacacctt gtgaaatcaa 3600
agcatgcagt ctaacatgct taaaagtaaa aagtatgtta actacagtca aagatcttac 3660
catgaagaca ttcaacccca ctcatgagat cattgctcta tgtgaatttg aaaatattat 3720
gacatcaaaa agagtaataa taccaaccta tctaagatca attagtgtca agaacaagga 3780
tctgaactca ctagaaaata tagcaaccac cgaattcaaa aatgctatca ccaatgcaaa 3840
aattattcct tatgcaggat tagtgttagt tatcacagtt actgacaata aaggagcatt 3900
caaatatatc aaaccacaga gtcaatttat agtagatctt ggtgcctacc tagaaaaaga 3960
gagcatatat tatgtgacta ctaattggaa gcatacagct acacgttttt caatcaaacc 4020
actagaggat taaacttaat tatcaacact gaatgacagg tccacatata tcctcaaact 4080
acacactata tccaaacatc ataaacatct acactacaca cttcatcaca caaaccaatc 4140
ccactcaaaa tccaaaatca ctaccagcca ctatctgcta gacctagagt gcgaataggt 4200
aaataaaacc aaaatatggg gtaaatagac attagttaga gttcaatcaa tcttaacaac 4260
catttatacc gccaattcaa cacatatact ataaatctta aaatgggaaa tacatccatc 4320
acaatagaat tcacaagcaa attttggccc tattttacac taatacatat gatcttaact 4380
ctaatctttt tactaattat aatcactatt atgattgcaa tactaaataa gctaagtgaa 4440
cataaagcat tctgtaacaa aactcttgaa ctaggacaga tgtatcaaat caacacatag 4500
agttctacca ttatgctgtg tcaaattata atcctgtata tataaacaaa caaatccaat 4560
cttctcacag agtcatggtg tcgcaaaacc acgctaacta tcatggtagc atagagtagt 4620
tatttaaaaa ttaacataat gatgaattgt tagtatgaga tcaaaaacaa cattggggca 4680
aatgcaacca tgtccaaaca caagaatcaa cgcactgcca ggactctaga aaagacctgg 4740
gatactctta atcatctaat tgtaatatcc tcttgtttat acagattaaa tttaaaatct 4800
atagcacaaa tagcactatc agttttggca atgataatct caacctctct cataattgca 4860
gccataatat tcatcatctc tgccaatcac aaagttacac taacaacggt cacagttcaa 4920
acaataaaaa accacactga aaaaaacatc accacctacc ctactcaagt ctcaccagaa 4980
agggttagtt catccaagca acccacaacc acatcaccaa tccacacaag ttcagctaca 5040
acatcaccca atacaaaatc agaaacacac catacaacag cacaaaccaa aggcagaacc 5100
accacttcaa cacagaccaa caagccaagc acaaaaccac gtccaaaaaa tccaccaaaa 5160
aaagatgatt accattttga agtgttcaac ttcgttccct gcagtatatg tggcaacaat 5220
caactttgca aatccatctg caaaacaata ccaagcaaca aaccaaagaa gaaaccaacc 5280
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atcaaaccca caaacaaacc aaccaccaaa accacaaaca aaagagaCCC aaaaacacca 5340
gccaaaacga cgaaaaaaga aactaccacc aacccaacaa aaaaactaac cctcaagacc 5400
acagaaagag acaccagcac ctcacaatcc actgcactcg acacaaccac attaaaacac 5460
acagtccaac agcaatccct cctctcaacc acccccgaaa acacacccaa ctccacacaa 5520
acacccacag catccgagcc ctccacacca aactccaccc aaaaaaccca gccacatgct 5580
tagttattca aaaactacat cttagcagag aaccgtgatc tatcaagcaa gaacgaaatt 5640
aaacctgggg caaataacca tggagttgat gatccacaag tcaagtgcaa tcttcctaac 5700
tcttgctatt aatgcattgt acctcacctc aagtcagaac ataactgagg agttttacca 5760
atcgacatgt agtgcagtta gcagaggtta ttttagtgct ttaagaacag gttggtatac 5820
tagtgtcata acaatagaat taagtaatat aaaagaaacc aaatgcaatg gaactgacac 5880
taaagtaaaa cttatgaaac aagaattaga taagtataag aatgcagtaa cagaattaca 5940
gctacttatg caaaacacac cagctgtcaa caaccgggcc agaagagaag caccacagta 6000
tatgaactac acaatcaata ccactaaaaa cctaaatgta tcaataagca agaagaggaa 6060
acgaagattt ctaggcttct tgttaggtgt gggatctgca atagcaagtg gtatagctgt 6120
atcaaaagtt ctacaccttg aaggagaagt gaacaagatc aaaaatgctt tgttgtctac 6180
aaacaaagct gtagtcagtt tatcaaatgg ggtcagtgtt ttaaccagca aagtgttaga 6240
tctcaagaat tacataaata accaattatt acccatagta aatcaacaga gctgtcgcat 6300
ctccaacatt gaaacagtta tagaattcca gcagaagaac agcagattgt tggaaatcac 6360
cagagaattt agtgtcaatg caggtgtaac aacaccttta agcacttaca tgttgacaaa 6420
cagtgagtta ctatcattaa tcaatgatat gcctataaca aatgatcaga aaaaattaat 6480
gtcaagcaat gttcagatag taaggcaaca aagttattcc atcatgtcta taataaagga 6540
agaagtcctt gcatatgttg tacagctgcc tatctatggt gtaatagata caccttgctg 6600
gaaattgcac acatcgcctc tatgcactac caacatcaaa gaaggatcaa atatttgttt 6660
aacaaggact gatagaggat ggtattgtga taatgcagga tcagtatcct tctttccaca 6720
ggctgacact tgtaaagtac agtccaatcg agtattttgt gacactatga acagtttgac 6780
attaccaagt gaagtcagcc tttgtaacac tgacatattc aattccaagt atgactgcaa 6840
aattatgaca tcaaaaacag acataagcag ctcagtaatt acttctcttg gagctatagt 6900
gtcatgctat ggtaaaacta aatgcactgc atccaacaaa aatcgtggga ttataaagac 6960
attttctaat ggttgtgact atgtgtcaaa caaaggagta gatactgtgt cagtgggcaa 7020
cactttatac tatgtaaaca agctggaagg caagaacctt tatgtaaaag gggaacctat 7080
aataaattac tatgaccctc tagtgtttcc ttctgatgag tttgatgcat caatatctca 7140
agtcaatgaa aaaatcaatc aaagtttagc ttttattcgt agatctgatg aattactaca 7200
taatgtaaat actggcaaat ctactacaaa tattatgata actacaatta ttatagtaat 7260
cattgtagta ttgttatcat taatagctat tggtttactg ttgtattgta aagccaaaaa 7320
cacaccagtt acactaagca aagaccaact aagtggaatc aataatattg cattcagcaa 7380
atagacaaaa aaccacctga tcatgtttca acaacaatct gctgaccacc aatcccaaat 7440
caacttacaa caaatatttc aacatcacag tacaggctga atcatttcct cacatcatgc 7500
tacccacata actaagctag atccttaact tatagttaca taaaaacctc aagtatcaca 7560
atcaaccact aaatcaacac atcattcaca aaattaacag ctggggcaaa tatgtcgcga 7620
agaaatcctt gtaaatttga gattagaggt cattgcttga atggtagaag atgtcactac 7680
agtcataatt actttgaatg gcctcctcat gcattactag tgaggcaaaa cttcatgtta 7740
aacaagatac tcaagtcaat ggacaaaagc atagacactt tgtctgaaat aagtggagct 7800
gctgaactgg atagaacaga agaatatgct cttggtatag ttggagtgct agagagttac 7860
ataggatcta taaacaacat aacaaaacaa tcagcatgtg ttgctatgag taaacttctt 7920
attgagatca atagtgatga cattaaaaag cttagagata atgaagaacc caattcacct 7980
aagataagag tgtacaatac tgttatatca tacattgaga gcaatagaaa aaacaacaag 8040
caaaccatcc atctgctcaa gagactacca gcagacgtgc tgaagaagac aataaagaac 8100
acattagata tccacaaaag cataaccata agcaatccaa aagagtcaac tgtgaatgat 8160
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caaaatgacc aaaccaaaaa taatgatatt accggataaa tatccttgta gtatatcatc 8220
catattgatc tcaagtgaaa gcatggttgc tacattcaat cataaaaaca tattacaatt 8280
taaccataac tatttggata accaccagcg tttattaaat catatatttg atgaaattca 8340
ttggacacct aaaaacttat tagatgccac tcaacaattt ctccaacatc ttaacatccc 8400
tgaagatata tatacagtat atatattagt gtcataatgc ttgaccataa cgactctatg 8460
tcatccaacc ataaaactat tttgataagg ttatgggaca aaatggatcc cattattaat 8520
ggaaactctg ctaatgtgta tctaactgat agttatttaa aaggtgttat ctctttttca 8580
gagtgtaatg ctttagggag ttatcttttt aacggccctt atcttaaaaa tgattacacc 8640
aacttaatta gtagacaaag cccactacta gagcatatga atcttaaaaa actaactata 8700
acacagtcat taatatctag atatcataaa ggtgaactga aattagaaga accaacttat 8760
ttccagtcat tacttatgac atataaaagt atgtcctcgt ctgaacaaat tgctacaact 8820
aacttactta aaaaaataat acgaagagcc atagaaataa gtgatgtaaa ggtgtacgcc 8880
atcttgaata aactaggatt aaaggaaaag gacagagtta agcccaacaa taattcaggt 8940
gatgaaaact cagtacttac aactataatt aaagatgata tactttcggc tgtggaaaac 9000
aatcaatcat atacaaattc agacaaaagt cactcagtaa atcaaaatat cactatcaaa 9060
acaacactct tgaaaaaatt gatgtgttca atgcaacatc ctccatcatg gttaatacac 9120
tggttcaatt tatatacaaa attaaataac atattaacac aatatcgatc aaatgaggta 9180
aaaagtcatg ggtttatatt aatagataat caaactttaa gtggttttca gtttatttta 9240
aatcaatatg gttgtatcgt ttatcataaa ggactcaaaa aaatcacaac tactacttac 9300
aatcaatttt tgacatggaa agacatcagc cttagcagat taaatgtttg cttaattact 9360
tggataagta attgtttaaa tacattaaac aaaagcttag ggctgagatg tggattcaat 9420
aatgttgtgt tatcacaatt atttctttat ggagattgta tactgaaatt atttcataat 9480
gaaggcttct acataataaa agaagtagag ggatttatta tgtctttaat tctaaacata 9540
acagaagaag atcaatttag gaaacgattt tataatagca tgctaaataa catcacagat 9600
gcagctatta aggctcaaaa ggacctacta tcaagagtat gtcacacttt attagacaag 9660
acagtgtctg ataatatcat aaatggtaaa tggataatcc tattaagtaa atttcttaaa 9720
ttgattaagc ttgcaggtga taataatctc aataacttga gtgagctata ttttctcttc 9780
agaatctttg gacatccaat ggtcgatgaa agacaagcaa tggattctgt aagaattaac 9840
tgtaatgaaa ctaagttcta cttattaagt agtctaagta cattaagagg tgctttcatt 9900
tatagaatca taaaagggtt tgtaaatacc tacaacagat ggcccacctt aaggaatgct 9960
attgtcctac ctctaagatg gttaaactac tataaactta atacttatcc atctctactt 10020
gaaatcacag aaaatgattt gattatttta tcaggattgc ggttctatcg tgagtttcat 10080
ctgcctaaaa aagtggatct tgaaatgata ataaatgaca aagccatttc acctccaaaa 10140
gatctaatat ggactagttt tcctagaaat tacatgccat cacatataca aaattatata 10200
gaacatgaaa agttgaagtt ctctgaaagc gacagatcga gaagagtact agagtattac 10260
ttgagagata ataaattcaa tgaatgcgat ctatacaatt gtgtagtcaa tcaaagctat 10320
ctcaacaact ctaatcacgt ggtatcacta actggtaaag aaagagagct cagtgtaggt 10380
agaatgtttg ctatgcaacc aggtatgttt aggcaaatcc aaatcttagc agagaaaatg 10440
atagctgaaa atattttaca attcttccct gagagtttga caagatatgg tgatctagag 10500
cttcaaaaga tattagaatt aaaagcagga ataagcaaca agtcaaatcg ttataatgat 10560
aactacaaca attatatcag taaatgttct atcattacag atcttagcaa attcaatcag 10620
gcatttagat atgaaacatc atgtatctgc agtgatgtat tagatgaact gcatggagta 10680
caatctctgt tctcttggtt gcatttaaca atacctcttg tcacaataat atgtacatat 10740
agacatgcac ctcctttcat aaaggatcat gttgttaatc ttaatgaggt tgatgaacaa 10800
agtggattat acagatatca tatgggtggt attgagggct ggtgtcaaaa actgtggacc 10860
attgaagcta tatcattatt agatctaata tctctcaaag ggaaattctc tatcacagct 10920
ctgataaatg gtgataatca gtcaattgat ataagcaaac cagttagact tatagagggt 10980
cagacccatg cacaagcaga ttatttgtta gcattaaata gccttaaatt gttatataaa 11040
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gagtatgcag gtataggcca taagcttaag ggaacagaga cctatatatc ccgagatatg 11100
cagttcatga gcaaaacaat ccagcacaat ggagtgtact atccagccag tatcaaaaaa 11160
gtcctgagag taggtccatg gataaacacg atacttgatg attttaaagt tagtttagaa 11220
tctataggca gcttaacaca ggagttagaa tacagaggag aaagcttatt atgcagttta 11280
atatttagga acatttggtt atacaatcaa attgctttgc aactccgaaa tcatgcatta 11340
tgtaacaata agctatattt agatatattg aaagtattaa aacacttaaa aacttttttt 11400
aatcttgata gcattgatat ggctttatca ttgtatatga atttgcctat gctgtttggt 11460
ggtggtgatc ctaatttgtt atatcgaagc ttttatagga gaactccaga cttccttaca 11520
gaagctatag tacattcagt gtttgtgttg agctattata ctggtcacga tttacaagat 11580
aagctccagg atcttccaga tgatagactg aacaaattct tgacatgtgt catcacattt 11640
gataaaaatc ccaatgccga gtttgtaaca ttgatgaggg atccacaggc tttagggtct 11700
gaaaggcaag ctaaaattac tagtgagatt aatagattag cagtaacaga agtcttaagt 11760
atagccccaa acaaaatatt ttctaaaagt gcacaacatt atactaccac tgagattgat 11820
ctaaatgaca ttatgcaaaa tatagaacca acttaccctc atggattaag agttgtttat 11880
gaaagtttac ctttttataa agcagaaaaa atagttaatc ttatatcagg aacaaaatcc 11940
ataactaata tacttgaaaa aacatcagca atagatacaa ctgatattaa tagggctact 12000
gatatgatga ggaaaaatat aactttactt ataaggatac ttccactaga ttgtaacaaa 12060
gacaaaagag agttattaag tttagaaaat cttagtataa ctgaattaag caagtatgta 12120
agagaaagat cttggtcatt atccaatata gtaggagtaa catcgccaag tattatgttc 12180
acaatggaca ttaaatatac aactagcact atagccagtg gtataataat agaaaaatat 12240
aatgttaata gtttaactcg tggtgaaaga ggacccacca agccatgggt aggctcatcc 12300
acgcaggaga aaaaaacaat gccagtgtac aacagacaag ttttaaccaa aaagcaaaga 12360
gaccaaatag atttattagc aaaattagac tgggtatatg catccataga caacaaagat 12420
gaattcatgg aagaactgag tactggaaca cttggactgt catatgaaaa agccaaaaag 12480
ttgtttccac aatatctaag tgtcaattat ttacaccgtt taacagtcag tagtagacca 12540
tgtgaattcc ctgcatcaat accagcttat agaacaacaa attatcattt tgatactagt 12600
cctatcaatc atgtattaac agaaaagtat ggagatgaag atatcgacat tgtgtttcaa 12660
aattgcataa gttttggtct tagcctgatg tcggttgtgg aacaattcac aaacatatgt 12720
cctaatagaa ttattctcat accgaagctg aatgagatac atttgatgaa acctcctata 12780
tttacaggag atgttgatat catcaagttg aagcaagtga tacaaaagca gcacatgttc 12840
ctaccagata aaataagttt aacccaatat gtagaattat tcttaagtaa caaagcactt 12900
aaatctggat ctcacatcaa ctctaattta atattagtac ataaaatgtc tgattatttt 12960
cataatgctt atattttaag tactaattta gctggacatt ggattctgat tattcaactt 13020
atgaaagatt caaaaggtat ttttgaaaaa gattggggag aggggtacat aactgatcat 13080
atgttcatta atttgaatgt tttctttaat gcttataaga cttatttgct atgttttcat 13140
aaaggttatg gtaaagcaaa attagaatgt gatatgaaca cttcagatct tctttgtgtt 13200
ttggagttaa tagacagtag ctactggaaa tctatgtcta aagttttcct agaacaaaaa 13260
gtcataaaat acatagtcaa tcaagacaca agtttgcgta gaataaaagg ctgtcacagt 13320
tttaagttgt ggtttttaaa acgccttaat aatgctaaat ttaccgtatg cccttgggtt 13380
gttaacatag attatcaccc aacacacatg aaagctatat tatcttacat agatttagtt 13440
agaatggggt taataaatgt agataaatta accattaaaa ataaaaacaa attcaatgat 13500
gaattttaca catcaaatct cttttacatt agttataact tttcagacaa cactcatttg 13560
ctaacaaaac aaataagaat tgctaattca gaattagaag ataattataa caaactatat 13620
cacccaaccc cagaaacttt agaaaatatg tcattaattc ctgttaaaag taataatagt 13680
aacaaaccta aattttgtat aagtggaaat accgaatcta tgatgatgtc aacattctct 13740
agtaaaatgc atattaaatc ttccactgtt accacaagat tcaattatag caaacaagac 13800
ttgtacaatt tatttccaat tgttgtgata gacaagatta tagatcattc aggtaataca 13860
gcaaaatcta accaacttta caccaccact tcacatcaga catctttagt aaggaatagt 13920
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gcatcacttt attgcatgct tccttggcat catgtcaata gatttaactt tgtatttagt 13980
tccacaggat gcaagatcag tatagagtat attttaaaag atcttaagat taaggacccc 14040
agttgtatag cattcatagg tgaaggagct ggtaacttat tattacgtac ggtagtagaa 14100
cttcatccag acataagata catttacaga agtttaaaag attgcaatga tcatagttta 14160
cctattgaat ttctaaggtt atacaacggg catataaaca tagattatgg tgagaattta 14220
accattcctg ctacagatgc aactaataac attcattggt cttatttaca tataaaattt 14280
gcagaaccta ttagcatctt tgtctgcgat gctgaattac ctgttacagc caattggagt 14340
aaaattataa ttgaatggag taagcatgta agaaagtgca agtactgttc ttctgtaaat 14400
agatgcattt taattgcaaa atatcatgct caagatgaca ttgatttcaa attagataac 14460
attactatat taaaaactta cgtgtgccta ggtagcaagt taaaaggatc tgaagtttac 14520
ttaatcctta caataggccc tgcaaatata cttcctgttt ttgatgttgt acaaaatgct 14580
aaattgatac tttcaagaac taaaaatttc attatgccta aaaaaactga caaggaatct 14640
atcgatgcag atattaaaag cttaatacct ttcctttgtt accctataac aaaaaaagga 14700
attaagactt cattgtcaaa attgaagagt gtagttaatg gagatatatt atcatattct 14760
atagctggac gtaatgaagt attcagcaac aagcttataa accacaagca tatgaatatc 14820
ctaaaatggc tagatcatgt tttaaatttt agatcagctg aacttaatta caatcattta 14880
tacatgatag agtccacata tccttactta agtgaattgt taaatagttt aacaaccaat 14940
gagctcaaga agctgattaa aataacaggt agtgtgctat acaaccttcc caacgaacag 15000
tagtttaaaa tatcattaac aagtttggtc aaatttagat gctaacacat cattatatta 15060
tagttattaa aaaatataca aacttttcaa taatttagca tattgattcc aaaattatca 15120
ttttagtctt aaggggttaa ataaaagtct aaaactaaca attatacatg tgcattcaca 15180
acacaacgag acattagttt ttgacacttt ttttctcgt 15219
<210> 13
<211> 15219
<212> DNA
<213> respiratory syncytial virus
<400> 13
acgggaaaaa aatgcgtact acaaacttgc acattcgaaa aaaatggggc aaataagaac 60
ttgataagtg ctatttaagt ctaacctttt caatcagaaa tggggtgcaa ttcactgagc 120
atgataaagg ttagattaca aaatttattt gacaatgacg aagtagcatt gttaaaaata 180
acatgttata ctgataaatt aattcttctg accaatgcat tagccaaagc agcaatacat 240
acaattaaat taaacggcat agtttttata catgttataa caagcagtga agtgtgccct 300
gataacaata ttgtagtgaa atctaacttt acaacaatgc caatactaca aaatggagga 360
tacatatggg aattgattga gttgacacac tgctctcaat taaacggttt aatggatgat 420
aattgtgaaa tcaaattttc taaaagacta agtgactcag taatgactaa ttatatgaat 480
caaatatctg acttacttgg gcttgatctc aattcatgaa ttatgtttag tctaattcaa 540
tagacatgtg tttattacca ttttagttaa tataaaaact catcaaaggg aaatggggca 600
aataaactca cctaatcaat caaaccatga gcactacaaa tgacaacact actatgcaaa 660
gattgatgat cacagacatg agacccctgt caatggattc aataataaca tctcttacca 720
aagaaatcat cacacacaaa ttcatatact tgataaacaa tgaatgtatt gtaagaaaac 780
ttgatgaaag acaagctaca tttacattct tagtcaatta tgagatgaag ctactgcaca 840
aagtagggag taccaaatac aaaaaataca ctgaatataa tacaaaatat ggcactttcc 900
ccatgcctat atttatcaat cacggcgggt ttctagaatg tattggcatt aagcctacaa 960
aacacactcc tataatatac aaatatgacc tcaacccgtg aattccaaca aaaaaaccaa 1020
cccaaccaaa ccaaactatt cctcaaacaa cagtgctcaa tagttaagaa ggagctaatc 1080
cattttagta attaaaaata aaagtaaagc caataacata aattggggca aatacaaaga 1140
68
CA 02323927 2000-09-25
WO 99149017 PCT/US99/06225
tggctcttag caaagtcaag ttgaatgata cattaaataa ggatcagctg ctgtcatcca 1200
gcaaatacac tattcaacgt agtacaggag ataatattga cactcccaat tatgatgtgc 1260
aaaaacacct aaacaaacta tgtggtatgc tattaatcac tgaagatgca aatcataaat 1320
tcacaggatt aataggtatg ttatatgcta tgtccaggtt aggaagggaa gacactataa 1380
agatacttaa agatgctgga tatcatgtta aagctaatgg agtagatata acaacatatc 1440
gtcaagatat aaatggaaag gaaatgaaat tcgaagtatt aacattatca agcttgacat 1500
cagaaataca agtcaatatt gagatagaat ctagaaagtc ctacaaaaaa atgctaaaag 1560
agatgggaga agtggctcca gaatataggc atgattctcc agactgtggg atgataatac 1620
tgtgtatagc tgcacttgtg ataaccaaat tagcagcagg agacagatca ggtcttacag 1680
cagtaattag gagggcaaac aatgtcttaa aaaacgaaat aaaacgatac aagggcctca 1740
taccaaagga tatagctaac agtttttatg aagtgtttga aaaacaccct catcttatag 1800
atgttttcgt gcactttggc attgcacaat catccacaag agggggtagt agagttgaag 1860
gaatctttgc aggattgttt atgaatgcct atggttcagg gcaagtaatg ctaagatggg 1920
gagttttagc caaatctgta aaaaatatca tgctaggaca tgctagtgtc caggcagaaa 1980
tggagcaagt tgtggaagtc tatgagtatg cacagaagtt gggaggagaa gctggattct 2040
accatatatt gaacaatcca aaagcatcat tgctgtcatt aactcaattt cccaacttct 2100
caagtgtggt cctaggcaat gcagcaggtc taggcataat gggagagtat agaggtacac 2160
caagaaacca ggatctttat gatgcagcta aagcatatgc agagcaactc aaagaaaatg 2220
gagtaataaa ctacagtgta ttagacttaa cagcagaaga attggaagcc ataaagcatc 2280
aactcaaccc caaagaagat gatgtagagc tttaagttaa caaaaaatac ggggcaaata 2340
agtcaacatg gagaagtttg cacctgaatt tcatggagaa gatgcaaata acaaagctac 2400
caaattccta gaatcaataa agggcaagtt cgcatcatcc aaagatccta agaagaaaga 2460
tagcataata tctgttaact caatagatat agaagtaact aaagagagcc cgataacatc 2520
tggcaccaac atcatcaatc caacaagtga agccgacagt accccagaaa caaaagccaa 2580
ctacccaaga aaacccctag taagcttcaa agaagatctc accccaagtg acaacccttt 2640
ttctaagttg tacaaggaaa caatagaaac atttgataac aatgaagaag aatctagcta 2700
ctcatatgaa gagataaatg atcaaacaaa tgacaacatt acagcaagac tagatagaat 2760
tgatgaaaaa ttaagtgaaa tattaggaat gctccataca ttagtagttg caagtgcagg 2820
acccacttca gctcgcgatg gaataagaga tgctatggtt ggtctaagag aagagatgat 2880
agaaaaaata agagcggaag cattaatgac caatgatagg ttagaggcta tggcaagact 2940
taggaatgag gaaagcgaaa aaatggcaaa agacacctca gatgaagtgt ctcttaatcc 3000
aacttccaaa aaattgagtg acttgttgga agacaacgat agtgacaatg atctatcact 3060
tgatgatttt tgatcagcga tcaactcact cagcaatcaa caacatcaat aaaacagaca 3120
tcaatccatt gaatcaactg ccagaccgaa caaacaaacg tccatcagta gaaccaccaa 3180
ccaatcaatc aaccaattga tcaatcagca acccgacaaa attaacaata tagtaacaaa 3240
aaaagaacaa gatggggcaa atatggaaac atacgtgaac aagcttcacg aaggctccac 3300
atacacagca gctgttcagt acaatgttct agaaaaagat gatgatcctg catcactaac 3360
aatatgggtg cctatgttcc agtcatctgt gccagcagac ttgctcataa aagaacttgc 3420
aagcatcaat atactagtga agcagatctc tacgcccaaa ggaccttcac tacgagtcac 3480
gattaactca agaagtgctg tgctggctca aatgcctagt aatttcatca taagcgcaaa 3540
tgtatcatta gatgaaagaa gcaaattagc atatgatgta actacacctt gtgaaatcaa 3600
agcatgcagt ctaacatgct taaaagtaaa aagtatgtta actacagtca aagatcttac 3660
catgaagaca ttcaacccca ctcatgagat cattgctcta tgtgaatttg aaaatattat 3720
gacatcaaaa agagtaataa taccaaccta tctaagatca attagtgtca agaacaagga 3780
tctgaactca ctagaaaata tagcaaccac cgaattcaaa aatgctatca ccaatgcaaa 3840
aattattcct tatgcaggat tagtgttagt tatcacagtt actgacaata aaggagcatt 3900
caaatatatc aaaccacaga gtcaatttat agtagatctt ggtgcctacc tagaaaaaga 3960
gagcatatat tatgtgacta ctaattggaa gcatacagct acacgttttt caatcaaacc 4020
69
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
actagaggat taaacttaat tatcaacact gaatgacagg tccacatata tcctcaaact 4080
acacactata tccaaacatc ataaacatct acactacaca cttcatcaca caaaccaatc 4140
ccactcaaaa tccaaaatca ctaccagcca ctatccgcta gacctagagt gcgaataggc 4200
aaataaaacc aaaatatggg gtaaatagac attagttaga gttcaatcaa tcttaacaac 4260
catttatacc gccaattcaa cacatatact ataaatctta aaatgggaaa tacatccatc 4320
acaatagaac tcacaagcaa attttggccc tattttacac taatacatat gatcttaact 4380
ctaatctttt tactaattat aatcactatc atgattgcaa cactaaataa gctaagtgaa 4440
cacaaagcat tctgcaacaa aactcttgaa ctaggacaga tgtaccaaat caacacacag 4500
agttccacca ttatgctgtg tcaaaccata atcctgtata tacaaacaaa caaatccaat 4560
cctctcacag agtcacggtg tcgcaaaacc acgctaacca tcatggtagc atagagtagt 4620
tatttaaaaa ttaacataat gatgaattgt tagtatgaga tcaaaaacaa cattggggca 4680
aatgcaacca tgtccaaaca caagaatcaa cgcactgcca ggactctaga aaagacctgg 4740
gatactctta atcatctaat tgtaatatcc tcttgtttat acagattaaa tttaaaatct 4800
atagcacaaa tagcactatc agttttggca atgataatct caacctctct cataattgca 4860
gccataatat tcatcatctc tgccaatcac aaagttacac taacaacggt cacagttcaa 4920
acaataaaaa accacactga aaaaaacatc accacctacc ctactcaagt ctcaccagaa 4980
agggttagtt catccaagca acccacaacc acatcaccaa tccacacaag ttcagctaca 5040
acatcaccca atacaaaatc agaaacacac catacaacag cacaaaccaa aggcagaacc 5100
accacttcaa cacagaccaa caagccaagc acaaaaccac gtccaaaaaa tccaccaaaa 5160
aaagatgatt accattttga agtgttcaac ttcgttccct gcagtatatg tggcaacaat 5220
caactttgca aatccatctg caaaacaata ccaagcaaca aaccaaagaa gaaaccaacc 5280
atcaaaccca caaacaaacc aaccaccaaa accacaaaca aaagagaccc aaaaacacca 5340
gccaaaacga cgaaaaaaga aactaccacc aacccaacaa aaaaactaac cctcaagacc 5400
acagaaagag acaccagcac ctcacaatcc actgcactcg acacaaccac attaaaacac 5460
acagtccaac agcaatccct cctctcaacc acccccgaaa acacacccaa ctccacacaa 5520
acacccacag catccgagcc ctccacacca aactccaccc aaaaaaccca gccacatgct 5580
tagttattca aaaactacat cttagcagag aaccgtgatc tatcaagcaa gaacgaaatt 5640
aaacctgggg caaataacca tggagttgat gatccacaag tcaagtgcaa tcttcctaac 5700
tcttgctatt aatgcattgt acctcacctc aagtcagaac ataactgagg agttttacca 5760
atcgacatgt agtgcagtta gcagaggtta ttttagtgct ttaagaacag gttggtatac 5820
tagtgtcata acaatagaat taagtaatat aaaagaaacc aaatgcaatg gaactgacac 5880
taaagtaaaa cttatgaaac aagaattaga taagtataag aatgcagtaa cagaattaca 5940
gctacttatg caaaacacac cagctgtcaa caaccgggcc agaagagaag caccacagta 6000
tatgaactac acaatcaata ccactaaaaa cctaaatgta tcaataagca agaagaggaa 6060
acgaagattt ctaggcttct tgttaggtgt gggatctgca atagcaagtg gtatagctgt 6120
atcaaaagtt ctacaccttg aaggagaagt gaacaagatc aaaaatgctt tgttgtctac 6180
aaacaaagct gtagtcagtt tatcaaatgg ggtcagtgtt ttaaccagca aagtgttaga 6240
tctcaagaat tacataaata accaattatt acccatagta aatcaacaga gctgtcgcat 6300
ctccaacatt gaaacagtta tagaattcca gcagaagaac agcagattgt tggaaatcac 6360
cagagaattt agtgtcaatg caggtgtaac aacaccttta agcacttaca tgttgacaaa 6420
cagtgagtta ctatcattaa tcaatgatat gcctataaca aatgatcaga aaaaattaat 6480
gtcaagcaat gttcagatag taaggcaaca aagttattcc atcatgtcta taataaagga 6540
agaagtcctt gcatatgttg tacagctgcc tatctatggt gtaatagata caccttgctg 6600
gaaattgcac acatcgcctc tatgcactac caacatcaaa gaaggatcaa atatttgttt 6660
aacaaggact gatagaggat ggtattgtga taatgcagga tcagtatcct tctttccaca 6720
ggctgacact tgtaaagtac agtccaatcg agtattttgt gacactatga acagtttgac 6780
attaccaagt gaagtcagcc tttgtaacac tgacatattc aattccaagt atgactgcaa 6840
aattatgaca tcaaaaacag acataagcag ctcagtaatt acttctcttg gagctatagt 6900
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
gtcatgctat ggtaaaacta aatgcactgc atccaacaaa aatcgtggga ttataaagac 6960
attttctaat ggttgtgact atgtgtcaaa caaaggagta gatactgtgt cagtgggcaa 7020
cactttatac tatgtaaaca agctggaagg caagaacctt tatgtaaaag gggaacctat 7080
aataaattac tatgaccctc tagtgtttcc ttctgatgag tttgatgcat caatatctca 7140
agtcaatgaa aaaatcaatc aaagtttagc ttttattcgt agatctgatg aattactaca 7200
taatgtaaat actggcaaat ctactacaaa tattatgata actacaatta ttatagtaat 7260
cattgtagta ttgttatcat taatagctat tggtttactg ttgtattgta aagccaaaaa 7320
cacaccagtt acactaagca aagaccaact aagtggaatc aataatattg cattcagcaa 7380
atagacaaaa aaccacctga tcatgtttca acaacaatct gctgaccacc aatcccaaat 7440
caacttacaa caaatatttc aacatcacag tacaggctga atcatttcct cacatcatgc 7500
tacccacata actaagctag atccttaact tatagttaca taaaaacctc aagtatcaca 7560
atcaaccact aaatcaacac atcattcaca aaattaacag ctggggcaaa tatgtcgcga 7620
agaaatcctt gtaaatttga gattagaggt cattgcttga atggtagaag atgtcactac 7680
agtcataatt actttgaatg gcctcctcat gcattactag tgaggcaaaa cttcatgtta 7740
aacaagatac tcaagtcaat ggacaaaagc atagacactt tgtctgaaat aagtggagct 7800
gctgaactgg atagaacaga agaatatgct cttggtatag ttggagtgct agagagttac 7860
ataggatcta taaacaacat aacaaaacaa tcagcatgtg ttgctatgag taaacttctt 7920
attgagatca atagtgatga cattaaaaag cttagagata atgaagaacc caattcacct 7980
aagataagag tgtacaatac tgttatatca tacattgaga gcaatagaaa aaacaacaag 8040
caaaccatcc atctgctcaa gagactacca gcagacgtgc tgaagaagac aataaagaac 8100
acattagata tccacaaaag cataaccata agcaatccaa aagagtcaac tgtgaatgat 8160
caaaatgacc aaaccaaaaa taatgatatt accggataaa tatccttgta gtatatcatc 8220
catattgatc tcaagtgaaa gcatggttgc tacattcaat cataaaaaca tattacaatt 8280
taaccataac tatttggata accaccagcg tttattaaat catatatttg atgaaattca 8340
ttggacacct aaaaacttat tagatgccac tcaacaattt ctccaacatc ttaacatccc 8400
tgaagatata tatacagtat atatattagt gtcataatgc ttgaccataa cgactctatg 8460
tcatccaacc ataaaactat tttgataagg ttatgggaca aaatggatcc cattattaat 8520
ggaaactctg ctaatgtgta tctaactgat agttatttaa aaggtgttat ctctttttca 8580
gagtgtaatg ctttagggag ttatcttttt aacggccctt atcttaaaaa tgattacacc 8640
aacttaatta gtagacaaag cccactacta gagcatatga atcttaaaaa actaactata 8700
acacagtcat taatatctag atatcataaa ggtgaactga aattagaaga accaacttat 8760
ttccagtcat tacttatgac atataaaagt atgtcctcgt ctgaacaaat tgctacaact 8820
aacttactta aaaaaataat acgaagagcc atagaaataa gtgatgtaaa ggtgtacgcc 8880
atcttgaata aactaggatt aaaggaaaag gacagagtta agcccaacaa taattcaggt 8940
gatgaaaact cagtacttac aaccataatt aaagatgata tactttcggc tgtggaaaac 9000
aatcaatcat atacaaattc agacaaaagt cactcagtaa atcaaaatat cactatcaaa 9060
acaacactct tgaaaaaatt gatgtgttca atgcaacatc ctccatcatg gttaatacac 9120
tggttcaatt tatatacaaa attaaataac atattaacac aatatcgatc aaatgaggta 9180
aaaagtcatg ggtttatatt aatagataat caaactttaa gtggttttca gtttatttta 9240
aatcaatatg gttgtatcgt ttatcataaa ggactcaaaa aaatcacaac tactacttac 9300
aatcaatttt tgacatggaa agacatcagc cttagcagat taaatgtttg cttaattact 9360
tggataagta attgtttaaa tacattaaac aaaagcttag ggctgagatg tggattcaat 9420
aatgttgtgt tatcacaatt atttctttat ggagattgta tactgaaatt atttcataat 9480
gaaggcttct acataataaa agaagtagag ggatttatta tgtctttaat tctaaacata 9540
acagaagaag atcaatttaa gaaacgattt tataatagca tgctaaataa catcacagat 9600
gcagctatta aggctcaaaa ggacctacta tcaagagtat gtcacacttt attagacaag 9660
acagtgtctg ataatatcat aaatggtaaa tggataatcc tattaagtaa atttcttaaa 9720
ttgattaagc ttgcaggtga taataatctc aataacttga gtgagctata ttttctcttc 9780
71
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
agaatctttg gacatccaat ggtcgatgaa agacaagcaa tggattctgt aagaattaac 9840
tgtaatgaaa ctaagttcta cttattaagt agtctaagta cattaagagg tgctttcatt 9900
tatagaatca taaaagggtt tgtaaatacc tacaacagat ggcccacctt aaggaatgct 9960
attgtcctac ctctaagatg gttaaactac tataaactta atacttatcc atctctactt 10020
gaaatcacag aaaatgattt gattatttta tcaggattgc ggttctatcg tgagtttcat 10080
ctgcctaaaa aagtggatct tgaaatgata ataaatgaca aagccatttc acctccaaaa 10140
gatctaatat ggactagttt tcctagaaat tacatgccat cacatataca aaattatata 10200
gaacatgaaa agttgaagtt ctctgaaagc gacagatcga gaagagtact agagtattac 10260
ttgagagata ataaattcaa tgaatgcgat ctatacaatt gtgtagtcaa tcaaagctat 10320
ctcaacaact ctaatcacgt ggtatcacta actggtaaag aaagagagct cagtgtaggt 10380
agaatgtttg ctatgcaacc aggtatgttt aggcaaatcc aaatcttagc agagaaaatg 10440
atagctgaaa atattttaca attcttccct gagagtttga caagatatgg tgatctagag 10500
cttcaaaaga tattagaatt aaaagcagga ataagcaaca agtcaaatcg ttataatgat 10560
aactacaaca attatatcag taaatgttct atcattacag atcttagcaa attcaatcag 10620
gcatttagat atgaaacatc atgtatctgc agtgatgtat tagatgaact gcatggagta 10680
caatctctgt tctcttggtt gcatttaaca atacctcttg tcacaataat atgtacatat 10740
agacatgcac ctcctttcat aaaggatcat gttgttaatc ttaatgaggt tgatgaacaa 10800
agtggattat acagatatca tatgggtggt attgagggct ggtgtcaaaa actgtggacc 10860
attgaagcta tatcattatt agatctaata tctctcaaag ggaaattctc tatcacagct 10920
ctgataaatg gtgataatca gtcaattgat ataagcaaac cagttagact tatagagggt 10980
cagacccatg cacaagcaga ttatttgtta gcattaaata gccttaaatt gttatataaa 11040
gagtatgcag gtataggcca taagcttaag ggaacagaga cctatatatc ccgagatatg 11100
cagttcatga gcaaaacaat ccagcacaat ggagtgtact atccagccag tatcaaaaaa 11160
gtcctgagag taggtccatg gataaacacg atacttgatg attttaaagt tagtttagaa 11220
tctataggca gcttaacaca ggagttagaa tacagaggag aaagcttatt atgcagttta 11280
atatttagga acatttggtt atacaatcaa attgctttgc aactccgaaa tcatgcatta 11340
tgtaacaata agctatattt agatatattg aaagtattaa aacacttaaa aacttttttt 11400
aatcttgata gcattgatat ggctttatca ttgtatatga atttgcctat gctgtttggt 11460
ggtggtgatc ctaatttgtt atatcgaagc ttttatagga gaactccaga cttccttaca 11520
gaagctatag tacattcagt gtttgtgttg agctattata ctggtcacga tttacaagat 11580
aagctccagg atcttccaga tgatagactg aacaaattct tgacatgtgt catcacattt 11640
gataaaaatc ccaatgccga gtttgtaaca ttgatgaggg atccacaggc tttagggtct 11700
gaaaggcaag ctaaaattac tagtgagatt aatagattag cagtaacaga agtcttaagt 11760
atagccccaa acaaaatatt ttctaaaagt gcacaacatt atactaccac tgagattgat 11820
ctaaatgaca ttatgcaaaa tatagaacca acttaccctc atggattaag agttgtttat 11880
gaaagtttac ctttttataa agcagaaaaa atagttaatc ttatatcagg aacaaaatcc 11940
ataactaata tacttgaaaa aacatcagca atagatacaa ctgatattaa tagggctact 12000
gatatgatga ggaaaaatat aactttactt ataaggatac ttccactaga ttgtaacaaa 12060
gacaaaagag agttattaag tttagaaaat cttagtataa ctgaattaag caagtatgta 12120
agagaaagat cttggtcatt atccaatata gtaggagtaa catcgccaag tattatgttc 12180
acaatgaaca ttaaatatac aactagcact atagccagtg gtataataat agaaaaatat 12240
aatgttaata gtttaactcg tggtgaaaga ggacccacca.agccatgggt aggctcatcc 12300
acgcaggaga aaaaaacaat gccagtgtac aacagacaag ttttaaccaa aaagcaaaga 12360
gaccaaatag atttattagc aaaattagac tgggtatatg catccataga caacaaagat 12420
gaattcatgg aagaactgag tactggaaca cttggactgt catatgaaaa agccaaaaag 12480
ttgtttccac aatatctaag tgtcaattat ttacaccgtt taacagtcag tagtagacca 12540
tgtgaattcc ctgcatcaat accagcttat agaacaacaa attatcattt tgatactagt 12600
cctatcaatc atgtattaac agaaaagtat ggagatgaag atatcgacat tgtgtttcaa 12660
72
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
aattgcataa gttttggtct tagcctgatg tcggttgtgg aacaattcac aaacatatgt 12720
cctaatagaa ttattctcat accgaagctg aatgagatac atttgatgaa acctcctata 12780
tttacaggag atgttgatat catcaagttg aagcaagtga tacaaaagca gcacatgttc 12840
ctaccagata aaataagttt aacccaatat gtagaattat tcttaagtaa caaagcactt 12900
aaatctggat ctcacatcaa ctctaattta atattagtac ataaaatgtc tgattatttt 12960
cataatgctt atattttaag tactaattta gctggacatt ggattctgat tattcaactt 13020
atgaaagatt caaaaggtat ttttgaaaaa gattggggag aggggtacat aactgatcat 13080
atgttcatta atttgaatgt tttctttaat gcttataaga cttatttgct atgttttcat 13140
aaaggttatg gtaaagcaaa attagaatgt gatatgaaca cttcagatct tctttgtgtt 13200
ttggagttaa tagacagtag ctactggaaa tctatgtcta aagttttcct agaacaaaaa 13260
gtcataaaat acatagtcaa tcaagacaca agtttgcgta gaataaaagg ctgtcacagt 13320
tttaagttgt ggtttttaaa acgccttaat aatgctaaat ttaccgtatg cccttgggtt 13380
gttaacatag attatcaccc aacacacatg aaagctatat tatcttacat agatttagtt 13440
agaatggggt taataaatgt agataaatta accattaaaa ataaaaacaa attcaatgat 13500
gaattttaca catcaaatct cttttacatt agttataact tttcagacaa cactcatttg 13560
ctaacaaaac aaataagaat tgctaattca gaattagaag ataattataa caaactatat 13620
cacccaaccc cagaaacttt agaaaatatg tcattaattc ctgttaaaag taataatagt 13680
aacaaaccta aattttgtat aagtggaaat accgaatcta tgatgatgtc aacattctct 13740
agtaaaatgc atattaaatc ttccactgtt accacaagat tcaattatag caaacaagac 13800
ttgtacaatt tatttccaat tgttgtgata gacaagatta tagatcattc aggtaataca 13860
gcaaaatcta accaacttta caccaccact tcacatcaga catctttagt aaggaatagt 13920
gcatcacttt attgcatgct tccttggcat catgtcaata gatttaactt tgtatttagt 13980
tccacaggat gcaagatcag tatagagtat attttaaaag atcttaagat taaggacccc 14040
agttgtatag cattcatagg tgaaggagct ggtaacttat tattacgtac ggtagtagaa 14100
cttcatccag acataagata catttacaga agtttaaaag attgcaatga tcatagttta 14160
cctattgaat ttctaaggtt atacaacggg catataaaca tagattatgg tgagaattta 14220
accattcctg ctacagatgc aactaataac attcattggt cttatttaca tataaaattt 14280
gcagaaccta ttagcatctt tgtctgcgat gctgaattac ctgttacagc caattggagt 14340
aaaattataa ttgaatggag taagcatgta agaaagtgca agtactgttc ttctgtaaat 14400
agatgcattt taattgcaaa atatcatgct caagatgaca ttgatttcaa attagataac 14460
attactatat taaaaactta cgtgtgccta ggtagcaagt taaaaggatc tgaagtttac 14520
ttaatcctta caataggccc tgcaaatata cttcctgttt ttgatgttgt acaaaatgct 14580
aaattgatac tttcaagaac taaaaatttc attatgccta aaaaaactga caaggaatct 14640
atcgatgcaa atattaaaag cttaatacct ttcctttgtt accctataac aaaaaaagga 14700
attaagactt cattgtcaaa attgaagagt gtagttaatg gagatatatt atcatattct 14760
atagctggac gtaatgaagt attcagcaac aagcttataa accacaagca tatgaatatc 14820
ctaaaatggc tagatcatgt tttaaatttt agatcagctg aacttaatta caatcattta 14880
tacatgatag agtccacata tccttactta agtgaattgt taaatagttt aacaaccaat 14940
gagctcaaga agctgattaa aataacaggt agtgtgctat acaaccttcc caacgaacag 15000
tagtttaaaa tatcattaac aagtttggtc aaatttagat gctaacacat cattatatta 15060
tagttattaa agaatataca aacttttcaa taatttagca tattgattcc aaaattatca 15120
ttttagtctt aaggggttaa ataaaagtct aaaactaaca attatacatg tgcattcaca 15180
acacaacgag acattagttt ttgacacttt ttttctcgt 15219
<210> 14
<211> 15219
<212> DNA
<213> respiratory syncytial virus
73
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WO 99/49017 PCT/US99/06225
<400> 14
acgggaaaaa aatgcgtact acaaacttgc acattcgaaa aaaatggggc aaataagaac 60
ttgataagtg ctatttaagt ctaacctttt caatcagaaa tggggtgcaa ttcactgagc 120
atgataaagg ttagattaca aaatttattt gacaatgacg aagtagcatt gttaaaaata 180
acatgttata ctgataaatt aattcttctg accaatgcat tagccaaagc agcaatacat 240
acaattaaat taaacggcat agtttttata catgttataa caagcagtga agtgtgccct 300
gataacaata ttgtagtgaa atctaacttt acaacaatgc caatactaca aaatggagga 360
tacatatggg aattgattga gttgacacac tgctctcaat taaacggttt aatggatgat 420
aattgtgaaa tcaaattttc taaaagacta agtgactcag taatgactaa ttatatgaat 480
caaatatctg acttacttgg gcttgatctc aattcatgaa ttatgtttag tctaattcaa 540
tagacatgtg tttattacca ttttagttaa tataaaaact catcaaaggg aaatggggca 600
aataaactca cctaatcaat caaaccatga gcactacaaa tgacaacact actatgcaaa 660
gattgatgat cacagacatg agacccctgt caatggattc aataataaca tctcttacca 720
aagaaatcat cacacacaaa ttcatatact tgataaacaa tgaatgtatt gtaagaaaac 780
ttgatgaaag acaagctaca tttacattct tagtcaatta tgagatgaag ctactgcaca 840
aagtagggag taccaaatac aaaaaataca ctgaatataa tacaaaatat ggcactttcc 900
ccatgcctat atttatcaat cacggcgggt ttctagaatg tattggcatt aagcctacaa 960
aacacactcc tataatatac aaatatgacc tcaacccgtg aattccaaca aaaaaaccaa 1020
cccaaccaaa ccaaactatt cctcaaacaa cagtgctcaa tagttaagaa ggagctaatc 1080
cattttagta attaaaaata aaagtaaagc caataacata aattggggca aatacaaaga 1140
tggctcttag caaagtcaag ttgaatgata cattaaataa ggatcagctg ctgtcatcca 1200
gcaaatacac tattcaacgt agtacaggag ataatattga cactcccaat tatgatgtgc 1260
aaaaacacct aaacaaacta tgtggtatgc tattaatcac tgaagatgca aatcataaat 1320
tcacaggatt aataggtatg ttatatgcta tgtccaggtt aggaagggaa gacactataa 1380
agatacttaa agatgctgga tatcatgtta aagctaatgg agtagatata acaacatatc 1440
gtcaagatat aaatggaaag gaaatgaaat tcgaagtatt aacattatca agcttgacat 1500
cagaaataca agtcaatatt gagatagaat ctagaaagtc ctacaaaaaa atgctaaaag 1560
agatgggaga agtggctcca gaatataggc atgattctcc agactgtggg atgataatac 1620
tgtgtatagc tgcacttgtg ataaccaaat tagcagcagg agacagatca ggtcttacag 1680
cagtaattag gagggcaaac aatgtcttaa aaaacgaaat aaaacgatac aagggcctca 1740
taccaaagga tatagctaac agtttttatg aagtgtttga aaaacaccct catcttatag 1800
atgttttcgt gcactttggc attgcacaat catccacaag agggggtagt agagttgaag 1860
gaatctttgc aggattgttt atgaatgcct atggttcagg gcaagtaatg ctaagatggg 1920
gagttttagc caaatctgta aaaaatatca tgctaggaca tgctagtgtc caggcagaaa 1980
tggagcaagt tgtggaagtc tatgagtatg cacagaagtt gggaggagaa gctggattct 2040
accatatatt gaacaatcca aaagcatcat tgctgtcatt aactcaattt cccaacttct 2100
caagtgtggt cctaggcaat gcagcaggtc taggcataat gggagagtat agaggtacac 2160
caagaaacca ggatctttat gatgcagcta aagcatatgc agagcaactc aaagaaaatg 2220
gagtaataaa ctacagtgta ttagacttaa cagcagaaga attggaagcc ataaagcatc 2280
aactcaaccc caaagaagat gatgtagagc tttaagttaa caaaaaatac ggggcaaata 2340
agtcaacatg gagaagtttg cacctgaatt tcatggagaa gatgcaaata acaaagctac 2400
caaattccta gaatcaataa agggcaagtt cgcatcatcc aaagatccta agaagaaaga 2460
tagcataata tctgttaact caatagatat agaagtaact aaagagagcc cgataacatc 2520
tggcaccaac atcatcaatc caacaagtga agccgacagt accccagaaa caaaagccaa 2580
ctacccaaga aaacccctag taagcttcaa agaagatctc accccaagtg acaacccttt 2640
ttctaagttg tacaaggaaa caatagaaac atttgataac aatgaagaag aatctagcta 2700
ctcatatgaa gagataaatg atcaaacaaa tgacaacatt acagcaagac tagatagaat 2760
74
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tgatgaaaaa ttaagtgaaa tattaggaat gctccataca ttagtagttg caagtgcagg 2820
acccacttca gctcgcgatg gaataagaga tgctatggtt ggtctaagag aagagatgat 2880
agaaaaaata agagcggaag cattaatgac caatgatagg ttagaggcta tggcaagact 2940
taggaatgag gaaagcgaaa aaatggcaaa agacacctca gatgaagtgt ctcttaatcc 3000
aacttccaaa aaattgagtg acttgttgga agacaacgat agtgacaatg atctatcact 3060
tgatgatttt tgatcagcga tcaactcact cagcaatcaa caacatcaat aaaacagaca 3120
tcaatccatt gaatcaactg ccagaccgaa caaacaaacg tccatcagta gaaccaccaa 3180
ccaatcaatc aaccaattga tcaatcagca acccgacaaa attaacaata tagtaacaaa 3240
aaaagaacaa gatggggcaa atatggaaac atacgtgaac aagcttcacg aaggctccac 3300
atacacagca gctgttcagt acaatgttct agaaaaagat gatgatcctg catcactaac 3360
aatatgggtg cctatgttcc agtcatctgt gccagcagac ttgctcataa aagaacttgc 3420
aagcatcaat atactagtga agcagatctc tacgcccaaa ggaccttcac tacgagtcac 3480
gattaactca agaagtgctg tgctggctca aatgcctagt aatttcatca taagcgcaaa 3540
tgtatcatta gatgaaagaa gcaaattagc atatgatgta actacacctt gtgaaatcaa 3600
agcatgcagt ctaacatgct taaaagtaaa aagtatgtta actacagtca aagatcttac 3660
catgaagaca ttcaacccca ctcatgagat cattgctcta tgtgaatttg aaaatattat 3720
gacatcaaaa agagtaataa taccaaccta tctaagatca attagtgtca agaacaagga 3780
tctgaactca ctagaaaata tagcaaccac cgaattcaaa aatgctatca ccaatgcaaa 3840
aattattcct tatgcaggat tagtgttagt tatcacagtt actgacaata aaggagcatt 3900
caaatatatc aaaccacaga gtcaatttat agtagatctt ggtgcctacc tagaaaaaga 3960
gagcatatat tatgtgacta ctaattggaa gcatacagct acacgttttt caatcaaacc 4020
actagaggat taaacttaat tatcaacact gaatgacagg tccacatata tcctcaaact 4080
acacactata tccaaacatc ataaacatct acactacaca cttcatcaca caaaccaatc 4140
ccactcaaaa tccaaaatca ctaccagcca ctatctgcta gacctagagt gcgaataggt 4200
aaataaaacc aaaatatggg gtaaatagac attagttaga gttcaatcaa tcttaacaac 4260
catttatacc gccaattcaa cacatatact ataaatctta aaatgggaaa tacatccatc 4320
acaatagaat tcacaagcaa attttggccc tattttacac taatacatat gatcttaact 4380
ctaatctttt tactaattat aatcactatt atgattgcaa tactaaataa gctaagtgaa 4440
cataaagcat tctgtaacaa aactcttgaa ctaggacaga tgtatcaaat caacacatag 4500
agttctacca ttatgctgtg tcaaattata atcctgtata tataaacaaa caaatccaat 4560
cttctcacag agtcatggtg tcgcaaaacc acgctaacta tcatggtagc atagagtagt 4620
tatttaaaaa ttaacataat gatgaattgt tagtatgaga tcaaaaacaa cattggggca 4680
aatgcaacca tgtccaaaca caagaatcaa cgcactgcca ggactctaga aaagacctgg 4740
gatactctta atcatctaat tgtaatatcc tcttgtttat acagattaaa tttaaaatct 4800
atagcacaaa tagcactatc agttttggca atgataatct caacctctct cataattgca 4860
gccataatat tcatcatctc tgccaatcac aaagttacac taacaacggt cacagttcaa 4920
acaataaaaa accacactga aaaaaacatc accacctacc ctactcaagt ctcaccagaa 4980
agggttagtt catccaagca acccacaacc acatcaccaa tccacacaag ttcagctaca 5040
acatcaccca atacaaaatc agaaacacac catacaacag cacaaaccaa aggcagaacc 5100
accacttcaa cacagaccaa caagccaagc acaaaaccac gtccaaaaaa tccaccaaaa 5160
aaagatgatt accattttga agtgttcaac ttcgttccct gcagtatatg tggcaacaat 5220
caactttgca aatccatctg caaaacaata ccaagcaaca aaccaaagaa gaaaccaacc 5280
atcaaaccca caaacaaacc aaccaccaaa accacaaaca aaagagaccc aaaaacacca 5340
gccaaaacga cgaaaaaaga aactaccacc aacccaacaa aaaaactaac cctcaagacc 5400
acagaaagag acaccagcac ctcacaatcc actgcactcg acacaaccac attaaaacac 5460
acagtccaac agcaatccct cctctcaacc acccccgaaa acacacccaa ctccacacaa 5520
acacccacag catccgagcc ctccacacca aactccaccc aaaaaaccca gccacatgct 5580
tagttattca aaaactacat cttagcagag aaccgtgatc tatcaagcaa gaacgaaatt 5640
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
aaacctgggg caaataacca tggagttgat gatccacaag tcaagtgcaa tcttcctaac 5700
tcttgctatt aatgcattgt acctcacctc aagtcagaac ataactgagg agttttacca 5760
atcgacatgt agtgcagtta gcagaggtta ttttagtgct ttaagaacag gttggtatac 5820
tagtgtcata acaatagaat taagtaatat aaaagaaacc aaatgcaatg gaactgacac 5880
taaagtaaaa cttatgaaac aagaattaga taagtataag aatgcagtaa cagaattaca 5940
gctacttatg caaaacacac cagctgtcaa caaccgggcc agaagagaag caccacagta 6000
tatgaactac acaatcaata ccactaaaaa cctaaatgta tcaataagca agaagaggaa 6060
acgaagattt ctaggcttct tgttaggtgt gggatctgca atagcaagtg gtatagctgt 6120
atcaaaagtt ctacaccttg aaggagaagt gaacaagatc aaaaatgctt tgttgtctac 6180
aaacaaagct gtagtcagtt tatcaaatgg ggtcagtgtt ttaaccagca aagtgttaga 6240
tctcaagaat tacataaata accaattatt acccatagta aatcaacaga gctgtcgcat 6300
ctccaacatt gaaacagtta tagaattcca gcagaagaac agcagattgt tggaaatcac 6360
cagagaattt agtgtcaatg caggtgtaac aacaccttta agcacttaca tgttgacaaa 6420
cagtgagtta ctatcattaa tcaatgatat gcctataaca aatgatcaga aaaaattaat 6480
gtcaagcaat gttcagatag taaggcaaca aagttattcc atcatgtcta taataaagga 6540
agaagtcctt gcatatgttg tacagctgcc tatctatggt gtaatagata caccttgctg 6600
gaaattgcac acatcgcctc tatgcactac caacatcaaa gaaggatcaa atatttgttt 6660
aacaaggact gatagaggat ggtattgtga taatgcagga tcagtatcct tctttccaca 6720
ggctgacact tgtaaagtac agtccaatcg agtattttgt gacactatga acagtttgac 6780
attaccaagt gaagtcagcc tttgtaacac tgacatattc aattccaagt atgactgcaa 6840
aattatgaca tcaaaaacag acataagcag ctcagtaatt acttctcttg gagctatagt 6900
gtcatgctat ggtaaaacta aatgcactgc atccaacaaa aatcgtggga ttataaagac 6960
attttctaat ggttgtgact atgtgtcaaa caaaggagta gatactgtgt cagtgggcaa 7020
cactttatac tatgtaaaca agctggaagg caagaacctt tatgtaaaag gggaacctat 7080
aataaattac tatgaccctc tagtgtttcc ttctgatgag tttgatgcat caatatctca 7140
agtcaatgaa aaaatcaatc aaagtttagc ttttattcgt agatctgatg aattactaca 7200
taatgtaaat actggcaaat ctactacaaa tattatgata actacaatta ttatagtaat 7260
cattgtagta ttgttatcat taatagctat tggtttactg ttgtattgta aagccaaaaa 7320
cacaccagtt acactaagca aagaccaact aagtggaatc aataatattg cattcagcaa 7380
atagacaaaa aaccacctga tcatgtttca acaacaatct gctgaccacc aatcccaaat 7440
caacttacaa caaatatttc aacatcacag tacaggctga atcatttcct cacatcatgc 7500
tacccacata actaagctag atccttaact tatagttaca taaaaacctc aagtatcaca 7560
atcaaccact aaatcaacac atcattcaca aaattaacag ctggggcaaa tatgtcgcga 7620
agaaatcctt gtaaatttga gattagaggt cattgcttga atggtagaag atgtcactac 7680
agtcataatt actttgaatg gcctcctcat gcattactag tgaggcaaaa cttcatgtta 7740
aacaagatac tcaagtcaat ggacaaaagc atagacactt tgtctgaaat aagtggagct 7800
gctgaactgg atagaacaga agaatatgct cttggtatag ttggagtgct agagagttac 7860
ataggatcta taaacaacat aacaaaacaa tcagcatgtg ttgctatgag taaacttctt 7920
attgagatca atagtgatga cattaaaaag cttagagata atgaagaacc caattcacct 7980
aagataagag tgtacaatac tgttatatca tacattgaga gcaatagaaa aaacaacaag 8040
caaaccatcc atctgctcaa gagactacca gcagacgtgc tgaagaagac aataaagaac 8100
acattagata tccacaaaag cataaccata agcaatccaa aagagtcaac tgtgaatgat 8160
caaaatgacc aaaccaaaaa taatgatatt accggataaa tatccttgta gtatatcatc 8220
catattgatc tcaagtgaaa gcatggttgc tacattcaat cataaaaaca tattacaatt 8280
taaccataac tatttggata accaccagcg tttattaaat catatatttg atgaaattca 8340
ttggacacct aaaaacttat tagatgccac tcaacaattt ctccaacatc ttaacatccc 8400
tgaagatata tatacagtat atatattagt gtcataatgc ttgaccataa cgactctatg 8460
tcatccaacc ataaaactat tttgataagg ttatgggaca aaatggatcc cattattaat 8520
76
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ggaaactctg ctaatgtgta tctaactgat agttatttaa aaggtgttat ctctttttca 8580
gagtgtaatg ctttagggag ttatcttttt aacggccctt atcttaaaaa tgattacacc 8640
aacttaatta gtagacaaag cccactacta gagcatatga atcttaaaaa actaactata 8700
acacagtcat taatatctag atatcataaa ggtgaactga aattagaaga accaacttat 8760
ttccagtcat tacttatgac atataaaagt atgtcctcgt ctgaacaaat tgctacaact 8820
aacttactta aaaaaataat acgaagagcc atagaaataa gtgatgtaaa ggtgtacgcc 8880
atcttgaata aactaggatt aaaggaaaag gacagagtta agcccaacaa taattcaggt 8940
gatgaaaact cagtacttac aactataatt aaagatgata tactttcggc tgtggaaaac 9000
aatcaatcat atacaaattc agacaaaagt cactcagtaa atcaaaatat cactatcaaa 9060
acaacactct tgaaaaaatt gatgtgttca atgcaacatc ctccatcatg gttaatacac 9120
tggttcaatt tatatacaaa attaaataac atattaacac aatatcgatc aaatgaggta 9180
aaaagtcatg ggtttatatt aatagataat caaactttaa gtggttttca gtttatttta 9240
aatcaatatg gttgtatcgt ttatcataaa ggactcaaaa aaatcacaac tactacttac 9300
aatcaatttt tgacatggaa agacatcagc cttagcagat taaatgtttg cttaattact 9360
tggataagta attgtttaaa tacattaaac aaaagcttag ggctgagatg tggattcaat 9420
aatgttgtgt tatcacaatt atttctttat ggagattgta tactgaaatt atttcataat 9480
gaaggcttct acataataaa agaagtagag ggatttatta tgtctttaat tctaaacata 9540
acagaagaag atcaatttag gaaacgattt tataatagca tgctaaataa catcacagat 9600
gcagctatta aggctcaaaa ggacctacta tcaagagtat gtcacacttt attagacaag 9660
acagtgtctg ataatatcat aaatggtaaa tggataatcc tattaagtaa atttcttaaa 9720
ttgattaagc ttgcaggtga taataatctc aataacttga gtgagctata ttttctcttc 9780
agaatctttg gacatccaat ggtcgatgaa agacaagcaa tggattctgt aagaattaac 9840
tgtaatgaaa ctaagttcta cttattaagt agtctaagta cattaagagg tgctttcatt 9900
tatagaatca taaaagggtt tgtaaatacc tacaacagat ggcccacctt aaggaatgct 9960
attgtcctac ctctaagatg gttaaactac tataaactta atacttatcc atctctactt 10020
gaaatcacag aaaatgattt gattatttta tcaggattgc ggttctatcg tgagtttcat 10080
ctgcctaaaa aagtggatct tgaaatgata ataaatgaca aagccatttc acctccaaaa 10140
gatctaatat ggactagttt tcctagaaat tacatgccat cacatataca aaattatata 10200
gaacatgaaa agttgaagtt ctctgaaagc gacagatcga gaagagtact agagtattac 10260
ttgagagata ataaattcaa tgaatgcgat ctatacaatt gtgtagtcaa tcaaagctat 10320
ctcaacaact ctaatcacgt ggtatcacta actggtaaag aaagagagct cagtgtaggt 10380
agaatgtttg ctatgcaacc aggtatgttt aggcaaatcc aaatcttagc agagaaaatg 10440
atagctgaaa atattttaca attcttccct gagagtttga caagatatgg tgatctagag 10500
cttcaaaaga tattagaatt aaaagcagga ataagcaaca agtcaaatcg ttataatgat 10560
aactacaaca attatatcag taaatgttct atcattacag atcttagcaa attcaatcag 10620
gcatttagat atgaaacatc atgtatctgc agtgatgtat tagatgaact gcatggagta 10680
caatctctgt tctcttggtt gcatttaaca atacctcttg tcacaataat atgtacatat 10740
agacatgcac ctcctttcat aaaggatcat gttgttaatc ttaatgaggt tgatgaacaa 10800
agtggattat acagatatca tatgggtggt attgagggct ggtgtcaaaa actgtggacc 10860
attgaagcta tatcattatt agatctaata tctctcaaag ggaaattctc tatcacagct 10920
ctgataaatg gtgataatca gtcaattgat ataagcaaac cagttagact tatagagggt 10980
cagacccatg cacaagcaga ttatttgtta gcattaaata gccttaaatt gttatataaa 11040
gagtatgcag gtataggcca taagcttaag ggaacagaga cctatatatc ccgagatatg 11100
cagttcatga gcaaaacaat ccagcacaat ggagtgtact atccagccag tatcaaaaaa 11160
gtcctgagag taggtccatg gataaacacg atacttgatg attttaaagt tagtttagaa 11220
tctataggca gcttaacaca ggagttagaa tacagaggag aaagcttatt atgcagttta 11280
atatttagga acatttggtt atacaatcaa attgctttgc aactccgaaa tcatgcatta 11340
tgtaacaata agctatattt agatatattg aaagtattaa aacacttaaa aacttttttt 11400
77
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WO 99/49017 PCT/US99/06225
aatcttgata gcattgatat ggctttatca ttgtatatga atttgcctat gctgtttggt 11460
ggtggtgatc ctaatttgtt atatcgaagc ttttatagga gaactccaga cttccttaca 11520
gaagctatag tacattcagt gtttgtgttg agctattata ctggtcacga tttacaagat 11580
aagctccagg atcttccaga tgatagactg aacaaattct tgacatgtgt catcacattt 11640
gataaaaatc ccaatgccga gtttgtaaca ttgatgaggg atccacaggc tttagggtct 11700
gaaaggcaag ctaaaattac tagtgagatt aatagattag cagtaacaga agtcttaagt 11760
atagccccaa acaaaatatt ttctaaaagt gcacaacatt atactaccac tgagattgat 11820
ctaaatgaca ttatgcaaaa tatagaacca acttaccctc atggattaag agttgtttat 11880
gaaagtttac ctttttataa agcagaaaaa atagttaatc ttatatcagg aacaaaatcc 11940
ataactaata tacttgaaaa aacatcagca atagatacaa ctgatattaa tagggctact 12000
gatatgatga ggaaaaatat aactttactt ataaggatac ttccactaga ttgtaacaaa 12060
gacaaaagag agttattaag tttagaaaat cttagtataa ctgaattaag caagtatgta 12120
agagaaagat cttggtcatt atccaatata gtaggagtaa catcgccaag tattatgttc 12180
acaatggaca ttaaatatac aactagcact atagccagtg gtataataat agaaaaatat 12240
aatgttaata gtttaactcg tggtgaaaga ggacccacca agccatgggt aggctcatcc 12300
acgcaggaga aaaaaacaat gccagtgtac aacagacaag ttttaaccaa aaagcaaaga 12360
gaccaaatag atttattagc aaaattagac tgggtatatg catccataga caacaaagat 12420
gaattcatgg aagaactgag tactggaaca cttggactgt catatgaaaa agccaaaaag 12480
ttgtttccac aatatctaag tgtcaattat ttacaccgtt taacagtcag tagtagacca 12540
tgtgaattcc ctgcatcaat accagcttat agaacaacaa attatcattt tgatactagt 12600
cctatcaatc atgtattaac agaaaagtat ggagatgaag atatcgacat tgtgtttcaa 12660
aattgcataa gttttggtct tagcctgatg tcggttgtgg aacaattcac aaacatatgt 12720
cctaatagaa ttattctcat accgaagctg aatgagatac atttgatgaa acctcctata 12780
tttacaggag atgttgatat catcaagttg aagcaagtga tacaaaagca gcacatgttc 12840
ctaccagata aaataagttt aacccaatat gtagaattat tcttaagtaa caaagcactt 12900
aaatctggat ctcacatcaa ctctaattta atattagtac ataaaatgtc tgattatttt 12960
cataatgctt atattttaag tactaattta gctggacatt ggattctgat tattcaactt 13020
atgaaagatt caaaaggtat ttttgaaaaa gattggggag aggggtacat aactgatcat 13080
atgttcatta atttgaatgt tttctttaat gcttataaga cttatttgct atgttttcat 13140
aaaggttatg gtaaagcaaa attagaatgt gatatgaaca cttcagatct tctttgtgtt 13200
ttggagttaa tagacagtag ctactggaaa tctatgtcta aagttttcct agaacaaaaa 13260
gtcataaaat acatagtcaa tcaagacaca agtttgcgta gaataaaagg ctgtcacagt 13320
tttaagttgt ggtttttaaa acgccttgat aatgctaaat ttaccgtatg cccttgggtt 13380
gttaacatag attatcaccc aacacacatg aaagctatat tatcttacat agatttagtt 13440
agaatggggt taataaatgt agataaatta accattaaaa ataaaaacaa attcaatgat 13500
gaattttaca catcaaatct cttttacatt agttataact tttcagacaa cactcatttg 13560
ctaacaaaac aaataagaat tgctaattca gaattagaag ataattataa caaactatat 13620
cacccaaccc cagaaacttt agaaaatatg tcattaattc ctgttaaaag taataatagt 13680
aacaaaccta aattttgtat aagtggaaat accgaatcta tgatgatgtc aacattctct 13740
agtaaaatgc atattaaatc ttccactgtt accacaagat tcaattatag caaacaagac 13800
ttgtacaatt tatttccaat tgttgtgata gacaagatta tagatcattc aggtaataca 13860
gcaaaatcta accaacttta caccaccact tcacatcaga catctttagt aaggaatagt 13920
gcatcacttt attgcatgct tccttggcat catgtcaata gatttaactt tgtatttagt 13980
tccacaggat gcaagatcag tatagagtat attttaaaag atcttaagat taaggacccc 14040
agttgtatag cattcatagg tgaaggagct ggtaacttat tattacgtac ggtagtagaa 14100
cttcatccag acataagata catttacaga agtttaaaag attgcaatga tcatagttta 14160
cctattgaat ttctaaggtt atacaacggg catataaaca tagattatgg tgagaattta 14220
accattcctg ctacagatgc aactaataac attcattggt cttatttaca tataaaattt 14280
78
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WO 99/49017 PCT/US99/06225
gcagaaccta ttagcatctt tgtctgcgat gctgaattac ctgttacagc caattggagt 14340
aaaattataa ttgaatggag taagcatgta agaaagtgca agtactgttc ttctgtaaat 14400
agatgcattt taattgcaaa atatcatgct caagatgaca ttgatttcaa attagataac 14460
attactatat taaaaactta cgtgtgccta ggtagcaagt taaaaggatc tgaagtttac 14520
ttaatcctta caataggccc tgcaaatata cttcctgttt ttgatgttgt acaaaatgct 14580
aaattgatac tttcaagaac taaaaatttc attatgccta aaaaaactga caaggaatct 14640
atcgatgcag ttattaaaag cttaatacct ttcctttgtt accctataac aaaaaaagga 14700
attaagactt cattgtcaaa attgaagagt gtagttaatg gagatatatt atcatattct 14760
atagctggac gtaatgaagt attcagcaac aagcttataa accacaagca tatgaatatc 14820
ctaaaatggc tagatcatgt tttaaatttt agatcagctg aacttaatta caatcattta 14880
tacatgatag agtccacata tccttactta agtgaattgt taaatagttt aacaaccaat 14940
gagctcaaga agctgattaa aataacaggt agtgtgctat acaaccttcc caacgaacag 15000
tagtttaaaa tatcattaac aagtttggtc aaatttagat gctaacacat cattatatta 15060
tagttattaa aaaatataca aacttttcaa taatttagca tattgattcc aaaattatca 15120
ttttagtctt aaggggttaa ataaaagtct aaaactaaca attatacatg tgcattcaca 15180
acacaacgag acattagttt ttgacacttt ttttctcgt 15219
<210> 15
<211> 24
<212> DNA
<213> Measles virus
<400> 15
catatcactc actctgggat ggag 24
<210> 16
<211> 20
<212> DNA
<213> Measles virus
<400> 16
tcagaacatc aagcaccgcc 20
<210> 17
<211> 20
<212> DNA
<213> Measles virus
<400> 17
acagtcaaga ctgagatgag 20
<210> 18
<211> 20
<212> DNA
<213> Measles virus
<400> 18
aagagtcaga tacatgtgga 20
79
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
<210> 19
<211> 20
<212> DNA
<213> Measles virus
<400> 19
acatgaatca gcctaaagtc 20
<210>20
<211>25
<212>DNA
<213>Measles
virus
<400> 20
ccgaaagagt tcctgcgtta cgacc 25
<210>21
<211>20
<212>DNA
<213>Measles virus'
<400> 21
cagtccacac aagtaccagg 20
<210> 22
<211> 20
<212> DNA
<213> Measles virus
<400> 22
gtcagaagct gtggaccatc 20
<210> 23
<211> 20
<212> DNA
<213> Measles virus
<400> 23
aatattgcta caacaatggc ~ 20
<210>24
<211>20
<212>DNA
<213>Measles
virus
<400> 24
actcttcatt cctagactgg 20
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
<210> 25
<211> 20
<212> DNA
<213> Measles virus
<400> 25
gtccaattat gactatgaac 20
<210> 26
<211> 20
<212> DNA
<213> Measles virus
<400> 26
agaacagaca tgaagcttgc 20
<210> 27
<211> 20
<212> DNA
<213> Measles virus
<400> 27
ccaacaagga atgcttctag 20
<210> 28
<211> 25
<212> DNA
<213> Measles virus
<400> 28
acagcactat ctatgattga cctgg 25
<210>29
<211>20
<212>DNA
<213>Measles
virus
<400> 29
gcaacatggt ttacacatgc 20
<210> 30
<211> 20
<212> DNA
<213> Measles virus
<400> 30
agattgagag ttgatccagg 20
81
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
<210> 31
<211> 20 ' ...
<212> DNA
<213> Measles virus
<400> 31
aggagatact taaactaagc 20
<210>32
<211>20
<212>DNA
<213>Measles
virus
<400> 32
taagcttatg cctttcagcg 20
<210> 33
<211> 20
<212> DNA
<213> Measles virus
<400> 33
ttaacggacc taagctgtgc 20
<210>34
<211>20
<212>DNA
<213>Measles
virus
<400> 34
gaaacagatt attatgacgg 20
<210> 35
<211> 24
<212> DNA
<213> Measles virus
<400> 35
cgggctatct aggtgaactt cagg 24
<210> 36
<211> 20
<212> DNA
<213> Measles virus
<400> 36
atttggatat ggaatatgag
82
CA 02323927 2000-09-25
WO 99/49017 PCT/US99/06225
<210> 37
<211> 20
<212> DNA
<213> Measles virus
<400> 37
actcaactga actaccagtg 20
<210> 3B
<211> 20
<212> DNA
<213> Measles virus
<400> 38
aagaacatca tgtatttcag 20
<210> 39
<211> 20
<212> DNA
<213> Measles virus
<400> 39
ttatcaacgc actgctcatg 20
<210> 40
<211> 25
<212> DNA
<213> Measles virus
<400> 40
attttcagca atcacttggc atgcc 25
<210> 41
<211> 20
<212> DNA
<213> Measles virus
<400> 41
gcctctgtgc aaacaagctg 20
<210> 42
<211> 20
<212> DNA
<213> Measles virus
<400> 42
tctctagtta ctctagcagc 20
83
CA 02323927 2000-09-25
WO 99/49017 PCTNS99/06225
<210>43
<211>20
<212>DNA
<213>Measles
virus
<400> 43
aggtcgttgt ttgtgaggag 20
<210> 44
<211> 20
<212> DNA
<213> Measles virus
<400> 44
tcgtcctctt ctttactgtc 20
<210> 45
<211> 20
<212> DNA
<213> Measles virus
<400> 45
ccgtcctcga gctagcctcg 20
<210> 46
<211> 20
<212> DNA
<213> Measles virus
<400> 46
ctcctccagg ctcacattgg 20
<210> 47
<211> 20
<212> DNA
<213> Measles virus
<400> 47
gggttggtac atagctctgc 20
<210> 48
<211> 25
<212> DNA
<213> Measles virus
<400> 48
cacccatctg atatttccct gatgg 25
84
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WO 99/49017 PCT/US99/06225
<210>49
<211>20
<212>DNA
<213>Measles
virus
<400> 49
tggttgacag tacaaatctg 20
<210> 50
<211> 20
<212> DNA
<213> Measles virus
<400> 50
ctgaaatggg aagattgtgc
<210>51
<211>20
<212>DNA
<213>Measles
virus
<400> 51
agcaatctac actgcctacc 20
<210> 52
<211> 20
<212> DNA
<213> Measles virus
<400> 52
tcacagatga ttcaattatc 20
<210>53
<211>20
<212>DNA
<213>Measles
virus
<400> 53
gatcctagat ataagttctc 20
<210> 54
<211> 21
<212> DNA
<213> Measles virus
<400> 54
accaaacaaa gttgggtaag g 21
CA 02323927 2000-09-25
WO 99/49017 ~ PCT/US99/06225
<210>55
<211>32
<212>DNA
<213>Measles
virus
<400> 55
gggggatcca tccctaatcc tgctcttgtc cc 32
<210>56
<211>20
<212>DNA
<213>Measles
virus
<400> 56
gattcctctg atggctccac 20
<210> 57
<211> 21
<212> DNA
<213> Measles virus
<400> 57
taacagtcaa ggagaccaaa g 21
<210> 58
<211> 32
<212> DNA
<213> Measles virus
<400> 58
gggaagctta accctaatcc tgccctaggt gg 32
<210> 59
<211> 22
<212> DNA
<213> Measles virus
<400> 59
accagacaaa gctgggaata ga 22
86
