AU767193B2 - Mutations responsible for attenuation in measles virus or human respiratory syncytial virus subgroup B - Google Patents

Description

16.SEP. 2003 10:03 SPRUSON FERGUSON 61 2 92615486 NO. 5932 P. 12/16 MUTATIONS RESPONSIBLE FOR ATTENUATION IN MEASLES VIRUS OR HUMAN RESPIRATORY SYNCYTIAL VIRUS SUBGROUP B Field Of The Invention

S

This invention relates to isolated, recombinantly-generated, attenuated measles virus or human respiratory syncytial virus subgroup B having specified attenuating mutations.

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 20 nucleocapsid: as a template for the synthesis of messenger RNAs (mRRAs) and as a template for the n -nthek as of the antigenome strand. Negativesense, single stranded RNA viruses encode and package their own RNA dependent RNA Polymerase. Messenger RNAs are only synthesized once the nucleoaapsid 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 Ssynthesized 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 cisacting signals at the 3* end of the genome, in .particular, the promoter region. Viral genes are then COMS ID No: SMBI-00416777 Received by IP Australia: Time 10:08 Date 2003-09-16 WO 99/49017 PCT/US99/06225 2 transcribed from the genome template unidirectionally from its 3' to its 5' end. There is always less mRNA made from the downstream genes the polymerase gene relative to their upstream neighbors the nucleoprotein gene 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 18mm, 1mm 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, Rubulavirus 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 (SH) in Rubulaviruses.

WO 99/49017 PCT/US99/06225 3 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 that is very different from that of Paramyxovirinae. Although the paramyxoviruses and pneumoviruses have six proteins that appear to correspond in function P, M, G/H/HN, F and 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 NS1 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 Paramvxoviridae 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 WO 99/49017 PCT/US99/06225 4 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 WO 99/49017 PCT/US99/06225 5 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: purified individual viral protein vaccines (subunit vaccines); inactivated whole virus preparations; and 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 formalininactivated 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 It has been WO 99/49017 PCT/US99/06225 6 suggested that this formalinized RSV antigen elicited an abnormal or unbalanced immune response profile, predisposing the vaccinee to RSV disease 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 underattenuated when given to seronegative infants; in some cases, they also were found to lack genetic stability Another vaccination approach using parenteral administration of live virus was ineffective and efforts along this line were discontinued Notably, these live RSV vaccines were never associated with disease enhancement as observed with the formalininactivated 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-l.

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 MHC 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 WO 99/49017 PCT/US99/06225 7 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 diseaseproducing potential 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 WO 99/49017 PCT/US99/06225 8 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 host 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 As a result, vaccineimmunized 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 WO 99/49017 PCT/US99/06225 9 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 16. SEP. 2003 10:04 SPRUSON FERGUSON 61 2 92615486 NO. 5932 P. 13/16 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.

Therefore, according to a first-aspect of this invention there is provided an isolated, recombinantly-generated, attenuated measles virus having one or more attenuating mutations selected from the group consisting of: for the N gene, nucleotide changes which produce a change in the amino acid residue 479 (serine threonine); for the C gene, nucleotide changes which produce a changes in the amino acid residue 104 (methionine -threonine); and for the F gene-end signal, the change at nucleotide 7243 (T C), is where these nucleotides are presented in positive strand, antigenomic, message sense.

According to a second aspect of this invention there is provided an isolated, recombinantly-generated, attenuated human respiratory syncytial virus (RSV) subgroup B having an attenuating mutation in the M gene-end signal at nucleotide 4199 (T C), where these nucleotides are presented in positive strand, antigenomic, message sense.

According to a third aspect of this invention there is provided a vaccine comprising an isolated, recombinantly-generated, attenuated measles virus according to the first aspect and a physiologically acceptable carrier.

S* According to a fourth aspect of this invention there is provided a vaccine comprising an isolated, rccombinantly-generated, attenuated RSV subgroup B according 25 to the second aspect and a physiologically acceptable carrier.

According to a fifth aspect of this invention there is provided a composition which comprises a transcription vector comprising an isolated nucleic acid molecule encoding a genome or antigenome of a measles virus according to the first aspect, together with at least one expression vector which comprises at least one isolated nucleic acid molecule encoding the transacting proteins N, P and L necessary for encapsidation, transcription and replication, whereby upon expression an infectious attenuated virus is produced.

According to a sixth aspect of this invention there is provided a composition which comprises a transcription vector comprising an isolated nucleic acid molecule encoding a genome or antigenome of an RSV subgroup B according to the second aspect, together with at least one expression vector which comprises at least one isolated nucleic acid molecule encoding the transacting proteins N, P, L and M2 necessary for encapsidation, transcription and replication, whereby upon expression an infectious attenuated RSV subgroup B is produced.

[(:\LIuMUV J 77 doS.Jir COMS ID No: SMBI-00416777 Received by IP Australia: Time 10:08 Date 2003-09-16 16. SEP. 2003 10:04 SPRUSON FERGUSON 61 2 92615486 NO. 5932 P. 14/16 11 isolated nucleic acid molecule encoding the transacting proteins N, P, L and M2 necessary for eneapsidation, transcription and replication, whereby upon expression an infectious attenuated RSV subgroup B is produced.

In another embodiment of this invention, these attenuated measles or human rdspiratory syncytial subgroup B viruses are used to prepare vaccines which elicit a protective immune response against the wildtype 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 wildtype 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 20 to prepare vaccines which elicit a protective immune response against the wild-type form of each virus.

e0 BriefDepaription Of The Fiures Figure 1 depicts the passage history of the Edmonston measles virus The abbreviations have the following meanings HK human kidney; HA human amnion; CE(am) chick embryo; CEF chick embryo fibroblastl DK dog kidney; WI-38 human diploid S 30 cells; SK sheep kidney; plaque cloning. The number following each abbreviation represent the number of passages.

Figure 2 depicts a map of the measles virus genome showing putative cia-acting regulatory elements 35 at and near the genome and antigenome termini. Top a COMS ID No: SMBI-00416777 Received by IP Australia: Time 10:08 Date 2003-09-16 WO 99/49017 PCT/US99/06225 12 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 Gene boundaries are denoted by 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 2B 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 2B strain has one more nucleotide in each of the NS-1, 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 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, Bl; lane 4, 2B; lane 5, 2B33F; lane 6, 2B33F lane 7, 18537. Monocistronic M gene WO 99/49017 PCT/US99/06225 13 and bicistronic M:SH gene transcripts are indicated by arrows.

Figure 5 depicts a ribonuclease protection assay of poly RNA extracted from Vero cells infected with RSV subgroup B wild-type 2B, mutant 2B33F, and 2B33F 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 were included as size standards: Lane 1, 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 2Bspecific 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 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, Bl; lane 4, 2B; lane 5, 2B33F; lane 6, 2B33F lane 7, 18537). Monocistronic SH gene and bicistronic M:SH gene transcripts are indicated by arrows.

Detailed Description Of The Invention Transcription and replication of negativesense, single stranded RNA viral genomes are achieved through the enzymatic activity of a multimeric protein WO 99/49017 PCT/US99/06225 14 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 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: a putative RNA template WO 99/49017 PCT/US99/06225 15 recognition and/or phosphodiester bond formation domain; an RNA binding element; and 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 WO 99/49017 PCT/US99/06225 16 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 virulent than the wild-type.

The attenuating mutations described herein may be introduced into viral strains by two methods: 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 attenuation 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 is then carried out.

A preferred means of introducing attenuating mutations comprises making predetermined mutations using site-directed mutagenesis. These mutations are identified either by method 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 B 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 WO 99/49017 PCT/US99/06225 17 the viral genome. This may be a wild-type or a modified viral genome background (such as viruses modified by method 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 measles virus respiratory syncytial virus PIV-3 (21); rabies vesicular stomatitis virus (VSV) and rinderpest virus these references are hereby incorporated by reference. See, for measles virus rescue, published International patent application WO 97/06270, designating the United States for RSV rescue, published International patent application WO 97/12032, designating the United States 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 the T7 RNA polymerase promoter) and a self-cleaving ribozyme sequence 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 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 trans-acting proteins needed to encapsidate the naked, single-stranded viral antigenome or genome RNA WO 99/49017 PCT/US99/06225 18 transcripts into functional nucleocapsid templates: the viral nucleocapsid (N or NP) protein, the polymerase-associated phosphoprotein and the polymerase protein. These proteins comprise the active viral RNA-dependent RNA polymerase which must engage this nucleocapsid template to achieve transcription and replication.

The trans-acting proteins required for measles virus rescue are the encapsidating protein N, and the polymerase complex proteins, P and L. For RSV, the virus-specific trans-acting proteins include N, P and L, plus an additional protein, M2, the RSV-encoded transcription elongation factor.

Typically, these viral trans-acting proteins are generated from one or more plasmid expression vectors encoding the required proteins, although some or all of the required trans-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 polymerase 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 polymerase components produced concurrently from cotransfected expression plasmids encoding the required virus-specific trans-acting proteins. These events and processes lead to the prerequisite transcription of viral mRNAs, the replication and amplification of new WO 99/49017 PCT/US99/06225 19 genomes and, thereby, the production of novel viral progeny, rescue.

For the rescue of rabies, VSV and Sendai, T7 polymerase is provided by recombinant vaccinia virus 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 polymerase, 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 polymerase, 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 polymerase 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 for measles virus, at least one attenuating mutation in the N, P or C genes or the F gene-end signal; and for RSV subgroup B, at least one attenuating mutation in the M gene-end signal, together with at least one expression vector which comprises at WO 99/49017 PCT/US99/06225 20 least one isolated nucleic acid molecule encoding the trans-acting proteins necessary for encapsidation, transcription and replication 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 coexpression 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 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 trans-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 For evaluating attenuation levels of RSV mutants, the WO 99/49017 PCT/US99/06225 21 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 "recombinantlygenerated", 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 cDNA "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 diseasecausing 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 (Attenuvax'; Merck Sharp Dohme, West Point, PA) and was licensed in 1968 and has proven to be efficacious.

WO 99/49017 PCT/US99/06225 22 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. 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 (Rubeovax": Merck Sharp Dohme; this may be the same as the Edmonston B 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) 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 The virion envelope is a host cell-derived plasma membrane modified by three virus-specified proteins: The hemagglutinin (H; approximately 80 kilodaltons and fusion (F 1 2 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 WO 99/49017 PCT/US99/06225 23 infection (35,36,37). The matrix 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 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 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 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 B laboratory strain and the AIK-C vaccine strain), coding potential, and organization of the MV genome had been reported The six virion structural proteins are encoded by six contiguous, non-overlapping genes which are arrayed as follows: 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).

WO 99/49017 PCT/US99/06225 24 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 order, are: a semi-conserved transcription termination/polyadenylation signal (A/G U/C UA A/U NN

A

4 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 WO 99/49017 PCT/US99/06225 25 abundance of each virus-specified protein. This indicates that MV protein expression is ultimately controlled at the transcriptional level 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 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 For measles, these regions encompass the 107 3' genomic nucleotides (the 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 WO 99/49017 PCT/US99/06225 26 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 been 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 WO 99/49017 PCT/US99/06225 27 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 ends No accessory internal CDV genomic domainsharing 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 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, BPV-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 MV 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 trans-acting elements for functionality are WO 99/49017 PCT/US99/06225 28 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.

The attenuation potential in the cis-acting sequence elements and in the trans-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 Independent other wildtype 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 Sequence Wild-Type Edmonston SEQ ID NO:1 1977 SEQ ID NO:2 1983 SEQ ID NO:3 Montefiore SEQ ID NO:4 Vaccine Rubeovax M SEQ ID Moraten SEQ ID NO:6 Zagreb SEQ ID NO:7 WO 99/49017 PCT/US99/06225 29 AIK-C SEQ ID NO: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-end 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 in SEQ ID NO:3. In fact, the base is actually a mixture of and Also note that nucleotide 2143 of Rubeovax" vaccine virus is indicated as in SEQ ID NO:5. In nine clones sequenced, this base was in seven and in two; thus, this base can be or In addition, the Schwarz vaccine virus genome is identical to that of the Moraten vaccine virus genome (SEQ ID NO:6).

An analysis of the coding and noncoding (intercistronic) regions of the MV genome was carried out. Nucleotide and amino acid differences WO 99/49017 PCT/US99/06225 30 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 to an at nucleotide 492 resulted in a mutation from glutamine to lysine at amino acid 129 for the AIK-C vaccine strain; a change from an to a at nucleotide 550 resulted in a mutation from glutamic acid to glycine at amino acid 148 for the Moraten and Schwarz vaccine strains; and a change from a to an at nucleotide 1542 resulted in a mutation from serine to threonine at amino acid 479 for the Rubeovax

T

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 WO 99/49017 PCT/US99/06225 -31 found. It interacts with the polymerase 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. the changes observed in the Edmonston vaccine lineage fall into areas that affect the functionality of the N protein as outlined below: 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.

The change at amino acid 479 (serine to threonine in Rubeovax

T

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 WO 99/49017 PCT/US99/06225 32 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 to 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 However, because this unique mutation is common to all the MV vaccine strains examined, but was not present in the later wild-type isolates, it 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 between nucleotides 2498 and 2499 of the P mRNA. Editing takes place during transcription when an extra non-templatedirected 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 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 to at nucleotide 2630, resulted in a mutation from cysteine to tyrosine at amino acid 275. The third change in the P gene, from to at nucleotide 3122, resulted in a mutation from leucine to proline at WO 99/49017 PCT/US99/06225 33 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 to at nucleotide 2046, resulted in a mutation from alanine to valine at amino acid 73 for all later wildtype 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 to at nucleotide 2139, resulted in a mutation from methionine to threonine at amino acid 104 for the Rubeovax

TM

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 to 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 (in antigenomic, message sense) WO 99/49017 PCT/US99/06225 34 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 whereas the wild-type isolates and the other vaccine strains had a 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 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 ts 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 (serine 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 WO 99/49017 PCT/US99/06225 35 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 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 More recently, the A and B lineages WO 99/49017 PCT/US99/06225 36 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, lower respiratory tract disease (LRD), is most prevalent in infants less than six months of age. It most 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, 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 WO 99/49017 PCT/US99/06225 37 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 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 WO 99/49017 PCT/US99/06225 38 envelope. The virions of pneumoviruses are similar in size and shape to those of all other paramyxoviruses.

When visualized by negative staining and electron microscopy, virions are irregular in shape and range in diameter from 150-300 nm 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 18nm. 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) 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 NO: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 F and SH); three are the proteins associated with genomic RNA to form the viral nucleocapsid P and two are nonstructural proteins (NS1 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 and the last is M2, another nonglycosylated protein recently shown to be an RSVspecified transcription elongation factor (see Figure WO 99/49017 PCT/US99/06225 39 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 and is associated with the phosphoprotein and the large polymerase protein. These three proteins have been shown to be necessary and sufficient for directing RNA replication of cDNA encoded RSV minigenomes Further studies have shown that for transcription to proceed with full processing, the M2 protein (ORF 1) is required When the M2 protein is missing, truncated transcripts predominate, and rescue of the full length genome does not occur Both 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 NS1 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 The function of the SH protein is unknown, although a recent report has implicated its involvement in the fusion function of the virus (79).

WO 99/49017 PCT/US99/06225 40 As discussed below, the genomes of two wildtype RSV subgroup B 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 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. 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 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 semiconserved 12-14 nucleotide gene end G U/G U/A ANNN U/A A 3 (where N can be any of the four bases) that directs transcription termination and polyadenylation (Fig. 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. 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. The last two RSV genes overlap by 68 nucleotides (Fig. The gene-start signal of the L gene is located inside of, WO 99/49017 PCT/US99/06225 41 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 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 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 The end of the mRNAs are capped with the structure m7G(5')ppp(5')Gp (where the underlined G is the first template nucleotide of the mRNA) and the mRNAs are polyadenylated at their 3' ends Both of these modifications are thought to be made cotranscriptionally by the viral polymerase. Three regions of the RSV 3' genomic promoter have been found to be important as cis acting elements 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 Unlike other Paramyxovirinae, such as measles, Sendai and PIV- WO 99/49017 PCT/US99/06225 42 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 Utract located at nucleotides 6-10 was shown to be quite intolerant of substitutions 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 fourto 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 selfcontained and largely independent of the nature of adjoining sequence The L gene start signal lies 68 nucleotides upstream of the M2 gene-end signal, resulting in gene overlap (Fig. 3) 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 It is also possible that the L gene is accessible by a small fraction of polymerases that fail WO 99/49017 PCT/US99/06225 43 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 polymerase fall-off during sequential transcription 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 SH 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 replicationintermediate (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 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 WO 99/49017 PCT/US99/06225 44 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 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 Sequence Genome Wild-Type Length 2B SEQ ID NO:9 15218 18537 SEQ ID NO:10 15229 Vaccine 2B33F SEQ ID NO:11 15219 2B20L SEQ ID NO:12 15219 Revertant 2B33F SEQ ID NO:13 15219 2B20L SEQ ID NO: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 WO 99/49017 PCT/US99/06225 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 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, wildtype 2B virus had a whereas the 2B33F and 2B33F strains had a 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 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 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.

WO 99/49017 PCT/US99/06225 46 As shown by Northern blot analyses (Figures 4 and 6) and a ribonuclease protection assay (Figure 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 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 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 WO 99/49017 PCT/US99/06225 47 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 B 3' genomic promoter region, the mutations are nucleotide 4 (C 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 virulencecompared 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 WO 99/49017 PCT/US99/06225 48 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 MPL T (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 albumin, gelatin), sugars sucrose, lactose, sorbitol), amino acids 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 WO 99/49017 PCT/US99/06225 49 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, 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 2B wild-type RSV virus were deposited by Applicants on August 21, 1997 with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, 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.

WO 99/49017 PCT/US99/06225 50 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 Attenuvax T vaccine vial (Lot #0716B), the Schwarz vaccine virus was grown once (Lot 96G04/M179 G41D), while the Zagreb and Rubeovax 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 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 T 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 specific primer pairs spanning the 3' and 5' promoter regions and the L gene of the viral WO 99/49017 WO 9949017PCT/US99/06225 51 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 9 0 47

CATATCACTCACTCTGGGATGGAG

90 70Q (SEQ ID 937 1

TCAGAACATCAAGCACCGCC

93 9 (SEQ ID NO:16) 974 1

ACAGTCAAGACTGAGATGAG

97 60 (SEQ ID NO:17) 1 00 1

AAGAGTCAGATACATGTGGA

10020 (SEQ ID NO:18) 1 0 351

ACATGAATCAGCCTAAAGTC

1037 0 (SEQ ID NO:19) 10 674

CCGAAAGAGTTCCTGCGTTACGACC

10 698 (SEQ ID 1108 3

CAGTCCACACAAGTACCAGG

11102 (SEQ ID NO:21) 114

,GTCAGAAGCTGTGGACCATC

11480 (SEQ ID NO:22) 11 1 4

AATATTGCTACAACAATGGC

1 860 (SEQ ID NO:23) 1 1 9 6

ACTCTTCATTCCTAGACTGG

12 21 5 (SEQ ID NO:24) 1 25 42

GTCCAATTATGACTATGAAC

12 61 (SEQ ID 3.

2 9 1

AGAACAGACATGAAGCTTGC

1 29 10 (SEQ ID NO:26) 13 2 32

CCAACAAGGAATGCTTCTAG

1 32 51 (SEQ ID NO:27) 13 5 5

,ACAGCACTATCTATGATTGACCTGG

13 75 (SEQ ID NO:28) 1393 0

GCAACATGGTTTACACATGC

1394 9 (SEQ ID NO:29) 142

,AGATTGAGAGTTGATCCAGG

4299 (SEQ ID NO: 1462 9

AGGAGATACTTAAACTAAGC

1464 8 (SEQ ID NO:31) 1498

TAAGCTTATGCCTTTCAGCG

1500 0 (SEQ ID NO:32) 1 1 337

TTAACGGACCTAAGCTGTGC

1 356 (SEQ ID NO:33) 156

.JGAAACAGATTATTATGACGG

15690 (SEQ ID NO:34) 92 9

CGGGCTATCTAGGTGAACTTCAGG

926 7 (SEQ ID NO: 950 0

ATTTGGATATGGAATATGAG

94 81 (SEQ ID NO:36) 984 0

ACTCAACTGAACTACCAGTG

9 821 (SEQ ID NO:37) 1 0 181 AAGAACATCATGTATTTCAG 1 1 6 2 (SEQ ID NO:38) WO 99/49017 WO 9949017PCTIUS99/06225 52 10 5 4 9

TTATCACGCACTGCTCATG

10530 10 9 19

ATTTTCAGCAATCACTTGGCATGCC

1 0 89 5 11 2 8

GCCTCTGTGCAA-CAAGCTG

1 1 2 6 3.

1 63 8

TCTCTAGTTACTCTAGCAGC

1 16 1 9 12 1

,AGGTCGTTGTTTGTGAGGAG

1 1 99 1236

TCGTCCTCTTCTTTACTGTC

12 342 126 89

CCGTCCTCGAGCTAGCCTCG

267 0 13 05 2

CTCCTCCAGGCTCACATTGG

1 3 03 3 13 42 0

GGGTTGGTACATAGCTCTGC

1 34 0 1 13767

CACCCATCTGATATTTCCCTGATGG

1374 3 14 0 99

TGGTTGACAGTACAA.ATCTG

1408 0 4 46 0

CTGAAATGGGAAGATTGTGC

1 44 4 1 14 8 20

AGCAATCTACACTGCCTACC

1 4 8 0 1 1518

TCACAGATGATTCAATTATC

5 16 1 1 53 0

GATCCTAGATATAGTTCTC

1 551 1

,ACCAAACAAAGTTGGGTAAGG

2

GGGGGATCC

1 0 0

ATCCCTAATCCTGCTCTTGTCCC

7 8 200

GATTCCTCTGATGGCTCCAC

1 157 21

TACAGTCAGGAGACCAAAG

1 74 1

GGGAAGCTT

1 5 80 1

AACCCTAATCCTGCCCTAGGTGG

1 5 82 3 15 1 94

ACCAGACAAAGCTGGGAATAGA

5 8 7 3 (SEQ ID NO:39) (SEQ ID (SEQ ID NO:41) (SEQ ID NO:42) (SEQ ID NO:43) (SEQ ID NO:44) (SEQ ID (SEQ ID NO:46) (SEQ ID NO:47) (SEQ ID NO:48) (SEQ ID NO:49) (SEQ ID (SEQ ID NO:51) (SEQ ID NO:52) (SEQ ID NO:53) (SEQ ID NO:54) (SEQ ID (SEQ ID NO:56) (SEQ ID NO:57) (SEQ ID NO:58) (SEQ ID NO: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 was used (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.

WO 99/49017 PCT/US99/06225 53 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 56 129 148 172 479 Edmonston w-t V Q E A S Rubeovax T 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 WO 99/49017 WO 9949017PCTIUS99/06225 54 Table 4 Differences in MV P and C Between Wild-Type Nucleotides and Vaccine and Amino Acids Strains Gene Nucleotide Edmonston w-t Mutation Amino Acid Ednionston w-t 1977 w-t 1983 w-t Montefiore w-t Rubeovax" vac.

Moraten vac.

Schwarz vac.

Zagreb vac.

AIK-C vac.

C

2046

GCC

GTC

C

2139

ATG

ACG

C

2229

TCT

TAT

2480

GAG

GGG

P

2630

TGT

TAT

P

3122

CTA

CCA

73 104 134 225 275 439 Identical change in V protein WO 99/49017 WO 9949017PCTIUS99/06225 55 Table Differences in MV F Gene-End Signal Between Edmonston Wild-Type and Vaccine Strains Nucleotides 7237-7247 Edzuonston w-t Rubeovax" vac.

Moraten vac.

Schwarz vac.

Zagreb vac.

AIK-C vac.

G TT A AT TA AA A G TT A AT TA AA A G TTA AT CA AA A G T TA AT CA AAA G TT A AT TA AAA GT TA AT TA AA A 7243 WO 99/49017 PCT/US99/06225 56 Example 2 RSV Subgroup B The temperature-sensitive (ts) phenotype is strongly associated with attenuation in vivo; in addition, some non-ts mutations may also be attenuating. Identification of ts and non-ts attenuating mutations was achieved by sequence analysis and evaluation of ts, cold-adapted 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 wildtype parent, a ts and ca derivative thereof designated 2B33F and one revertant designated 2B33F The 2B33F strain is described in U.S. Serial No.

08/059,444 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 passaging at 39°C and in vivo passaging in African green monkeys or chimpanzees have been sequenced in those previouslyidentified mutant regions. The ts, ca, and attenuation phenotypes of many of these revertants have now been characterized and assessed. Correlations between ts phenotype, virus attenuation and sequence changes have been identified.

A summary of results is presented in Tables 6-11.

WO 99/49017 PCT/US99/06225 57 Table 6 Sequence comparison between RSV 2B and 2B33F strains Nucl.

pos.t Nucleotide changes

-I

Gene/ 3' end RSV 2B RSV RSV 2B33F Amino acid region of vRNA 2B33F 5a changes revertant Genomic 4 C G G non-coding Promoter 6 extra A extra A non-coding M 4175 T C C non-coding 4199 T C C non-coding SH 4329 T C C Phe-Leu 4409 T C C none Ile (36) 4420 T C C Ile-Thr 4442 T C C none His (47) 4454 T C C none Cys (51) 4484 T C C none Tyr (61) 4497 T C C Stop-Gin (66) 4505 T C C none Ser (68) 4525 T C C Ile-Thr 4526 T C C Ile-Thr 4542 T C C Stop-Gin (81) 4561 T C C Leu-Pro (87) 4575 T C C Trp-Arg (92) 4598 T C C none Thr (99) 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 For 2B33F and 2B33F 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 strain WO 99/49017 WO 9949017PCT/US99/06225 58 Table 7 Differences in M Gene-End Signal Between RSV 2B and 2B33F strains Nucleotide Nucleotide Numbers Sequence 2B 4196-4207 A G GTA AA TA AA A 2B33F 4197-4208 A GG CA AA TA AA A 2B33F 4197-4208 A G GCAA AT A AA A Table 8 RSV 2B, ts and Revertant Strains Sample Source In Vitro Phenotype In Vivo Growth* tsca Cotton Rat AGM 39/32 0 C EOP 20/32 0 C Nasal Lungs Nasal Bronchial plaque morph Yield turbinates Wash Lavage RSV 2B Wild-type Parent 0.7 0.0001 5. 5a 5. 88 5.58 4.7e Strain (WT) 3 b 5 2 b (4/4) (4/4)1 RSV 2B33F ca, ts mutant isolated 0.00007 0.04 3 3.0O <0.9* from 2B cold-passaged (sp/int/wt) 1 9 b 1 2 b (0/4) x 33 (0/4) RSV 2B33F 5a 2B33F spinner passage, 0.5 0.03 ,1.7a 3.5a 4.2e 4. 0" plaque picked at 39'C (WT) (4/4) RSV 2B33F 4a 2B33F spinner passage, 0.7 0.01 ,1.7a 3.88 ND ND plaque picked at 39'C (WT) (4/4) RSV 2B33F 3b 2B33F spinner passage, 0.5 0.04 2. 5a 2. 9a ND ND plaque picked at 39*C (WT) (4/4) AGM pp2 2B33F-infected AGM 0.3 0.00002 :5 2 0 b 1 6 b ND ND #A2,d7 nasal wash (sp,int) (4/4) plaque picked at 32'C AGM pp4 2B33F-infected AGM 0.1 0.008 16b 1 2 b ND N #A2,d7 nasal wash (sp,int) (4/4) plaque picked at 32'C Table 8 (continued) RSV 2B, ts and Revertant Strains Sample Source In Vitro Phenotype In Vivo Growth* ts ca Cotton Rat AGM 39/32 0 C HOP 20/32 0 C Nasal Lungs Nasal Bronchial plaque morph Yield turbinates Wash Lavage AGM pp6 2B33F-infected AGM 0.000004 0.00005 1 5 b< 1 1 b ND ND #A4,d12 nasal wash (WT) (0/4) plaque picked at 32'C AGM pp7 2B33F-infected AGM 0.000004 0.007 14b< 1 b ND ND #A4,d12 nasal wash (sp/int/wt) (0/4) plaque picked at 32'C Chimp pplA 2B33F-infected Chimp 0.5 ND ND ND ND ND #1552, dN tracheal

(WT)

lavage plaque picked at 32'C Chimp pp3A 2B33F-infected Chimp 0.7 ND 2 .4V :0.0v ND ND #1560, d6 tracheal (WT)(4) lavage(44(3) plaque picked at 32*C Chimp pp5A 2B33F-infected Chimp 0.7 ND ,2.3c 3.0c ND ND #1563, dlO nasal swab (T E i7 ~plaque picked at 32,C(34(/) In Vivo growth measured in log 10 mean virus titer ND not done W!T wild-type plaque size sp sin a Dose 106,7 PPU IN' Dose 105" PFU IN c Dose= d Dose 105'9 PFU INe Dose 106.6 PFU IN+IT f Dose= 0# infected/# total) all plaque size mnt= 106.3 PFU IN 10". PFU IN+IT intermediate plaque size WO 99/49017 WO 9949017PCT/US99/06225 61 Table 9 2B33F Revertants lts vitro AGM 1 Chimp Sa 4a 3b[Ipp2 pp4 pp6 pp7 J lA 3A base no.t 14M 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 23 2B 23 S S S S 23 23 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 1s23 23 2B r r S S B 23 23 cte a~e S S S 2B S 23 S ND N ND Ateutd r r r S S N t These 2B33F revertant SH and L genes base nos. are one larger than for 23 for 14, *bases 4330,4410,4421,4443,4455,4485,4498,4506,4526,4527,4543, 4562,4576,4599 S same base as 2333F 2B reversion to,23 base or complete reversion in phenotype r moderate reversion in phenotype slight reversion in phenotype ND not done WO 99/49017 WO 9949017PCT/US99/06225 62 Table ts and Revertant Strains: Phenotype Sumnmary RSV 2B, Virus Isolate Source In Vi tro In Vi va Phenotype Attenuation ts ca Cotton AGM j Rat RSV 2B [Wi~dtype Parent Strain I RSV 2B33F ca, ts mutant isolated from 2B, cold-passaged x 33 RSV 2B33F 5a 2B33F spinner passage plaque picked at 39 0

C

RSV 2B33F 4a 2B33F spinner passage

ND

TS(+ plaque picked at 3 9 0

CI

RSV 2B33F 3b 2B33F spinner passage

ND

TS(+ plaque picked at 3 9 0

CI

AGM pp2 2B33F-infected AGM A2,

ND

d7 nasal wash plaque picked at 32 0

C

AGM pp4 2B33P'-infected AGM A2,

ND

d7 nasal wash plaque picked at 32 0

C

AGM pp6 2B33F-infected AGM A4,

ND

d12 nasal wash plaque picked at 32 0

C

AGM pp7 2B33F-infected AGM A4,

ND

d12 nasal wash plaque picked at 32 0

C

Chimp pplA 2B33F-infected chimp ND ND ND #1552, d4 tracheal lavage, plaque picked at 32 0

C

Chimp pp3A 2B33F-infected chimp ND ND #1560, d6 tracheal lavage, plaque picked at 32 0

C

Chimp pp5A 2B33F-infected chimp ND ND #1563, dia tracheal lavage, plaque picked at 32 0

C

ND) not dlone -=wild-type phenotype, not temperature sensitive, not cold adapted, not attenuated to increasing levels of temperature sensitivity, coldadaptation or attenuation WO 99/49017 PCT/US99/06225 63 Northern blot analysis of poly RNA isolated from RSV-infected Vero cells was performed using a mixture of 32 P-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 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 At the other extreme from what was observed for the 2B mutant strains was the M gene transcription pattern of S 30 the A2 virus (lane For this strain, monocistronic M transcripts were produced in abundance, while readthrough transcription was minimal.

Northern blot results were confirmed by a ribonuclease protection assay which was performed on the same poly RNA that was used for the Northern WO 99/49017 PCT/US99/06225 64 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 "P-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 104 cpm of probe; thereafter, the hybridized RNA was then digested with RNase T1 (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 (Fig. To evaluate the influence of the M gene-end signal on expression of the downstream SH gene, Northern blot analysis of poly 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 The pattern of SH gene transcripts produced WO 99/49017 PCT/US99/06225 65 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 gene-end signal were also compromised in the synthesis of monocistronic SH transcripts. The 2B33F mutant and its revertant synthesized practically no monocistronic product, but accumulated abundant M:SH transcripts. The wild-type 3A, 2B, 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 2B33F 0.23 2B33F 0.29 B1 18537 0.76 A2 11.1 3A 2.2 WO 99/49017 PCT/US99/06225 66 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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EDITORIAL NOTE APPLICATION NUMBER 31095/99 The following Sequence Listing pages 1 to 86 are part of the description. The claims pages follow on pages "73" to "78".

WO 99/49017 WO 9949017PCTIUS99/06225 SEQUENCE LISTING <110> American Cyanamnid 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> Patentln Ver. <210> 1 <211> 15894 <212> DNA <213> Measles virus <400> 1 accaaacaaa tcaagatcct taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat tccagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tagttggtga aggacctctc gaaacaaacc gattagccag gactgcatga aaatggggga gtgcaggatc actccatggg ggcaagagat gtatcactgc agatcagtag gttgggtaag attatcaggg agcattgttc cagaggaatc atccagactt actaacaggg tcagaggatc ccagtcacaa ccaatacttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct ttttatcctg atttgctggt aactgcaccc ataccctctg aggtttgaac ggtaaggagg cgaggatgca agcggttgga gatagatcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc tctggcctta tcacatgatg atctcagata gcccaaattt gagc taagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt cccagacaag tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaattag t tgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aggtcagttc cagagattgc cccaagtatc tattctagtg atccgagatg acccattaca aatccctgga aattggaaac cttatttgtg cataaggctg aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaac ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg tccaggttcg ggattcaaca gttacggccc caaagaaggg aggattgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 WO 99/49017 WO 9949017PCT/US99/06225 gtgagaatga gagaagccag Cccatcttcc cgcaggacag cggaagaaca actaggtgcg aaaac t tagg gagccgatgg ctcaaggccg atatcagaca ggtctcagca cgcggccagg aatctccagg gcggttaagg agcaccctct gataccgagg gcttctgatg agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctgttat agcatatcca aaggatccca ggcagagatt ctccaaggaa ctaaagccga gcatcacgca cgttacctga cagatgctga ccagtcgacc gcctcccaag aagggtcgat tcagagtcat tgctgggggt ccctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct gctaccgaga ggagagctac aaccggcaca tcgaaggtca aggctcagac agaggccgag aaccaggtcc cagaagagca agcccatcgg acccaggaca aaccatgcct gacctggaga catcaagcac gaatccaaga caggaggaga gatatgctat ttgaaactgc actttccgaa gcacttccga agatcgcgtc catcagggcc tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggc cgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tgaagataat caactagtac ttccacaatg cgctccgata agatcctggt tgttgagggc aggtgttggc catagttgtt actaactctc ccaagtgtgc ttatatgagc ggaattcaga qgcgataggc ggt cc acat c aatgaaaatc tcacattaga ttggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc gaccagaaca acacagccgc ggca cg ccat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggaccagt gatgagctca ctccattata tgatgatatc aatgaagtag aacctaaatc acagagatct caacccacca ctaggcgaca agcgatcccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca aggaagatag ggcccagcag ttgacactgc tgcttaggct ctatagtgta acatccgcct cagcccatca gtcaaaaacg at cgaggaag acctgcaggg ggatcaactg gacgctgaaa tgttattatg atcatggtt c gaaaacagcg gga tctgct c gagatccacg actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca ctacagctca cattataaaa acgacttcga cctacagtga ggaaggatga tagggcctcc caaagcccga cagggctcaa ggagaaaggt atctgatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gcctggtttt agatgagcaa gagggtcaaa agcaagtgat atcggagtcc gcaagccatg caatgacaga accctccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ct ttgggaat tttatgatca aatcaggcct atgtggatat ccatctctat agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctctgatgt taatctccaa agatcaacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga atgatcttgc acttacctgc aacttaggag caagtcggca tggcaggctg atgctttatg aatcgggcga agaactcctc tgaaaaactg cctaacaaca gctcgatacc cgggtattac caacctgctg tacagagcaa gagtgaagtc tgcacttggt gactctccat cagagt cgag gcgagagctg agccaagatc gcaggaatct aatcttctag attgttataa cccacgattg catccgggct atggtcagaa aggcagttcg acctcgcatc ccccccaaga cagcggtgaa tgatggtgat tggcgaacct ggggttcagg actccaatcc cccggacccc attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagatatt gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcag ca ccgg ccc t ggatcggaag caagttccac caaccccatg caaagtgatt tgggacatca gtgccccagg tacatgtttc gcatttgggt aaagaggcca gtgttctaca gggagtgtct ccgcagaggt accgttccta gtgaccctta cttcctgagg tactctgccg gggatagggg gcacaactcg 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 WO 99/49017 WO 9949017PCTIUS99/06225 ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gccgacggca ccaccagcca tgcccccgat attggaaggc gaccgaggtg actaaacaaa Cggcgccgcg ccccggtgcc aatccaagac gaggaagccc gggccaccag accccagccc cgaaggaccc CtCctccttt cccaccccta ggtctcaagg a ccggt caaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ctgaactctc gaggcaatca atcaataatg ctcgggctca cgggacccca atcaataagg agcagaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tccaccaagt tcacaaggga acgatcatta gtagtcgagg tact tgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acat caaaat gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcgcgaaca ccccaatctg ccaaaccacc ccctccccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca ctcccagact cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga tgttagaaaa taaaggcccg atccgacgct a cat aggct c ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggt tgat gagaacaagt cctatgtaag tacccgctga atagtaagaa gacgtgatca aatgcccgaa tccgaaagac ccaggcggcc catcctcctc aaccgcatcc cttcctcaac aggcatccga aaggaacata ccgacaacca gacaccaacc ccccaaaaaa cacacgacca cggccatcac gggagccacc aaggacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc gctcggatac gataactcac gtccgagatt tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggtcctccc taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tggatatcaa tccaggcagt taaatgatga aacgaccccc tccacggacc ccagcacaga gtgggacccc ccaccacccc acaagaactc ctccctagac cacacccaac gagggagccc cccgaacaga aggc ccc cag cggcaaccaa cccgcagaaa caacccgaac gtatcccaca caatccacca agaat caaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcgg acagccggca gcgagcctgg atattggctg caactatctt gaaatcctgt caggctttga agtggaggtg gt cgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tcctctacaa tgaagacctt tttgcagcca ccaaggacta ctcacaatga aagcgagagg acagccctga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagaaccc ggaaaggcca cagcacccaa gcctctccaa cacccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cat tat ttgg gctatgcgct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg qcaagtgtta ttgctgccga ggaggtatcc agaggttgga aattgttgga tagtctacat gttgctgcag taaagcctga ctcttgaaac aatcgattac 4320 tcagttcctc 4380 ttcaaagttc 4440 cagccagaag 4500 ccagccagca 4560 cacaaggcca 4620 cccccaaggc 4680 acccccagca 4740 ccgcacaagc 4800 tccccggcaa 4860 ccccggccca 4920 ccgccggttc 4980 aaccatcgac 5040 ccagcaccgc 5100 agaccaccct 5160 caacccgcgc 5220 gagcgatccc 5280 gtcccccggt 5340 cactcaactc 5400 gtccatcatg 5460 ccagacaccc 5520 aggaagtgca 5580 aatgcccaat 5640 actactgaga 5700 aagaccggtt 5760 ggcaggtgcg 5820 ccagtccatg 5880 tcaggcaatt 5940 ccaagactac 6000 cggccagaag 6060 ccccagctta 6120 tggaggagac 6180 catcttagag 6240 cattgtcctc 6300 gctagagggg 6360 tgttgcaacc 6420 agaggggact 6480 cctccggggg 6540 gttcatttta 6600 cacaacagga 6660 tcactgcccg 6720 agacgctgtg 6780 cgtagggaca 6840 gtcatcggac 6900 cctgattgca 6960 ggggcgttgt 7020 tcttacggga 7080 acaaatgtcc 7140 WO 99/49017 WO 9949017PCT[US99/06225 cacaagtctc tatctccggc atcatccaca tcccaaggga tttgctggc t cattagactt tctagatgta aatcatcggt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc gcaaccagtc agccctttgt cagcttccag ccccttatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcaa tgtggtttat gcctataaag ctggtgc cgt tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc cgaggaagat aggttttcca aggacatcaa agccc tt tc t cccatacttg tgctaatctc tgacatttga ccgctatgac ctcttcgtca ttccctctgg atgtcaccac agtaggatag gttctgtttg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actatgacat agcaaaaggt agaaatccgg agtaatgatc cacggggaag ctcgtcaagc acggatgatc aatcaagcaa tgcttccaac ccattgaagg gttgagctta atggacctat aacctagcct aacctcttca cctgcggagg gatctccaat tacgtttaca ggggtcccca cacttctgtg ggcatgggag tagtgaacca catcagaatt caaccagatc agccatcctg tcagaacatc ggaagttggg atatccaaat ccgtgaactc atgcttaagg ggagaaagtt gttttggttt ccataggagg tcgtgacctt actggttttg tattgatgct tcaagcaacc ccgaacaata aacgagaccg tcattaacag tcatgtctct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa atgcattggt caaagggaaa ccctgttaga cccagggaat cagagttgtc gtttgggggc tcagcaactg attctatcac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaatccaa taggigtaat ctgtcccaat tggatggtga atgttttggc gcccaggccg tcgaattaca tgcttgcgga tcagctgcac atcacatgat aagaaaaacg ttataccdtg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaact attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatacag accgcaccca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtatggggga acaactgagc tccggtgttc tatggtggct aattccctat gaaatcccca caggctttac cccgacaaca ggg ta aaat c tccttcatac tgcttcggga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctacgat ctcattttct agtggaatgc ctcagaatct agtcacccgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa ggaattcgct cacggcttgg gagtttacat ctgagatgag ctgtattctt tcagtaaaga atgtcataga agcttctagg gcatcaagcc attaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggaga cccactacaa agt cgaggtt acttacctag atgtaccgag catatgacaa ttgggggagc cagggat cag accgacatgc ctctcatctc cgaacagatg caagcactct ggggtcttgt ttcgggccat gtgtattggc gagtggatac ggcgaagact agttccaatc acttccaggg tacttttatc ttcacatggg ggtggacata gaagatggaa catcaggcat gtggtt cccc agatagcccg cgcttacagc attttccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagt caga cacctgaaat agggtgcaag ataaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggtca acaatgtgtc tggaaaagcc tgtttgaagt actatcttga tcaaactcgc ggaaaggtgt aatcctgggt acagaggtgt acaagttgcg gcgagaatcc ctgttgatct tgatcacaca tgactatccc cgagattcaa gccatgcccc tggtgattct ttgaacatgc cttttaggtt accaaaaact tcactcactc ccaatcgcag acccactagt gttatggact atagttacca ctggaggacc caaatgatta c cggc ccact aaagagtcaa gtcagtgata gaattgaggg cagtggtttg aaatcacaaa tcagttgagt gtatattacc atgacagaga tacatgtgga 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 WO 99/49017 WO 9949017PCTIUS99/06225 aactgataga tggagcctct ctttccttaa atgaaggtac tacatcigac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa atttgactaa gtcacagggg ggaacgtgag acactgatca atctcaagaa taaatgagat ctgtcctgta ataaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta ctct tggctt acaacgacct tgaatatgag atctcaagag cacaacaacc ttgtatgtgt tccatagtcc agggactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat .gatcagtcaa aggaaacatc tggtttcttc ttcacttgct ccactgcttt ttatcatgag aggggagatt tgctgaaaat gaaaggtcat cagttggcca ttcaggtgaa gaaatttggc caaggcactt ttacgaccct gagctttgac tgagttcaac tgctaaaatg cgggattggc ggcactccac ggggccagtc agcagcaaaa tccggagaat gtactgcctt ttacggattg tgtaagtgac caatgatcaa gtggaccatc tgcttcgtta atggccctac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa gaggctagct gcgaggccac ctacggatgg atccttgaga cctgcactcg tacctgcagc actgaaatac ttaattgaag ttctcatttt gt taggaaat gccatatttt ccgctgaccc gggttaacac tgctttatgc gctgctctcc cccaagggaa ccatatgatg ctgtcttaca acttacaaaa aaatatttta actctagctg ttaaaaacct gggtttatag atggaagctt aattggagat ccctcatttt cctcattgcc atcttcatta agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta tccctgaacg tcaaccatga atggcactgt gtcagaaaca gcctcactaa tcattcctag actagactcc ttaaaaggat atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata ggaatccaac tgagggatat atgatgttct ctctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ccgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg tctcaggagt actcccgaag ggt tccctca acgagacagt atgagaccat tccagtggct cccccgacct agtaccctat cctatctata acaatcagac aacgggaagc atattggcca caaaaggaat gtgtattctg caacaatggc tcctaaaagt cccgggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg ttggttctac ttatcaaatt aacagtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggcttgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag ccccaaagat cccagtccac agtaattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagccgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa agtcataccc tattgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgctg ctctcgagtg gctattgaca ggcgagagct ccttgaggtc atgtgtcatc ccaactggat cactgatgag gtagccatgc ctcagaggtg gggttttctg actgatgaca agacttgaag attgtgtatg tatcgtgaca acaatccgga tggaaatctt ctgacaatgt tacccgaaag gatgttttcc ggagcttacc aaggaaacag gctgaaaatc gatgagcacg ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggc tacttg atagttgatg gagagaggtt attctgatct ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 WO 99/49017 WO 9949017PCTIUS99/06225 tgaagcttgc cttcgtaaga gccccaagtc gatccttgcg atctgctgtt agaatagcaa 12960 cagtgtactc ctaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta ga cca tcagg aaggagtgt t ggcattgtgg caactgtgtg aagagttaga gattcgacaa ggac ctgc cc atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggcaatct cttgctacaa acggcttgtt aactaaacaa aattagcacc ttgtcaaagt tcaatttcat agaccttgcc tggctctgct gggattttgt tataccctag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ccaagtcaga taacagtcaa atgggcttac ggccaatgtg agcgcatagg agtggcgagg ggttgatact attgtttcga aacagattgt agagctgagg cagagatgca atggtccaca cc tggt aaca cgatatcaat cttgggccag gaaatatcag taaggtgctt tattatagag caacatggtt agagttcaca cat cc aggc a accaattcga agaggctagg ttactcatgc tgat ccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agttagtaat taacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagtt ggtgctgatc ccatgatgtt gttggcaaga attggtaagt cattcttctt cggctatc tg gaaacagatt ggagaccaaa ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc cctatccatg tacacatgct tttctcttgt aaacacttat ggtctaagac ttatctccag tctctgactt ttcattttcg atctcaaata aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagttggcc gggaggcccg atccctacct actatagaga ataggatcaa ataagttatg ttcatatcta cctgaaaaga ggtcacatcc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggcaac tactccggga atactagact attatgacgg gaatggtata atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg ataccggatc cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcatc taagccaccc gtccttcact atatgaccta gtgaaagcga gtgttctggc cggtagagaa caggatcttc at c tccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa ttgtcgaaca aagtcacgtg ctagtgtggg agctagagga tactggtgat tagggtctca ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa aagatggatt accaaagaag gagaacttat acagaaagtt tacaccagaa ggggtttgaa gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gctcatagag atttgatgta gttcctttct aaagatctac tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggatttcaga gcacaatctt aatcgggttg atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt gtttatccat attggcagcc taagcttatg ttatagagaa tt tggt tatg gataattgaa gcaactaagc tactctgaaa cggacctaag gcttaattct tcaacaaggg atctaggatc gataaataag tatcttcgtt acgtgagtgg tggttgttgg atctcaactt tcaggtacat tttgtcatat gggttgggtg gtattacatc atacccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagtcagc cccccacacg cccatttcag aactcatctg ccaggggaag gagatactta ggtcaaaggg gtaggtaata gtagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtga tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg acccgcaaat tttatccaga aagaatctat gtttttaagg 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 agttagtcgg atacagtgcc ctgattaagg WO 99/49017 WO 9949017PCT[US99/06225 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 tcaagatcct taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat tccagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tagttggtga aggacctctc ggaacaaacc gattagccag gactgcatga aaatggggga gtgcaggatc actccatggg ggcaagagat gtatcactgc ggatcagtag atgaaaatga gagaagccag cccatcctcc cgcaggacag cggaagaaca actaggtgca aaaacttagg gggccgatgg ctcaaggccg atatcagaca ggtctcagca cgcggtcagg aatctccagg gcggttaagg agcaccctct gataccgagg gttgggtaag attatcaggg agcattgttc cagaggaatc atctagactt actaacaggg tcagaggatc ccagtcacaa ccaatatttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct t t ttat cctg atttgctggt aactgcacca ataccctctg aggtttgaac ggtgaggagg cgaagatgca agcggttgga gctaccgaga agagagctac aaccgacaca tcgaaggtca aggctcagac agaggccgag aaccaggtcc cagaagagca agcccatcgg acccaggaca aaccatgcct gatctggaga catcaagcac gaatccaaga caggaggaga gatatgctat gatagatcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc t ctggcct ta tcacatgatg atctcagata gctcaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt cccagacaat tgggggggta agagaaacca cccttagaca gctgacgccc acggacaccc gaccagaaca acacagccgc ggcacgccat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaagtag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttacttcga aggtcagttc cagagatcgc cccaagtgtc aggaagatat ggcccagcag ttgacactgc tgctcaggct ctagagtgta acatccgcct cag cccacc a gtcaaaaacg atcgaggaag gcctgcaagg ggatcaactg gacgctgaaa tgttattatg atcatggttc gaaaacagcg ggatctgctc tattctagta atccgagatg acccattaca aatcccggga aattggaaac cttatttgtg cataaggctg aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaat ctcaattcag agtaggagtg tccagcatat caca ttggca aatgcatact attcctacac gagggtcaaa agcaagtgac atcggagtcc gcaagccatg caatgacaga accctccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ct ttgggaat tttatgatca aatcaggcct atgtggatat ccatctctat cacttaggat gccacacttc tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg t ccaggttcg ggattcaaca gttacggccc caaagaaggg aggattgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa ttcagactag tctgaactcg acagaggaca ggtgatcaaa cagagt cggg gcgagagcta agccaagatc gcaggaatct gatcttctag attgttataa cccacgattg catccgggct atggtcagaa aagcagtccg acctcgcatc cccc t cagga cagcggtgaa tgatggtgat tggcgaacc t ggggttcagg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 WO 99/49017 WO 9949017PCT/US99/06225 gcttctgatg ttgaaactgc agaaggaggg gagatccacg agctcctgag actccaatcc 2400 agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgtactga aataatgaag aaaacagcct ctgctgttat agcatatcca aaggatccca ggcagagatt atccaaggaa ctaaagccga gcatcacgca cgttacctga cagatgctga ccagtcgacc gcctcccaag aagggtcgat tcagagtcat tgctgggggt ctctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct ggtt caagaa tctggaggag aagaattccg tgtagaccgt gc ccggaaaa gctgacggca ccaccagcca tgccccccac actggaagag gaccgaggtg actaaacaaa cggcgccgcg CCCcggtgcc aatccaagac gaggaagccc gggccaccag actttccaaa gcacttccga agatcgcgtc catcagggcc tacaggagtg aagggggaga tggc caaaat tgaaggggga ccttggaagg acgaccccac caggccgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tgaagataat tagctaatac ttccacaatg cgctccgata agatcctggt tgttgaggac aggtgt tggc catagttgtt actaactctc ccaagtgtgc ttatatgagc ggaattcaga ggcgattggc ggtccacatc aatgaaaatc tcacattaga gaccctatgt cagatgcaag catttacgac agtgcccagc aaaggccccc agcacgaaca tcccaatctg ccaaaccacc cccttcccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca ttcccagact gcttaggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ttattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggctgaa acggaccagt gatgagctca ctccattata tgatgacatc aatgaagtag aacctaaatc acagagatct caacccacca ctaggcgaca agcgatctcc agatccacag agacgtacag ctcatacctt aatgcggtta atcacccgtc tcggtcaatg catgggaaga gggaacttca gaaaagatgg agcacaggca tacccactga atagtaagaa gacgttatca aatgcccgaa tccgaaagac ccaggcggcc catcctcctc aaccqcatcc ttccctcaac aggcacccga aaggaacata ccgacaacca cacaccaacc ccccaaaaaa cacacgacca cggccatcac actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga atcaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca ctacagctca cattataaaa acgacttcga cctacagtga gaaaagatga tagggcctcc caaaacccga cagggc tcaa ggagaaaggt atctgatacc tttcagataa cagtggcctt tcatcgacaa ggagaaagaa gc ctggt tt t aaatgagcaa tggatatcaa tccaggcagt taaatgatga gacgaccctc tccacagacc ccagcacaga gtaggacccc ctaccacccc acaagaactc Ctccctagac cacacccaac gagggagccc cccgaacaga aggcccccag cgacaaccaa cccgcagaaa ttcccccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctctgatgt taatcaccaa agat caacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttccgga ggctagagga acgatcttgc acttacctgc aacttaggag caagtcggca tggcaggctg atgttttatg aatcgggcga agaactcctc tgaaaaactg cctaacaaca gctggatacc cgggtattac caacctgctg tgcagagcaa aagtgaagtc tgcacttggt gactctccat tgaagacctt tttgcagcca ccaaggatta ctcacaatga aaatgagagg acagccctga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagaaccc ggaaaggcca cccggaccct 2460 attagcctca 2520 tcgaaagtca 2580 tgtgagcaat 2640 gagatcccag 2700 ccaagatatt 2760 gctagaatca 2820 gcaaaatatc 2880 tggacttggg 2940 acccatcata 3000 cagccgacaa 3060 ggaatttcag 3120 caccggccct 3180 ggatcggaag 3240 caagttccac 3300 caaccccatg 3360 caaagtgatt 3420 tgggacatca 3480 gtgccccagg 3540 tacatgtttc 3600 gcatttgggt 3660 aaagaggcca 3720 gtgttctaca 3780 gggagtgtct 3840 ccgcagaggt 3900 accgttccta 3960 gtgaccctta 4020 cttcctgagg 4080 tactctgccg 4140 gggatagggg 4200 gcacaactcg 4260 aatcgattac 4320 tcagttcctc 4380 ttcaaagttc 4440 cagccagaag 4500 ccagccagca 4560 cataaggcca 4620 cccccaaggt 4680 acccccagca 4740 ccacacaagc 4800 cccctggcaa 4860 ccccggccca 4920 ccgccggctc 4980 agccatcgac 5040 ccagcaccgc 5100 agaccaccct 5160 caacctgcgc 5220 WO 99/49017 WO 9949017PCT/US99/06225 accccagccc cgaaggaccc ctcttcctct cccgtcccta ggtctcaagg accggtcaaa agctacaaag ataactctcc acagt t ttgg cagagtgtag gccctaggcg ctgaactctc gaggcaatca atcaataatg ctcgggctca cgggacccca atcaataagg agcagaggaa agtatagcct gtctcgtaca caagggtac c gtgtgcagcc tccaccaagt tcacaaggga acgatcatta gtagtcgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcgaaat cacaagtctc tatctccggc atcatccaca t cc caaggga tt tgc tggct cattagactt tctagatgta aatcatcggt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg t tatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga tgttagaaaa taaaggcccg acccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggttgat gagaacaagt cctatgtaag ctcttcgtca tcccctttgg atgtcaccac agtaggatag gttctgttcg catcgggcag actaactcaa gatgaagtgg aagat taaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actatgacat agcaaagggt agaaatccgg ggcagc ca cc aaggacatca actaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgagg gcaggagatg gtctatgaac atactataca gatatctatc gctcggatat gataactcac gtccgagatc tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggtcctccc taagt tggag aggtttgtcg agggatcccc tggtatgtca gtcgctctga tcaagcaacc ccgaacaata aacgagaccg ttatcaacag tcatgtttct ccatctacac ttgagcatca gcctgaggac tccttaaccc agagaatcaa atgcattggt caaagggaaa ccctgttgga cccagggaat cagagttgtc gtttgggggc caaccctaac gtatcccaca caatccacca ggaattaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcag acagccggca gcaagtctgg atat tggctg caactatctt gaaatcctgt caggctttga agtggaggtg gtcgacacag aagggggtga tatacgactg tcatcgtgta agtcctctgc tctgggtctt tcaatccttt ctaacataca gtcgggagca atatcattg gatgccaagg agcactagca gctttaatat agaccaggcc tcctctacaa accgcatcca tcggtagtta gataaatgcc agaacacctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtacggggga acaactgagc tccggtgttc cagcacccaa gcctctccaa catccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaggt tgga aattgttgga tagtctacat gttgctgcag taaagcctga ctcttggaac gcatcaagcc attaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggaga cccactacaa agtcgaggtt acttacctag atgtaccgag catatgacaa gagcgatccc gtcccccggt cactcaactc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccgttt ggcaggtgcg ccagtccatg tcaggcaatt ccaagactac cggccagaag ccc tagc tta cggaggagat catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggact cctccggggg gttcattttg cacaacagga tcactgcccg agacgctgtg cgtagggaca gtcatcggac cctgattgca ggggcgttgt tcttacagga acaaatgtcc cacctgaaat agggtgcaag ataaccccca gaccttatgt caattgcagg t cagca ccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggtca acaatgtgtc tggaaaagc tqtttgaagt actattttga 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 WO 99/49017 WO 9949017PCTIUS99/06225 gcaaccagtc agccctttgt cagctttcag ccccttctca tatcgctgac aatggagaca cgagtgggca gagtctaaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcaa tgtggtttat gcctataaag ctggtgccgt tgggatggtg atagggctgc gtgaaataga cgctatctgt acaagatagt ctacactgtg taaacaatgt ctcatattcc cgaggaagat aggttttcca aggacatcaa agccctttct cccatacttg tgctaatctc taacatttga ctgctatgac aattgataga tggagcctct ctttccttaa atgaaggtac tacacctgac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa agtaatgatc cacgggggag ctcgtcaagc acggatgacc aatcaagcaa tgcttccagc ccattgaagg gttgagctta atggacctat aacctagccc aacctcttca cctgcggagg gatctccaat tacgtttaca gggatcccca cacttctgtg ggcatgggag cagtgaacca catcagaatt caaccagatc agccatcctg tcagaacatc ggaagt tggg atatccaaac ccgtgaactc atgcttgagg ggagaaagtt gttttggttt ccataggagg tcgtgacctt gctggttttg cattgatgct tggtttcttc ttcacttgct ccactgcttt ttatcacgag aggggagatt tgctgaaaat gaaaggtcat cagttggcca ctcaggtgaa gaaatttggc caaggcactt ttacgacccc gagctttgac tgagttcaac tgctaaaatg cgggattggc tcagcaactg attctatcac taggtgtctg cagtgataga aatgggctat aggcgtgtaa ataacaggat aaatcaaaat acaagtccaa taggtgtaat ctgtcccaat tggatggtga atgttttggc gcccaagccg tcgaattaca tgcttgcgga tcagctgcac atcacatgat aagaaaaacg ttataccccg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaatt attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg agatatacag cctgcactcg tacctgcagc actgaaatac ttagttgaag ttctcatttt gt taggaaat gccatatttt ccgctgaccc ggat taacac tgcttcatgc gctgctctcc cc caagggaa ccatatgata ctgtcttaca acttacaaaa aaatatttta tatggtggct aattccctat gaaatcccca caggctttac cccgacaaca gggtaaaatc tccttcatac tgcttcggga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctacgat ctcattttct agtggaatgc ctcagaatct agtcacccgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa gaaattcgct cacggcttgg gagtttacat ctgagatgag ctgtattctt tcagtaaaga atgtcataga agcttctagg ggaatccaac tgagggatat atgatgttct ctctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ccgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg t tgggggagc cagggatcag accgacatgc ctctcatctc agaacagatg caagcactct ggagtcttgt ttcgggccat gagtattggc gagtggatac ggcgaagact agttccaatc acttccaggg tacttttatc ttcacatggg ggtggacata gaagatggaa catcaggcat gtggttcccc agatagcccg cgcttacagc attttccaac taggagttat catagaagac gtactctaaa tctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagtcaga ttatcaaatt aacggtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggcttgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag tcaaactcgc 8160 ggaaaggtgt 8220 aatcctgggt .8280 acagaggtgt 8340 acaagttgcg 8400 gcgagaatcc 8460 ctgttgatct 8520 tgatcacaca 8580 tgactatccc 8640 cgagattcaa 8700 gccatgcccc 8760 tggtgatcct 8820 ttgaacatgc 8880 cttttaggtt 8940 accaaaaact 9000 tcactcactc 9060 ccaatagcag 9120 acccactagt 9180 gttatggact 9240 atagttacca 9300 ctggaggacc 9360 caaatgatta 9420 ccggcccact 9480 aaagagtcaa 9540 gtcagtaata 9600 gaattgaggg 9660 caatggtttg 9720 aaatcacaaa 9780 tcagttgagt 9840 gtatattacc 9900 atgacagaga 9960 tacatgtgga 10020 gtagccatgc 10080 ctcagaggtg 10140 gggttttctg 10200 actgatgaca 10260 agacttgaag 10320 attgtgtatg 10380 tatcgtgaca 10440 acaatccgga 10500 tggaaatctt 10560 ctgacaatgt 10620 tacccgaaag 10680 gatgttttcc 10740 ggagcttacc 10800 aaggaaacag 10860 gctgaaaatc 10920 gatgagcacg 10980 WO 99/49017 WO 9949017PCT/US99/06225 atttgactaa gtcacagagg ggaacgtgag acactaatca atctcaagaa taaatgagat ctgtcctgta gcaaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta Ctcttggctt acaacgacct tgaatatgag atctcaagag cacagcaacc ttgtatgtgt tccacagtcc agggactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tgaagcttgc cagtgtactc caaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga ctcgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gaccatcagg aaggagtgtt ggcactccac ggggccagtc ggcagcaaaa tccggagaat gtactgcctt ttacggatta tgtaagtgac caatgaccaa qtggaccatc tgcttcatta atggccttac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg agcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa gaggctagct gcgaggc cac ctacggatgg atccttgaga cttcgtaaga atgggcttac ggctaatgtg agcacatagg agtggcaagg ggttgatact attgtttcga aacagattgt agagctgagg cagagatgca atggtccaca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt actctggctg ctaaaaacct gggtttatag atggaagctt aattggagat ccctcatttt cctcattgcc atcttcatta agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtttatt atcgcaagat aatattgcta tccctgaacg tcaaccatga a tgg ca ctgt gtcagaaaca gcatcactga tcattcctag actagactcc ttaaagggat atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata gccccaagtc ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctgt acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc tctcaggagt actcccgaag ggtt ccctca acgagacagt atgagaccat ttcagtggct CCCccgacct agtaccctat cctatttata acaatcagac aatgggaagc acattggcca caaaaggaat gtgtattctg caacaa tgg C tcctaaaagt cccaggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg ttggttctac gatccttgcg atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg ataccggatc caatgataga gtaccaaccc acacccagag atcacattct aggaccatat ctgagtttct tcaattgggc tgttgtcatc taagccaccc ccctaaagat cccagcccac gataattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagctgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcag agt cataccc tattgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgcta ctctcgagtg gctattaaca ggcgagagcc ccttgaggtc atgtgtcatc ccaactggat cactgatgag atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgctccta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gcttatagag atttgatgta gttcctttct aaagatctac ctcaaagaaa acaaatacca caggaccaag atcacaactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggtt attctgatct ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctaa gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca agaatagcaa tggttgttgg atctcaactt tcaggtacat tttgtcatat gggttgggcg gtattacatc atacccagct gataatgcac caccttgtag acagcactat tcagctctca ccaagattat cattaicata agaatgagca aagaaattct 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 WO 99/49017 WO 9949017PCT[US99/06225 ggcac tgtgg caactgtgtg aagagttaga gattcgacaa ggac ctgc cc atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgt tgc ggggcaatct cttgctacaa acggcttatt aactaaacaa aattagcacc ttgtcaaggt tcaattacat agaccttacc tggctctgct gggattttgt t atac ccc ag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ccaagtcaga taacagtcaa actaattggt tatattaaag tattatagag caacatggt t agagtttaca catccaggca accaattcga ggaggctagg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agttagtaat taacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagtt ggtgctgatc ccatgatgtt gttggcaaga attggtaagt cattcitctt cggttatctg gaaacagatt ggagaccaag tgaactccgg aaaactttga cctatccatg tacacatgct tttcttttgt aaacacttgt ggtctaagac ttatctccag tctctgactt ttcattttcg atctcaaata aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagttggcc gggaggcccg atccctacct actatagaga ataggatcaa ataagttatq ttcatatcta cctgaaaaga ggtcaca tcc agtagaggtg aattgcgggt gcctcagggc ttcaaggaca agcaggcaac tactccggga atactagact attatgacgg gaatggtata aaccctaatc aaatacgaag gtccttcact atatgaccta gtgaaagtga gtgtt Ctggc cggtagagaa caggatcttc atcttcggcg acgccctcgc tgagcatcaa atacaagcaa ctttccgcag taattaggag ctatgttgat tctctgccaa ttgtcgaaca aagtcacatg ctagtgtggg agctagagga tactggtgat tagggtctca ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa aagatggatt accaaagaag gagaacttat acagaaagtt tacaccagaa ggggtttgaa agttagtcgg ctgccccagg tttctattcc tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggatttcaga gcacaatctt aatcgggttg atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt gtttatccat at tggcagcc taagcttatg ttatagagaa tttggttatg gataattgaa gcaactaagc tactctgaaa cggac ct aaa gcttaattct tcaacaaggg atctagaatc gataaataag tatcttcgtt acgtgagtgg atacagtgcc tggttaggca cagctttgtc aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagt cagc cccccacacg cccatttctg aactcatctg ccaggggaag gagatactta ggtcaaaggg gtaggtaata gtagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagat ctca tcatctgtgc tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg actcgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg ttatttgtaa tggt 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15894 <210> 3 <z211> 15894 <212> DNA <213> Measles virus <400> 3 accaaacaaa tcaagatcct taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat gttgggtaag attatcaggg agcattgttc cagaggaatc atccagacta actaacaggg tcagaggatc gatagatcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag tattctagta atccgagatg acccattaca aatccctgga aattggaaac cttgtttgtg catcaggctg cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg 120 180 240 300 360 420 WO 99/49017 WO 9949017PCTIUS99/06225 tccagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tagttggtga aggacctctc ggaa caaa cc gattagccag gactgcatga aaatgggaga gtgcaggatc actccatggg ggcaagagat gtatcactgc ggaccagtag gtgagaatga gagaagccag cccatcttcc cgcaggacag tggaagaaca actaggtgcg aaaacttagg gggccgatgg ctcaaggccg a tat caga ca ggtctcagca tgcggtcagg aatctccagg gcggttaagg agcaccctct gataccgagg gcttctgatg agaggcaaca ggtagggcca t ttggagcgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctgttat agcatatcca aaggatccca ggcagagatt ctccaaggaa ctaaagccga gcatcacgca cgttacctga ccagtcacaa ccaatacttt gaacaaggaa taccattcta agctgattcg attcagattg cttacgccga aaggattgct ttttatccta atttgctggt aactgcaccc ataccccctg aggtttgaac ggtgaggagg tgaggatgca agcggttgga gctac cagga ggagagctac aaccagcgca tcgacggtca aggctcagac agaggccgag aaccaggtcc cagaagagca agcccatcgg acccaggaca aaccatgcct gatctggaga catcaagcac gaatccaaga caggaggaga gatatgctat ttgaaactgc acttcccgaa gcacttccga agatcgcgtc catcagggcc tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggccgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tctggcctta tcacatgatg atctcagata gcccaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggtcgat tcagctggga aggcttgttt cccagacaag ttggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc gaccagaaca acacagccgc ggcacgccat ctcactggcc ggaccgaacc ctcagcaatt gagcgatgac tgggttacag tgctgactct cgatgaatct cactgaccgg agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ttattatgat a cacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggaccagt gatgagctca ctccattata tgatgatatc ccttcgcatc atccaagtag ttgaagtgca gggtct tgc t ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aagtcagttc cagagattgc cccaagtgtc aggaagatag ggtctagcag ttgacactgc tgctcaggct ctagggtgta acatccgcct cagccaacca gtcaaaaacg gtcgaggaag acccgcaagg ggatcaactg aacgctgaaa tgttatcatg atcatggttc gaaaacagcg ggatctgc tc gagatccacg actctcaatg aaaaagggga ggtggtgcaa gtggggaatg tctggtacca gatgagctgt aatcagaaga attaaaaagc agcatcatga gaactcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca aagaggtacc tagtgatcaa agaccctgag cgcgaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaat ctcaattcag agtaggggtg tccagcatat cacattagca aatgcacact atttctacac gagggt caaa agcaagcgat atcggagtca gcaagccatg caatgacaga accctccatc accatccact gactggaatg ccatggcagc aagaggaggc aaggcagtgc ctttgggaat tttatgatca aatcaggcct a tg tggata t ccatctctat agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctccgatgt taatctccaa agatcaacag tcgccattcc ccgacctgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga acgatcttgc aacatggagg tccaggtccg ggattcaaca gttacggccc caaagaaggg aggattgccg aggacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa cagagtcggg gcgagagctg ggccaagatc gcaggaatct gatcttctag attgttataa cctacgactg catccgggct atggtcacaa aggcagttcg acctcgcatc cccctcaaga cagcggtgaa tgatggtgat tggcgaacct ggggttcagg actccaatct cccgaacccc attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagacatc gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcaa caccggcccc ggatcggaag caagttccac 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 WO 99/49017 WO 9949017PCTIUS99/06225 cagatgctga ccaatcgacc gcctcccaag aagggt cgat tcagagtcat tgctgggggt ccctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgc t ggattgacaa caacatttat attattgcaa gcaccagtct ggt tcaaaaa tctggaggag aagaattccg tgtagaccgt gc ccggacaa gctgacggca ccaccagcca cgcccccgac actggaaggc gatcgaggtg actaaacaaa Cggcgccgcg ccc cgg tgc c aattcaagac gaggaagccc gggccaccag acccctgccc cgaagggccc ctccccctct cccaccccta ggtc tcaagg accggtcaaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ttgaactctc gaggcaatca atcaataatg ctagggctca cggga ccc ca tgaagataat taattagtac ttccacaatg cgctccgata agatcctggt tgttgaggac aggtgttggt catagtcgtt actaactctc ccaagtgtgc ttatatgagc agaattcaga agcgattggc ggtccacatc aatgaaaatc tcacattaga gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcgtgaaca tcccaatctg ccagaccacc ccctccccct acccaaccgc acttagggcc cccccacctc cacaggcagg ggggggcccc acccacccca ttcccagact tgatccggtg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tat ctgcgga aatgaagtag agcctaaatc acagagatct caacctacca ctaggcgaca agcgatcccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca tacccactga atagtaagaa gacgtgatca aatacccgaa tccaaaagac ccaggcggcc cgtcctcctc aaccgcatcc ttccctcaac aggcatccga aaggaacata ccgacaacca cacaccaacc ccccaaaaaa cacacgacca cggc Cat cac ggcggccacc aaagacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc ctacagctca cattataaaa acgacttcga cctacagtga ggaaggatga tagggcct CC caaaacccga cagggctcaa ggagaaaggt atctgatacc tttcggataa cagtggcttt tcatcgataa ggagaaagaa gcctggtttt aaatgagcaa tggatatcaa tccaggcagt taaatgatga aacgaccccc tccacggacc tgggcacaga gtgggaCccc ccacagc ccc gcaagaactc ctccctagac cacacccgac gagggagccc ctcgaacaga aggC CC C Cag caggaaccga cccgcagaaa caacccgaac gtatcccaca caatccacca agaatcaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgctg acagccggca gcgagcctgg atattggctg caactatctt gaaatcctgt caggctttga acttacctgc aacttaggag caagtcggca tggcaggctg atgctttacg aatcgggcga agaactcctc tgaaaaactg cctaacaaca gctggatacc cgggtattac caacctgctg tgcagagcaa gagtgaagtc tgcacttggt gactctccat tgaagacctt tttgcagcca ccaaggacta ctcataatga aagtgagagg acagccccga cgaggaccaa cgggaaagag cacaaccgaa agatcctctc agaacccaga ccaaccaatc C CCagCaCCC gggccgacag accagaatcc ggaaaggcca cagcacccaa gcctctccaa caccgacga ctcatccaat tgttaaCtct tggtagggat t Cataaaatt aatacaggag CCCagaatat gagttgtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cactatttgg gctatgcgct caacctcatg Caaagtgatt tgggacatca gtgccccagg taCatgtttc gcatttgggt aaagaggcca gtgttctaca gggagtgtct C CgCagaggt accgttccta gtgaccctta cttcctgagg tactctgctg gggatagggg gcacaactcg aatcgattac tcagttcccc ttcaaagttc cagccagaag ccagccagca cacaaggcaa CCCCCaaggt acccccagca ccgcacaagc cccccggcaa ccccggccca C CgCCggC tC agccatcgac ccagcaccgc agaccaccct caacccgcgc gagcgatccc gtcccccggt cactcaattc gtccatcatg ccaaacaccc aggaagtgca aatgCCCaat actactgaga aagaccggtt ggcgggtgCg ccagtCCatg tcaggcaatt CCaagactac cggccagaag Ccccagctta tggaggagat 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 WO 99/49017 WO 9949017PCT[US99/06225 at caat aagg agcagaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tccaccaagt tcacaaggga acgatcatta gtggtcgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcaaaat cacaagtctc tgtctccgga atcatccaca tcctagggga tttgctggct cataagactt tctagatgta gatcatcggt cat ct ctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc gcaa ccagt c agccctttgt cagcttccag ccccctatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta ac Ctgg tcaa tgtggtttat gcctataagg ctggtgccgt tgttagaaaa taaaggcccg atccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg atctaatagc atcaggaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggt tgat gagaacaagt cctatgtaag ctcttcgtca ttccctctgg atgtcaccac agtaggatag gttctattcg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccqccag gaactcatga ctagctgtct atgtcgctgt actatgacat agtaaagggt agaaatccgg agtaatgatt cacagggaag ctcgtcaagc acggatgatc aatcaagcaa tgcttccagc ccattgaagg gttgagctta atggacctat aacctagcct tacctcttca cctgcggagg gatctccaat tacgtttaca ggggtcccca cacttctgtg gctcggatac gataactcac gtccgagatt t caagagtgg ttttgatgag gtacccgatg tacacttgta caattgtgca tgacaagatc gaccatccaa cggtcctccc taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tcaagcaacc ccgaacaata aacgagaccg ttattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa atgcattggt caaagggaaa cc ctgttgga cccagggaat cagagttgtc gtttgggggc tcagcaactg attctatcac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaatccaa taggtgtaat ctgttccaat tggatggtga atgttttggc g ccc aagc cg tcgaattaca tgcttgcgga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tcctctacaa accgcatcca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagat c ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtacggggga acaactgagc tccggtgttc catggtggct aattccctat gaaatcccca caggctctac cccgacaaca gggtaaaatc tccttcatac tgcttcagga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctatgat ctcattttct agtggaatgc ctcagaatct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggcggtatcc agaggttgga aattgttgga tagtttacat gttgctgcag taaagcctga ctcttgaaac gcatcgagcc attaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcaccgacc tacgacttca gatcaatact ctactggagg cccactacaa aatcgaggtt acttacctag atgcaccgag catatgacaa ttgggggagc cagggatcag accgacatgc ctctcatctc cggacagatg caagcactct ggggtcttgt ttcgggccat gtgtattggc gagtggatac ggcgaggact agttccaatc acttccagag tacttttatc ttcacatggg ggtggatata catcttagag cattgtactc gctagaaggg tgttgcaacc agaggggac t cctccggggg gttcatttta cacaacagga tcactgcccg ggacgctgtg cgtagggaca gtcatcggac cctgattgca ggggcgttgt tcttacagga acaaatgtcc cacctgaaat agggtgcaag acaaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagggtaac tcagaggtca acaatgtgtc tggaaaagcc tgtttgaagt actattttga tcaaattcgc ggaaaggtgt aatcctgggt acagaggcgt acaagttgcg gcgagaatcc ctgttaatct tgatcacaca tgactatccc cgagattcaa gccatgcccc tggtgat tct ttgaacatgc cttttaggtt accaaaaact tcactcactc 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 WO 99/49017 WO 9949017PCT/US99/06225 tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc caaggaagat aggttttcca ggcatgggag cagtgaacca catcagaatt caaccagatc agctatcctg tcagaacatc ggaagttggg atatccaaat ccgtgagctc atgcctgagg aggacatcaa ggagaaaatt agccctttct gttttggttt cccatacttg tgctaatctc tgacgtttga ccgctatgac aactgataga tggagcctct ctttccttaa atgaaggtac tacatctgac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa atttgactaa gtcacagggg agaacgtgag acactgatca atctcaagaa taaatgagat ctgtcctcta gcaaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtctc tgtcccaatc aaacaagggc atgaccgtta ccataggagg tcgtgacctt actqgtct tg cattgatgct tggtttcttc ttcacttgct ccactgcttt ttatcatgag aggggagat t tgctgaaaat gaaaggtcat cagttggcca ttcaggtgaa gaaatttggc caaggcact t ttacgaccct gagctttgac tgagttcaac tgctaaaatg cgggattggc ggcac tcca c ggggccagtc agcagcaaaa tccggagaat gtactgcctt ttacggatta tgtaagtgac caatgaccaa gtggaccatc tgcttcgtta atggccttac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat tcagctgcac atcacatgat aagaaaaacg ttataccctg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaact at taact tgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatacag cctgcactcg tacctgcagc actgaaatac ttaattgaag ttctcatttt gttaggaaat gccatattct cccctgaccc gggttaacac tgctttatgc gctgctctcc cccaaaggaa ccatatgaca ctgtcttaca acttacaaaa aattatttta actctagctg ttaaaaaccc gggtttatag atggaggctt aattggagat ccctcatttt cctcattgcc atcttcatta agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta t ccc tgaa cg agtcactcgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa gaaattcgct cacggcttgg gagtttacat Ctgagatgag cagtattctt tcagtaaaga atgtcataga agcttctagg ggaatccaac tgagggatat atgatgttct ccctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ctgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg tctcaggagt actcccgaag gattccctca acgagacagt atgagaccat tccagtggct cccctgacct agtaccctat cctatttata acaatcagac aacgggaagc acataggcca caaaaggaat gtgtattctg caacaatggc tcctaaaagt gaagatggaa catcaggcat gtggttcccc agatagcccg cgcatacagc attttccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagtcaga ttaccaaatt aa cagt agaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggcttgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag ccccaaagat cccagtccac tgtaatt cgg cagtgcattt cagcttattt gcataagagg tgacgcccat gggaggtata cctggctgct catagccgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa ccaaccgcag acccactagt gttatggact atagttacca ctggaggacc caaatgatta ccgacccact aaagagtcaa gtcagtgata gaattgaggg caatggtttg aaatcacaaa tcagttgagt gtatattacc atgacagaga tacatgtgga gtagccatgc ctcagaggtg gggttttctg actgatgaca agacttgaag attgtgtatg tatcgtgaca acaatccgga tggaaatctt ctgacaatgt tacccgaaag aatgttttcc ggagcttacc aaggaaacag gctgaaaatc gacgagcacg ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacaaaggc cttgaaacct gtcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggt t atcctgatct 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 WO 99/49017 WO 9949017PCTIUS99/06225 Ctcttggctt acaacgatct tgaatatgag atctcaagag cacaacaacc ttgtatgcgt tccatagtcc agggactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tgaagcttgc cagtgtactc caaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gaccatcagg aaggagtgtt ggcattgtgg caactgtgtg aagagttaga gattcgacaa ggacctgccc atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggtaatct cttgctacaa acggcttgtt aactaaacaa aattagcacc t tgtcaaagt cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa aaggctagct gcgaggccac ctacggatgg atccttgaga cttcgtaaga atgggcttat ggccaatgtg agcgcatagg agtggcaagg ggttgatact attgtttcga aacagattgt agagcttagg cagagatgca atggtccaca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt tattatagag caacatgatt agagttcaca tatccaggca accaattcga agaggctagg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag ct tgggt gag gtgcttctat Ctatccctcc gctctttaac tcaaccatga atggcactgt gtcagaaaca tcatcactaa tcattcctag actagactcc ttaaaagggt atggacaggc ggggcaagag atgaggaagg caatttagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata gccccaagtc ggtgatgatg agcctggagg t tgagggat c tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcagcca atgggtgagc gtcaatgctc cctatccatg tacacatgct tttcttctgt aaacacttgt ggtctacgac ttatctccag tctctgactt ttcatttttg atctcaaata aaagatatca gaaatccacg atatcaacat gggtcgggtt aatagtgggg gaagttggtc gggaggcccg cccgggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gccatgagac cctcgggttg ttggttctac gatccttgcg atagctcttg agctaagggt gtaccactca tctccaacga accaacaggg ataccggatc cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcttc taagccaccc gtccttcact atatgaccta gtgaaagcga gtgttctagc ctgtagagaa cagggtcttc atctccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa ttgtcgaaca aagtcacgtg agtcataccc tatcgggggg agtaacatca gacccttcat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgcta ctctcgagtg gctattgaca ggctagagcc ccttgaggtc atgtgtcatc ccaactggat cactgatgag atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gcttatagag atttgatgta gttcctttct aaagatctac tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggatttcaga gcacaatctt aatcgggtta atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca agaatagcaa tggttgttgg atctcaactt tcaggtacat tttgtcatat gggttgggtg gtattacatc at acc cagc t gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct aacttacaca ttgttgaatg gtac cgga ca tgtcaaccag ctaaccgatc aatccaatta aaacagataa gtcagtcagc cctccacacg cccatttcag aactcatccg ccaggggaag gagatactaa ggt caaaggg gtaggtaata gtagattgct 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 WO 99/49017 WO 9949017PCTIUS99/06225 tcaatttcat agaccttacc tggctctgct gggattttgt tctaccctag aagctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ctaagtcaga taacaatcaa attaattggt tatattaaag agtcagtaat taacaaagat ccttggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagt t ggtgctgatc ccatgatgtt gt tggcaaga attggtaagt tattcttctt cggttacctg gaaacagatt ggagaccaaa tggactccgg aaaactttga atccctacct actatagaga ataggatcaa ataagttatg ttcatatcta cctgaaaaga ggtcacatcc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggc aac tactccggga atactagact attatgacgg gaatggtata gaccctaatc aaatacgaag ctagtgtggg agctagagga tactggtgat tagggtctta ctgaatctta ttaagcagca tatccattaa gtatcaaccc tggcaattaa aagatggatt accaaagaag gagaacttat acagaaagtt tacaccagaa ggggtttaaa agttagtcgg ctgccctagg tttctattcc gtttatccat attagcagoc taagcttatg ttatagagaa tttagtcatg gataattgaa gcaactaagc tattctgaag cggacctaaa gcttaactct tcaacaaggg atctaggatc gataaatcgg tatcttcgtt acgtgagtgg atacagtgcc tagttaggca cagctttgtc tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtgc tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccatg acccgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg ttatttgcaa tggt 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15894 <210> 4 <211> 15894 <212> DNA <213> Measles virus <400> 4 accaaacaaa tcaagatcct tgaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat ttcagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tagt tggtga aggacctctc ggaacaaacc gattagccag gactgcatga aaatgggaga gcgcaggatc actc cat ggg ggcaagagat gtatcactgc ggatcagtag gttgggtaag attatcaggg agcattgttc cagaggaatc atccagacta actaacaggg tcagaggatc ccagtcacaa ccaatacttt gaacaaggaa taccattcta agctgattcg atttagattg tttacgccga taggattgct ttttatcttg atttgctgqt aactgcaccc ataccctctg aggtttgaac ggtgaggagg cgaggatgca agcggtcgga gatagatcaa acaagagcag aaaagaaaca aaa cac at ta ctggaccggt gcactaatag accgatgacc t ctggcctta tcacatgatg atctcagata gcccagatct gagctaagaa gagagaaaat ttcatggtgg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggtcgat tcagctggaa aggcttgtt t cccagacaag tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaagcag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ct ctaa tcc t gtgacattga ttgggataga cacttgagtc tcctagagaa atgccatggg cttactttga aggtcagttc cagagattgc cccaagtatc tattctagta atccgagatg acccattaca aattcctgga aattggaaac cttatttgtg catcaggctg aagaggtacc tagtgatcaa agatcctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaat ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg tccaggtccg ggattcaaca gt tacggccc caaagaaggg aggattgccg aggacacccg gtagaggcag cctgctcttg Ct ttac cag c aacaagttca gaacttgaaa tttagattag tccgaactcg actgaggaca ggtgatcaaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 WO 99/49017 WO 9949017PCTIUS99/06225 gtgagaatga gctaccagga gagaagccag ggagagctac cccatcctcc aaccagcatg cgcaggacag tcgaaggtca tggaagaaca aggctcagac attaggtgcg agaggccgag aaaacttagg aaccaggtcc gagccgatgg cagaagagca ctcaaggccg agcccatcgg atatcagaca atccaggaca ggtctcagca aaccatgctt cgcggtcagg gatctggaga aatctccagg catcaagcac gcggttaagg gaatccaaga agcaccctct caggaggaga gataccgagg gatatgctat gcttctgatg ttgaaactgc agaggcaaca actttccgaa agtagggcca gcacttccga tttggaacgg agatcgegtc ccctcggaac cgtcagggcc gccgcactga tacaggagtg aataatgaag aagggggaga aaaacagcct tggccaaaat ttgctgttat tgaagggaga agcatatcca ccctggaagg aaggatccca acgaccccac ggcagagatt caggccgagc Ctccagggaa tgactaatgg Ctaaagccga tcgggaaaaa gcatcacgca gtgtaatccg Cgttacctgt tgactctcct cagatgctga tgaagataat ccagtcgacc taattagtac gcctcctaag ttccacaatg aagggtcgat cgctccgata tcagagtcat agatcctggt tgctgggggt tgttgaggac ccctgccctt aggtgttggt Ctgagcttga catagttgtt acaacacccc actaaccctc tcaatgcaaa ccaagtgtgc tccgtgttgt ttatatgagc gaagaatgct ggaattcaga ggattgacaa ggcgattggc caacatttat ggtccacatc attattgcaa aatgaaaatc gcaccagtct tcacattaga ttggggggca agagaaaccg ccc ctaga Ca gctgacgctc a cggaca CCC gaccagaaca acacagccgc ggcacgccat Ctcactggcc ggaccgagcc ctcagcaatt aagcgatgac tgggttacag tgctgactct Cgatgaatct cactgaccgg agaaggaggg gcttgggaaa gacacccatt tttattgaca agatgcacct gacacccgaa Ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggac Cagt ggtgagctca ctccattata tgatgatatc aatgaagtag aacctaaatc acagagatct caacctacCa Ctaggtgata agagatcccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc t Cggtcaatg CC tgggaaga gggaacttca gaaaagatgg agcacaggca aggaagacag agtccagcag ttgacactgc tgctcaggct Ctagggtata acatccgcct cagccaacca gtcaaaaacg gtcgaggaag gcctgcaagg ggatcaaCtg gacgctgaaa tgttatcatg atcatggttc gaaaacagcg ggatCtgCt C gagatccacg actctcaatg aaaaagggga ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaactcaatc gttctcaaga tccagaggac gccgtCgggt aaatccagcc aaaggagcca ctacagctca Cattataaaa acgacttcga cctacagtga ggaaggatga tagggcctcc caaaacccga cagggctcaa ggagaaaggt atctaatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gCCtggtttt aaatgagcaa gagggtcaaa agcaagtgat atcggagtca gcaagccatg caatgacaga accctccatc accatccact gactggaatg ccatggcagc aagaggaggc aaggcggtgc Ctttgggaat tttatgatca aatcaggcct atgtggatat ccatctctat agctcctgaa ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctccgatgt taatctccaa agatcaacag ttgccattcc ccgacctgaa agcccgttgc agctgctgaa ttgtccctga ggctagagga acgatcttgc acttacctgc aacttaggag caagtcggca tggcaggctg atgctttatg aatcgggcga ggaactcctc tgaaaaactg cctaacaaca gctggacacc cgggtattac caacctgcta tgcagagcaa gagtgaagtc tgCaCt tggt gactctccat cagagtcggg gcgagagctg ggccaagatc gcaggaatct gatcttctag attgttataa cccacgactg catccgggct atggtcagaa aggcagttcg acctcgcatc cccctcaaga cagcggtgaa tgatggtgat t gg cga a CCt ggggttcagg actccaatcc C CcgaaC CC C at tggCCtCa tcgaaagtca tgtgagcaat gagatcccag ccaagacatc gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcaa caccggccct ggatcggaag caagttccac caaccccatg Caaagtgatt tgggacatca gtgccccagg tacatgtttc gcattcgggt aaagaggcca gtgttctaca gggagtgtct CCgcagaggt accgttccca gtgaccctca cttcctgagg tactctgccg gggatagggg gcacaactcg 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 WO 99/49017 WO 9949017PCT[US99/06225 ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gccgacagca ccaccagcca cgctccggac actggaaggc gaccgaggtg actaaacaaa cggcaccgcg ccccggtgcc aatccaagac gaggaagccc gggccaccag accccaggcc tgggggaccc ctcctcctct cccaccccta ggtctcaagg accggtcaaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ctgaactctc gaggcaatca atcaataatg ctagggctca cgggacccca at caa taagg agcagaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tccaccaagt tcacaaggga acgatcatta gtggtcgagg tacctgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agtgtggaca tcccaatccg acagaccacc cccttccccc acccaaccgc acttagggcc cccccacccc cacaggtagg ggggggcccc acccacccca ctcccagact cgatccggcg ccaaaccgca tctcgaaggg aaggagacac tgaatgtctt tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga ggcaagcagg agctgatacc aattgctcag tatctgcgga tattagaaaa taaaggcccg atccgacgct atataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggtgt gaattgacct atgcaattgc ggagtatgaa gagggttgat gggaacaagt tacccactga atagtaagaa gacgtgatca aatacccgaa tccaaaagac ccaggcggcc cgtcctcctc agccgcatcc ctcccccaac aggcatccga aaggaacaca ccgaaaacca cacaccaacc ccccaaaaaa cacacgacca cggccatcac ggaagccacc aaagacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatccatc gctcggatac gataactcac gtccgagatt tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggtcctccc taagctggag aggtttatcg agggatcccc tggtatgtca tggatatcaa tccaggcagt taaatgatga aacgaccccc ttcacggacc caagcacaga gtaggacccc ccacagccct gcaagaaccc ctccctagac cacacccgac gagggagccc cccgaacaga aggcccccag cggcaaccaa cccgaaaaaa caacccgaac gtatcccacc caatccacca agaatcaaga atggcagtac aagatagggg caatcattgg gaaattgcag aatgcaatga agatttgcgg acagccggca gcaagcctgg atattggctg caactatctt gaaatcctgt caggctttga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatcctct ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tcccctacaa tgaagacctt tttgcagcca cc aaggac ta ctcataatga aagcgagagg acagccccga cgaggaccaa cgggaaagga cacaaccgaa agaccctccc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagagccc ggaaaggcca cagcacccaa gcctctccaa catccgacga ctcatccaat tgttaactct tggtagggat tcataaaatt aatacaggag cccagaatat gagttgtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaagttgga aattgctgga tagtttacat gttgctgcag taaagcctga ctcttgaaac aatcggttac tcagttcctc ttcaaagttc cagccagaag ccagccagca cacaaggcca cccccaaggt acccccagca ccgcacaagc tccccggcat ccccggcccg ccgccgcccc agccaccgac ccagcatcgc agaccaccct caacccgcgc gagcgatccc gtcccccggt cactcaattc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccggtt ggcaggtgcg ccagtccatg tcaggcaatt ccaagactac cggccagaag ccccagctta tgggggagat catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggact cctccggggg gttcatttta cacaacagga tcactgcccg ggacgcggtg cgtagggaca gtcatcggac cctgattgca ggggcgttgt tcttacaggg acagatttcc 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 acatcaaaat cctatgtaag gtcgctctga WO 99/49017 WO 9949017PCT/US99/06225 cacaagtctc tgtctccggc atcatccaca tcctaaggga tttgctggct cattagactc tctagatgta gatcatcqgt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggggttatc gcaaccagtc agccctctgt cagcttccag ccccctatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcag tgtggtttat gcctataaag Ctggtgccgt tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc caaggaagat aggttttcca aggacatcaa agccctttct cccatacttg tgttaatctc tgacgtttga ccgctatgac ctctccgtca ttccctctgg atgtcaccac agtaggatag gttctattcg catcgggcag actaactcaa gatgaagtgg aaaattaaat aacccgccag gaactcatga ctagctgtct atgtcgctgt accatgacat agtaaagggt agaaatccgg agtaatgatt cacagggaag ctcgtcaagc acggatgatc aatcaagcaa tgcttccagc ccattgaagg gttgagctta atggacctat aacctagcct aacctcttca cctgcggagg gatctccaat tatgtttaca ggggtcccaa cacttctgtg ggcatgggag cagtgaaccg catcagaatt caaceagatc agctatcctg t'cagaacatc ggaagttggg atatccaaat ccgtgagctc atgcctgagg ggagaaaatt gttttggttt ccataggagg tcgtgacctt actggttttg cattgatgct tcaagcaacc ccgaacgata accgagaccg ttattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa a tg ca ttgg t caaagggaaa ccctgttgga cccagggaat cagagttgtc gt ttgggggc tcagcaactg attctgtcac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaaaccaa taggtgtaat ctgttccaat tggatggtga atgttttggc gcccaggccg tcgaattaca tgcttgcgga tcagctgcac atcacatgat aagaaaaacg ttgtaccctg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctaaaaaagg gacactaact attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatgcag accgcatcca tcggtagtta aataaatgcc agaacatctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtacggggga acaactgagc tc cggtgt tc catggtggct ggt tcccta t gaaatcccca taggctttac cccgacaaca gggtaaaaac tccttcatac tgcttcagga ccacaacaat caacacattg caaggaagca tgtcaaactc aacctacgat ctcattttct agtggaatgc ttcagaatct agtcactcgg gtcactcaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa gaaattcgct cacggcttgg gagtttacat ctgagatgag ctgtattctt tcagtaagga atgtcataga aacttctagg gcatcaaggc attaaaactt ttctacaaag atgattgata gggttgctag cataagagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggagg cccactacaa agtcgaggtt act tac ctag atgcaccgag catatgacaa ttgggggagc caggggtcag accgacatgc ctctcatctc cggacagatg caagcactct ggggtcttgt ttcgggccat gtgtat tggc gagtggatac ggcgaggact agttccaatc acttccaggg tacttttatc ttcacatggg ggtggacata gaagatggaa caccaggcat gtggtttccc agatagcccg cgcttacagc attctccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagt caga cacccgaaat agggtgcaag acaaccccca gaccttatgt ccattgcagg t cag ca ccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagggcaac tcagaggtca acaatgtgtc tgggaaagc c tgtttgaagt actattttga tcaggttcgc ggaaaggtgt aatcctgggt acagaggtgt acaagt tgcg gcgagaatcc ctgttaatct tgatcacaca tgactatccc cgagattcaa gccatgcccc tggtaattct ttgaacatgc cttttaggtt accaaaaact tcactcactc ccaatcgcag acccactagt gtcatggact atagttacca cttgaggacc caaatgatta ccggcccact aaagagtcaa gtcagtgata gaattgaggg caatggtttg aaatcacaaa tcagttgagc gtatattacc atgacagaga tacatgtgga 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 WO 99/49017 WO 9949017PCTIUS99/06225 aactgataga tggagccact ctttccttaa atgaaggtac tacatctgac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acct aaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa atttgactaa gtcacagggg ggaacgttaa acactgatca atctcaagaa taaatgagat ctgtcctcta gcaaagtccc gtcagaagct gggtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta ctct tggct t acaacgatct tgaacatgag atctcaagag cacaacaacc ttgtatqcgt tccatagtcc agagactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tggtttcttc ttcacttgct ccactgcttt ttatcatgag aggggagatt tqctgaaaat gaagggtcat cagttggcca ttcaggtgaa gagatttggc caaggcactt ttacgatcct gagctttgac tgagttcaat cgctaaaatg cgggattggc ggcactccac ggggccagtc agcagaaaaa tccggagaat gtactgcctt ttacggatta tgtaagtgat caatgaccaa gtggaccatc tgcctcgtta atggcct tac tcttaggcaa atcacatttt actcaagagc agcatgcagt tcttgcatat cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa aagactagct gcgaggccac ctacggatgg atccttgaga cctgcactcg tacctgcaac actgaaa tac ttaattgaag ttctcatttt gtcaggaaat gccatatttt cccctgaccc gggttaacac tgttttatgc gctgctctcc cccaagggaa ccatatgata ctgtcttaca acttacaaaa aagtatttta act ctggc tg ttaaaaacct gggtttgtag atagaaacct aattggagat ccctcatttt cctcattgcc atcttcatca agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtctatt attgcaagat aatattgcta tccctgaacg tcaaccatga atggcactgt gtcagaaaca gcatcactaa tcattcctag actagactcc ttaaaagggt atggacaggc ggggcaagag atgaggaagg caatttagag gagtcatgtt cgaggacggc cttattcggc ttt t ttgt cc gtcccatata ggaatccaac tgagggacat atgatgttct ccttagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ccgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg tctcaggagt actcccgaag gattccctca acgagacagt atgagaccat ttcagtggct cccccgacct agtaccctat cctacttata acaatcagac aacgggaagc aca ttggc ca caaaaggaat gtgtattctg caacaatggc tcctaaaagt cc cgagatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg t tggttctac ttatcaaatt aacagtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggacagtgat ggat tcagtt gaggcttgta tgtcgtaagt aaaggagatc ccaagtgatc gatggccaag ccccaaagat cccagtccac tgtaattcgg cagcgcattt cagcttattt gcataagagg tgacgcccat gggaggtata cctggc tgct catagccgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa agt cat ac cc tattgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgcta ctctcgagtg gctattgaca ggctagagcc ccttgaggtc atgtgtcatc ccaactggat cactgatgag gtagctatgc ctcagaggtg gggttttctg actgatgaca agacttgaag attgtgtatg tatcgtgaca acaa tccgga tggagatcat ctgacaatgt tacccgaaag gatgtt t tcc ggagcctacc aaggaaacaq gctgaaaatc gatgagcacg ctcaaagaaa acaagtacca cagaatcaag atcacgactg gcacagaggc cttgaaacct gtcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggtt attttgatct ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctaa gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 WO 99/49017 WO 9949017PCTIUS99/06225 tgaagcttgc cagtgtactc caaggcaaag cgactaattt cccttgtcag cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcaccatcta gaccatcagg aaggagtgt t ggcattgtgg caactgtgtg aagagttaga gattcgacaa ggacctgccc atatcaaggc ttgtagacca gattgagagt caaaggtcgg atgatgttgc ggggtagtct cttgctacaa acggcttgtt aactaaacaa aattagcacc ttgtcaaggt tcaatttcat agaccttacc tggctctact gggattttgt tctaccctag aagctaaccg ggac t tcac c caattgtggg ctatagagca aattaatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ccaagtcaga taacagtcaa cttcgtaaga atgggcttac ggccaatgtg agcgcatagg agtggcaagg agttgatact attgtttcga aacagattgt agagc tgagg cagagatgca a tggt cca ca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt tattatagag caacatggtt agagttcaca cat ccaggca accgattcga agaggctagg ttactcatgc tgat ccagga cagcaacaac aaaattgctc tgccaattat agctqttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agtcagtaat caacaaagat ccttggcaaa tcagggattt gtacagcaac gctaatgaat tggacttata aggcgcagtt ggtgctgatc ccatgatgtt gttggcaaga attggtaagt tattcttctt cggttatcta gaaacagatt ggagaccaaa gccccaagta ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcagcca atgggtgagc gtcaatgctc cctatccatg tacacatgct tttcttttgt aaacacttgt ggtctaaggc ttatctccag tctctgactt ttcatttttg atctcaaata aaagatatca gaaatccatg atatcaacat gggtcgggtt aatagtgggg gaagttggcc gggaggcccg atccctacct actatagaga ataggatcaa ataagctatg ttcatatcta cctgaaaaga ggtcacatcc agtagaggtg agttgcgggt gcctcagggc ttcaaagaca agtaggcaac tactccggga atactagact attatgacgg gaatggtata gatccttgcg atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg atactggatc cgatgataga gtaccaaccc acacccagag atcacattct aggaccatat ctgagtttct tcaattgggc tgttgtcttc taagccaccc gtccttcact atatgaccta gtgaaagcga gtgttc tggc cggtagagaa caggatcttc atctccgtcg atgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa ttgtcgaaca aagt cacgtg ctagtgtggg agttagagga tactggtgat tagggtctca ctgaatctta ttaagcagca tatctatcaa atatcaaccc tggcaattaa aagatggatt accaaagaag gagaacttgt acagaaagtt tacaccagaa ggggtttaaa atctgccgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gcttatagag atttgatgta gttcctttct aaagatctac tgatgctcaa ccttgacctg tgaggatgta agatttgtac atgtgcagtt gtggaacata aggatctatc tgaggtaaat ggatttcaga gcacaatctt aatcgggtta atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt atttatccat attggcagcc taagcttatg ttatagagaa tttagttatg gataattgaa gcaactaagc tattctgaaa cggacctaag gcttaactct tcaacaaggg atctaggatc gataaatcgg tatcttcgtt acgtgagtgg agaatagcaa tggttgttgg atctcgactt tcaggtacat tttgtcatat gggttgggtg gtattacatc atacccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgatc aatccaatta aaacagataa gtcagtcagc cctccacacg cccatttcag aactcatctg ccaggggaag gagatactaa ggtcaaaggg gtaggtaata atagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtgc tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg actcgcaaat tttatccaga aagaat ctat gtttttaagg 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 agttagtcgg atacagcgct ctgattaagg 15780 WO 99/49017 WO 9949017PCTIUS99/06225 attaattggt tgaactccgg aaccctaatc ctaccctagg tagttaggca ttatttgcaa 15840 tatattaaag aaaactttga aaatacgaag tttctattcc cagctttgtc tggt 15894 <210> <211> 15894 <212> DNA <213> Measles virus <400> accaaacaaa t caagat act taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat tccagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tggt tggtga agga cct ct C gaaacaaacc gattagccag gactgcatga aaatggggga gtgcaggatc actccatggg ggcaagagat gtatcactgc agatcagtag gtgagaatga gagaagccag cccatcttcc cgcaggacag cggaagaaca actaggtgcg aaaacttagg gagccaatgg ctcaaggccg atatcagaca ggtctcagca cgcggtcagg aatctccagg gcggttaagg agcaccctct gataccgagg gttgggtaag attatcaggg agcattgttc cagaggaatc atccagactt actaacaggg tcagaggatc ccagtcacaa ccaatacttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct ttttatcctg atttgctggt aactgcaccc ataccctctg aggtttgaac ggtaaggagg cgaggatgca agcggttgga gctaccgaga ggagagctac aaccggcaca tcgaaggtca aggctcagac agaggccgag aaccaggtcc cagaagagca agcccatcgg acccaggaca aaccatgcct gacctggaga catcaagcac gaatccaaga caggaggaga gatatgctat gatagttcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc tctggcctta tcacatgatg atctcagata gcccaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt C ccagacaag ttggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc ggccagaaca acacagccgc ggcacgccat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaattag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aggtcagttc cagagat tgc cccaagtatc aggaagatag ggcccagcag ttgacactgc tgcttaggct ctatagtgta acatccgcct cagcccatca gtcaaaaacg atcgaggaag acctgcaggg ggatcaactg gacgctgaaa tgttattacg atcatggttc gaaaacagcg tcttctagtg atccgagatg acccattaca aatccctgga aattggaaac cttatttgtg cataaggctg aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaac ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac gagggtcaaa agcaagtgat aacggagtcc gcaagccatg caatgacaga accctccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ctttgggaat tttatgatca aatcaggcct atgtggatat cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg tccaggttcg ggattcaaca gttacggccc caaagaaggg aggattgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa cagagtcgag gcgagagctg agccaagatc gcaggaat ct aatcttctag attgttataa cccacgattg catccgggct atggtcagaa aggcagttcg acctcgcatc ccccccaaga cagcggtgaa tgatggtgat tggcgaacct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 ggatctgctc ccatctctat ggggttcagg 2340 WO 99/49017 WO 9949917PCT/US99/06225 gcttctgatg agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctgttat agcatatcca aaggatccca ggcagagatt ctccaaggaa ctaaagccga gcatcacgca cgttacctga cagatgctga ccagtcgacc gcctcccaag aagggt cgat tcagagtcat tgctgggggt ccctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gc cga cggca ccaccagcca tgcccccgat attggaaggc gaccgaggtg actaaacaaa cggcgccgcg ccc cggtgcc aatccaagac gaggaagccc gggccaccag ttgaaactgc actttccgaa gcacttccgg agatcgcgtc catcagggcc tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggccgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tgaagataat caactagtac ttccacaatg cgctccgata agatcctggt tgttgaggac aggtgttggc catagttgtt actaactctc ccaagtgtgc ttatatgagc ggaattcaga ggcgataggc ggtccacatc aatgaaaatc tcacattaga gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcgcgaaca ccccaatctg ccaaaccacc ccctccccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca ctcccagact agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggaccagt gatgagctca ctccattata tgatgatatc aatgaagtag aacctaaatc acagagacct caacccacca ctaggcgaca agcgattccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca tacccgctga atagtaagaa gacgtgatca aatgcccgaa tccgaaagac cc aggcggc c catcctcctc aaccgcatcc cttcctcaac aggcatccga aaggaacata ccgacaacca gacaccaacc ccccaaaaaa cacacgacca cggccatcac gagatccacg actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca ctacagctca cattataaaa acgacttcga cctacagtga ggaaggatga tagggcctcc caaagcccga cagggctcaa ggagaaaggt atctgatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gcctggtttt aaatgagcaa tggatatcaa tccaggcagt taaatgatga aacgaccccc tccacggacc ccagcacaga gtgggacccc ccaccacccc acaagaactc ctccctagac cacacccaac gagggagccc cccgaacaga aggcccccag cggcaaccaa cccgcagaaa agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctctgatgt taatctccaa agatcaacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga atgatcttgc acttacctgc aacttaggag caagtcggca tggcaggctg atgctttatg aatcgggcga aaaactcctc tgaaaaactg cctaacaaca gctcgatacc cgggtattac caacctgctg tacagagcaa gagtgaagtc tgcacttggt gactctccat tgaagacctt tttgcagcca ccaaggacta ctcacaatga aagcgagagg acagccccga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagaaccc ggaaaggcca actccaatcc cccggacccc attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagatatt gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcag caccggccct ggatcggaag caagttccac caaccccatg caaagtgatt tgggacatca gtgccccagg tacatgtttc gcatttgggt aaagaggcca gtgttctaca gggagtgtct ccgcagaggt accgttccta gtgaccctta cttcctgagg tactctgccg gggatagggg gcacaactcg aatcgattac tcagttcctc ttcaaagttc cagccagaag ccagccagca cacaaggcca cccccaaggc ac ccc cagca ccgcacaagc tccccggcaa ccccggccca ccgccggctc aaccatcgac ccagcaccgc agaccaccct caacccgcgc 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 WO 99/49017 WO 9949017PCT/US99/06225 accccagccc cgaaggaccc ctcctcctct cccaccccta ggtctcaagg a ccggt caaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ctgaactctc gaggcaatca atcaataatg ctcgggctca cggga cccca atcaataagg agcggaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tacaccaagt t cacaaggga acgatcatta gtagtcgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcaaaat cacaagtctc tatctccggc atcatccaca tcccaaggga tttgctggc t cattagactt tctagatgta aatcatcggt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgt tatc cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga tgttagaaaa taaaggcccg atccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggttgat gagaacaagt cctatgtaag ctcttcgtca t tccct ctgg atgtcaccac agtaggatag gttctgtttg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actatgacat agcaaaaggt agaaatccgg gggagccacc aaggacacca accaaaagat cgggaa tccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc gctcggatac gataactcac gtccgagatt tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gatcatccaa cggtcc tccc taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tcaagcaacc ccgaacaata aacgagaccg tcattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaat caa atgcattggt caaagggaaa ccctgttaga cccagggaat cagagttgtc gtttgggggc caacccgaac gtatcccaca caatccacca agaatcaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcgg acagccggca gcgagcctgg atattggctg caactatctt gaaatcctgt caggctttga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tCctctacaa accgcaccca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtatggggga acaactgagc tccggtgtt c cagcacccaa gcctctccaa cacccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaggttgga aat tgttgga tagtctacat gttgctgcag taaagcctga ctcttgaaac g cat caagc c attaaaactt ttctacaaag atgattgata gggt tgc tag cataaaagcc gtgctgacac t tcac tgac c tacgacttca gatcaatact ctactggaga cccactacaa ggt cgaggtt act tacctag atgtaccgag catatgacaa gagcgatccc gtcccccggt cactcaactc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccggtt ggcaggtgcg ccagtccatg tcaggcaatt ccaagactac cggccagaag ccccagttta tggaggagac catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggact cctccggggg gttcatttta cacaacagga tcactgcccg agacgctgtg cgtagggaca gtcatcggac cctgattgca ggggcgt tgt tcttacggga acaaatgtcc cacctgaaat agggtgcaag ataaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggt ca acaatgtgtc tggaaaagcc tgtttgaagt actatcttga 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 WO 99/49017 WO 9949017PCT[US99/06225 gcaaccagrtc agccctttgt cagcttccag ccccttatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcaa tgtggttat gcctataaag ctggtgccgt tgggatggtg atagggc tgc gtgaaataga cgctatctgt ataagatagt ctacacigtg taaacaatgt ctcatattcc cgaggaagat aggttitcca aggacatcaa agccctttc t cccatacttg tgctaaictc tgacatttga ccgctatgac aactgataga tggagcctct ctttccttaa atgaaggtac tacaicigac cagtaacggc agacicigat ggcacggagg aigcicaagc tigciggagt acciaaagga agticcigcg itaatgattc tccatgaccc gtagacitttt taatctcaaa agtaatgatc cacggggaag ctcgicaagc acggatgatc aatcaagcaa tgcttccaac ccaitgaagg gttgagctta aiggacciat aacciagcct taccictica ccigcggagg gatctccaat tacgtttaca ggggicccca cactictgtg ggcatgggag tagtgaacca catcagaatt caaccagaic agccatcctg tcagaacatc ggaagttggg atatccaaai ccgtgaactc atgcttaagg ggagaaagit gttiggiti ccataggagg tcgtgaccti actggtt tig tattgatgct tggtttcttc itcacitgci ccacigcttt itaicaigag aggggagatt tgctgaaaat gaaaggtcat cagtiggcca ticaggtgaa gaaatttggc caaggcactt tiacgaccct gagctigac tgagttcaac tgctaaaatg cgggattggc tcagcaactg atictaicac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa a taa caggat aaatcaaaat acaaatccaa taggtgtaai ctgtcccaai tggatggtga aigttttggc gcccaagccg tcgaattaca tgcttgcgga tcagctgcac atcacaigat aagaaaaacg ttataccctg gagiatgctc aagcaccgcc aaigtcatca igtaatcagg ctcaaaaagg gacactaact attaactigg acagtcaaga agacacacac gtigctataa atgtatigtg aggiatacag cctgcacicg iacctgcagc actgaaaiac ttaaiigaag ttctcatttt gttaggaaat gccatattt ccgctgaccc gggttaacac tgctttatgc gctgcictcc cccaagggaa ccatatgatg ctgtcttaca acttacaaaa aaatatttta tatggiggct aaticcctat gaaaicccca caggcttiac cccgacaaca gggiaaaatc tccttcatac tgcticggga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctacgat ctcatittct agiggaatgc ctcagaatct agtcacccgg gtcacccaga tagggtccaa aagticacci gagiccctca taaaaaacgg agiccaagct aiiiatitaa ggaaticgci cacggctigg gagitiacat cigagatgag cigiaticti tcagiaaaga aigicataga agctictagg ggaaiccaac tgagggatai atgaigitct ctctagatta tcagaagtti acaigaatca gtggaatcat tccccctgca aigagcagtg Ccictagcci aaagggaatg ccgggicacg igataatgta gccigaaaga tgagggcatg aggacaatgg ttgggggagc cagggaicag accgacaigc ctcicatctc cgaacagatg caagcacict ggggtcitgt iicgggccat gtgtatiggc gagiggatac ggcgaagact agttccaatc acttccaggg tactittatc itcacaiggg ggtggacata gaagaiggaa catcaggcat giggticccc agatagcccg cgcitacagc atittccaac taggagttat catagaagac gtactccaaa cctaggcicc gcacagcicc gicagigait cactggtagt gtctcaacat ggggaggt ta aagagtcaga itaicaaatt aacagtagaa igaccaaaac cattttcata cggccacccc gcciaaagtc aatcaacggc tgcigcagac cgttgataac ggaiagtgat ggaitcagtt gaggc ttgta tgtigtaagt aaaggagatc ccaagigatt gatggccaag icaaactcgc ggaaaggtgt aatccigggi acagaggigi acaagttgcg gcgagaatcc ctgttgatci tgaicacaca tgactatccc cgagattcaa gccatgcccc tggtgaiict t tgaacatgc ctitaggit accaaaaact tcactcacic ccaatcgcag acccaciagi gttaiggact atagttacca ctggaggacc caaatgatia ccggcccact aaagagtcaa gicagigata gaattgaggg cagiggtig aaatcacaaa tcagttgagt gtatatiacc atgacagaga tacaigigga gtagccatgc ctcagaggtg gggttitcig acigaigaca agacitgaag atigtgtaig taicgtgaca acaatccgga tggaaaictt cigacaaigt tacccgaaag gatgttiicc ggagctiacc aaggaaacag gctgaaaatc gatgagcacg 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 WO 99/49017 WO 9949017PCT/US99/06225 atttgactaa gtcacagggg ggaacgtgag acactgatca atctcaagaa ,taaatgagat ctgtcctgta ataaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta ctcttggctt acaacgacct tgaatatgag atctcaagag cacaacaacc ttgtatgtgt tccatagtcc agggactggc tcctggatca aaggcttgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tgaagc ttgc cagtgtactc ctaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gaccatcagg aaggagtgt t ggcactccac ggggccagtc agcagcaaaa tccggagaat gtactgcctt ttacggattg tgtaagtgac caatgatcaa gtggaccatc tgcttcgtta atggccctac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa gaggctagct gcgaggccac ctacggatgg atccttgaga cttcgtaaga atgggcttac ggccaatgtg agcgcatagg agtggcgagg ggttgatact attgtttcga aacagattgt agagctgagg cagagatgca atggt ccaca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt actctagctg ttaaaaacct gggtttatag atggaagctt aattggagat Ccctcatttt cctcattgcc atcttcatta agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta tccctgaacg tcaaccatga atggcactgt gtcagaaaca gcctcactaa tcattcctag actagactcc t taaaagga t atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata gccccaagtc ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggct at ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc tctcaggagt actcccgaag ggttccctca acgagacagt atgagaccat t ccagtggct cccccgacct agtaccctat cctatctata acaatcagac aacgggaagc atattggcca caaaaggaat gtgtattctg caacaatggc tcctaaaagt cccgggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg ttggt tctac gatccttgcg atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg ataccggatc cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcatc t aagc ca ccc ccccaaagat cccagtccac agtaattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagccgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa agt ca taccc tattgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgctg ctctcgagtg gctattgaca ggcgagagct ccttgaggtc atgtgtcatc ccaactggat cactgatgag atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg t cat ccc agg attgatatat ccataggagg agctaagtcc gaatgaaatt gctcatagag atttgatgta gttcctttct aaagatctac ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggtt attctgatct ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaagc ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca agaatagcaa tggttgttgg atctcaactt tcaggtacat tttgtcatat gggt tgggtg gtattacatc at ac ccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 WO 99/49017 WO 9949017PCTIUS99/06225 ggcattgtgg caactgtgtg aagagttaga gattcgacaa ggac ctgcc C atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggcaatct cttgctacaa acggct tgt t aactaaacaa aattagcacc ttgtcaaagt tcaatttcat agaccttgcc tggctctgc t gggattttgt tataccctag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tctgggggca at c tcaag tc ccaagtcaga taacagtcaa actaattggt tatattaaag tattatagag caacatggtt agagttcaca catccaggca accaattcga agaggctatg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agttagtaat tgacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagtt ggtgctgatc ccatgatgtt gttggcaaga attggtaagt cattcttctt cggctatctg gaaacagatt ggagaccaaa tgaact ccgg aaaactttga cctatccatg tacacatgct tttctcttgt aaacacttat ggtctaagac ttatctccag tctctgactt ttcattttcg atctcaaata aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagttggcc gggaggcccg atccctacct actatagaga ataggatcaa ataagttatg ttcatctcta cctgaaaaga ggtCa cat cc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggcaac tactccggga atactagact attatgacgg gaatggtata aaccctaatc aaatacgaag gtccttcact atatgaccta gtgaaagcga gtgttctggc cggtagagaa caggatcttc atct ccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat t t tccgccaa ttgtcgaaca aagtcacgtg ctagtgtggg agctagagga tactggtgat tagggtctca ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa aagatggat t accaaagaag gagaacttat acagaaagtt tacaccagaa ggggtttgaa agttagtcgg C tg C cc tagg tttctattcc tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat gqctttcaga gcacaatctt aatcgggttg atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt gtttatccat attggcagcc taagcttatg ttatagagaa tttggttatg gataattgaa gcaactaagc tactctgaaa cggacctaag gcttaattct tcaacaaggg atctaggatc gataaataag tatcttcgtt acgtgagtgg atacagtgcc tggttaggca cagctttgtc aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagtcagc cccccacacg cccatttcag aactcatctg ccaggggagg gagatactta ggtcaaaggg gtaggtaata gtagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtga tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg acccgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg ttatttgcaa tggt 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15894 <210> 6 <211> 15894 <212> DNA <213> Measles virus <400> 6 acCaaacaaa tcaagatcct taaggagct t gtggagccat ttaccactcg gcgggcccaa gtcaattgat gttgggtaag attatcaggg agcattgttc cagaggaatc atccagactt actaacaggg tcagaggatc gatagttcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc tcaatgatca gattagggat aggacaaa cc ttatagtacc tggtgaggtt gtatattatc ctgacgttag tcttctagtg atccgagatg acccattaca aatccctgga aattggaaac cttatttgtg cataaggctg cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg WO 99/49017 WO 9949017PCTIUS99/06225 tccagagtga atgaggcgga gatggttcgg tgattctggg cagacacggc tagt tggtga aggacctctc gaaacaaacc gattagccag gactgcatga aaatggggga gtgcaggatc actccatggg ggcaagagat gtatcactgc agatcagtag gtgagaatga gagaagccag cccatcttcc cgcaggacag cggaagaaca actaggtgcg aaaacttagg gagccaatgg ct caaggccg atatcagaca ggtctcagca cgcggtcagg aatctccagg gcggttaagg agcaccctct gataccgagg gcttctgatg agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctqttat agcatatcca aaggatccca ggcagagatt ctccaaggaa ctaaagccga gcatcacgca cgttacctga ccagtcacaa ccaatacttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct ttttatcctg atttgctggt aactgcaccc ataccctctg aggtttgaac ggtaaggagg cgaggatgca agcggt tgga gctaccgaga ggagagctac aaccggcaca tcgaaggtca aggctcagac agaggccgag aa ccaggt cc cagaagagca agcccatcgg acccaggaca aaccatgcct gacctggaga catcaagcac gaatccaaga caggaggaga gatatgctat ttgaaactgc actttccgaa gcacttccgg agatcgcqtc catcagggcc tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggccgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tctggcctta tcacatgatg atctcagata gcccaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt cccagacaag t tggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc ggccagaaca acacagccgc ggcacgccat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggaccagt gatgagctca ctccattata tgatgatatc ccttcgcatc atccaattag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aggtcagttc cagagattgc cccaagtatc aggaagatag ggcccagcag ttgacactgc tgcttaggct ctatagtgta acatccgcct cagc ccat ca gtcaaaaacg atcgaggaag acctgcaggg ggatcaactg gacgctgaaa tgttattacg atcatggttc gaaaacagcg ggatctgctc gagatccacg actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatat caag tacatatatc aactatgtat cttgatgaac ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac gagggtcaaa agcaagtgat aacggagtcc gcaagccatg caatgacaga accatccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ctttgggaat tttatgatca aatcaggcct atgtggatat ccatctctat agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctctgatgt taatctccaa agatcaacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga atgatcttgc aacatggagg tccaggttcg ggattcaaca gttacggccc caaagaaggg aggat tgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa cagagtcgag gcgagagctg agccaagatc gcaggaatct aatcttctag attgttataa cccacgattg catccgggct atggtcagaa aggcagttcg acctcgcatc ccccccaaga cagcggtgaa tgatggtgat tggcgaacct ggggttcagg actccaatcc cccggacccc attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagatatt gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcag cac cggcc ct ggatcggaag caagttccac 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 WO 99/49017 WO 9949017PCTIUS99/06225 cagatgctga ccagtcgacc gcctcccaag aagggtcgat tcagagtcat tgctgggggt tcctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gccgacggca ccaccagcca tgcccccgat attggaaggc gaccgaggtg actaaacaaa cggtgccgcg ccccggtgcc aatccaagac gaggaagccc gggccaccag accccagccc cgaaggaccc ctcctcctct cccaccccta ggtctcaagg accggtcaaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ctgaactctc gagacaatca atcaataatg ctcgggctca cgggacccca tgaagataat caactagtac gtccacaatg cgctccgata agatcctggt tgttgaggac aggtgt tggc catagttgtt actaactctc ccaagtgtgc ttatatgagc ggaattcaga ggcgataggc ggtccacatc aatgaaaatc tcacattaga gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcgcgaaca ccccaatctg ccaaaccacc ccctccccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca ctcccagact cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga aatgaagtag aacctaaatc acagagacct caacccacca ctaggcgaca agcgattccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca tacccgctga atagtaagaa gacgtgatca aatgcccgaa tccgaaagac ccaggcggcc catcctcctc aaccgcatcc cttcctcaac aggcatccga aaggaacata ccgacaacca gacaccaacc ccccaaaaaa cacacgacca cggc cat cac gggagccacc aaggacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc ctacagctca cattataaaa acgacttcga cctacagtga ggaaggatga tagggcctcc caaagcccga cagggctcaa ggagaaaggt atctgatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gcctggtt tt aaatgagcaa tggatatcaa tccaggcagt taaatgatga aacgaccccc tccacggacc ccagcacaga gtgggacccc ccaccacccc acaagaactc ctccctagac cacacccaac gagggagccc cccgaacaga aggcccccag cggcaaccaa cccgcagaaa caacccgaac gtatcccaca caatccacca agaatcaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcgg acagccggca gcgagcctgg atattggctg caactatctt gaaatcctgt caggctttga acttacctgc aacttaggag caagtcggca tggcaggctg atgctttatg aat cgggcga aaaactcctc tgaaaaactg cctaacaaca gctcgatacc cgggtattac caacctgctg tacagagcaa gagtgaagtc tgcacttggt gactctccat tgaagacctt tttgcagcca ccaaggacta ctcacaatga aagcgagagg acagccctga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagaaccc ggaaaggcca cagcacccaa gcctctccaa cacccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct caaccccatg caaagtgatt tgggacatca gtgccccagg tacatgtttc gcatttgggt aaagaggc ca gtgttctaca gggagtgtct ccgcagaggt accgttccta gtgaccctta cttcctgagg tactctgccg gggatagggg gcacaactcg aatcgattac tcagttcctc ttcaaagttc cagccagaag ccagccagca cacaaggcca cccccaaggc acccccagca ccgcacaagc tccccggcaa ccccggtcca ccgccggctc aaccatcgac ccagcaccgc aga ccac cc t caacccgcgc gagcgatccc gt cc C Ccggt cactcaactc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccggtt ggcaggtgcg ccagtccatg tcaggcaatt ccaagactac cggccagaag ccccagttta tzggaggagac 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 WO 99/49017 WO 9949017PCT/US99/06225 atcaataagg agcggaggaa agtatagcct gtctcgtaca caagggta cc gtgtgcagcc tacaccaagt tcacaaggga acgatcatta gtagtcgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcaaaat cacaagtctc tatctccggc atcatccaca tcccaaggga tttgctggct cattagactt tctagatgta aatcat cggt aatctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc gcaaccagtc agccctttgt cagcttccag Ccccttatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcaa tgtggtttat gcctataaag ctggtgccgt tgttagaaaa taaaggcccg atccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcqt gaattgacct atgcaattgc ggagtatgaa gagggt tgat gagaacaagt cctatgtaag ctcttcgtca t tccct ctgg atgtcaccac agtaggatag gttctgtttg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actaigacat agcaaaaggt agaaatccgg agtaatgatc cacggggaag ctcgtcaagc acggatgatc aat caagcaa tgcttccaac ccattgaagg gttgagctta atggacctat aacctagcct tacctcttca cctgcggagg gatctccaat tacgtttaca ggggtcccca cacttctgtg gctcggatac gataactcac gtccgagatt tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggtcctccc taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tcaagcaacc ccgaacaata aacgagaccg tcattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa atgcattggt caaagggaaa ccctgttaga cccagggaat cagagttgtc gtttgggggc tcagcaactg attctatcac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaatccaa taggtgtaat ctgtcccaat tggatggtga atgttttggc gcccaagccg tcgaattaca tgcttgcgga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tcctctacaa accgcaccca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtatggggga acaactgagc tccggtgttc tatggtggct aattccctat gaaatcccca caggctttac cccgacaaca gggtaaaatc tccttcatac tgcttcggga ccacaacaat caacacattg taaggaagca tgtcaaact c aacctacgat ctcattttct agtggaatgc ctcagaatct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaggttgga aattgttgga tagtctacat gttgctgcag taaagcctga ctcttgaaac gcatcaagcc atcaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggaga cccactacaa ggtcgaggtt acttacctag atgtaccgag catatgacaa ttgggggagc cagggatcag accgacatgc ctctcatctc cgaacagatg caagcactct ggggtcttgt ttcgggccat gtgtattggc gagtggatac ggcgaagact agttccaatc acttccaggg tacttttatc ttcacatggg ggtggacata catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggact cctccggggg gttcatttta c acaa cagga tcactgcccg agacgctgtg cgtagggaCa gtcatcggac cctgattgca ggggcgt tgt tcttacggga acaaatgtcc cacctgaaat agggtgcaag ataaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggtca acaatgtgtc tggaaaagcc tgtttgaagt actatcttga tcaaactcgc ggaaaggtgt aatcctgggt acagaggtgt acaagttgcg gcgagaatcc ctgttgatct tgatcacaca tgactatccc cgagattcaa gccatgcccc tggtgattct ttgaacatgc cttttaggtt accaaaaact tcactcactc 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 WO 99/49017 WO 9949017PCT/US99/06225 tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc cgaggaagat aggt tt tcca aggacat caa agccctttct cccatacttg tgctaatctc tgacatttga ccgctatgac aactgataga tggagcctct ctttccttaa atgaaggtac tacatctgac cagtaacggc agactctgat ggcacggagg atgc tcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa atttgactaa gtcacagggg ggaacgtgag acactgatca atctcaagaa taaatgagat ctgtcctgta ataaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta gqcatgggag tagtgaacca catcagaatt caaccagatc agccatcctg tcagaacatc ggaagt tggg atatccaaat ccgtgaactc atgcttaagg ggagaaagtt gt t ttggt tt ccataggagg tcgtgacctt actggttttg tattgatgct tggtttcttc ttcacttgct ccactgcttt ttatcatgag aggggagatt tgctgaaaat gaaaggtcat cagttggcca ttcaggtgaa gaaatt tggc caaggcactt ttacgaccct gagctttgac tgagttcaac tgctaaaatg cgggattggc ggcactccac ggggccagtc agcagcaaaa tccggagaat gtactgcctt ttacggattg tgtaagtgac caatgatcaa gtggaccatc tgcttcgtta atggccctac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat tcagctgcac atcacatgat aagaaaaacg ttataccctg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaact attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatacag cctgcactcg tacctgcagc actgaaatac ttaactgaag ttctcatttt gttaggaaat gccatatttt ccgctgaccc gggttaacac tgctttatgc gctgctctcc cccaagggaa ccatatgatg ctgtcttaca acttacaaaa aaatatttta actctagctg ttaaaaacct gggtttatag atggaagctt aattggagat ccctcatttt cctcattgcc atcttcatta agcaccattc gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta tccctgaacg agtcacccgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa ggaattcgct cacggcttgg gagtttacat o tgagatgag ctgtattctt tcagtaaaga atgtcataga agcttctagg ggaa tocaa c tgagggata t atgatgttct ctctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ccgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg tctcaggagt actcccgaag ggticcctca acgagacagt atgagaccat tccagtggct cccccgacct agtaccctat cctatctata acaatcagac aacgggaagc atattggcca caaaaggaat gtgtattctg caacaatggc tcctaaaagt gaagatggaa catcaggcat gtggttcccc agatagcccg cgcttacagc attttccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagt caga ttatcaaatt aacagtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggcttgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag ccccaaagat cccagtccac agtaattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagccgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa ccaatcgcag a occact agt qttatggact atagttacca ctggaggacc caaatgatta ccggcccact aaagagtcaa gtcagtgata gaattgaggg cagtggtt tg aaatcacaaa tcagttgagt gtatattacc atgacagaga tacatgtgga gtagccatgc ctcagaggtg gggttttctg actgatgaca agacttgaag attgtgtatg tatcgtgaca acaatccgga t ggaa at ct t ctgacaatgt tacccgaaag gatgttttcc ggagcttacc aaggaaacag gctgaaaatc gatgagcacg ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt qcaaatgaga gggctacttg atagttgatg gagagaggt t attctgatct 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 WO 99/49017 WO 9949017PCTIUS99/06225 ctcttgqctt acaacgacct tgaatatgag atctcaagag cacaacaacc ttgtatgtgt tc catagt cc agggactggc tcctggatca aaggcttgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tgaagcttgc cagtgtactc ctaggcaaag cgactaattt CCcttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gac cat cagg aaggagtgtt ggcattgtgg caactgtgtg aagagt taga gattcgacaa gga cc tgc cc atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggcaatct cttgctacaa acqgcttgtt aactaaacaa aattagcacc ttgtcaaagt cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcattcctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa gaggctagct gcgaggccac ctacggatgg atccttgaga cttcgtaaga atgggcttac ggccaatgtg agcgcatagg agtggcgagg ggttgatact attgtttcga aacagattgt agagctgagg cagagatgca a tggt ccaca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt tattatagag caacatggtt agagttcaca catccaggca accaattcga agaggctatg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac tcaaccatga atggcactgt gtcagaaaca gcctcactaa tcattcctag actagactcc ttaaaaggat atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata gccccaagtc ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc cctatccatg tacacatgct tttctcttgt aaacacttat ggtctaagac ttatctccag tctctgactt ttcattttcg atctcaaata aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagttggcc gggaggcccg cccgggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg ttggttctac gatccttgcg atagctcttg agctaagggt gt agcac tca tctccaacga accaacaagg a ta ccggat c cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcatc taagccaccc gtccttcact atatgaccta gtgaaagcga gtgttctggc cggtagagaa caggatcttc atctccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa ttgtcgaaca aagtcacgtg agtcataccc tattgggggg agtaacatca gaccctccat cgacccttac aac tgcaagg tgacagtaaa acctagggca aggcatgctg ctctcgagtg gctattgaca ggcgagagct ccttgaggtc atgtgtcatc ccaactggat cactgatgag atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gctcatagag atttgatgta gttcctttct aaagatctac tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggctttcaga gcacaatctt aatcgggttg atgccttgag cacttataaa ttctagatct cagaatggga ggtaggcagt ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca agaatagcaa tggttgttgg atctcaactt tcaggtacat tttgtcatat gggttgggtg gtattacatc atacccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagtcagc cccccacacg cccatttcag aactcatctg ccaggggagg gagatactta ggtcaaaggg gtaggtaata gtagattgct 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 WO 99/49017 WO 9949017PCT/US99/06225 tcaatttcat agaccttgcc tggctctgct gggattttgt tataccctag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tctgggggca atctcaagtc ccaagtcaga taacagtcaa actaattggt tatattaaag agttagtaat tgacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagt t ggtgctgatc ccatgatgtt gttggcaaga attggtaagt cattcttctt cggctatctg gaaacagatt ggagaccaaa tgaactccgg aaaactttga atccctacct actatagaga a tagga tcaa ataagttatg ttcatctcta cctgaaaaga ggtcacatcc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggcaac tactccggga at a ctagac t at tatgacgg gaatggtata aaccctaatc aaatacgaag ctagtgtggg agctagagga tactggtgat tagggtctca ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa aagatggatt accaaagaag gagaacttat acaaaaagtt tacaccagaa ggggtttgaa agttagtcgg ctgccctagg tttctattcc gtttatccat attggcagc taagcttatg ttatagagaa tttggttatg gataattgaa gcaactaagc tactctgaaa cggacctaag gcttaattct tcaacaaggg atctaggatc gataaataag tatcttcgtt acgtgagtgg atacagtgcc tggttaggca cagctttgtc tcagatatag atcttatcga cctttcagcg gtgaaccttg a caga tct ca tcatctgtga tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg acccgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg ttatttgcaa tggt 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15894 <210> 7 <211> 15894 <212> DNA <213> Measles virus <400> 7 accaaacaaa tcaagatcct taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat tccagagtga atgaggcgga gatggttcga tgattctggg cagacacggc tagttggtga aggacctctc gaaacaaacc gattagccag gactgcatga aaatggggga gtgcaggatc actccatggg ggcaagagat gtatcactgc agatcagtag gttgggtaag attatcaggg agcattgttc cagaggaatc atccagactt actaacaggg tcagaggatc ccagtcacaa ccaatacttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct ttttatcctg atttgctggt aactgcaccc ataccctctg aggtttgaac ggtaaggagg cgaggatgca agcggttgga gatagttcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt gcactaatag accgatgacc tctggcctta tcacatgatg atctcagata gctcaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt cccagacaag tcaatgatca gattaaggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaattag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aggtcagttc cagagattgc cccaagtatc ttttctagtg atccgagatg acccattaca aatccctgga aattggaaac cttatttgtg cataaggctg aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac gga tatcaag tacatatatc aactatgtat cttgatgaac ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg tccaggttcg ggattcaaca gttacggccc caaagaaggg aggattgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 WO 99/49017 WO 9949017PCT/US99/06225 gtgagaatga gctaccgaga gagaagccag cccatcttcc cgcaggacag cggaagaaca actaggtgcg aaaacttagg gagccgatgg ctcaaggccg atatcagaca ggtctcagca cgcggtcagg aatctccagg qcggt taagg agcaccctct gataccgagg gcttctgatg agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctgttat agcatatcca aagga t ccca ggcagagatt ctccaaggaa ctaaagccga gcatcacgca cgttacctga cagatgctga ccagtcgacc gcctcccaag aagggttgat tcagagtcat tgctgggggt cctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct ggagagctac aaccggcaca tcgaaggtca aggctcagac agaggc cgag aaccaggtcc cagaagagca agcccatcgg acccaggaca aaccatgcct gacctggaga catcaagcac gaatccaaga caggaggaga gatatgctat ttgaaactgc actttccgaa gcacttccgg agatcgcgtc catcagggcc tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggccgagc tgacaaatgg t cgggaaaaa gtgtaatccg tgactctcct tgaagataat caactagtac ttccacaatg cgctccgata agatcctggt tgttgaggac aggtgttggc 6atagttgtt actaactctc ccaagtgtgc ttatatgagc ggaattcaga ggcgataggc ggtccacatc aatgaaaatc tcacattaga ttggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc ggccagaaca acacagccgc ggca cgc cat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc ac tgg ccgaa acggaccagt gatgagctca ctccattata tgatgatatc aatgaagtag aacctaaatc acagagatct caacccacca ctaggcgaca agcgatcccc aaatccacag agacgtacag ctcacacctt agtgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca aggaagatag ggcccagcag ttgacactgc tgcttaggct ctatagtgta acatccgcct cagcccatca gtcaaaaacg at cgaggaag acctgcaggg ggatcaactg gacgc tgaaa tgttattatg atcatggttc gaaaacagcg ggatctgctc gagatccacg actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgt cgggt aaatccagcc aaaggagcca ctacagctca cattataaaa acgacttcga cctacagtga ggaagga tga tagggcctcc caaagcccga c aggg ct caa ggagaaaggt atctgatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gcctggtttt aaatgagcaa gagggtcaaa agcaagtgat atcggagtcc gcaagccatg caatgacaga accctccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ctttgggaat tttatgatca aa tcaggc ct atgtggatat ccatctctat agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagtg caatctcccc tctctgatgt taatctccaa agatcaacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga atgatcttgc acttacctgc aacttaggag caagtcggca tggcaggctg atgctttatg aatcgggcga aaaactcctc tgaaaaactg cctaacaaca gctcgatacc cgggtattac caacctgctg tacagagcaa gagtgaagtc tgcact tggt gactctccat cagagtcgag gcgagagctg agccaagatc gcaggaatct aatcttctag attgttataa cccacgattg catccgggct atggtcagaa aggcagttcg acCt cgc a t ccccccaaga cagcggtgaa tgatggtgat tggcgaacct ggggttcagg actccaatcc to ogga CCCC attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagatatt gctagaatca gcaaaatatc tggact tggg acccatcata cagccgacaa ggaatttcag caccggccct ggatcggaag caagttccac caaccccatg caaagtgatt tgggacatca gtgccccagg tacatgtttc gcatttgggt aaagaggcca gtgttctaca gggagtgtct ccgcagaggt accgttccta gtgaccctta cttcctgagg tactctgccg gggatagggg gcacaactcg 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 WO 99/49017 WO 9949017PCT[US99/06225 ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gccgacggca ccaccagcca tgcccccgat attggaaggc gac cgaggtg actaaacaaa cggcgccgcg ccccggtgcc aatccaagac gaggaagccc gggccaccag accccagccc cgaaggaccc ctcctcccct cccaccccta ggtctcaagg accggtcaaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg ctgaactctc gaggcaatca atcaataatg ctcgggctca cgggacccca atcaataagg agcagaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tccaccaagt tcacaaggga acgatcatta gtagtcgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcaaaat gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcgcgaaca ccccaatctg ccaaaccacc ccctccccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca c tc ccaga ct cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga tgttagaaaa taaaggcccg atccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggttgat gagaacaagt cctatgtaag tacccgctga atagtaagaa gacgtgatca aatgcccgaa tccgaaagac ccaggcggcc catcctcctc aaccgcatcc cttcctcaac aggcatccga aaggaacata ccgacaacca gacaccaacc ccccaaaaaa cacacgacca cggccatcac gggagccacc aaggacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc gctcggatac gataactcac gtccgagatt t caagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggt cc tccc taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tagatatcaa tccaggcagt taaatgatga aacgaccccc tccacggacc ccagcacaga gtgggacccc ccaccacccc acaagaactc ctccctagac cacacccaac gagggagccc cccgaacaga aggcccccag cggcaaccaa cccgcagaaa caacccgaac gtatcccaca caatccacca agaatcaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcgg acagccggca gcgagcctgg atattggc tg caactatctt gaaatcctgt caggctttga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atatcattgg gatgccaagg agcactagca gctttaatat agaccaggcc tcctctacaa tgaagacctt tttgcagcca ccaaggacta ctcacaatga aagcgagagg a cagc cc tga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcaccc gggccgacag accagaaccc ggaaaggcca cagcacccaa gcctctccaa cacccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct atttactggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaggttgga aattgttgga tagtctacat gttgctgcag taaagcctga ctcttgaaac aatcgattac tcagttcctc ttcaaagttc cagccagaag ccagccagca t acaaggcc a ccc cc aagg C acccccagca ccgcacaagc tccccggcaa ccc cggcc ca C cgc cggct c aaccatcgac ccagcaccgc agaccaccct caacccgcgc gagcgatccc gtcccccggt cactcaactc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccggtt ggcaggtgcg ccagtccatg tcaggcaatt ccaagactac cggccagaag ccccagctta tggaggagac catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggact cctccggggg gttcatttta cacaacagga tcactgcccg agatgctgtg cgtagggaca gtcatcggac cctgattgca ggggcgttgt tcttacggga acaaatgtcc 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 Sib00 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 WO 99/49017 WO 9949017PCT/US99/06225 cacaagtctc tatctccggc atcatccaca t ccc aaggga tttgctggct cattagactt tctagatgta aatcatcggt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc gcaaccagcc agccctttgt cagcttccag ccccttatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg gccaatgaag ggttagtccc aacataccta acctggtcaa tgtggtttat gcctataaag ctggtgccgt tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc cgaggaagat aggttttcca aggacatcaa agccctttct cccatacttg tgctaatctc tgacatttga ccgctatgac ctcttcgtca ttccctctgg atgtcaccac agtaggatag gttctgtttg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actatgacat agcaaaaggt agaaatccgg agtaatgatc cacggggaag ctcgtcaagc acggatgatc aatcaagcaa tgcttccaac ccattgaagg gttgagctta atggacctat aacctagcct tacctcttca cctgcggagg gatctccaat tacgtttaca ggggtcccca cacttctgtg ggcatgggag tagtgaac ca catcagaatt caaccagatc agccatcctg tcagaacatc ggaagt tggg atatccaaat ccgtgaactc atgcttaagg ggagaaagtt gttttggttt ccataggagg tcgtgacctt actggttttg tattgatgct tcaagcaacc ccgaacaata aacgagaccg tcattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa atgcattggt caaagggaaa ccctgttaga cccagggaat cagagttgtc gtttgggggc tcagcaactg attctatcac taggtgtctg cay tgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaatccaa taggtgtaat atgtcccaat tggatggtga atgt tttggc gcccaggccg tcgaattaca tgcttgcgga tcagctgcac atctcatgat aagaaaaacg ttataccctg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaact attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatacag accgcaccca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagatc ggtcaaggac acctcagaga ggatagggag attggattat gaactcaact ctgctcaggg cttgtattta gtatggggga acaactgagc tccggtgttc tatggtggct aattccctat gaaatcccca caggctttac cccgacaaca gggtaaaatc tccttcatac tgcttcggga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctacgat ctcattttct agtggaatgc ctcagaatct agt ca cccgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa ggaattcgct cacggcttgg gagtttacat ctgagatgag ctgtattctt tcagtaaaga atgtcataga agcttctagg gcatcaagcc attaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggaga cccactacaa ggtcgaggtt acttacctag atgtaccgag catatgacaa ttgggggagc cagggat cag accgacatgc ctctcatctc cgaacagatg caagcactct ggggtcttgt ttcgggccat gtgtattggc gagtggatac ggcgaagact agttccaatc ac ttccaggg tacttttatc tt cacatggg ggtggacata gaagatggaa catcaggcat gtggttcccc agatagcccg cgcttacagc attttccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagtcaga cacctgaaat agggtgcaag ataaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggtca acaatgtgtc tggaaaagcc tgtttgaagt actatcttga tcaaactcgc ggaaaggtgt aat cc tgggt acagaggtgt acaagttgcg gcgagaatcc ctgttgatct tgatcacaca tgactatccc cgagattcaa gccatgcccc tggtgattct ttgaacatgc cttttaggtt accaaaaact tcactcactc ccaatcgcag acccactagt gttatggact atagttacca ctggaggacc caaatgatta c cggcc ca ct aaagagtcaa gtcagtgata gaattgaggg cagtggtttg aaatcacaaa tcagttgagt gtatattacc atgacagaga tacatgtgga 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 WO 99/49017 WO 9949017PCTIUS99/06225 aactgataga tggagcctct ctttccttaa atgaaggtac tacatctgac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa atttgactaa gtcacagggg ggaacgtgag a cac tga tea atctcaagaa taaatgagat ctgtcetgta ataaagtcec gtcagaagct gagtaaggat tacccagcae actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta ctcttggctt acaacgacct tgaatatgag atetcaagag cacaacaacc ttgtatgtgt tccatagtcc agggactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtggge tagaatctat gatcagtcaa aggaaacat c tggtttcttc ttcaettgct ccactgcttt ttatcatgag aggggagatt tgctgaaaat gaaaggtcat cagttggcca ttcaggtgaa gaaatttggc eaaggcactt ttacgaccct gagctttgac tgagttcaac tgetaaaatg cgggattggc ggca etc cac ggggccagte agcagcaaaa tccggagaat gtactgectt ttacggattg tgtaagtgac caatgatcaa gtggaccatc tgcttcgtta atggccctac tettaggeaa atcacatttt act caagagc agcatgcagt ecttgcatat cacaatcaat cttaataagg caggc tgttt aatgattctc gggggaetct ccagageatc aaacccaatg ggeattcctc tagtgteaca tegagccagc tgactatgaa cattgacaaa gaggctagct gcgaggccac ctacggatgg atccttgaga cctgcactcg tacctgcagc actgaaatac ttaattgaag ttctcatttt gttaggaaat gceatatttt ccgctgaccc gggttaacae tgetttatgc gctgctctcc cccaagggaa ccatatgatg ctgtcttaca acttacaaaa aaatatttta actctagctg ttaaaaacct gggtttatag atggaagctt aattggagat cccteatttt cctcattgcc atcttcatta agcac eatt c gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta tccctgaacg tcaaccatga atggcactqt gtcagaaaca gcctcactaa tcattcctag actagactcc ttaaaaggat atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc cttattcggc ttttttgtcc gtcccatata ggaa t ccaa c tgagggatat atgatgttct ctctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg Ctcttagcct aaagggaatg ccgggteacg tgataatgta gcctgaaaga tgagggeatg aggaeaatgg tctcaggagt actcegaag ggttccctca acgagacagt atgagaccat tccagtgget ccccgacct agtaccctat cctatctata acaatcagac aacgggaagc at attgg cc a caaaaggaat gtgtattctg caacaatggc tcctaaaagt cccgggatgt tgcecgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattecatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac ectcgggttg ttggttctac ttatcaaatt aacagtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggettgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag ccccaaagat cccagtccac agtaattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagccgta tgctagagta tcacctcaag atattatgat gteagagact taaaagcatc gatacagcaa agt catacee tattgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgctg ctctcgagtg gctattgaca ggcgagagct ccttgaggtc atgtgtcatc e caa ctgga t cactgatgag gtagccatgc ctcagaggtg gggttttctg actgatgaca agacttgaag attgtgtatg tatcgtgaca acaatccgga tggaaatctt ctgacaatgt tacccgaaag gatgttttcc ggagcttacc aaggaaaeag gctgaaaate gatgagcacg ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggtt attctgatct etcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaca 100.80 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 WO 99/49017 WO 9949017PCTIUS99/06225 tgaagcttgc cagtgtactc ctaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gaccatcagg aaggagtgtt ggcattgtgg caactgtgtg aagagttaga gattcgacaa ggacctgccc atatcaaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggcaatct cttgctacaa acggcttgt t aactaaacaa aattagcacc ttgtcaaagt tcaatttcat agaccttgcc tggctctgct gggattttgt tataccctag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ccaagtcaga taacagtcaa cttcgtaaga atgggcttac ggccaatgtg agcgcatagg agtggcgagg ggttgatact attgtttcga aacagattgt agagctgagg cagagataca atggt ccaca cctggtaaca cgatatcaat cttgggccag gaaatatcag taaggtgctt tattatagag caacatggtt agagttcaca catccaggca accaattcga agaggctagg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agttagtaat taacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggac ttata agacgcagtt ggtgctgatc ccatgatgtt gttggcaaga attggtaagt cattcttctt cggctatctg gaaacagatt ggagac caaa gccccaagtc ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ct Cgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc cctatccatg tacacatgct tttctcttgt aaacacttat ggtctaagac tt atct cc ag tctctgactt ttcattttcg atctcaaata aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagt tggcc gggaggcccg atccctacct actatagaga ataggatcaa ataagttatg ttcatatcta CCtgaaaaga ggtcacatcc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggcaac tactccggga atactagact attatgacgg gaatggtata gatccttgcg atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg ataccggatc cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcatc taagccaccc gtccttcact atatgaccta gtgaaagcga gtgttctggc cggtagagaa caggatcttc atctccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa ttgtcgaaca aagtcacgtg ctagtgtggg agctagagga tactggtgat tagggtccca ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa aagatggatt accaaagaag gagaacttat acagaaagtt tacaccagaa ggggt ttgaa agttagtcgg atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gctcatagag atttgatgta gttcctttct aaagatctac tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggct ttcaga gcacaatctt aatcgggttg atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt gtttatccat attggcagcc taagcttatg ttatagagaa tttggttatg gataattgaa gcaactaagc tactctgaaa cggacctaag gcttaattct tcaacaaggg atctaggatc gataaataag tatcttcgtt acgtgagtgg atacagtgcc agaatagcaa tggttgttgg atctcaactt tcaggtacat tttgtcatat gggttgggtg gtattacatc atacccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattct aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagtcagc cccccacacg cc catt t cag aactcatctg c caggggagg gagatactta ggtcaaaggg gtaggtaata gtagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtga tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg acccgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg 12960 13020 13080 13140 13200 13260 13320 13380 13440 135S00 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 WO 99/49017 WO 9949017PCTIUS99/06225 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 t caagat cc t taaggagctt gtggagccat ttaccactcg gcgggcccaa gtcaattgat tccagagtga atgaggcgga gatgqt tcga tgattctggg cagacacggc tagttggtga aggacctctc gaaacaaacc gattagccag gactgcatga aaatggggga qtgcaggatc actccatggg ggcaagagat gtatcactgc agatcagtag gtgagaatga gagaagccag cccatcttcc cgcaggacag cggaagaaca actaggtgcg aaaacttagg gagccgatgg ctcaaggccg atatcagaca ggtctcagca cgcggtcagg aatctccagg gcggttaagg agcaccctat gataccgagg gttgggtaag attatcaggg agcattgttc cagaggaat c atccagactt actaacaggg tcagaggatc ccagtcacaa caaatacttt gaacaaggaa taccatccta agctgattcg atttagattg cttacgccga caggattgct ttttatcctg att tgctggt aactgcaccc ataccctctg aggtttgaac ggtaaggagg cgaggatgca agcggttgga gctaccgaga ggagagctac aa ccggcaca tcgaaggtca aggctcagac agaggccgag aa ccaggt cc cagaagagca agcccatcgg acccaggaca aaccatgcct gacctggaga catcaagcac gaatccaaga caggaggaga gatatgctat gatagttcaa acaagagcag aaaagaaaca aaacacatta ctggaccggt qcactaatag accgatgacc tctggcctta tcacatgatg atctcagata gcccaaattt gagctaagaa gagagaaaat ttcatggtcg gaaatgatat actattaagt gagttatcca tacatggtaa ctctggagct tttggccgat tcagctggaa aggcttgttt cccagacaag ttggggggca agagaaaccg cccctagaca gctgacgccc acggacaccc gaccagaaca acacagccgc ggcacgccat ctcactggcc ggagcgagcc ctcagcaatt gagcgatgac tgggttacag tgctgactct caatgaatct cactgaccgg tcaatgatca gattagggat aggacaaacc ttatagtacc tggtcaggtt gtatattatc ctgacgttag ccttcgcatc atccaattag ttgaagtgca gggtcttgct ggtggataaa ggttggatgt ctctaatcct gtgacattga ttgggataga cacttgagtc tcctggagaa atgccatggg cttactttga aggtcagttc cagagattgc cccaagtatc aggaagatag ggcccagcag ttgacactgc tgcttaggct Ctatagtgta acatccgcct cagcccatca gtcaaaaacg atcgaggaag acctgcaggg ggatcaactg gacgctgaaa tgttattatg atcatggttc gaaaacagcg ggatctgctc tcttctagtg atccgagatg acccattaca aatccctgga aa ttggaaac cttatttgtg cataaggctg aagaggtacc tagtgatcaa agaccctgag cgcaaaggcg gtacacccaa ggtgaggaac ggatatcaag tacatatatc aactatgtat cttgatgaac ctcaattcag agtaggagtg tccagcatat cacattggca aatgcatact atttctacac gagggtcaaa agcaagtgat atcggagtcc gcaagccatg caatgacaga accctccatc accatccact gactggaatg ctatggcagc aagagaaggc aaggcggtgc ctttgggaat tttatgatca aatcaggcct atgtggatat ccatctctat cacttaggat gccacacttt tcaggatccg gattcctcaa ccggatgtga gagtctccag ttagaggttg aacatggagg tccaggttcg ggattcaaca gttacggccc caaagaaggg aggattgccg agaacacccg gtagaggcag cctgctcttg ctttaccagc aacaagttca gaacttgaaa tttagattag tctgaactcg actgaggaca ggtgatcaaa cagagtcgag gcgagagctg agccaagatc gcaggaatct aatcttctag attgttataa cccacgattg catccgggct atggtcagaa aggcagttcg acctcgcatc ccccccaaga cagcggtgaa tgatggtgat tggcgaacct ggggt tcagg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 WO 99/49017 WO 9949017PCT/US99/06225 gcttctgatg agaggcaaca ggtagggcca tttggaacgg ccctcggaac gccgcactga aataatgaag aaaacagcct ctgctgttat agcatatcca aaggatccca ggcagagatt ctccaaggaa ccaaagccga gcatcacgca cgttacctga cagatgctga ccagtcgacc gcctcccaag aagggtcgat tcagagtcat tgctgggggt ccctgccctt ctgagcttga acaacacccc tcaacgcaaa tccgtgttgt gaagaatgct ggattgacaa caacatttat attattgcaa gcaccagtct ggttcaagaa tctggaggag aagaattccg tgtagaccgt gcccggacaa gccgacggca ccaccagcca tgcccccgat attggaaggc gaccgaggtg actaaacaaa cggcgccgcg ccccgqtgcc aatccaagac gaggaagccc gggccaccag ttgaaactgc actttccgaa gcacttccgg agat cgcgtc cat cagggc c tacaggagtg aagggggaga tggccaaaat tgaagggaga ccctggaagg acgaccccac caggc cgagc tgacaaatgg tcgggaaaaa gtgtaatccg tgactctcct tgaagataat caactagtac ttccacaatg cgctccgata agatcctggt tgttgaggac aggtgt tggc catagttgtt actaactctc ccaagtgtgc ttatatgagc ggaat tcaga ggcgataggc ggtccacatc aatgaaaatc tcacattaga gaccttatgt cagatgcaag catttacgac agtgcccagc aaaagccccc agcacgaaca ccccaatctg ccaaaccacc ccctccccct acccaaccgc acttagggcc cccccaaccc cacaggcagg gggggggccc acccacccca ctcccagact agaaggaggg gcttgggaaa gacacccatt tttattgaca aggtgcacct gacacccgaa ctattatgat acacgaggat agttgagtca acacctctca tgcagatgtc actggccgaa acggaccagt gatgagctca ctccattata tgatgatatc aatgaagtag aacctaaatc acagagatct caaccgacca ctaggcgaca agcgatcccc agatccacag agacgtacag ctcacacctt aatgcggtta atcacccgtc tcggtcaatg cctgggaaga gggaacttca gaaaagatgg agcacaggca tacccgctga atagtaagaa gacgtgatca aatgcccgaa tccgaaagac ccaggcggcc catcctcctc aaccgcatcc cttcctcaac aggcatccga aaggaacata ccgacaacca gacaccaacc ccccaaaaaa cacacgacca cggccat cac gagatccacg actctcaatg aaaaagggca ggtggtgcaa gcggggaatg tctggtacca gatgagctgt aatcagaaga attaagaagc agcatcatga gaaatcaatc gttctcaaga tccagaggac gccgtcgggt aaatccagcc aaaggagcca ctacagctca cattataaaa acgacttcga cctacagtga ggaaggatga tagggcctcc caaagcccga cagggctcaa ggagaaaggt atctgatacc tttcggataa cagtggcctt tcatcgacaa ggagaaagaa gcctggtttt aaatgagcaa tggatatcaa tccaggcagt taaatgatga aacgaccccc tccactgacc ccagcacaga gtgggacccc ccaccacccc acaagaactc ctccctagac cacacccaac gagggagccc cccgaacaga aggcccccag cggc aa ccaa cccgcagaaa agctcctgag ttcctccgcc cagacgcgag cccaatgtgc tccccgagta caatctcccc tctctgatgt taatctccaa agatcaacag tcgccattcc ccgacttgaa aacccgttgc agctgctgaa ttgttcctga ggctagagga atgatcttgc acttacctgc aact taggag caagtcggca tggcaggctg atgctttatg aatcgggcga aaaactcctc tgaaaaactg cctaacaaca gctcgatacc cgggtattac caacctgctg tacagagcaa gagtgaagtc tgcacttggt gactctccat tgaagacctt tttgcagcca ccaaggacta ctcacaatga aagcgagagg acagccctga cgaggaccaa cgggaaagaa cacaaccgaa agatcctctc agaacccaga ccaaccaatc cccagcacct gggccgacag accagaaccc ggaaaggcca actccaatcc cccggacccc attagcctca tcgaaagtca tgtgagcaat gagatcccag ccaagatatt gctagaatca gcaaaatatc tggacttggg acccatcata cagccgacaa ggaatttcag caccggccct ggatcggaag caagttccac Caaccccatg caaagtgatt tgggacatca gtgccccagg tacatgtctc gcatttgggt aaagaggcca gtgttctaca gggagtgtct ccgcagaggt accgttccta gtgaccctta cttcctgagg tactctgccg gggatagggg gcacaactcg aatcgattac tcagttcctc ttcaaagttc cagccagaag ccagccagca tacaaggcca cccccaaggc acccccagca ccgcacaagc tccccggcaa ccccggccca ccgccggctc aac cat cgac ccagcaccgc agaccaccct caacccgcgc 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 516 0 5220 WO 99/49017 WO 9949017PCTIUS99/06225 accccagccc cgaaggaccc ctcctcctct cccaccccta ggtctcaagg accggtcaaa agctacaaag ataactctcc acagttttgg cagagtgtag gccctaggcg c tgaa ct tc gaggcaatca atcaataatg ctcgggctca cgggacccca atcaataagg agcagaggaa agtatagcct gtctcgtaca caagggtacc gtgtgcagcc tacaccaagt tcacaaggga acgatcatta gtagt cgagg tacttgcaca aatctgggga cagatattga gtgtgtcttg aacaaaaagg acatcaaaat cacaagtctc tatctccggc atcatccaca tcccaaggga t ttgctggct cattagactt tctagatgta aatcatcggt catctctgac ttggtgtatc ggctgctgaa caatcagttc attctcaaac atctatagtc taatctgagc aggtgttatc cgatccggcg ccgaaccgca tctcgaaggg aaggagacac tgaacgtctc tccattgggg ttatgactcg tcaataactg aaccaattag cttcaagtag ttgccacagc aagccatcga gacaagcagg agctgatacc aattgctcag tatctgcgga tgttagaaaa taaaggcccg atccgacgct acataggctc ttatctcgaa aaaatgcctt cctgtgctcg acctaatagc atcaagaccc tgaacggcgt gaattgacct atgcaattgc ggagtatgaa gagggttgat gagaacaagt cctatgtaag ctcttcgtca ttccctctgg atgtcaccac agtaggatag gttctgtttg catcgggcag actaactcaa gatgaagtgg aagattaaat aacccgccag gagctcatga ctagctgtct atgtcgctgt actatgacat agcaaaaggt agaaatccgg gggagccacc aaggacatca accaaaagat cgggaatccc tgccatattc caatctctct ttccagccat cacgagggta agatgcactt gagacacaag tgctcagata caatctgaga gcaggagatg gtctatgaac atactataca gatatctatc gctcggatac gataactcac gtccgagatt tcaagagtgg ttttgatgag gtacccgatg tacactcgta caattgtgca tgacaagatc gaccatccaa cggt cc tcc c taagttggag aggtttatcg agggatcccc tggtatgtca gtcgctctga tcaagcaacc ccgaacaata aacgagaccg tcattaacag tcatgtttct ccatctacac tcgagcatca gcctgaggac tccttaatcc agagaatcaa atgcattggt caaagggaaa ccctgttaga cccagggaat cagagttgtc gtttgggggc caacccgaac gtatcccaca caatccacca agaatcaaga atggcagtac aagatagggg caatcattag gagattgcag aatgcaatga agatttgcgg acagccggca gcgagcctgg atattggctg caactatctt gaaatcctgt caggctttga agtggaggtg gtcgacacag aagggggtga tataccactg tcatcgtgta agtcctctgc tccgggtctt tcaatccttt ctaacataca gtcgggagca atattattgg gatgccaagg agcacttgca gctttaatat agaccaggec tcctctacaa accgcaccca tcggtagtta gataaatgcc agaacatctt gagcttgatc cgcagagat c ggt caaggac acctcagaga ggatagggag attggat tat gaactcaact ctgctcaggg cttgtattta gtatggggga acaactgagc tccggtgttc cagcacccaa gcctctccaa cacccgacga ctcatccaat tgttaactct tggtaggaat tcataaaatt aatacaggag cccagaatat gagtagtcct ttgcacttca aaactactaa ttcagggtgt gtgatttaat cattatttgg gctatgcgct at ttac tggg agtcctactt ttgtccaccg tgcccaagta ctttcatgcc tccaagaatg ttgggaaccg gcaagtgtta ttgctgccga ggaggtatcc agaggttgga aat tgttgga tagtctacat gttgctgcag taaagcctga ctcttgaaac gcatcaagcc attaaaactt ttctacaaag atgattgata gggttgctag cataaaagcc gtgctgacac ttcactgacc tacgacttca gatcaatact ctactggaga cccactacaa ggtcgaggtt acttacctag atgtaccgag catatgacaa gagcgatccc gtcccccggt cactcaactc gtccatcatg ccaaacaccc aggaagtgca aatgcccaat actactgaga aagaccggtt ggcaggtgcg c cagt cca tg tcaggcaatt ccaagactac cggccagaag cc ecag t ta tggaggagac catcttagag cattgtcctc gctagagggg tgttgcaacc agaggggac t cctccggggg gttcatttta cacaacagga t aa ctgc c g agacgctgtg cgtagggaca gtcatcggac cctgattgca ggggcgttgt tcttacggga acaaatgtcc cacctgaaat agggtgcaag ataaccccca gaccttatgt ccattgcagg tcagcaccaa cactcttcaa tagtgaaatt gagatctcac gtgcagatgt ccagaacaac tcagaggtca acaatgtgtc tggaaaagcc tgtttgaagt actatcttga 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 WO 99/49017 WO 9949017PCTIUS99/06225 gcaaccagtc agccctttgt cagcttccag caccttatca tatcgctgac aatggagaca cgagtgggca gagtctgaca cggttcaggg accaatgaag ggttagtccc aacataccta acctggtcaa tgtggtttat gcctataaag ctggtgccgt tgggatggtg atagggctgc gtgaaataga cgctatctgt ataagatagt ctacactgtg taaacaatgt ctcatattcc cgaggaagat aggttttcca aggacatcaa agccctttct cccatacttg tgctaatctc tgacatttga ccgctatgac aactgataga tggagcctct ctttccttaa atgaaggtac tacatctgac cagtaacggc agactctgat ggcacggagg atgctcaagc ttgctggagt acctaaagga agttcctgcg ttaatgattc tccatgaccc gtagactttt taatctcaaa agtaatgatc caccgggaag ctcqtcaagc acggatgatc aatcaagcaa tgcttccaac ccattgaagg gttgagctta atggacctat aa cc tagc ct tacctcttca cctgcggagg gatctccaat tacgtttaca ggggtcccca cacttctgtg ggcatgggag tagtgaacta cat cagaat t caaccagatc agccatcctg tcagaacatc ggaagttggg atatccaaat ccgtgaactc atgcttaagg ggagaaagtt gttttggttt ccataggagg tcgtgacctt actggttttg tattgatgct tggtttcttc ttcacttgct ccactgcttt ttatcatgag aggggagat t tgctgaaaat gaaaggtcat cagttggcca ttcaggtgaa gaaatttggc caaggcactt ttacgaccct gagctttgac tgagttcaac tgctaaaatg cgggat tggc tcagcaactg attctatcac taggtgtctg cagtgataga aatgggctgt aggcgtgtaa ataacaggat aaatcaaaat acaaatccaa taggtgtaat a tgt ccc aa t tggatggtga atgttttggc gcccaagccg tcgaattaca tgcttgcgga tcagctgcac atctcatgat aagaaaaacg ttataccctg gagtatgctc aagcaccgcc aatgtcatca tgtaatcagg ctcaaaaagg gacactaact attaacttgg acagtcaaga agacacacac gttgctataa atgtattgtg aggtatacag cctgcactcg tacctgcagc actgaaatac ttaattgaag ttctcatttt gttaggaaat gccatatttt ccgctgaccc gggttaacac tgctttatgc gctgctctcc cccaagggaa ccatatgatg ctgtcttaca acttacaaaa aaatatttta tatggtggct aattccctat gaaatcccca caggctttac cccgacaaca gggtaaaatc tccttcatac tgcttcggga ccacaacaat caacacattg taaggaagca tgtcaaactc aacctacgat ctcattttct agtggaatgc ctcagaatct agtcacccgg gtcacccaga tagggtccaa aagttcacct gagtccctca taaaaaacgg agtccaagct atttatttaa ggaattcgct cacggcttgg gagtttacat ctgagatgag ctgtattctt tcagtaaaga atgtcataga agct tctagg ggaatccaac tgagggatat atgatgttct ctctagatta tcagaagttt acatgaatca gtggaatcat tccccctgca atgagcagtg ctcttagcct aaagggaatg ccgggtcacg tgataatgta gcctgaaaga tgagggcatg aggacaatgg ttgggggagc cagggatcag accgacatgc ctctcatctc cgaacagatg caagcactct ggggtcttgt ttcgggccat gtgtattggc gagtggatac ggcgaagact agttccaatc acttccaggg tacttttatc ttcacatggg ggtggacata gaagatggaa catcaggcat gtggtt cccc agatagcccg cgcttacagc attttccaac taggagttat catagaagac gtactccaaa cctaggctcc gcacagctcc gtcagtgatt cactggtagt gtctcaacat ggggaggtta aagagt caga ttatcaaatt aacagtagaa tgaccaaaac cattttcata cggccacccc gcctaaagtc aatcaacggc tgctgcagac cgttgataac ggatagtgat ggattcagtt gaggcttgta tgttgtaagt aaaggagatc ccaagtgatt gatggccaag tcaaactcgc ggaaaggtgt aatcctgggt acagaggtgt acaagttgcg gcgagaatcc ctgttgatct tgatcacaca tgac tatc cc cgagattcaa gccatgcccc tggtgattct ttgaacatgc cttttaggtt accaaaaact tcactcactc ccaatcgcag ac cca c tagt gttatggact atagttacca ctggaggac c caaatgatta ccggcccact aaagagtcaa gtcagtgata gaattgaggg cagtggtttg aaatcacaaa tcagttgagt gtatattacc atgacagaga tacatgtgga gtagccatgc ctcagaggtg gggt tt tctg actgatgaca agdcttgaag attgtgtatg tatcgtgaca acaatccgga tggaaatctt ctgacaatgt tacccgaaag gatgttttcc ggagcttacc aaggaaacag gctgaaaatc gatgagcacg 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 WO 99/49017 WO 9949017PCTIUS99/06225 atttgactaa gtcacagggg ggaacgtgag acactgatca atctcaagaa taaatgagat ctgtcctgta ataaagtccc gtcagaagct gagtaaggat tacccagcac actttgtaat caattgtttc tgtcccaatc aaacaagggc atgaccgtta ctcttggctt acaacgacct tgaatatgag atctcaagag cacaacaacc ttgtatgtgt tccatagtcc agggactggc tcctggatca aaggcctgat tgtccaatta gaaatgtcct atatgtgggc tagaatctat gatcagtcaa aggaaacatc tgaagcttgc cagtgtactc ctaggcaaag cgactaattt cccttgtccg cagataagaa ttttagaaac ttcacgtcga cccgcaagct ctttaattga aatttgttac ctatgattga taggggatga tcactatcta gaccatcagg aaggagtgtt ggcactccac ggggccagtc agcagcaaaa tccggagaat gtactgcctt ttacggattg tgtaagtgac caatgatcaa gtggaccatc tgcttcgtta a tggc cc tac tcttaggcaa atcacatttt actcaagagc agcatgcagt ccttgcatat cacaatcaat cttaataagg caggctgttt aatgattctc gggggactct ccagagcatc aaacccaatg ggcatt cctc tagtgtcaca tcgagccagc tgactatgaa cattgacaaa gaggctagct gcgaggccac ctacggatgg atccttgaga cttcgtaaga atgggcttac ggccaatgtg agcgcatagg agtggcgagg ggttgatact attgtttcga aacagattgt agagctgagg cagagataca a tggtc caca c ctqgt aaca cgatatcaat cttgggccag gaaatatcag taaggtgctt actctagctg ttaaaaacct gggtttatag atggaagctt aattggagat ccctcatttt cctcattgcc atcttcatta agcaccattc' gtgcaagggg aaccttaaga aggctacatg tttgtctatt atcgcaagat aatattgcta tccctgaacg tcaaccatga atggcactgt gtcagaaaca gcctcactaa tcattcctag actagactcc ttaaaaggat atggacaggc ggggcaagag atgaggaagg caattcagag gagtcatgtt cgaggacggc ct tattcggc ttttttgtcc gtcccatata gccccaagtc ggtgatgatg agcctggagg ttgagggatc tataccacaa aactttatat ctcgagaaag tgcgtgatcc gcagagctat acaaggctat ccccaactat aaatttgaga agtttcataa tgtgcggcca atgggtgagc gtcaatgctc tctcaggagt actcccgaag ggttccctca acgagacagt atgagaccat tccagtggct CCCCcgacct agtaccctat cctatctata acaatcagac aacgggaagc atat tggcca caaaaggaat gtgtattctg caacaatggc tcctaaaagt cccgggatgt tgcccgctcc tcggtgatcc tgcctgaaga actgggctag tcaagaacat tattccatga atattatagt agtctattgc gggggttaac cagggatggt cagtgcagct ctatttacgg gtcatgagac cctcgggttg ttggttctac gatccttgcg atagctcttg agctaagggt gtagcactca tctccaacga accaacaagg ataccggatc cgatgataga gtaccaaccc acacccagag atcacatttt aggaccatat ctgagtttct tcaattgggc tgttgtcatc taagccaccc ccccaaagat cccagtccac agtaattcgg cagtgcattt cagcttgttt gcataagagg tgacgcccat gggaggtata cctggctgct catagcCgta tgctagagta tcacctcaag atattatgat gtcagagact taaaagcatc gatacagcaa agtcatacc tat tgggggg agtaacatca gaccctccat cgacccttac aactgcaagg tgacagtaaa acctagggca aggcatgctg ctctcgagtg gctattgaca ggcgagagct ccttgaggtc atgtgtcatc ccaactggat cactgatgag atctgctgtt gaacgaagcc gatcactccc agtgaaatac caatctctca aatgcttcta atctaacacg tcatcccagg attgatatat ccataggagg agctaagtcc gaatgaaatt gctcatagag atttgatgta gttcctttct aaagatctac ctcaaagaaa acaagtacca caggaccaag atcacgactg gcacagaggc cttgagacct atcccgttat gaagggtatt tatgagagcg acaaaaaggg actagagatt gcaaatgaga gggctacttg atagttgatg gagagaggt t attctgatct ctcctcacaa atgaattatc tcaattgctg caagtaatga tcagcaaatc tttgtcctga gaagaggacg gctcatgaaa gataccacaa ataaccagat ggaagaaaga ctaagaagcc cctgatgtac tgcgagtgtg gatattgaca agaacagaCa agaatagcaa tggttgt tgg atctcaactt tcaggtacat tttgtcatat gggttgggtg gtattacatc atacccagct gataatgcac caccttgtgg acagcactat tcagctctca ccaagattat cattatcata agaatgagca aagaaattCt 11040 11100 11160 11220 11280 11340 11400 11460 11520' 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 WO 99/49017 WO 9949017PCTIUS99/06225 ggcattgtgg caactgtgtg aagagttaga gattcgacaa gggcctgccc a tat caaggc ttgtagacca gattgagagt caaagatcgg atgatgttgc ggggcaatct cttgctacaa acggcttgtt aactaaacaa aattagcacc ttgtcaaagt tcaatttcat agaccttgcc tggCtctgct gggattt tgt tat ac cctag aggctaaccg ggacttcacc caattgtggg ctatagagca aattgatcca tctacaggga cttaccccgt tttgggggca atctcaagtc ccaagtcaga taacagtcaa actaattgat tatattaaag tattatagag caacatggt t agagttcaca catccaggca accaattcga agaggctagg ttactcatgc tgatccagga cagcaacaac aaaattgctc cgccaattat agctgttgag cttgggtgag gtgcttctat ctatccctcc gctctttaac agttagtaat taacaaagat cctgggcaaa tcagggattt atacagcaac gctaatgaat tggacttata agacgcagtt ggtgctgat c ccatgatgtt gttggcaaga attggtaagt cattcttctt cggctatctg gaaacagatt ggagaccaaa tgaactccgg aaaactttga cctatccatg tacacatgct tttCtcttgt aaacacttat ggtctaagac ttatctccag tctctgactt ttcattttcg at ct caaa ta aaagatatca gaaatccatg atatcaacat ggatcgggtt aatagtgggg gaagttggc c gggaggcccg atccctacct actatagaga ataggatcaa ataagttatg ttcatatcta cctgaaaaga ggtcacatcc agtagaggtg aattgcgggt gcctcagggc ttcaaagaca agcaggcaac tactccggga atactagact attatgacgg gaatggtata aaccctaatc aaatacgaag gtccttcact atatgaccta gtgaaagcga gtgttctggc cggtagagaa caggatcttc atctccggcg acgccctcgc tgagcatcaa acacaagcaa ctttccgcag taattaggag ctatgttgat tttccgccaa.

ttgtcgaaca aagtcacgtg ctagtgtggg agctagagga tactggtgat tagggtctta ctgaatctta ttaagcagca tatccattaa atatcaatcc tggcaattaa.

aagatggatt accgaagaag gagaacttat acagaaagtt t aca ccagaa ggggtttgaa agttagtcgg ctgccctagg tttctattec tgatgctcaa cctcgacctg cgaggatgta agatttgtac atgtgcagtt gtggaacata aggatcgatc tgaggtaaat ggctttcaga gcacaatctt aatcgggttg atgccttgag cacttataag ttctagatct cagaatggga ggtaggcagt gtttatccat attggcagcc taagcttatg ttatagagaa tttggt tatg gataattgaa gcaactaagc tactctgaaa cggacctaag gcttaattct tcaacaaggg atctaggatc gataaataag tatcttcgtt acgtgagtgg atacagtgcc tggttaggca cagctttgtc aacttgcaca ttgttgaatg gtaccggaca tgtcaaccag ctaaccgacc aatccaatta aaacagataa gtcagtcagc cccccacacg cccatttcag aactcatctg ccaggggagg gagatactta ggtcaaaggg gtaggtaata gtagattgct tcagatatag atcttatcga cctttcagcg gtgaaccttg acagatctca tcatctgtga tgcatacaag aaacttacac ctgtgcaaag atactcatcc atgttccacg acccgcaaat tttatccaga aagaatctat gtttttaagg ctgattaagg ttatttgcaa tggt 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15240 15300 15360 15420 15480 15540 15600 15660 15720 15780 15840 15894 <z210> 9 <211> 15218 <212> DNA '213> respiratory syncytial virus <~400> 9 acgcgaaaaa tgataagtgc tgataaaggt catgttatac caattaaatt ataacaatat acatatggga atgcgtacta tatttaagtc tagattacaa tgataaatta aaacggcata tgtagtgaaa attgattgag caaacttgca taaccttttc aatttatttg attcttctga gtttttatac tctaacttta ttgacacact cattcgaaaa aatcagaaat acaatgacga ccaatgcatt atgttataac caacaatgcc gctctcaatt aaatggggca ggggtgcaat agtagcattg agccaaagca aagcagtgaa aatactacaa aaacggttta aataagaact tcactgagca ttaaaaataa gcaatacata gtgtgCcctg aatggaggat atggatgata 120 180 240 300 360 420 WO 99/49017 WO 9949017PCT/US99/06225 attgtgaaat aaatatctga agacatgtgt ataaactcac attgatgatc agaaatcatc tgatgaaaga agtagggagt catgcctata acacactcct ccaaccaaac attttagtaa ggctcttagc caaatacact aaaacaccta cacaggatta gatacttaaa tcaagatata agaaatacaa gatgggagaa gtgtatagct agtaattagg accaaaggat tgttttcgtg aatctttgca agttttagcc ggagcaagtt ccatatattg aagtgtggtc aagaaaccag agtaataaac actcaacccc gtcaacatgg aaattcctag agcataatat ggcaccaaca tacccaagaa tctaagttgt tcatatgaag gatgaaaaat cccacttcag gaaaaaataa aggaatgagg acttccaaaa gatgattttt caatccattg caatcaatca aaagaacaag caaattttct ct tact tggg ttattaccat ctaatcaatc acagacatga acacacaaat caagctacat accaaataca tttatcaatc ataatataca caaactattc ttaaaaataa aaagtcaagt attcaacgta aacaaactat ataggtatgt gatgctggat aatggaaagg gtcaatattg gtggctccag gcacttgtga agggcaaaca atagctaaca cactttggca ggattgttta aaatctgtaa gtggaagtct aacaatccaa ctaggcaatg gatctttatg tacagtgtat aaagaagatg agaagtttgc aatcaataaa ctgttaactc tcatcaatcc aacccctagt acaaggaaac agataaatga taagtgaaat ctcgcgatgg gagcggaagc aaagcgaaaa aattgagtga gatcagcgat aatcaactgc accaattgat atggggcaaa aaaagactaa cttgatctca tttagttaat aaaccatgag gacccctgtc tcatatactt ttacattctt aaaaatacac acggcgggtt aatatgacct ctcaaacaac aagtaaagcc tgaatgatac gtacaggaga gtggtatgct tatatgctat atcatgttaa aaatgaaatt agatagaatc aatataggca taaccaaatt atgtcttaaa gtttttatga ttgcacaatc tgaatgccta aaaatatcat atgagtatgc aagcatcatt cagcaggtct atgcagctaa tagacttaac atgtagagct acctgaattt gggcaagttc aatagatata aacaagtgaa aagcttcaaa aatagaaaca tcaaacaaat attaggaatg aataagagat at taa tgac c aatggcaaaa cttgttggaa caactcactc cagaccgaac caatcagcaa tatggaaaca gtgactcagt attcatgaat ataaaaactc cactacaaat aatggattca gataaacaat agtcaattat tgaatataat tctagaatgt caacccgtga agtqctcaat aataacataa attaaataag taatattgac attaatcact gtccaggtta agctaatgga cgaagtatta tagaaagtcc tgattctcca agcagcagga aaacgaaata agtgtttgaa atccacaaga tggt tcaggg gctaggacat acagaagttg gctgtcatta aggcataatg agcatatgca agcagaagaa ttaagttaac catggagaag gcatcatcca gaagtaacta gccgacagta gaagatctca tttgataaca gacaacatta ctccatacat gctatggttg aatgataggt gacacctcag gacaacgata agcaatcaac aaacaaacgt cccgacaaaa tacgtgaaca aatgactaat tatgtttagt atcaaaggga gacaacacta ataataacat gaatgtattg gagatgaagc acaaaatatg attggcatta attccaacaa agt taagaag attggggcaa gatcagctgc actcccaatt gaagatgcaa ggaagggaag gtagatataa acattatcaa tacaaaaaaa gactgtggga gacagatcag aaacgataca aaacaccctc gggggtagta caagtaatgc gctagtgtcc ggaggagaag actcaatttc ggagagtata gagcaactca ttggaagcca aaaaaatacg atgcaaataa aagatcctaa aagagagccc ccccagaaac ccccaagtga atgaagaaga cagcaagact tagtagttgc gtctaagaga tagaggctat atgaagtgtc gtgacaatga aacatcaata ccatcagtag ttaacaatat agcttcacga tatatgaatc ctaattcaat aatggggcaa ctatgcaaag ctcttaccaa taagaaaact tactgcacaa gcactttccc agcctacaaa aaaaaccaac gagctaatcc atacaaagat tgtcatccag atgatgtgca atcataaatt acactataaa caacatatcg gcttgacatc tgctaaaaga tgataatact gtcttacagc agggcctcat atcttataga gagttgaagg taagatgggg aggcagaaat ctggatt cta ccaacttctc gaggtacacc aagaaaatgg taaagcatca gggcaaataa caaagctacc gaagaaagat gataacatct aaaagccaac caaccctttt atctagctac agatagaatt aagtgcagga agagatgata ggcaagactt tcttaatcca tctatcactt aaacagacat aaccaccaac agtaacaaaa aggctccaca 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 WO 99/49017 WO 9949017PCTIUS99/06225 tacacagcag atatgggtgc agcatcaata attaactcaa gtatcattag gcatgcagtc atgaagacat acatcaaaaa ctgaactcac attattcctt aaatatatca agcatatatt ctagaggatt cacactatat cactcaaaat aataaaacca atttataccg caatagaatt taatcttttt ataaagcatt gttctaccat ttctcacaga atttaaaaat atgcaaccat atactcttaa tagcacaaat ccataatatt caataaaaaa gggttagttc catcacccaa c cac t tcaac aagatgatta aactttgcaa tcaaacccac ccaaaacgac cagaaagaga cagtccaaca cacccacagc agttattcaa aacctggggc cttgctatta tcgacatgta agtgtcataa aaagtaaaac ctacttatgc atgaactaca cgaagatttc tcaaaagttc ctgttcagta ctatgttcca tactagtgaa gaagtgctgt atgaaagaag taacatgctt tcaaccccac gagtaataat tagaaaatat atgcaggatt aaccacagag atgtgactac aaacttaatt ccaaacatca ccaaaatcac aaatatgggg ccaattcaac cacaagcaaa actaattata ctgtaacaaa tatgctgtgt gtcatggtgt taacataatg gtccaaacac tcatctaatt agc a ctat ca catcatctct ccacactgaa atccaagcaa tacaaaatca acagaccaac ccattttgaa atccatctgc aaacaaacca gaaaaaagaa caccagcacc gcaatccctc at ccgagc cc aaactacatc aaataaccat atgcattgta gtgcagttag caatagaatt t ta tgaaa ca aaaacacacc caatcaatac taggcttctt tacaccttga caatgttcta gtcatctgtg gcagatctct gctggctcaa caaattagca aaaagtaaaa tcatgagatc accaacctat agcaaccacc agtgttagtt tcaatttata taattggaag atcaacactg taaacatcta taccagccac taaatagaca acatatacta ttttggccct atcactatta actcttgaac caaattataa cgcaaaacca atgaattgtt aagaatcaac gtaatatcct gttttggcaa gccaatcaca aaaaacatca cccacaacca gaaacacacc aagccaagca gtgttcaact aaaacaatac accaccaaaa actaccacca tcacaatcca ctctcaacca tccacaccaa ttagcagaga ggagttgatg cctcacctca cagaggttat aagtaatata agaattagat agctgtcaac cact aaaaa c gttaggtgtg aggagaagtg gaaaaagatg ccagcagact acgcccaaag atgcctagta tatgatgtaa agtatgttaa attgctctat ctaagatcaa gaattcaaaa atcacagtta gtagatcttg catacagcta aatgacaggt cactacacac tatctgctag ttagttagag taaatcttaa attttacact tgattgcaat taggacagat tcctgtatat cgctaactat agtatgagat gcactgccag cttgtttata tgataatctc aagttacact ccacctaccc catcaccaat atacaacagc caaaaccacg tcgttccctg caagcaacaa ccacaaacaa acccaacaaa ctgcactcga cccccgaaaa actccaccca accgtgatct atccacaagt agtcagaaca tttagtgctt aaagaaacca aagtataaga aaccgggcca ctaaatgtat ggatctgcaa aacaagatca atgatcctgc tgctcataaa gaccttcact atttcatcat ctacaccttg ctacagtcaa gtgaatttga ttagtgtcaa atgctatcac ctgacaataa gtgcctacct cacgtttttc ccacatatat ttcatcacac acctagagtg ttcaatcaat aatgggaaat aatacatatg actaaataag gtatcaaatc ataaacaaac catggtagca caaaaacaac gactctagaa caga t taaat aacctctctc aacaacggtc tactcaagtc ccacacaagt acaaaccaaa tccaaaaaat cagtatatgt accaaagaag aagagaccca aaaactaacc cacaaccaca cacacccaac aaaaacccag atcaagcaag caagtgcaat taactgagga taagaac agg aatgcaatgg atgcagtaac gaagagaagc caataagcaa tagcaagtgg aaaatgcttt atcactaaca agaacttgca acgagtcacg aagcgcaaat tgaaat caaa agatcttacc aaatattatg gaacaaggat caatgcaaaa aggagcattc agaaaaagag aatcaaacca cctcaaacta aaaccaatcc cgaataggta cttaacaacc acatccatca atcttaactc ctaagtgaac aacacataga aaatccaatc tagagtagtt attggggcaa aagacctggg ttaaaatcta ataattgcag acagttcaaa tcaccagaaa tcagctacaa ggCagaacca ccaccaaaaa ggcaacaatc aaaccaacca aaaacaccag ctcaagacca ttaaaacaca tccacacaaa ccacatgctt aacgaaatta cttcctaact gttttaccaa ttggtatact aactgacact agaattacag accacagtat gaagaggaaa tatagctgta gttgtctaca 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 WO 99/49017 WO 9949017PCTJUS99/06225 aacaaagctg ctcaagaatt tccaacattg agagaattta agtgagttac tcaagcaatg gaagtccttg aaattgcaca acaaggactg gctgacactt ttaccaagtg attatgacat tcatgctatg ttttctaatg actttatact ataaattact gtcaatgaaa aatgtaaata attgtagtat acaccagtta tagacaaaaa aacttacaac acccacataa tcaaccacta gaaatccttg gtcataatta acaagatact ctgaactgga taggatctat ttgagatcaa agataagagt aaaccatcca cattagatat aaaatgacca atattgatct aaccataact tggacaccta gaagatatat catccaacca gaaactctgc agtgtaatgc acttaattag cacagtcatt tccagtcatt acttacttaa tcttgaataa atgaaaactc atcaatcata tagtcagttt acataaataa aaacagttat gtgtcaatgc tatcattaat ttcagatagt catatgttgt catcgcctct atagaggatg gtaaagtaca aagtcagcct caaaaacaga gtaaaactaa gttgtgacta atgtaaacaa atgaccctct aaatcaatca ctggcaaatc tgttatcatt cactaagcaa accacctgat aaatatttca Ctaagctaga aatcaacaca taaatttgag ctttgaatgg caagtcaatg tagaacagaa aaacaacata tagtgatgac gtacaatact tctgctCaag ccacaaaagc aaccaaaaat caagtgaaag atttggataa aaaacttatt atacagtata taaaactatt taatgtgtat tttagggagt tagacaaagc aatatctaga acttatgaca aaaaataata actaggatta agtacttaca tacaaattca atcaaatggg ccaattatta agaattccag aggtgtaaca caatgatatg aaggcaacaa acagctgcct atgcactacc gtattgtgat gtccaatcga ttgtaacact cataagcagc atgcactgca tgtgtcaaac gctggaaggc agtgtttcct aagtttagct tactacaaat aatagctatt agaccaacta catgtttcaa acatcacagt tccttaactt tcattcacaa attagaggtc cctcctcatg gacaaaagca gaatatgctc acaaaacaat attaaaaagc gttatatcat agactaccag ataaccataa aatgatatta catgqttgct ccaccagcgt agatgccact tatattagtg ttgataaggt ctaactgata tatcttttta ccactactag tatcataaag tataaaagta cgaagagcca aaggaaaagg accataatta ga caaaagt c gtcagtgttt cccatagtaa cagaagaaca acacctttaa cctataacaa agttattcca atctatggtg aacatcaaag aatgcaggat gtattttgtg gaCa tat ica tcagtaatta tccaacaaaa aaaggagtag aagaaccttt tctgatgagt tttattcgta attatgataa ggtttactgt agtggaatca C aa Caat Ctg acaggctgaa atagttacat aattaacagc attgcttgaa cattactagt tagacacttt ttggtatagt cagcatgtgt ttagagataa acattgagag cagacgtgct gcaatccaaa ccggataaat acattcaatc ttattaaatc caacaatttc teataatgct tatgggacaa gttatttaaa acggccctta agcatatgaa gtgaactgaa tgtcctcgtc tagaaataag acagagttaa aagatgatat actcagtaaa taaccagcaa atcaacagag gcagattgtt gcacttacat atgatcagaa tcatgtctat taatagatac aaggatcaaa cagtatcctt acactatgaa attccaagta Ct tct Cttgg atcgtgggat atactgtgtc atgtaaaagg ttgatgcatc gatctgatga ctacaattat tgtattgtaa ataatattgc ctgaccacca tcatttcctc aaaaacctca tggggcaaat tggtagaaga gaggcaaaac gtctgaaata tggagtgcta tgctatgagt tgaagaacC caatagaaaa gaagaagaca agagtcaact atccttgtag ataaaaacat atatatttga tccaacatct tgaccataac aatggatCc aggtgttatc tcttaaaaat tcttaaaaaa attagaagaa tgaacaaatt tgatgtaaag gcccaacaat actttcggct tcaaaatatc agtgttagat ctgtcgcatc ggaaatca cc gttgacaaac aaaattaatg aataaaggaa accttgctgg tatttgttta ctttccacag cagtttgaca tgactgcaaa agctatagtg tataaagaca agtgggcaac ggaacctata aatatctcaa attactacat tatagtaatc agccaaaaac attcagcaaa atcccaaatc acatcatgct agtatcacaa atgtcgcgaa tgtcactaca ttcatgttaa agtggagC tg gagagttaca aaacttctta aattcaccta aacaacaagC ataaagaaca gtgaatgatc tatatcatcc attacaattt tgaaattcat taa cat CCCt gaCtctatgt attattaatg tctttttcag gattacacCa Ctaactataa ccaacttatt gctacaacta gtgtacgcca aattcaggtg gtggaaaaca actatcaaaa 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8*16 0 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 WO 99/49017 WO 9949017PCT/US99/06225 caacactctt ggtt caatt t aaagtcatgg atcaatatgg atcaattttt ggataagtaa atgttgtgtt aaggcttcta cagaagaaga cagctattaa cagtgtctga tgattaagct gaatctttgg gtaatgaaac atagaatcat ttgtcctacc aaatcacaga tgcctaaaaa atctaatatg aacatgaaaa tgagagataa tcaacaactc gaatgtttgc tagctgaaaa ttcaaaagat actacaacaa catttagata aatctctgtt gacatgcacc gtggattata ttgaagctat tgataaatgg agacccatgc agtatgcagg agttcatgag tcctgagagt ctataggcag tatttaggaa gtaacaataa atcttgatag gtggtgatcc aagctatagt agctccagga ataaaaatcc aaaggcaagc tagccccaaa taaatgacat aaagtttacc gaaaaaattg atatacaaaa gtttatatta ttgtatcgtt gacatggaaa ttgtttaaat atcacaatta cataataaaa tcaatttagg ggctcaaaag taatatcata tgcaggtgat acatccaatg taagttctac aaaagggttt tctaagatgg aaatgatttg agtggatctt gactagtttt gttgaagttc taaattcaat taatcacgtg tatgcaacca tattttacaa attagaatta ttatatcagt tgaaacatca c tct tggttg tcctttcata cagatatcat atcattatta tgataatcag acaagcagat tataggccat caaaacaatc aggtccatgg cttaacacag catttggtta gctatattta cattgatatg taatttgtta acattcagtg tcttccagat caatgccgag taaaattact caaaatattt tatgcaaaat tttttataaa atgtgttcaa ttaaataaca atagataatc tatcataaag gacatcagcc acattaaaca tttctttatg gaagtagagg aaacgatttt gacctactat aatggtaaat aataatctca gtcgatgaaa ttattaagta gtaaatacct ttaaactact attattttat gaaatgataa cctagaaatt tctgaaagcg gaatgcgatc gtatcactaa ggtatgttta ttcttccctg aaagcaggaa aaatgttcta tgtatctgca catttaacaa aaggatcatg atgggtggta gatctaatat tcaattgata tatttgttag aagcttaagg cagcacaatg ataaacacga gagttagaat tacaatcaaa gatatattga gctttatcat tatcgaagct tttgtgttga gatagactga tttgtaacat agtgagatta tctaaaagtg atagaaccaa gcagaaaaaa tgcaacatcc tattaacaca aaactttaag gactcaaaaa ttagcagatt aaagcttagg gagattgtat gatttattat ataatagcat caagagtatg ggataatcct ataacttgag gacaagcaat gtctaagtac acaacagatg ataaacttaa caggattgcg taaatgacaa acatgccatc acagatcgag tatacaattg ctggtaaaga ggcaaatcca agagtttgac taagcaacaa tcattacaga gtgatgtatt tacctcttgt ttgttaatct ttgagggctg ctctcaaagg taagcaaacc cattaaatag gaacagagac gagtgtacta tacttgatga acagaggaga ttgctttgca aagtattaaa tgtatatgaa tttataggag gctattatac acaaattctt tgatgaggga atagattagc cacaacatta cttaccctca tagttaatct tccatcatgg a tat cga tca tggt tti cag aatcacaact aaatgtttgc gctgagatgt actgaaatta gtctttaatt gctaaataac tcacacttta attaagtaaa tgagctatat ggattctgta attaagaggt gcccacctta tacttatcca gttctatcgt agccatttca acatatacaa aagagtacta tgtagtcaat aagagagctc aatcttagca aagatatggt gtcaaatcgt tcttagcaaa agatgaactg cacaataata taatgaggtt gtgtcaaaaa gaaattctct agttagactt ccttaaattg ctatatatcc tccagccagt ttttaaagtt aagcttatta actccgaaat acacttaaaa tttgcctatg aactccagac tggtcacgat gacatgtgtc tccacaggct agtaacagaa tactaccact tggattaaga tatatcagga ttaatacact aatgaggtaa tttattttaa actacttaca ttaattactt ggattcaata tttcataatg ctaaacataa atcacagatg ttagacaaga tttcttaaat tttctcttca agaattaact gctttcattt aggaatgcta tctctacttg gagtttcatc cctccaaaag aattatatag gagtattact caaagctatc agtgtaggta gagaaaatga gatctagagc tataatgata ttcaatcagg catggagtac tgtacatata gatgaacaaa ctgtggacca atcacagctc atagagggtc ttatataaag cgagatatgc atcaaaaaag agtttagaat tgcagtttaa catgcattat acttttttta ctgtttggtg ttccttacag ttacaagata atcacatttg ttagggtctg gtcttaagta gagattgatc gttgtttatg acaaaatcca 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 WO 99/49017 WO 9949017PCTIUS99/06225 taactaatat atatgatgag acaaaagaga gagaaagatc caatggacat atgttaatag cgcaggagaa accaaataga aattcatgga tgtttccaca gtgaattccc ctatcaatca attgcataag ctaatagaat ttacaggaga taccagataa aatctggatc ataatgctta tgaaagattc tgttcattaa aaggttatgg tggagttaat tcataaaata ttaagttgtg ttaacataga gaatggggtt aattttacac taacaaaaca acccaacccc acaaacctaa gtaaaatgca tgtacaattt caaaatctaa catcacttta ccacaggatg gttgtatagc ttcatccaga ctattgaatt ccattcctgc cagaacctat aaattataat gatgcatttt ttactatatt taatccttac aattgacact tcgatgcaaa ttaagacttc tagctggacg acttgaaaaa gaaaaatata gttattaagt ttggtcatta taaatataca tttaactcgt aaaaacaatg tttattagca agaactgagt atatctaagt tqcatcaata tgtattaaca ttttggtctt tattctcata tgttgatatc aataagttta tcacatcaac tattttaagt aaaaggtatt tttgaatgtt taaagcaaaa agacagtagc catagtcaat gtttttaaaa ttatcaccca aataaatgta atcaaatctc aataagaatt agaaact t ta attttgtata tattaaatct atttccaatt ccaactttac ttgcatgctt caagatcagt attcataggt cataagatac tctaaggtta tacagatgca tagcatcttt tgaatggagt aattgcaaaa aaaaacttac aataggccct ttcaagaact tattaaaagc attgtcaaaa taatgaagta acatcagcaa actttactta ttagaaaatc tccaatatag actagcacta ggtgaaagag ccagtgtaca aaattagact actggaacac gtcaattatt ccagcttata gaaaagtatg agcctgatgt ccgaagctga atcaagttga acccaatatg tctaatttaa actaatttag tttgaaaaag ttctttaatg ttagaatgtg tactggaaat caagacacaa cgccttaata acacacatga gataaattaa ttttacatta gctaattcag gaaaatatgt agtggaaata tccactgtta gttgtgatag accaccactt ccttggcatc atagagtata gaaggagctg atttacagaa tacaacgggc actaataaca gt ctgcgatg aagcatgtaa tatcatgctc gtgtgcctag gcaaatatac aaaaatttca ttaatacctt ttgaagagtg ttcagcaaca tagatacaac taaggatact ttagtataac taggagtaac tagccagtgg gacccaccaa acagacaagt gggtatatgc ttggactgtc tacaccgttt gaacaacaaa gagatgaaga cggttgtgga atgagataca agcaagtgat tagaattatt tattagtaca ctggacattg attggggaga cttataagac atatgaacac ctatgtctaa gtttgcgtag atgctaaatt aagctatatt ccattaaaaa gttataactt aattagaaga cattaattcc ccgaatctat ccacaagatt acaagattat cacatcagac atgtcaatag ttttaaaaga gtaacttatt gtttaaaaga atataaacat ttcattggtc ctgaattacc gaaagtgcaa aagatgacat gtagcaagtt ttcctgtttt ttatgcctaa tcctttgtta tagttaatgg agcttataaa tgatattaat tccactagat tgaattaagc atcgccaagt tataataata gccatgggta tttaaccaaa atccatagac atatgaaaaa aacagtcagt ttatcatttt tatcgacatt acaattcaca tttgatgaaa acaaaagcag cttaagtaac taaaatgtct gattctgatt ggggtacata ttatttgcta ttcagatctt agttttccta aataaaaggc taccgtatgc atcttacata taaaaacaaa ttcagacaac taattataac tgttaaaagt gatgatgtca caattatagc agatcattca atctttagta atttaacttt tcttaagatt attacgtacg ttgcaatgat agattatggt ttatttacat tgttacagcc gtactgttct tgatttcaaa aaaaggat ot tgatgttgta aaaaactgac ccctataaca agatatatta ccacaagcat agggctactg tgtaacaaag aagtatgtaa attatgttca gaaaaatata ggctcatcca aagcaaagag aacaaagatg gccaaaaagt agtagaccat gatactagtc gtgtttcaaa aacatatgtc cctcctatat cacatgttcc aaagcactta gattattttc attcaactta actgatcata tgttttcata ctttgtgttt gaacaaaaag tgtcacagtt ccttgggttg gatttagtta ttcaatgatg actcatttgc aaactatatc aataatagta acattctcta aaacaagact ggtaatacag aggaatagtg gtatttagtt aaggacccca gtagtagaac catagtttac gagaatttaa ataaaatttg aattggagta tctgtaaata ttagataaca gaagtttact caaaatgcta aaggaatcta aaaaaaggaa tcatattcta atgaatatcc 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 WO 99/49017 WO 99490!7PCTIUS99/06225 taaaatggct acatgataga agctcaagaa agtttaaaat agttattaaa tttagtctta cacaacgaga agatcatgtt gtccacatat gctgattaaa atcattaaca aaatatacaa aggggttaaa cattagtttt ttaaatttta ccttacttaa a taac agg ta agtttggtca acttttcaat taaaagtcta tgacactttt gatcagctga gtgaattgtt gtgtgctata aatttagatg aatttagcat aaactaacaa tttctcgt acttaattac aaatagttta caaccttccc ctaacacatc attgattcca ttatacatgt aatcatttat acaaccaatg aacgaacagt attatattat aaattatcat gcattcacaa 14880 14940 15000 15060 15120 15180 15218 '<210> <211> 15229 '<212> DNA <213> respiratory syncytial virus <400> acgcgaaaaa tgataagtgc tgataaaggt catgttatac caattaaatt acaacaatat acatatggga attgtgaaat aaatatctga agacatgtgt ataaactcac attgatgatc agaaat cat a tgatgaaaga agtagggagt catgcctata acacactcct catccaaact ttttagtaat gctcttagca aaatacacta aaacacctaa a caggat taa atacttaaag caagatataa gaaatacaag atgggagaag tgtatagctg gtaattagga cc aaagga ta gtttttgtgc atctttgcag gttctagcca gaacaagttg atgcgtacta tatttaaatc tagat tacaa tgacaaatta aaacggcata tgtagtgaaa attgattgag caaattttct tttacttggg ttatcaccat ctaatcagtc acagacatga acacacaaat caagctacat accaaataca tttatcaatc ataatataca aagctattcc taaaaataaa aagtcaagtt ttcaacgtag acaaactatg taggtatgtt atgctggata acggaaagga tcaatattga tggctccaga cacttgtaat gggcaaacaa tagctaacag actttggcat gattatttat aatctgtaaa tggaagttta caaacttgca taaccttttc aatttatttg attcttctga gtttttatac tctaacttta ttgacacact aaaagactaa cttgatctca tttagttaat aaaccatgag gacccctgtc tcatatactt ttacattctt agaaatacac atgacgggtt aatatgacct tcaaacaaca ggcagagcca aaatgataca tacaggagat tggtatgcta atatgctatg tcatgttaaa aatgaaattc gatagaatct a ta tagg cat aaccaagtta tgtcttaaaa tttttatgaa tgcacaatca gaatgcctat aaatatcatg tgagtatgca cattcggaaa aatcagaaat acaatgacga ccaatgcatt atgttataac caacaatgcc gctctcaatc gtgactcagt attcatgaat ataaaacctc cactacaaat gatggaatca gataaacaat agtcaattat tgaatataat tctagaatgt caacccgtaa gtgctcaaca ataacataaa ttaaataagg aatattgaca ttaatcactg tccaggttag gctaatggag gaagtattaa agaaagtcct gattctccag gcagcaggag aacgaaataa gtgtttgaaa tccacaagag ggttcagggc ctaggacatg cagaagttgg aaatggggca ggggtgcaat agtagcattg agccaaagca aagcagtgaa aatattacaa aaatggtcta aatgactaat tatgtttagt atcaaaggga gacaacacta ataataacat gaatgtattg gagatgaagc acaaaatatg attggcatta attccaacaa gttaagaagg ttggggcaaa atcagctgct ctcccaatta aagatgcaaa gaagggaaga tagatataac cattatcaag acaaaaaaat actgtgggat atagatcagg aacgctacaa aacaccctca ggggtagtag aagtaatgct ctagtgtcca gaggagaagc aataagaatt tcactgagca ttaaaaataa gtaatacata gtgtgCcctg aacggaggat atggatgata tatatgaatc ctaatttaat aatggggcaa ctatgcaaag ctctcaccaa taagaaaact tattgcacaa gcactttccc agcctac aaa aaaactaacc agctaatcca tacaaagatg gtcatccagc tgatgtgcaa tcataaattc cactataaag aacatatcgt cttgacatca gctaaaagag gataatactg tcttacagca gggcctcata tcttatagat agttgaagga aagatgggga ggcagaaatg tggattctac 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 WO 99/49017 WO 9949017PCTIUS99/06225 catatattga agtgtggtcc agaaaccaag gtaataaact ctcaacccca tcaacatgga aattcctaga gcataatatc gcaccaacat acccaagaaa ctaagttgta catatgaaga atgaaaaatt ccacctcagc aaaaaataag ggaatgagga cttccaaaaa atgatttttg aatccattga aatcaatcaa aagaacaaga acacagcagc tatgggtgcc gcatcaacat ttaactcaag tatcattaga catgcagtct tgaaaacatt catcaaaaag tgaactcact ttattcccta aatatatcaa gcatatatta tagaggatta acattatatc catttaaaat aataaaacca atttataccg caatagaatt taatctcttt ataaaacatt gttctaccat ttctcacaga atttaaaaat atgcagccat atactcttaa tagcacaaat ccataatatt acaatccaaa taggcaatgc atctatatga acagtgtatt aagaagatga gaagtttgca atcaataaag tgttaactca catcaatcca acccctagta caaagaaa ca aataaatgat aagtgaaata tcgcgatgga agcggaagca aagcgaaaaa attgagtaat atcagtgat c atcaactgcc ccaattgatc tggggcaaat tgttcagtac tatgttccag actagtgaag aagtgctgtg tgaaagaagc aacatgctta caatcccact agtaataata agaaaatata tgcaggatta gccacagagt tgtgactaca aacttaatta caaacatcat ccaaaattac aaatatgggg ccaattcagt cacaagcaaa actaattata ctgcaacaaa tatgctgtgt gtcatggtgg taacataatg gtccaagcac tcatctaatt agcactgtca catcatctct agcatcattg agcaggtcta tgcagccaaa agacttaaca tgtagagctt cctgaatttc ggcaagtttg atagatatag ataagtgaag agcttcaaag atagaaacat caaacaaatg ttaggaatgc ataagagatg ttaatgacca atggcaaaag ttgttggaag aactcactca agactgaaca aatcagcgac atggaaacat aatgttctag tcatctgtgc cagatctcca ctggcacaaa aaattagcat aaagtaaaaa catgagatta ccaacctatc gcaaccaccg gtattagtta caatttatag aattggaagc tcaacactaa gagcatttac ttccagctat taaatagaca acatatacta ttttggcctt atcactatta actcttgaac caaattataa cgcaaaacca atgaattatt aagaatcggc gtaatatcct gttt tggcaa gccaatcaca ctgtcattaa ggcataatgg gcatatgcag gcagaagaat taagttaaca atggagaaga catcatccaa aagtaactaa ctgatagtac aagatctcac ttgataacaa acaacattac tccatacatt ctatggttgg atgataggtt acacctcaga acaacgatag gcaatcaaca cacaaacgtc ctaacaaaat acgtgaacaa aaaaagatga cagcagactt cgc ccaaagg tgcctagtag atgatgtaac gtatgttaac ttgctctatg taagatcaat aattcaaaaa tcacagttac tagatcttgg atacagctac atgacaggtc actacacact catctgttag ttagttagag taaatctcaa attttacact tgattgcaat taggacagat tcttgtatat cgc caac cat ggtatgagat gcactgccgg cttgtttata tgataatctc aagttacact ctcaatttcc gagagtatag agcaactcaa tggaagccat aaaaatacgg tgcaaacaac agatcctaag agagagcccg cccagaagct cccaagtgac tgaagaagaa agcaagacta agtagttgca tctaagagaa agaggctatg tgaagtgtct tgacaatgat acatcaatga catcagcaga taacaatata gcttcacgag tgatcctgca gctcataaaa accttcacta ttttatcata tacaccttgt tacagtcaaa tgaatttgaa tagtgtcaaa tgctatcacc tgacaataaa ggcctaccta acgtttttca cacatatatc tttaccatat acctagagtg ttcaatcaat aatgggaaat aatacatatg actaaataag gtatcaaatc ataaacaaac catgatagca caggaacaac gactctagaa cagattaaat aacctctctc aacaacggtt taacttctca aggtacacca agaaaatgga aaagcatcaa ggcaaataag aaagctacca aagaaagata ataacatctg aaagccaact aacccctttt tctagctact gatagaattg agtgcaggac gaaatgatag gcaagactta cttaatccaa ctatcacttg aacagacatc actaccaacc gtaacaaaaa ggctccacat tcactaacaa gaacttgcaa cgagtcacga agtgcaaatg gaaatcaaag gatcttacca aatattatga aa caagga cc aatgcgaaaa ggagcattca gaaaaagaga atcaaaccac ttcaaactat aaatcaatct cgaataggta ctcaacaacc acatccatca atcttaactc ctaagtgaac aacacatagt aaatccaatc tagagtagtt attggggcaa aggacctggg ttaaaatcta ataattgcag acagttcaaa 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 WO 99/49017 WO 9949017PCTIUS99/06225 caataaaaaa gggtcaactc tatcaccaaa ccacttcaac aaccaaaaga ataatcaact caaccatcaa caccagccaa agaccacaga aatacacaat cacaaatacc atgcttagtt aaattaaacc ctaactcttg taccaatcga tataccagtg gacactaaag ttacagctac cagtacatga aggaaacgaa gctgtatcca tctacaaaca ttagatctca cgcatctcca atcaccagag acaaacagtg ttaatgtcaa aaggaagaag tgctggaaat tgtttaacaa c cacaggc tg ttaacattac tgcaaaatta atagtgtcat aagacatttt ggcaacact t cctataataa tctcaagtca ctacataatg gtaatcattg aaaaacacac agcaaataga caaatcaact tcatgctacc atcacaatca tcgcgaagaa cactacagtc atgttaaaca ccacactgaa atccaaacaa tacaaaatca acagaccaac tgattaccat ctgcaaatcc acccacaaac aatgccaaaa aagagacacc ccaacagcaa cacagcatcc attcaaaaac tggggcaaat ctgttaatgc catgtagtgc tcataacaat taaaacttat ttatgcaaaa actacacaat gatttctggg aagttttaca aagctgtagt agaattacat acattgaaac aatttagtgt agttactatc gcaatgttca tccttgcata tacacacatc ggactgatag atacttgcaa caagtgaagt tgacatcaaa gctatggaaa ctaatggttg tatactatgt attactatga atgaaaaaat taaatactgg tagtattgtt cagttacact caaaaaacta taacaacaaa tacacaacta aacactaaat atccttgtaa ataattattt agatacttaa aaaaacatct cccacaacca gaaacacacc aagccaagca tttgaagtgt atctgcaaaa aaaccaacca aaagaaatca agcatttcac tccctccact gagccctcca tacatcttag aac ca tggag attgtacctc agttagcaga agaattaagt aaaacaagaa cacgccagct caataccaca cttcttgtta ccttgaagga cagtctatca aaataaccga agttatagaa taatgcaggt attgatcaat gatagtaagg tgttgtacag acctctatgc aggatggtat agtacagtcc cagcctttgt aacagacata aactaaatgc tgactatgtg aaacaagctg tcctctagtg caatcaaagt caaatctact atcattaata aagcaaagac cttaatcatg tatttcaaca agctagatct cgacacatca atttgagatt tgaatggcct gtcaatggac ccacctacct catcaccaat atacaacagc caaaatcacg tcaattttgt caataccaag ccaaaaccac tcaccaaccc aatccaccgt caaccacctc cattaaatcc cagagaaccg ttgctgatcc acctcaagtc ggttatttta aatataaaag ttagataagt gccaacaacc aaaaacctaa ggtgtaggat gaagtgaaca aatggggtca atattaccca ttccagcaga gtaacaacac gatatgccta caacaaagtt ctacctatct accaccaaca tgtgataatg aatcgagtat aacactgaca agcagctcag actgcatcca tcaaacaaag gaaggcaaaa tttccttctg ttagctttta acaaatatta gctattggtt caactaagtg tttcaacaac tcatagcaca tcaactcata ttcacaaaat agaggtcatt cctcatgcat aaaagcatag tactcaagtc ccacacaaat acaaaccaaa ttcaaaaaat tccctgtagt caacaaacca aaacaaaaga agcaaaaaaa gctcgacaca cgaaaacaca taattaaaaa tgatctatca acaggtcaag agaacataac gtgctttaag aaaccaaatg ataagaatgc gggccagaag atgtatcaat ctgcaatagc aaatcaaaaa gtgttttaac tagtaaatca agaatagcag ctttaagcac taacaaatga attctatcat atggtgtaat t caaagaagg caggatcagt tttgtgacac tattcaattc taattacttc ataaaaatcg gagtagatac acctttatgt atgagtttga ttcgtagatc tgataactac tactgttgta gaatcaataa aatctgctga ggctgaatca gttacataaa taacaactgg gcttgaatgg tactagtgag acactttgtc ccaccagaaa tcagccacaa ggcagaatca ccaccaaaaa atatgtggta aagaaaaaac gaccccaaaa ccaaccctca atcactccaa cccagctcca acctagtcac agcaagaaca tgcaatcttc tgaggagttt aacaggttgg caatggaact agtaacagaa agaagcacca aagcaagaaa aagtggtata tgctttgttg cagcaaagtg acagagctgt attgttggaa ttacatgtta ccagaaaaaa gtctataata agatacacct atcaaatatt atccttcttc tatgaacagt caagtatgac tcttggagct tgggattata tgtgtcagtg aaaaggggaa tgcatcaata tgatgaatta aattattata ttgcaaagcc tattgcattc ccaccaatcc tttcctcata aaccccaagt ggcaaatatg tagaagatgt gcaaaacttc ggaaataagt 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 WO 99/49017 WO 9949017PCTIUS99/06225 ggagctgctg agttacatag cttcttattg tcgcctaaga aacaagcaaa aagaacacat aatgatcaaa atcatccata acaatttaac aattcattgg catccctgaa tttatatcat attaatggaa ttttcagaat tacaccaact actataacac acttatttcc acaactaatt tacgccatct t caggtgatg gaaaacaatc atcaaaacaa atacac tggt gaggtaaaaa attttaaatc acttacaatc attacttgga ttcaataatg cataatgaag aacataacag acagatgcag gacaagacag cttaaattga ctcttcagaa attaactgta ttcatttata aatgctattg ctacttgaaa tttcatctgc ccaaaagatt tatatagaac tattacttga agctatctca gtaggtagaa aaaatgatag ctagagcttc aatgataact aatcaagcat aactggatag gatcaataaa agatcaacag taagagtgta ccatccatct tagatatcca atgaccaaac ttgatttcaa cataaccatt acacctaaaa gatatatata tcaaccataa actctgccaa gtaatgcttt taattagtag agtcattaat agtcattact tact taaaaa tgaataaact aaaactcagt aatcatatac cactcttgaa tcaatttata gtcatgggtt aatatggttg aatttttgac taagtaattg ttgtgttatc gcttctacat aagaagatca ctattaaggc tgtctgataa ttaagcttgc t ctttggaca atgaaaccaa gaatcataaa ttctacctct tcacagagaa c taaaaaagt taatatggac atgaaaagt t gagataataa acaactctaa tgtttgctat ccgaaaatat aaaagatatt acaacaatta ttagatatga aacagaagaa caacataaca tgatgacatt caatactgtt gctcaaaaga caaaagcata caaaaataat gtgaaagcat tggataacca acttattaga cagtatatat aacaacctta tgtgtatcta agggagttac acaaagccca atctagatat tatgacatat aataatacga gggactaaag tcttacaacc aaattcagac aaaattgatg tacaaaatta tatattaata tatcgtttat atggaaagac tttaaataca acaactattt aataaaagaa atttaggaaa tcaaaaaaac tatcataaat aggtgataat t ccaatggt c gttctactta ggggtttgta aagatggttg agatttgatt ggatcttgaa tagttttcct gaagttctct attcaatgaa ccatgtggta gcaaccaggt tttacaattc agaattaaaa tatcagtaaa aacatcatgt tatgctcttg aaacaatcag aaaaaactga atatcataca ctaccagcag accataagca gatattaccg gattgctaca ccagtgttta tgccactcaa attagtgtca ataaggttat actgatagtt ctttttaacg ctactagagc cataaaggtg aaaagtatgt agagctatag gaaaaggaca ataatcaaag aaaaatcatt tgttcaatgc aataacatat gataatcaaa cataaaggac atcagcctta ttaaataaaa ctttatggag gtagagggat cgattttata ctactatcaa ggtaaatgga aatctcaata gatgaaagac ttaagtaatc aatacctaca aactattata attttatcag atgataataa agaaattaca gaaagtgaca tgcgatctat tcactaactg atgtttaggc ttccctgaga gcaggaataa tgttctatca atctgcagtg gtatagttgg catgtgttgc gagataacga ttgagagcaa acgtgctgaa actcaaaaga gataaatatc ttcaatcata ttaaatcata caatttctcc taatgcttga gggacaaaat atctaaaagg gcccctatct atatgaatct aactgaagtt cctcgtctga aaataagtga gagttaagcc atgatatact cagtaaatca aacatcctcc taacacaata ctttaagtga tcaaaaaaat gcagattaaa gcttagggct attgtatact ttattatgtc atagcatgct gagtatgtca taatcctatt acttgagtga aagcaatgga taagtacgtt acagatggcc aacttaatac gattgcggtt atgacaaagc tgccatcaca gatcaagaag acaattgtgt gtaaagaaag aaattcaaat gtttgacaag gcaacaagtc ttacagacct atgtattaga agtgctagag tatgagtaaa agaacccaat tagaaaaaac gaagacaata gtcaaccgtg cttgtagtat aaaacatatt tatttgatga aacatcttaa ccataacaat ggatcccatt tgttatctct taaaaatgat aaaaaaacta agaagaacca acaaattgct tgtaaaggtg caacaataat ttcagctgtg aaatatcact atcatggtta tcgatcaaat ttttcagttt cacaactact tgtttgctta gagatgtgga gaaattattc tttaattcta aaataacatc cactttatta aagtaaattt gctttatttt tgctgtaaga aagaggtgc t cactttaagg ttatccatct ctatcgtgag catttcacct tatacaaaat agtactagag ggtcaatcaa agagctcagt cttagcagag atatggtgat aaatcgttat tagcaaattc tgaactgcat 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 WO 99/49017 WO 9949017PCTIUS99/06225 ggagtacaat acatatagac gaacaaagtg tggaccattg acagctctaa gagggt caga tataaagagt gatatgcaat aaaaaagtcc ttagaatcta agtttaatat gcattatgtc ttttttaatc tttggtggtg cttacagaag caagataagc acgtttgata gggtctgaaa ttaagtatag attgatctaa gtttatgaaa aaatccataa gctactgata aacaaagaca tatgtaagag atgttcacaa aaatataatg tcatctacgc caaagagacc aaagatgaat aaaaaattgt agaccatgtg actagtccta tttcaaaatt atatgtccta cctatattta atgttcctac gcacttaaat tattttcata caacttatga gatcatatgt tttcataaag tgtgttttgg caaaaagtca catagtttta tgggttgtta ttagttagaa aatgatgaat ctctgttctc atgcacctcc gattatacag aagctatatc taaatggtga cccatgctca atgcgggcat tcatgagcaa tgagagtagg taggtagctt ttaggaacat acaataagct ttgatagtat gtgatcctaa ctatagtaca tccaggatct aaaatcccaa ggcaagcaaa ctccaaacaa atgatattat gtttaccttt ctaatatact tgatgaggaa aaagagagtt aaagatcttg tggacattaa ttaatagttt aggagaaaaa aaatagattt tcatggaaga ttccacaata aattccctgc tcaaccatgt gcataagttt atagaattat caggagatgt cagataaaat ctggatctca atgcttatat aggattcaaa tcattaattt gttatggtaa agctaataga taaaatacat agttatggtt acatagatta tggggttaat tttacacatc ttggttgcat ttttataaag atatcatatg attattagat t aa t cagt ca agcagattat aggccacaag aacaatccag tccatggata aacacaggag ttggt tatac atatttagat tgatatggct tttgttatat ttcagtgttt tccagatgat tgccgagttt aattactagt aatattttct gcaaaatata ttataaagca tgaaaaaaca aaatataact attaagttta gtcgttatcc atatacaact aactcgtggt aacaatgc ca at tagcaaaa actgagtact tctaagtgtc atcaatacca attaacagaa tggtcttagc tctcataccg tgatatcatc aagtttaacc catcaactct tttaagtact aggtattttt gaatgttttc agcaaaatta cagtagctac aatcaatcaa tttaaaacgc tcacccaaca aaatgtagat aaatctcttt ttaacaatac gatcatgttg ggtggtattg ctaatatctc attgatataa ttgttagcat ctcaagggaa cacaatggag aatacaatac ttagaatata aatcaaattg atattgaaag ttaacattgt cgaagctttt gtgttgagct agactgaaca gtaacattga gagattaata aaaagtgcac gaaccaactt gaaaaaatag tcagcaatag ttacttataa gaaaatctta aatatagtag agcactatag gaaagaggac gtgtacaata ttagactggg ggaacacttg aattatttac gcttatagaa aagtatggag ttaatgtcgg aagctgaatg aagttgaagc caatatgtag aatttaatat aatttagctg gaaaaagatt tttaatgctt gaatgtgata tggaaatcta gacacaagtt cttaataatg cacatgaaag aaattaacca tacattagtt ctcttgtcac ttaatcttaa aaggctggtg tcaaagggaa gtaaaccagt taaatagcct cagagaccta tgtactatcc ttgatgattt gaggagagag ctttgcaact tattaaaaca atatgaattt ataggagaac attatactgg aattcttgac tgagagatcc gattagcagt aacattatac acc ct ca tgg ttaatcttat attcaactga ggatacttcc gtataactga gagtaacatc ccagtggtat ctactaagcc gacaagtttt tatatgcatc gactgtcata accgcttaac caacaaatta atgaagatat ttgtggaaca agatacattt aagtgataca aattattcct tagtacataa gacattggat ggggagaggg ataagactta tgaacacttc tgtctaaagt tgcatagaat ctaaatttac ctatattatc ttaaaaataa ataacttttc aataatatgt taaagttgat tcaaaaactg attctctatc tagacttata taaattgcta tatatcccga agccagtatc taaagttagt cttattatgc ccgaaatcat cttaaaaact gcctatgctg tccagacttc tcacgattta atgtatcatc acaggcttta gacagaagtc taccactgag attaagagtt atCaggaaca tattaatagg actagattgt attaagcaag gccaagtatt aattatagaa atgggtaggt aaccaaaaag catagacaac tgagaaagcc agtcagtagt tcatttcgat cgacattgtg attcacaaac gatgaaacct aaaacagcac aagtaacaaa aatgtctgat tctgattatt gtatataact tttgctatgt agatcttctt tttcctagaa aaaaggttgt cgtatgccct ttacatagat aaataaattC agataacact 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 WO 99/49017 WO 9949017PCTIUS99/06225 catttgctaa ctatatcacc aatagtaata ttctccaata caagacttgt aatacagcaa aatagtgcat tttagttcca gaccccagtt gtagaacttc agtttaccta aatttaacca aaatttgcag tggagtaaaa gtaaatagat gataacatta gtttacttag aatgctaaat gaatctatcg aaaggaatta tattctatag aatatcctaa catttatata accaatgagc gaacagtaac atattatagt aaagttatca caaaacaaat caaccccaga aacctaaatt aaacgcatat acaatttatt aatctaacca cactttattg caggatgcaa gtatagcatt atccagacat ttgaatttct ttcctgctac aacctattag ttataattga gcattttaat ctatattaaa tccttacaat tgattctttc atgcaaatat agacttcatt ctggacgtaa aatggctaga tgatagagtc tcaagaagct ttaaaacatc tattaaaaaa ttttggtctt aagaattgct aactttagaa tggtataagt taaatcttcc tccaattgtc actctacact catgcttcct gatcagtata cataggtgaa aagatacatt aaggttatac agatgcaact cat tt ttgt c atggagtaag tgcaaaatat aacttacgtg aggccctgca aaggactaaa taaaagctta gtcaaaattg tgaagtattc tcatgtttta cacatatcct gattaaaata attaacaagt tatatatgca aaggggttga aattcagaat aatatgtcat ggaaa tao cg gctgttatta gtgatagaca accacttcac tggcatcatg gagtatattt ggagctggta tacagaagtt aacgggcata aataacattc tgcgatgctg catgtaagaa catgcccaag tgcctaggta aatatacttc aatttcatta atacctttcc aagagtgtag agcaacaagc aactttagat tacttaagtg acaggtagtg ttgatcaaat aacttttcaa ataaaaatct tagaaaataa taattcctgt aatctatgat caagattcaa ggattataga atcagacatc tcaatagatt taaaagatct acttattatt taaaagattg taaacataga at tggtctta aattacctgt agtgcaagta atgatattga gcaagttaaa ctgtttttaa tgcctaaaaa tttgttaccc ttagtggaga ttataaacca cagctgaact aattgttaaa tactatacaa ttagatgcta taatttagca aaaactaaca ttataacaaa caaaagtaat gacgtcaaca ttatagtaaa tcattcaggt tttagtaagg taactttgta taagattaaa acgtacagta caatgatcat ttatggtgag t ttacatata tacagccaat ctgttcCtct tttcaaatta aggatctgaa tgttgtgcaa aactgacaaa tataacaaaa tatattatca caagcatatg taattacaat cagtttaaca ccttcccaac acacatcata tattgattcc attatacatg 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15229 tgcatttaca acacaacgag acattagttt ttgacacttt ttttctcgt <210> 11 <211> 15219 <212> DNA <213> respiratory syncytial virus <400> 11 acgggaaaaa ttgataagtg atgataaagg acatgttata acaattaaat gataacaata tacatatggg aattgtgaaa caaatatctg tagacatgtg aataaactca gattgatgat aagaaatcat aatgcgtact ctatttaagt ttagattaca ctgataaatt taaacggcat ttgtagtgaa aattgattga tcaaattttc acttacttgg tttattacca cctaatcaat cacagacatg cacacacaaa acaaacttgc ctaacctttt aaatttattt aattcttctg agtttttata atctaacttt gttgacacac taaaagacta gcttgatctc ttttagttaa caaaccatga agacccctgt ttcatatact acattcgaaa caatcagaaa gacaatgacg accaatgcat catgttataa acaacaatgc tgctctcaat agtgactcag aattcatgaa tataaaaact gcactacaaa caatggattc tgataaacaa aaaatggggc tggggtgcaa aagtagcatt tagccaaagc caagcagtga caatactaca taaacggttt taatgactaa ttatgtttag catcaaaggg tgacaacact aataataaca tgaatgtatt aaataagaac ttcactgagc gttaaaaata agcaatacat agtgtgccct aaatggagga aatggatgat ttatatgaat tctaattcaa aaatggggca actatgcaaa tctcttacca gtaagaaaac 120 180 240 300 360 420 480 540 600 660 720 780 WO 99/49017 WO 9949017PCT/US99/06225 ttgatgaaag aagtagggag ccatgcctat aacacactcc cccaaccaaa cattttagta tggctcttag gcaaatacac aaaaacacct tcacaggatt agatacttaa gtcaagatat cagaaataca agatgggaga tgtgtatagc cagtaattag taccaaagga atgttttcgt gaatctttgc gagttttagc tggagcaagt accatatatt caagtgtggt caagaaacca gagtaataaa aactcaaccc agtcaacatg caaattccta tagcataata tggcaccaac ctacccaaga ttctaagttg ctcatatgaa tgatgaaaaa acccacttca agaaaaaata taggaatgag aacttccaaa tgatgatttt tcaatccatt ccaatcaatc aaaagaacaa atacacagca aatatgggtg aagcatcaat gattaactca tgtatcatta agcatgcagt acaagctaca taccaaatac atttatcaat tataatatac ccaaactatt attaaaaata caaagtcaag tattcaacgt aaacaaacta aataggtatg agatgctgga aaatggaaag agtcaatatt agtggctcca tgcacttgtg gagggcaaac tatagctaac gcactttggc aggattgttt caaatctgta tgtggaagtc gaacaatcca cctaggcaat ggatctttat ctacagtgta caaagaagat gagaagtttg gaatcaataa tctgttaact atcatcaatc aaacccctag tacaaggaaa gagataaatg ttaagtgaaa gctcgcgatg agagcggaag gaaagcgaaa aaattgagtg tgatcagcga gaatcaactg aaccaattga gatggggcaa gctgttcagt cctatgttcc atactagtga agaagtgctg gatgaaagaa ctaacatgct tttacattct aaaaaataca cacggcgggt aaatatgacc cctcaaacaa aaagtaaagc ttgaatgata agtacaggag tgtggtatgc ttatatgcta tatcatgtta gaaatgaaat gagatagaat gaatataggc ataaccaaat aatgtcttaa agtttttatg attgcacaat atgaatgcct aaaaatatca tatgagtatg aaagcatcat gcagcaggtc gatgcagcta ttagacttaa gatgtagagc cacctgaatt agggcaagtt caatagatat caacaagtga taagcttcaa caatagaaac atcaaacaaa tattaggaat gaataagaga cattaatgac aaatggcaaa acttgttgga tcaactcact ccagaccgaa tcaatcagca atatggaaac acaatgttct agtcatctgt agcagatctc tgc tggctca gcaaattagc taaaagtaaa tagtcaatta ctgaatataa ttctagaatg tcaacccgtg cagtgctcaa caataacata cattaaataa ataatattga tattaatcac tgtccaggtt aagctaatgg tcgaagtatt ctagaaagtc atgattctcc tagcagcagg aaaacgaaat aagtgtttga catccacaag atgqttcagg tgctaggaca cacagaagtt tgctgtcatt taggcataat aagcatatgc cagcagaaga tttaagttaa tcatggagaa cgca tcat cc agaagtaact agccgacagt agaagatctc atttgataac tgacaacatt gctccataca tgctatggtt caatgatagg agacacctca agacaacgat cagcaatcaa caaacaaacg acccgacaaa atacgtgaac agaaaaagat gccagcagac tacgcccaaa aatgcctagt atatgatgta aagtatgtta tgagatgaag tacaaaatat tattggcatt aattccaaca tagttaagaa aattggggca ggatcagctg cactcccaat tgaagatgca aggaagggaa agtagatata aacattatca ctacaaaaaa agactgtggg agacagatca aaaacgatac aaaacaccct agggggtagt gcaagtaatg tqctagtgtc gggaggagaa aactcaattt gggagagtat agagcaactc attggaagcc caaaaaatac gatgcaaata aaagatccta aaagagagc c accccagaaa accccaagtg aatgaagaag acagcaagac ttagtagttg ggtctaagag ttagaggcta gatgaagtgt agtgacaatg caacatcaat tccatcagta attaacaata aagcttcacg gatgatcctg ttgctcataa ggaccttcac aatttcatca actacacctt actacagtca ctactgcaca ggcactttcc aagcctacaa aaaaaaccaa ggagctaatc aatacaaaga ctgtcatcca tatgatgtgc aatcataaat gacactataa acaacatatc agcttgacat atgctaaaag atgataatac ggtcttacag aagggcctca catcttatag agagttgaag ctaagatggg caggcagaaa gc tggattc t cccaacttct agaggtacac aaagaaaatg ataaagcatc ggggcaaata acaaagctac agaagaaaga cgataacatc caaaagccaa acaacccttt aatctagcta tagatagaat caagtgcagg aagagatgat tggcaagact ctcttaatcc atctatcact aaaacagaca gaaccaccaa tagtaacaaa aaggctccac catcactaac aagaacttgc tacgagtcac taagcgcaaa gtgaaatcaa aagatcttac 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 WO 99/49017 WO 9949017PCT[US99/06225 catgaagaca gacatcaaaa tctgaactca aattattcct caaatatatc gagcatatat actagaggat acacactata ccactcaaaa aaataaaacc catttatacc acaatagaac ctaatctttt cacaaagcat agttccacca cctctcacag tatttaaaaa aatgcaacca gatactctta atagcacaaa gccataatat acaataaaaa agggttagtt acatcaccca accacttcaa aaagatgatt caactttgca atcaaaccca qccaaaacga acagaaagag acagtccaac acacccacag tagttattca aaacctgggg tcttgctatt atcgacatgt tagtgtcata taaagtaaaa gctacttatg tatgaactac acgaagattt atcaaaagtt aaacaaagct tctcaagaat ctccaacatt cagagaattt cagtgagtta gtcaagcaat ttcaacccca agagtaataa ctagaaaata tatgcaggat aaaccacaga tatgtgacta taaacttaat tccaaacatc tccaaaatca aaaatatggg gccaattcaa tcacaagcaa tactaattat tctgcaacaa ttatgctgtg agtcacggtg ttaacataat tgtccaaaca atcatctaat tagcactatc tcatcatctc accacactga catccaagca atacaaaatc cacagaccaa accattttga aatccatctg caaacaaacc cgaaaaaaga acaccagcac agcaatccct catccgagcc aaaactacat caaataacca aatgcattgt agtgcagtta acaatagaat cttatgaaac caaaacacac acaatcaata ctaggcttct ctacaccttg gtagtcagtt tacataaata gaaacagtta agtgtcaatg ctatcattaa gttcagatag ctcatgagat taccaaccta tagcaaccac tagtgttagt gtcaatttat ctaattggaa tatcaacact ataaacatct ctaccagcca gtaaatagac cacatatact attttggccc aatcactatc aactcttgaa tcaaaccata tcgcaaaacc gatgaattgt caagaatcaa tgtaatatcc agttttggca tgccaatcac aaaaaacatc acccacaacc agaaacacac caagccaagc agtgttcaac caaaacaata aaccaccaaa aactaccacc ctcacaatcc cctctcaacc ctccacacca cttagcagag tggagttgat acctcacctc gcagaggtta taagtaatat aagaattaga cagctgtcaa ccactaaaaa tgttaggtgt aaggagaagt tat caaatgg accaattatt tagaattcca caggtgtaac tcaatgatat taaggcaaca cattgctcta tctaagatca cgaattcaaa tatcacagt t agtagatct t gcatacagct gaatgacagg acactacaca ctatccgcta attagttaga ataaatctta tattttacac atgattgcaa ctaggacaga atcctgtata acgctaacca tagtatgaga cgcactgcca tcttgtttat atgataatct aaagttacac accacctacc acatcaccaa catacaacag acaaaaccac ttcgttccct ccaagcaaca accacaaaca aacCcaacaa actgcactcg acccccgaaa aactccaccc aaccgtgatc gatccacaag aagtcagaac ttttagtgct aaaagaaacc taagtataag caaccgggcc cctaaatgta gggatctgca gaacaagatc ggtcagtgtt acccatagta gcagaagaac aacacCttta gcctataaca aagttattcc tgtgaatttg attagtgtca aatgctatca actgacaata ggtgcctacc acacgttttt tccacatata cttcatcaca gacctagagt gttcaatcaa aaatgggaaa taatacatat cactaaataa tgtaccaaat tacaaacaaa tcatggtagc tcaaaaacaa ggactctaga acagattaaa caacctctct taacaacggt ctactcaagt tccacacaag cacaaaccaa gtccaaaaaa gcagtatatg aaccaaagaa aaagagaccc aaaaactaac acacaaccac acacacccaa aaaaaaccca tatcaagcaa tcaagtgcaa ataactgagg ttaagaacag aaatgcaatg aatgcagtaa agaagagaag tcaataagca atagcaagtg aaaaatgctt ttaaccagca aatcaacaga agcagattgt agcacttaca aatgatcaga atcatgtcta aaaatattat agaacaagga ccaatgcaaa aaggagcatt tagaaaaaga caatcaaacc tcctcaaact caaaccaatc gcgaataggc tcttaacaac tacatccatc gatcttaact gctaagtgaa caacacacag caaatccaat atagagtagt cattggggca aaagacctgg tttaaaatct cataattgca cacagttcaa ctcaccagaa ttcagctaca aggcagaacc tccaccaaaa tggcaacaat gaaaccaacc aaaaacacca cctcaagacc attaaaacac ctccacacaa gccacatgct gaacgaaatt tcttcctaac agttttacca gttggtatac gaactgacac cagaattaca caccacagta agaagaggaa gtatagctgt tgttgtctac aagtgttaga gctgtcgcat tggaaat cac tgttgacaaa aaaaattaat taataaagga 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 WO 99/49017 WO 9949017PCT/US99/06225 agaagtcctt gaaattgcac aacaaggact ggctgacact attaccaagt aattatgaca gtcatgctat attttctaat cactttatac aataaat tac agtcaatgaa taatgtaaat cattgtagia cacaccagtt atagacaaaa caacttacaa tacccacata atcaaccact agaaatcctt agtcataatt aacaagatac gctgaactgg ataggatcta attgagatca aagataagag caaaccatcc acattagata caaaatgacc catattgatc taaccataac ttggacacct tgaagatata tcatccaacc ggaaactctg gagtgtaatg aacttaatta acacagtcat ttccagtcat aacttactta atcttgaata gatgaaaact aatcaatcat acaacactct tggttcaatt aaaagtcatg aatcaatatg aatcaatttt tggataagta gcatatgttg acatcgcctc gatagaggat tgtaaagtac gaagtcagcc tcaaaaacag ggt aaaact a ggt tgtgact tatgtaaaca tatgaccctc aaaatcaatc actggcaaat ttgttatcat acactaagca aaccacctga caaatatttc actaagctag aaatcaacac gtaaatttga actttgaatg tcaagtcaat atagaacaga taaacaacat atagtgatga tgtacaatac atctgctcaa tccacaaaag aaaccaaaaa tcaagtgaaa tatttggata aaaaacttat tatacagtat ataaaactat ctaatgtgta ctttagggag gtagacaaag taatatctag tacttatgac aaaaaataat aactaggatt cagtacttac atacaaattc tgaaaaaatt tatatacaaa ggtt tatatt gttgtatcgt tgacatggaa attgtttaaa tacagctgcc tatgcactac ggtattgtga agtccaatcg tttgtaacac acataagcag aatgcactgc atgtgtcaaa agctggaagg tagtgtttcc aaagtttagc ctactacaaa taatagctat aagaccaact tcatgtttca aacatcacag atccttaact atcattcaca gattagaggt gcctcctcat ggacaaaagc agaatatgct aacaaaacaa cattaaaaag tgttatatca gagactacca cataaccata taatgatatt gcatggttgc ac ca ccagcg tagatgccac atatattagt tttgataagg tctaactgat ttatcttttt cccactacta atatcataaa atataaaagt acgaagagcc aaaggaaaag aaccataatt agacaaaagt gatgtgttca attaaataac aatagataat ttatcataaa agacatcagc tacattaaac tatctatggt caacatcaaa taatgcagga agtattttgt tgacatattc ctcagtaatt atccaacaaa caaaggagta caagaacctt ttctgatgag ttttattcgt tattatgata tggtttactg aagtggaatc acaacaatct tacaggctga tatagttaca aaattaacag cattgcttga gcattactag atagacactt cttggtatag tcagcatgtg cttagagata tacattgaga gcagacgtgc agcaatccaa accggataaa tacattcaat tttattaaat tcaacaattt gtcataatgc ttatgggaca agttatttaa aacggccctt gagcatatga ggtgaactga atgtcctcgt, atagaaataa gacagagtta aaagatgata cactcagtaa atgcaacatc atattaacac caaactttaa ggactcaaaa cttagcagat aaaagcttag gtaatagata gaaggatcaa tcagtatcct gacactatga aattccaagt acttctcttg aatcgtggga gatactgtgt tatgtaaaag tttgatgcat agatctgatg actacaatta ttgtattgta aataatattg gctgaccacc atcatttcct taaaaacctc ctggggcaaa atggtagaag tgaggcaaaa tgtctgaaat ttggagtgct ttgctatgag atgaagaacc gcaatagaaa tgaagaagac aagagtcaac tatccttgta cataaaaaca catatatttg ctccaacatc ttgaccataa aaatggatcc aaggtgttat atcttaaaaa atcttaaaaa aattagaaga ctgaacaaat gtgatgtaaa agcccaacaa tactttcggc atcaaaatat ctccatcatg aatatcgatc gtggttttca aaatcacaac taaatgtttg ggc tgagatg caccttgctg atatttgttt tctttccaca acagtttgac atgactgcaa gagctatagt ttataaagac cagtgggcaa gggaacctat caatatctca aattactaca ttatagtaat aagccaaaaa cattcagcaa aatcccaaat cacatcatgc aagtatcaca tatgtcgcga atgtcactac cttcatgtta aagtggagct agagagttac taaacttctt caattcacct aaacaacaag aataaagaac tgtgaatgat gtatatcatc tattacaatt atgaaattca ttaacatccc cgactctatg cattattaat ctctttttca tgattacacc actaactata accaacttat tgctacaact ggtgtacgcc taattcaggt tgtggaaaac cactatcaaa gttaatacac aaatgaggta gtttatttta tactacttac cttaattact tggattcaat 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 WO 99/49017 WO 9949017PCT[US99/06225 aatgttgtgt tatcacaatt atttctttat ggagattgta tactgaaatt atttcataat 9480 gaaggcttct acagaagaag gcagctatta acagtgtctg ttgattaagc agaatctttg tgtaatgaaa tatagaatca attgtcctac gaaatcacag ctgcctaaaa gatctaatat gaacatgaaa ttgagagata ctcaacaact agaatgtttg atagctgaaa cttcaaaaga aactacaaca gcatttagat caatctctqt agacatgcac agtggattat attgaagcta ctgataaatg cagacccatg gagtatgcag cagttcatga gtcctgagag tctataggca atatttagga tgtaacaata aatcttgata ggtggtgatc gaagctatag aagc t ccagg gataaaaatc gaaaggcaag atagccccaa ctaaatgaca gaaagtttac ataactaata gatatgatga gacaaaagag agagaaagat acaatgaaca aatgttaata acataataaa atcaatttaa aggctcaaaa ataatatcat ttgcaggtga gacatccaat ctaggttcta taaaagggtt ctctaagatg aaaatgattt aagtggatct ggactagttt agttgaagtt ataaattcaa ctaatcacgt ctatgcaacc atattttaca tattagaatt attatatcag atgaaacatc tctcttggtt ctcctttcat acagatatca tatcattatt gtgataatca cacaagcaga gtataggcca gcaaaacaat taggtccatg gcttaacaca acatttggtt agctatattt gcattgatat ctaatttgtt tacattcagt atcttccaga ccaatgccga ctaaaattac acaaaatatt ttatgcaaaa ctttttataa tacttgaaaa ggaaaaa tat agttattaag cttggt catt ttaaatatac gtttaactcg agaagtagag gaaacgattt ggacctacta aaatggtaaa taataatctc ggtcgatgaa cttattaagt tgtaaatacc gttaaactac gattatttta tgaaatgata tcctagaaat ctctgaaagc tgaatgcgat ggtatcacta aggtatgttt attcttccct aaaagcagga taaatgttct atgtatctgc gcatttaaca aaaggatcat tatgggtggt agatctaata gtcaattgat ttatttgtta taagcttaag ccagcacaat gataaacacg ggagttagaa atacaatcaa agatatattg ggctttatca atatcgaagc gtttgtgttg tgatagactg gtttgtaaca tagtgagatt ttctaaaagt tatagaacca agcagaaaaa aacat cagca aactttactt tttagaaaat atccaatata aactagcact tggtgaaaga ggatttatta tataatagca tcaagagtat tggataatcc aataacttga agacaagcaa agtctaagta tacaacagat tataaactta tcaggattgc ataaatgaca tacatgccat gacagat cga ctatacaatt actggtaaag aggcaaatcc gagagtttga ataagcaaca atcattacag agtgatgtat atacctcttg gttgttaatc attgagggct tctctcaaag ataagcaaac gcattaaata ggaacagaga ggagtgtact atacttgatg tacagaggag attgctttgc aaagtattaa ttgtatatga ttttatagga agctattata aacaaattct ttgatgaggg aatagattag gcacaacatt acttaccctc atagttaatc atagatacaa ataaggatac cttagtataa gtaggagtaa atagccagtg ggacccacca tgtctttaat tgctaaataa gtcacacttt tattaagtaa gtgagctata tggattctgt cattaagagg ggcccacctt atacttatcc ggttctatcg aagccatttc cacatataca gaagagtact gtgtagtcaa aaagagagct aaatcttagc caagatatgg agtcaaatcg atcttagcaa tagatgaact tcacaataat ttaatgaggt ggtgtcaaaa ggaaattctc cagttagact gccttaaatt cctatatatc atccagccag attttaaagt aaagcttatt aactccgaaa aacacttaaa atttgcctat gaactccaga ctggtcacga tgacatgtgt atccacaggc cagtaacaga atactaccac atggattaag ttatatcagg ctgatattaa ttccactaga ctgaattaag catcgccaag gtataataat agccatgggt tctaaacata catcacagat attagacaag atttcttaaa ttttctcttc aagaattaac tgctttcatt aaggaatgct atctctactt tgagtttcat acctccaaaa aaattatata agagtattac tcaaagctat cagtgtaggt agagaaaatg tgatctagag ttataatgat attcaatcag gcatggagta atgtacatat tgatgaacaa actgtggacc tatcacagct tatagagggt gttatataaa ccgagatatg tatcaaaaaa tagtttagaa atgcagttta tcatgcatta aacttttttt gctgtttggt cttccttaca tttacaagat catcacattt tttagggtct agtcttaagt tgagattgat agttgtttat aacaaaatcc tagggctact ttgtaacaaa caagtatgta tattatgttc agaaaaatat aggctcatcc 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 WO 99/49017 WO 9949017PCTIUS99/06225 acgcaggaga gaccaaatag gaattcatgg ttgtttccac tgtgaattcc cctatcaatc aattgcataa cctaatagaa tttacaggag ctaccagata aaatctggat cataatgctt atgaaagatt atgttcatta aaaggttatg itggagttaa gtcataaaat tttaagttgt gttaacatag agaatggggt gaattttaca ctaacaaaac cacccaaccc aacaaaccta agtaaaatgc ttgtacaatt gcaaaatcta gcatcacttt tccacaggat agttgtatag cttcatccag cctattgaat accattcctg gcagaaccta aaaattataa agatgcattt attactatat ttaatcctta aaattgatac atcgatgcaa attaagactt atagctggac Ctaaaatggc tacatgatag gagctcaaga tagtttaaaa tagttattaa ttttagtctt aaaaaacaat atttattagc aagaactgag aatatctaag ctgcatcaat atgtattaac gttt tggtct ttattctcat atgttgatat aaataagttt ctcacatcaa atattttaag caaaaggtat atttgaatgt gtaaagcaaa tagacagtag acatagtcaa ggtttttaaa attatcaccc taataaatgt catcaaatct aaataagaat cagaaacttt aattttgtat atattaaatc tatttccaat accaacttta attgcatgct gcaagatcag cat tcatagg acataagata t tctaaggtt ctacagatgc ttagcatctt ttgaatggag taattgcaaa taaaaactta caataggccc tttcaagaac atattaaaag cattgtcaaa gtaatgaagt tagatcatgt agtccacata agctgattaa tatcattaac agaatataca aaggggttaa gccagtgtac aaaattagac tactggaaca tgtcaattat accagcttat agaaaagtat tagcctgatg accgaagctg catcaagttg aacccaatat ctctaattta tactaattta ttttgaaaaa tttctttaat attagaatgt ctactggaaa tcaagacaca acgccttaat aacacacatg agataaatta cttttacatt tgctaattca agaaaatatg aagtggaaat ttccactgtt tgttgtgata caccaccact tccttggcat tatagagtat tgaaggagc t catttacaga atacaacggg aactaataac tgtctgcgat taagcatgta atatcatgct cgtgtgccta tgcaaatata taaaaatttc cttaatacct attgaagagt attcagcaac tttaaatttt tccttactta aataacaggt aagtttggtc aacttttcaa ataaaagtct aacagacaag tgggtatatg cttggactgt ttacaccgtt agaacaacaa ggagatgaag tcggttgtgg aatgagatac aagcaagtga gtagaattat atattagtac gctggacatt gattggggag gcttataaga gatatgaaca tctatgtcta agtttgcgta aatgctaaat aaagctatat accattaaaa agttataact gaattagaag tcattaattc accgaatcta accacaagat gacaagatta tcacatcaga catgtcaata attttaaaag ggtaacttat agtttaaaag catataaaca attcat tggt gctgaattac agaaagtgca caagatgaca ggtagcaagt ct tcc tgt tt attatgccta ttcctttgtt gtagttaatg aagcttataa agatcagctg agtgaattgt agtgtgctat aaatttagat taatttagca aaaactaaca ttttaaccaa catccataga catatgaaaa taacagtcag attatcattt atatcgacat aacaattcac atttgatgaa tacaaaagca tcttaagtaa ataaaatgtc ggattctgat aggggtacat cttatttgct cttcagatct aagttttcct gaataaaagg ttaccgtatg tatcttacat ataaaaacaa tttcagacaa ataattataa ctgttaaaag tgatgatgtc tcaattatag tagatcattc catct ttagt gatttaactt atcttaagat tattacgtac attgcaatga tagattatgg cttatttaca ctgttacagc agtactgttc ttgatttcaa taaaaggatc ttgatgttgt aaaaaactga accctataac gagatatatt accacaagca aacttaatta taaatagttt acaaccttcc gctaacacat tattgattcc attatacatg aaagcaaaga caacaaagat agccaaaaag tagtagacca tgatactagt tgtgtttcaa aaacatatgt acctcctata gcacatgttc caaagcactt tgattatttt tattcaactt aactgatcat atgttttcat tctttgtgtt agaacaaaaa ctgtcacagt cccttgggtt agatttagtt attcaatgat cactcatttg caaactatat taataatagt aacattctct caaacaagac aggtaataca aaggaatagt tgtatttagt taaggacccc ggtagtagaa tcatagttta tgagaattta tataaaattt caattggagt ttctgtaaat attagataac tgaagtttac acaaaatgct caaggaatct aaaaaaagga atcatattct tatgaatatc caatcattta aacaaccaat caacgaacag cattatatta aaaattatca tgcattcaca 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 WO 99/49017 WO 9949017PCTIUS99/06225 acacaacgag acattagttt ttgacacttt ttttctcgt <210> 12 <211> 15219 <212> DNA <213> respiratory syncytial virus 15219 <400> 12 acgggaaaaa ttgataagtg atgataaagg acatgttata acaattaaat gataacaata tacatatggg aattgtgaaa caaatatctg tagacatgtg aataaactca gattgatgat aagaaatcat ttgatgaaag aagtagggag ccatgcctat aacacactcc cccaaccaaa cattttagta tggctcttag gcaaatacac aaaaacacct tcacaggatt agatacttaa gtcaagatat cagaaataca agatgggaga tgtgtatagc cagtaattag taccaaagga atgttttcgt gaatctttgc gagttttagc tggagcaagt accatatatt caagtqtggt caagaaacca gagtaataaa aactcaaccc agtcaacatg aatgcgtact ctatttaagt ttagattaca ctgataaatt taaacggcat ttgtagtgaa aattgattga tcaaattttc acttacttgg tttattacca cctaatcaat cacagacatg cacacacaaa acaagctaca taccaaatac atttatcaat tataatatac ccaaactatt attaaaaata caaagtcaag tattcaacgt aaacaaacta aataggtatg agatgctgga aaatggaaag agtcaatatt agtgqctcca tgcacttgtg gagggcaaac tatagctaac gcactttggc aggattgttt caaatctgta tgtggaagtc gaacaatcca cc taggcaat ggatctttat ctacagtgta caaagaagat gagaagt ttg acaaacttgc ctaac c ttt t aaat ttatt t aattcttctg agtttttata atctaacttt gttgacacac taaaagacta gcttgatctc ttttagttaa caaaccatga agacccctgt ttcatatact tttacattct aaaaaataca cacggcgggt aaatatgacc cctcaaacaa aaagtaaagc ttgaatgata agtacaggag tgtggtatgc ttatatgcta tatcatgtta gaaatgaaat gagatagaat gaa tat aggc ataaccaaat aatgtcttaa agtttttatg attgcacaat atgaatgcct aaaaatatca tatgagtatg aaagcatcat gcagcaggtc gatgcagcta ttagacttaa gatgtagagc cacctgaatt acattcgaaa caatcagaaa gacaatgacg accaatgcat catgttataa acaacaatgc tgctctcaat agtgactcag aattcatgaa tataaaaact gcactacaaa caatggattc tgataaacaa tagt caatta ctgaatataa ttctagaatg tcaacccgtg cagtgctcaa caataacata cattaaataa ataatattga tattaatcac tgtccaggtt aagctaatgg tcgaagtatt ctagaaagtc atgattctcc tagcagcagg aaaacgaaat aagtgtttga catccacaag atggttcagg tgctaggaca cacagaagtt tgctgtcatt taggcataat aagcatatgc cagcagaaga tttaagttaa tcatggagaa aaaatggggc tggggtgcaa aagtagcatt tagccaaagc caagcagtga caatactaca taaacggttt taatgactaa ttatgtttag catcaaaggg tgacaacact aataataaca tgaatgtatt tgagatgaag tacaaaatat tattgqcatt aattccaaca tagttaagaa aattggggca ggatcagctg cactcccaat tgaagatgca aggaagggaa agtagatata aacattatca ctacaaaaaa agactgtggg agacagatca aaaacgatac aaaacaccct agggggtagt gcaagtaatg tgctagtgtc gggaggagaa aactcaattt gggagagtat agagcaactc attggaagcc caaaaaatac gatgcaaata aaataagaac ttcactgagc gttaaaaata agcaatacat agtgtgccct aaatggagga aatggatgat ttatatgaat tctaattcaa aaatggggca actatgcaaa tctcttacca gtaagaaaac ctactgcaca ggcactttcc aagcctacaa aaaaaaccaa ggagctaatc aatacaaaga ctgtcatcca tatgatgtgc aatcataaat gacactataa acaacatatc agcttgacat atgctaaaag atgataatac ggtct tacag aagggcctca catcttatag agagttgaag ctaagatggg caggcagaaa gctggattct cccaacttct agaggtacac aaagaaaatg ataaagcatc ggggcaaata acaaagctac 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 WO 99/49017 WO 9949017PCT/US99/06225 caaattccta tagcataata tggcac caac ctacccaaga ttctaagttg ctcatatgaa tgatgaaaaa acccacttca agaaaaaata taggaatgag aacttccaaa tgatgatttt tcaatccatt ccaatcaatc aaaagaacaa at acacag ca aatatgggtg aagcatcaat gattaactca tgtatcatta agcatgcagt catgaagaca gacatcaaaa tctgaactca aattattcct caaatatatc gagcatatat actagaggat acacactata ccactcaaaa aaataaaacc catttatacc acaatagaat ctaatctttt cataaagcat agttctacca cttctcacag tatttaaaaa aatgcaacca gatactctta atagcacaaa gccataatat acaataaaaa agggttagtt acatcaccca accacttcaa aaagatgatt caactttgca gaatcaataa tctgttaact atcatcaatc aaacccctag tacaaggaaa gagataaatg ttaagtgaaa gctcgcgatg agagcggaag gaaagcgaaa aaattgagtg tgatcagcga gaatcaactg aaccaattga gatggggcaa gctgttcagt cctatgttcc atactagtga agaagtgctg gatgaaagaa ctaacatgct ttcaacccca agagtaataa ctagaaaata tatgcaggat aaaccacaga tatgtgacta taaacttaat tccaaacatc tccaaaatca aaaatatggg gccaattcaa tcacaagcaa tactaattat tctgtaacaa ttatgctgtg agtcatggtg ttaacataat tgtccaaaca atcatctaat tagcactatc tcatcatctc accacactga catccaagca atacaaaatc cacagaccaa accattttga aatccatctg agggcaagt t caatagatat caacaagtga taagcttcaa caatagaaac atcaaacaaa tattaggaat gaataagaga cattaatgac aaatggcaaa acttgttgga tcaactcact ccagaccgaa tcaatcagca atatggaaac acaatgttct agtcatctgt agcagatctc tgctggctca gcaaattagc taaaagtaaa ctcatgagat taccaaccta tagcaaccac tagtgttagt gtcaatttat ctaattggaa tatcaacact ataaacatct ctaccagcca gtaaatagac cacatatact attt tggccc aatcactatt aactcttgaa tcaaattata tcgcaaaacc gatgaattgt caagaatcaa tgtaatatcc agttttggca tgccaatcac aaaaaacatc acccacaacc agaaacacac caagccaagc agtgttcaac caaaacaata cgcatcatcc agaagtaact agccgacagt agaagatctc atttgataac tgacaacatt gctccataca tgctatggtt caatgatagg agacacctca agacaacgat cagcaatcaa caaacaaacg acccgacaaa atacgtgaac agaaaaagat gccagcagac tacgcccaaa aatgcctagt atatgatgta aagtatgtta cattgctcta tctaagatca cgaattcaaa tatcacagtt agtagatctt gcatacagct gaatgacagg acactacaca ctatctgcta attagttaga ataaatctta tattttacac atgattgcaa ctaggacaga atcctgtata acgctaacta tagtatgaga cgcactgcca tcttgtttat atgataatct aaagttacac accacctacc acatcaccaa catacaacag acaaaaccac ttcgttccct ccaagcaaca aaagatccta aaagagagcc accccagaaa accccaagtg aatgaagaag acagcaagac ttagtagttg ggtctaagag ttagaggcta gatgaagtgt agtgacaatg caacatcaat tccatcagta attaacaata aagcttcacg gatgatcctg ttgctcataa gga cc ttca c aatttcatca actacacctt actacagtca tgtgaatttg attagtgtca aatgctatca actgacaata gg tgC Ct ac C acacgttttt tccacatata cttcatcaca gacctagagt gttcaatcaa aaa tgggaaa taatacatat tactaaataa tgtatcaaat tataaacaaa tcatggtagc tcaaaaacaa ggactctaga acagattaaa caacctctct taacaa cggt ctactcaagt tccacacaag cacaaaccaa gtccaaaaaa gcagtatatg aaccaaagaa agaagaaaga cgataacatc c aaaagccaa acaacccttt aatctagcta tagatagaat caagtgcagg aagagatgat tggcaagact ctcttaatcc atctatcact aaaacagaca gaaccaccaa tagtaacaaa aaggct ccac catcactaac aagaacttgc tacgagtcac taagcgc aaa gtgaaatcaa aagatcttac aaaatattat agaacaagga ccaatgcaaa aaggagcatt tagaaaaaga caatcaaacc tcctcaaact caaaccaatc gcgaataggt tcttaacaac tacatccatc gatcttaact gctaagtgaa caacacatag caaatccaat atagagtagt cattggggca aaagacctgg tttaaaatct cataattgca cacagttcaa ctcaccagaa ttcagctaca aggcagaacc tccaccaaaa tggcaacaat gaaaccaacc 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 WO 99/49017 WO 9949017PCTIUS99/06225 atcaaaccca gccaaaacga acagaaagag acagtccaac acacccacag tagttattca aaacctgggg tcttgctatt atcgacatgt tagtgtcata taaagtaaaa gctacttatg tatgaactac acgaagattt atcaaaagtt aaacaaagct tctcaagaat ctccaacatt cagagaatt t cagtgagtta gtcaagcaat agaagtcctt gaaattgcac aacaaggact ggctgacact attaccaagt aattatgaca gtcatgctat attttctaat cactttatac aataaattac agtcaatgaa taatgtaaat cattgtagta cacaccagtt atagacaaaa caacttacaa tacccacata atcaaccact agaaatcctt agtcataatt aacaagatac gctgaactgg ataggatcta attgagatca aagataagag caaaccatcc caaacaaacc cgaaaaaaga acaccagcac agcaatccct catccgagcc aaaactacat caaataacca aatgcattgt agtgcagtta acaatagaat cttatgaaac caaaacacac acaatcaata ctaggcttct ctacaccttg gtagtcagtt tacataaata gaaacagtta agtgtcaatg ctatcattaa gttcagatag gcatatgttg acatcgcctc gatagaggat tgtaaagtac gaagtcagcc tcaaaaacag ggtaaaacta ggttgtgact tatgtaaaca tatgaccctc aaaatcaatc actqgcaaat ttgttatcat acactaagca aaccacctga caaatatttc actaagctag aaatcaacac gtaaatttga actttgaatg tcaagtcaat atagaacaga taaacaacat atagtgatga tgtacaatac atctgctcaa aaccaccaaa aactaccacc ctcacaatcc cctctcaacc ctccacacca cttagcagag tggagttgat acctcacctc gcagaggtta taagtaatat aagaattaga cagctgtcaa ccactaaaaa tgttaggtgt aaggagaagt tatcaaatgg accaattatt tagaattcca caggtgtaac tcaatgatat taaggcaaca t acagc tgcc tatgcactac ggtattgtga agtccaatcg tttgtaacac acataagcag aatgcactgc atgtgtcaaa agctggaagg tagtgtttcc aaagtttagc ctactacaaa taatagctat aagaccaact tcatgtttca aacatcacag atccttaact atcattcaca gattagaggt gcctcctcat ggacaaaagc agaatatgct aacaaaacaa cattaaaaag tgttatatca gagactacca accacaaaca aacccaacaa actgcactcg acccccgaaa aactccaccc aaccgtgatc gatccacaag aagtcagaac ttttagtgct aaaagaaacc taagtataag caaccgggcc cctaaatgta gggatctgca gaacaagatc ggtcagtgtt acccatagta gcagaagaac aacaccttta gcctataaca aagttattcc tat ctatggt caacatcaaa taatgcagga agtattttgt tgacatattc ctcagtaatt atccaacaaa caaaggagta caagaacctt ttctgatgag ttttattcgt tattatgata tggtttactg aagtggaatc acaacaatct tacaggctga tatagttaca aaattaacag cattgcttga gcattactag atagacactt cttggtatag tcagcatgtg cttagagata tacattgaga gcagacgtgc agcaatccaa aaagagaccc aaaaactaac acacaaccac acacacccaa aaaaaaccca tatcaagcaa tcaagtgcaa ataactgagg ttaagaacag aaatgcaatg aatgcagtaa agaagagaag tcaataagca atagcaagtg aaaaatgctt ttaaccagca aatcaacaga agcagattgt agcacttaca aatgatcaga atcatgtcta gtaatagata gaaggat caa tcagtatcct gacactatga aattccaagt acttctcttg aatcgtggga gatactgtgt tatgtaaaag tttgatgcat agatctgatg actacaatta ttgtattgta aataatattg gctgaccacc atcatttcct taaaaacctc ctggggcaaa atggtagaag tgaggcaaaa tgtctgaaat ttggagtgct ttgctatgag atgaagaacc gcaatagaaa tgaagaagac aagagtcaac aaaaacacca cctcaagacc attaaaacac ctccacacaa gccacatgct gaacgaaatt tcttcctaac agttttacc a gt tggtatac gaactgacac cagaattaca caccacagta agaagaggaa gtatagctgt tgttgtctac aagtgttaga gctgtcgcat tggaaatcac tgttgacaaa aaaaattaat taataaagga caccttgctg atatttgttt tctttccaca a cag tt tga c atgactgcaa gagctatagt ttataaagac cagtgggcaa gggaacctat caatatctca aattactaca ttatagtaat aagccaaaaa cattcagcaa aatcccaaat cacatcatgc aagtatcaca tatgtcgcga atgtcactac cttcatgtta aagtggagct agagagttac taaacttctt caattcacct aaacaacaag aataaagaac tgtgaatgat 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 acattagata tccacaaaag cataaccata WO 99/49017 WO 9949017PCTIUS99/06225 caaaatgacc catattgatc taaccataac ttggacacct tgaagatata tcatccaacc ggaaactctg gagtgtaatg aacttaatta acacagtcat ttccagtcat aacttactta atcttgaata gatgaaaact aatcaatcat acaacactct tggttcaatt aaaagtcatg aatcaatatg aatcaatttt tggataagta aatgttgtgt gaaggcttct acagaagaag gcagctatta acagtgtctg ttgattaagc agaatctttg tgtaatgaaa tatagaatca attgtcctac gaaatcacag ctgcctaaaa gatctaatat gaacatgaaa ttgagagata ctcaacaact agaatgtttg atagc tgaaa cttcaaaaga aactacaaca gcatttagat caatctctgt agacatgcac agtggattat attgaagcta ctgataaatg cagacccatg aaaccaaaaa tcaagtgaaa tatttggata aaaaacttat tatacagtat ataaaactat ctaatgtgta ctttagggag gtagacaaag taatatctag tacttatgac aaaaaataat aactaggatt cagtacttac atacaaattc tgaaaaaatt tatatacaaa ggtttatatt gttgtatcgt tgacatggaa attgtttaaa tatcacaatt acataataaa atcaatttag aggc tcaaaa ataatatcat ttgcaggtga gacatccaat ctaagttcta taaaagggtt ctctaagatg aaaatgattt aagtggatct ggactagttt agttgaagtt ataaattcaa ctaatcacgt ctatgcaacc atattttaca tattagaatt attatatcag atgaaacatc tctcttggtt Ctcctttcat acagatatca tatcattatt gtgataatca cacaagcaga taatgatatt gcatggttgc accaccagcg tagatgccac atatattagt tttgataagg tctaactgat ttatcttttt cccactacta atatcataaa atataaaagt acgaagagcc aaaggaaaag aactataatt agacaaaagt gatgtgttca attaaataac aatagataat ttatcataaa agacatcagc tacattaaac atttctttat agaagtagag gaaacgattt ggacctacta aaa tggtaaa taataatctc ggtcgatgaa cttattaagt tgtaaatacc gttaaactac gattatttta tgaaatgata tcctagaaat ctctgaaagc tgaatgcgat ggtatcacta aggtatgttt attcttccct aaaagcagga taaatgttct atgtatctgc gcatttaaca aaaggatcat tatgggtggt agatctaata gtcaattgat ttatttgtta accggataaa tacattcaat tttattaaat tcaacaattt gtcataatgc ttatgggaca agttatttaa aacggccctt gagcatatga ggtgaactga atgtcctcqt atagaaataa gacagagtta aaagatgata cactcagtaa atgcaacatc atattaacac caaactttaa ggactcaaaa cttagcagat aaaagcttag ggagattgta ggatttatta tataatagca tcaagagtat tggataatcc aataacttga agacaagcaa agtctaagta tacaacagat tataaactta tcaggattgc ataaatgaca tacatgccat gacagatcga ctatacaatt actggtaaag aggcaaatcc gagagtttga ataagcaaca atcattacag agtgatgtat atacctcttg gttgttaatc attgagggct tctctcaaag ataagcaaac gcattaaata tatccttgta cataaaaaca catatatttg ctccaacatc ttgaccataa aaatgga tcc aaggtgttat atcttaaaaa atcttaaaaa aattagaaga ctgaacaaat gtgatgtaaa agcccaacaa tactttcggc atcaaaatat ctccatcatg aatatcgatc gtggttttca aaatcacaac taaatgtttg ggctgagatg tactgaaatt tgtctttaat tgctaaataa gtcacacttt tattaagtaa gtgagctata tggattctgt cattaagagg ggcccacctt atacttatcc gqttctatcg aagccatttc cacatataca gaagagtact gtgtagtcaa aaagagagct aaatcttagc caagatatgg agtcaaatcg atcttagcaa tagatgaact tcacaataat ttaatgaggt ggtgtcaaaa ggaaattctc cagttagact gccttaaatt gtatatcatc tattacaatt atgaaattca ttaacatccc cgactctatg cattattaat ctctttttca tgattacacc actaactata accaacttat tgctacaact ggtgtacgcc taattcaggt tgtggaaaac cactatcaaa gttaatacac aaatgaggta gtttatttta tactacttac cttaattact tggattcaat atttcataat tctaaacata cat ca cagat attagacaag atttcttaaa ttttctcttc aagaattaac tgctttcatt aaggaatgct atctctactt tgagtttcat acctccaaaa aaattatata agagtattac tcaaagctat cagtgtaggt agagaaaatg tgatctagag ttataatgat attcaatcag gcatggagta atgtacatat tgatgaacaa actgtggacc tatcacagct tatagagggt gttatataaa 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 WO 99/49017 WO 9949017PCT/US99/06225 gagtatgcag cagttcatga gtcctgagag tctataggca atatttagga tgtaacaata aatcttgata ggtggtgatc gaagctatag aagctccagg gataaaaatc gaaaggcaag atagccccaa ctaaatgaca gaaagtttac ataactaata gatatgatga gacaaaagag agagaaagat acaatggaca aatgttaata acgcaggaga gaccaaatag gaattcatgg ttgtttccac tgtgaattcc cctatcaatc aattgcataa cctaatagaa tttacaggag ctaccagata aaatctggat cataatgctt atgaaagat t atgttcatta aaaggttatg ttggagttaa gtcataaaat tttaagttgt gttaacatag agaatggggt gaattttaca ctaacaaaac cacccaaccc aacaaaccta agtaaaatgc ttgtacaatt gcaaaatcta gta taggcca gcaaaacaat taggtccatg gcttaacaca acatttggtt agctatattt gcattgatat ctaatttgtt tacattcagt atcttccaga ccaatgccga ctaaaattac acaaaatatt ttatgcaaaa ctttttataa tacttgaaaa ggaaaaatat agttattaag cttggtcatt ttaaatatac gtttaactcg aaaaaacaat atttattagc aagaactgag aatatctaag ctgcatcaat atgtattaac gttt tggtct ttattctcat atgttgatat aaataagttt ctcacatcaa atattttaag c aaaaggtat atttgaatgt gtaaagcaaa tagacagtag acatagtcaa ggtttttaaa attatcaccc taataaatgt catcaaatct aaataagaat cagaaacttt aattttgtat atattaaatc tatttccaat accaacttta taagcttaag ccagcacaat gataaacacg ggagttagaa atacaatcaa agatatattg ggctt tat Ca atatcgaagc gtttgtgttg tgatagactg gtttgtaaca tagtgagatt ttctaaaagt tatagaacca agcagaaaaa aacatcagca aactttactt tttagaaaat atccaatata aactagcact tggtgaaaga gccagtgtac aaaattagac tac tggaac a tgtcaattat accagcttat agaaaagtat tagcctgatg accgaagctg catcaagttg aacccaatat ctctaattta tactaattta ttttgaaaaa tttctttaat attagaatgt ctactggaaa tcaagacaca acgccttaat aacacacatg agataaatta cttttacatt tgctaattca agaaaatatg aagtggaaat ttccactgtt tgttgtgata caccaccact ggaacagaga ggagtgtact atacttgatg tacagaggag attgctttgc aaagtattaa ttgtatatga ttttatagga agctattata aacaaattct ttgatgaggg aatagattag gcacaacatt acttaccctc atagttaatc atagatacaa ataaggatac cttagtataa gtaggagtaa atagccagtg ggacccacca aacagacaag tgggtatatg cttggactgt ttacaccgtt agaacaacaa ggagatgaag tcggttgtgg aatgagatac aagcaagtga gtagaattat atattagtac gctggacatt gattggggag gcttataaga gatatgaaca tctatgtcta agtttgcgta aatgctaaat aaagctatat accattaaaa agttataact gaattagaag tcattaattc accgaatcta accacaagat gacaagatta tcacatcaga cctatatatc atccagccag attttaaagt aaagcttatt aactccgaaa aacacttaaa atttgcctat gaactccaga ctggtcacga tgacatgtgt atccacaggc cagtaacaga atactaccac atggattaag ttatat cagg ctgatattaa ttccactaga ctgaattaag catcgccaag gtataataat agccatgggt ttttaaccaa catccataga catatgaaaa taacagtcag attatcattt atatcgacat aacaattcac atttgatgaa tacaaaagca tcttaagtaa ataaaatgtc ggattctgat aggggtacat cttatttgct cttcagatct aagttttcct gaataaaagg ttaccgtatg tatcttacat ataaaaacaa tttcagacaa ataattataa ctgttaaaag tgatgatgtc tcaattatag tagatcattc catctttagt ccgagatatg tatcaaaaaa tagtttagaa atgcagttta tCatgcatta aacttttttt gctgtttggt cttccttaca tttacaagat catcacattt tttagggtct agtcttaagt tgagattgat agttgtttat aacaaaatcc tagggctact ttgtaacaaa caagtatgta tattatgttc agaaaaatat aggc tcat cc aaagcaaaga caacaaagat agccaaaaag tagtagacca tgatactagt tgtgtttcaa aaacatatgt acctcctata gcacatgttc caaagcactt tgattatttt tattcaactt aactgatcat atgttttcat tctttgtgtt agaacaaaaa ctgtcacagt cccttgggtt agatttagtt attcaatgat cactcatttg caaactatat taataatagt aacattctct caaacaagac aggtaataca aaggaatagt 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 WO 99/49017 WO 9949017PCTIUS99/06225 gcatcacttt t cc acagga t agttgtatag cttcatccag cctattgaat accattcctg gcagaaccta aaaattataa agatgcattt attactatat ttaatcctta aaattgatac atcgatgcag attaagactt atagctggac ctaaaatgqc tacatgatag gagctcaaga tagtttaaaa tagttattaa ttttagtctt acacaacgag attgcatgct gcaagatcag catt cat agg acataagata ttctaaggtt ctacagatgc ttagcatctt ttgaatggag taattgcaaa taaaaactta caataggccc tttcaagaac atattaaaag cattgtcaaa gtaatgaagt tagatcatgt agtccacata agctgattaa tatcattaac aaaatataca aaggggttaa acattagttt tccttggcat'catgtcaata tatagagtat tgaaggagct catttacaga atacaacggg aactaataac tgtctgcgat taagcatgta atatcatgct cgtgtgccta tgcaaatata taaaaatttc cttaatacct attgaagagt attcagcaac tttaaatttt tccttactta aataacaggt aagtttggtc aacttttcaa ataaaagtct ttgacacttt attttaaaag ggtaacttat agtttaaaag catataaaca attcattggt gctgaattac agaaagtgca caagatgaca ggtagcaagt Cttcctgttt attatgccta ttcctttgtt gtagttaatg aagcttataa agatcagctg agtgaattgt agtgtgctat aaatttagat taatttagca aaaactaaca ttttCtcgt gatttaactt atcttaagat tattacgtac attgcaatga tagattatgg cttatttaca ctgttacagc agtactgttc ttgatttcaa taaaaggatc ttgatgttgt aaaaaactga accctataac gagatatatt accacaagca aacttaatta taaatagttt acaaccttcc gctaacacat tattgattcc attatacatg tgtatttagt taaggacccc ggtagtagaa tcatagttta tgagaattta tataaaattt caattggagt ttctgtaaat attagataac tgaagtttac acaaaatgct caaggaatct aaaaaaagga atcatattct tatgaatatc caatcattta aacaaccaat caacgaacag cattatatta aaaattatca tgcattcaca 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15219 <210> 13 <211> 15219 <212> DNA <213> respiratory syncytial virus <400> 13 acgggaaaaa ttgataagtg atgataaagg acatgttata acaattaaat gataacaata tacatatggg aattgtgaaa caaatatctg tagacatgtg aataaactca gattgatgat aagaaatcat t tgatgaaag aagtagggag ccatgcctat aacacactcc cccaaccaaa cattttagta aatgcgtact ctatttaagt ttagattaca ctgataaatt taaacggcat ttgtagtgaa aattgattga tcaaattttc acttacttgg tttattacca cctaatcaat cacagacatg cacacacaaa acaagctaca taccaaatac atttatcaat tataatatac ccaaactatt attaaaaata acaaacttgc ctaacctttt aaatttattt aattcttctg agtttttata atctaacttt gttgacacac taaaagacta gcttgatctc ttttagttaa caaaccatga agacccctgt ttcatatact tttacattct aaaaaataca cacggcgggt aaatatgacc cctcaaacaa aaagtaaagc acattcgaaa caatcagaaa gacaatgacg accaatgcat catgttataa acaacaatgc tgctctcaat agtgactcag aattcatgaa tataaaaact gcactacaaa caatggattc tgataaacaa tagtcaatta ctgaatataa ttctagaatg tcaacccgtg cagtgctcaa caataacata aaaatggggc tggggtgcaa aagtagcatt tagccaaagc caagcagtga caatactaca taaacggttt taatgactaa ttatqtttag catcaaaggg tgacaacact aataataaca tgaatgtatt tgagatgaag tacaaaatat tattggcatt aattccaaca tagttaagaa aattggggca aaataagaac ttcactgagc gttaaaaata agcaatacat agtgtgccct aaatggagga aatggatgat ttatatgaat tctaattcaa aaatggggca actatgcaaa tctcttacca gtaagaaaac ctactgcaca ggcactttcc aagcctacaa aaaaaaccaa ggagctaatc aatacaaaga 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 WO 99/49017 WO 9949017PCTIUS99/06225 tggctcttag gcaaatacac aaaaacacct tcacaggatt agatacttaa gtcaagatat cagaaataca agatgggaga tgtgtatagc cagtaattag taccaaagga atgttttcgt gaatctttgc gagttttagc tggagcaagt accatatatt caagtgtggt caagaaacca gagtaataaa aactcaaccc agtcaacatg caaattccta tagcataata tggcacc aac ctacccaaga ttctaagttg ctcatatgaa tgatgaaaaa acccacttca agaaaaaata taggaatgag aacttccaaa tgatgatttt tcaatccatt ccaatcaatc aaaagaacaa atacacagca aatatgggtg aagca tcaa t gattaactca tgtatcatta agcatgcagt catgaagaca gacatcaaaa tctgaactca aattattcct caaatatatc gagcatatat caaagtcaag tattcaacgt aaacaaacta aataggtatg agatgctgga aaatggaaag agtcaatatt agtggctcca tgcacttgtg gagggcaaac tat agc taac gcactttggc aggattgttt caaatctgta tgtggaagtc gaacaatcca cctaggcaat ggatctttat ctacagtgta caaagaagat gagaagtttg gaatcaataa tctgttaact atcatcaatc aaacccctag tacaaggaaa gagataaatg ttaagtgaaa gctcgcgatg agagcggaag gaaagcgaaa aaattgagtg tgatcagcga gaatcaactg aaccaattga gatggggcaa gctgttcagt cctatgttcc atactagtga agaagtgctg gatgaaagaa ctaacatgct ttcaacccca agagtaataa ctagaaaata tatgcaggat aaaccacaga tatgtgacta ttgaatgata agtacaggag tgtqgtatgc ttatatgcta tatcatgtta gaaatgaaat gagatagaat gaatataggc ataaccaaat aatgtcttaa agtttttatg attgcacaat atgaatgcct aaaaatatca tatgagtatg aaagcatcat gcagcaggtc gatgcagcta ttagacttaa gatgtagagc cacctgaatt agggcaagtt caatagatat caacaagtga taagcttcaa caatagaaac atcaaacaaa tattaggaat gaataagaga cattaatgac aaatggcaaa acttgttgga tcaactcact ccagaccgaa tcaatcagca atatggaaac acaatgttct agtcatctgt agcagatctc tgctggctca gcaaattagc taaaagtaaa ctcatgagat taccaaccta tagcaaccac tagtgttagt gtcaatttat ctaattggaa cattaaataa ataatattga tattaatcac tgtccaggtt aagctaatgg tcgaagtatt ctagaaagtc atgattctcc tagcagcagg aaaacgaaat aagtgtttga catccacaag atggttcagg tgctaggaca cacagaagt t tgctgtcatt taggcataat aagcatatgc cagcagaaga tttaagttaa tcatggagaa cgcatcatcc agaagtaact agccgacagt agaagatctc atttgataac tgacaacatt gctccataca tgctatggtt caatgatagg agacacctca agacaacgat cagcaatcaa caaacaaacg acccgacaaa atacgtgaac agaaaaagat gccagcagac tacgcccaaa aatgcctagt atatgatgta aagtatgtta cattgctcta tctaagatca cgaattcaaa tatcacagtt agtagatctt gcatacagc t ggatcagctg cactcccaat tgaagatgca aggaagggaa agtagatata aacattatca ctacaaaaaa agactgtggg agacagatca aaaacgatac aaaacaccct agggggtagt gcaagtaatg tgctagtgtc gggaggagaa aactcaattt gggagagtat agagcaactc attggaagcc caaaaaatac gatgcaaata aaagatccta aaagagagcc accccagaaa accccaagtg aatgaagaag acagcaagac ttagtagttg ggtctaagag t tagaggcta gatgaagtgt agtgacaatg caacatcaat tccatcagta attaacaata aagcttcacg gatgatcctg ttgctcataa ggaccttcac aatttcatca actacacctt actacagtca tgtgaatttg attagtgtca aatgctatca actgacaata ggtgcctacc acacgttttt ctgtcatcca tatgatgtgc aatcataaat gacactataa acaacatatc agcttgacat atgctaaaag atgataatac ggtcttacag aagggcctca catcttatag agagttgaag ctaagatggg caggcagaaa gctggattct cccaacttct agaggtacac aaagaaaatg ataaagcatc ggggcaaata acaaagctac agaagaaaga cgataacatc caaaagccaa acaacccttt aatctagcta tagatagaat caagtgcagg aagagatgat tggcaagact ctcttaatcc atctatcact aaaacagaca gaaccaccaa tagtaacaaa aaggctccac catcactaac aagaacttgc tacgagtcac taagcgcaaa gtgaaatcaa aagatcttac aaaatattat agaacaagga ccaatgcaaa aaggagcatt tagaaaaaga caatcaaacc 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 WO 99/49017 WO 9949017PCT[US99/06225 actagaggat acacactata ccactcaaaa aaataaaacc catttatacc acaatagaac ctaatctttt cacaaagcat agttccacca cctctcacag tatttaaaaa aatgcaacca gatactctta atagcacaaa gccataatat acaataaaaa agggttagtt acatcaccca accacttcaa aaagatgatt caactttgca atcaaaccca gccaaaacga acagaaagag acagtccaac acacccacag tagttattca aaacctgggg tcttgctatt atcgacatgt tagtgtcata taaagtaaaa gctacttatg tatgaactac acgaagattt atcaaaagtt aaacaaagct tctcaagaat ctccaacatt cagagaattt cagtgagtta gtcaagcaat agaagtcctt gaaattgcac aacaaggact ggctgacact attaccaagt aattatgaca taaacttaat tccaaacatc tccaaaatca aaaatatggg gccaattcaa tcacaagcaa tactaattat tctgcaacaa ttatgctgtg agtcacggtg ttaacataat tgtccaaaca atcatctaat tagcactatc tcatcatctc accacactga catccaagca atacaaaatc cacagaccaa accattttga aatccatctg caaacaaacc cgaaaaaaga acaccagcac agcaatccct catccgagcc aaaactacat caaataacca aatgcattgt agtgcagtta acaatagaat cttatgaaac caaaacacac acaatcaata ctaggcttct ctacaccttg gtagtcagtt tacataaata gaaacagtta agtgtcaatg ctatcattaa gttcagatag gcatatgttg acatcgcctc gatagaggat tgtaaagtac gaagtcagc tcaaaaacag tatcaacact ataaacatct ctaccagcca gtaaatagac cacatatact attttggccc aatcactatc aactcttgaa tcaaaccata tcgcaaaacc gatgaattgt caagaatcaa tgtaatatcc agttttggca tgccaatcac aaaaaacatc acccacaacc agaaacacac caagccaagc agtgttcaac caaaacaata aaccaccaaa aactaccacc ctcacaatcc cctctcaacc ctccacacca cttagcagag tggagttgat acctcacctc gcagaggtta taagtaatat aagaattaga cagctgtcaa ccactaaaaa tgttaggtgt aaggagaagt tatcaaatgg accaattatt tagaat tcc a caggtgtaac tcaatgatat taaggcaaca tacagctgcc tatgcactac ggtat tgtga agtccaatcg tttgtaacac acataagcag gaatgacagg acactacaca ctatccgcta attagttaga ataaatctta tattttacac atgattgcaa ctaggacaga atcctgtata acgctaacca tagtatgaga cgcactgcca tcttgtttat atgataatct aaagttacac accacctacc acatcaccaa catacaacag acaaaaccac ttcgttccct ccaagcaaca accacaaaca aacccaacaa actgcactcg acccccgaaa aactccaccc aaccgtgatc gatccacaag aagtcagaac ttttagtgct aaaagaaacc taagtataag caaccgggcc cctaaatgta gggatctgca gaacaagatc ggtcagtgtt acccatagta gcagaagaac aacaccttta gcctataaca aagttattcc tatctatggt caacatcaaa taatgcagga agtattttgt tgacatattc ctcagtaatt tccacatata cttcatcaca gacctagagt gttcaatcaa aaatgggaaa taatacatat cactaaataa tgtaccaaat tacaaacaaa tcatggtagc tcaaaaacaa ggactctaga acagattaaa caacctctct taacaacggt ctactcaagt tccacacaag cacaaaccaa gtccaaaaaa gcagtatatg aaccaaagaa aaagagaccc aaaaactaac acacaaccac acacacccaa aaaaaaccca tatcaagcaa tcaagtgcaa ataactgagg ttaagaacag aaatgcaatg aatgcagtaa agaagagaag tcaataagca atagcaagtg aaaaatgctt ttaaccagca aatcaacaga agcagattgt agcacttaca aatgatcaga atcatgtcta gtaatagata gaaggat caa tcagtatcct gacactatga aattccaagt acttctcttg tcctcaaact caaaccaatc gcgaataggc tcttaacaac tacatccatc gatcttaact gctaagtgaa caacacacag caaatccaat atagagtagt cattggggca aaagacctgg tttaaaatct cataattgca cacagttcaa ctcaccagaa ttcagctaca aggcagaacc tccaccaaaa tggcaacaat gaaaccaacc aaaaacacca cctcaagacc attaaaacac ctccacacaa gccacatgct gaacgaaatt tcttcctaac agttttacca gttggtatac gaactgacac cagaattaca caccacagta agaagaggaa gtatagctgt tgttgtctac aagtgttaga gctgtcgcat tggaaatcac tgttgacaaa aaaaattaat taataaagga caccttgctg atatttgttt tctttccaca acagtttgac atgactgcaa gagctatagt 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 WO 99/49017 WO 9949017PCTIUS99/06225 gtcatgctat attttctaat cactttatac aataaattac agtcaatgaa taatgtaaat cattgtagta cacaccagtt atagacaaaa caacttacaa tacccacata atcaaccact agaaatcctt agtcataatt aacaagatac gctgaactgg ataggatcta attgagatca aagataagag caaaccatcc acattagata caaaatgacc catattgatc taaccataac ttggacacct tgaagatata tcatccaacc ggaaactctg gagtgtaatg aacttaatta acacagtcat ttccagtcat aacttactta atcttgaata gatgaaaact aatcaatcat acaacactct tggttcaatt aaaagtcatg aatcaatatg aatcaatttt tggataagta aatgttgtgt gaaggctt ct acagaagaag gcagctatta acagtgtctg ttgattaagc ggtaaaacta ggttgtgact tatgtaaaca tatgaccctc aaaatcaatc actggcaaat ttgttatcat acactaagca aaccacctga caaatatttc actaagctag aaatcaacac gtaaatttga actt tgaatg tcaagtcaat atagaacaga taaacaacat atagtgatga tgtacaatac atctgctcaa tccacaaaag aaaccaaaaa tcaagtgaaa tatttggata aaaaacttat tatacagtat ataaaactat ctaatgtgta ctttagggag gtagacaaag taatatctag tacttatgac aaaaaataat aactaggat t cagtacttac atacaaattc tgaaaaaatt tatatacaaa ggtttatatt gttgtatcgt tgacatggaa attgtttaaa tatcacaatt acataataaa atcaatttaa aggctcaaaa ataatatcat ttgcaggtga aatgcactgc atgtgtcaaa agctggaagg tagtgtttcc aaagtttagc ctactacaaa taatagctat aagaccaact tcatgtttca aacatcacag atccttaact atcattcaca gattagaggt gcctcctcat ggacaaaagc agaatatgct aacaaaacaa cattaaaaag tgttatatca gagactacca cataaccata taatgatatt gcatggttgc accaccagcg tagatgccac atatattagt tttgataagg tctaactgat ttatcttttt cccactacta atatcataaa atataaaagt acgaagagcc aaaggaaaag aaccataatt agacaaaagt gatgtgttca attaaataac aatagataat ttatcataaa agacatcagc tacattaaac atttctttat agaagtagag gaaacgattt ggacctacta aaatggtaaa taataatctc atccaacaaa caaaggagta caagaacctt ttctgatgag ttttattcgt tattatgata tggtttactg aagtggaatc acaacaatct tacaggctga tatagttaca aaattaacag cattgcttga gcattactag atagacactt cttggtatag tcagcatgtg attagagata tacattgaga gcagacgtgc agcaatccaa ac cggataaa tacattcaat tttattaaat tcaacaattt gtcataatgc ttatgggaca agttatttaa aacggccctt gagcatatga ggtgaactga atgtcctcgt atagaaataa gacagagtta aaagatgata cactcagtaa atgcaacatc atattaacac caaactttaa ggactcaaaa cttagcagat aaaagcttag ggagattgta ggatttatta tataatagca tcaagagtat tggataatcc aataacttga aatcgtggga gatactgtgt tatgtaaaag tttgatgcat agatctgatg actacaatta ttgtattgta aataatattg gctgaccacc atcatttcct taaaaacctc ctggggcaaa atggtagaag tgaggcaaaa tgtctgaaat ttggagtgct ttgctatgag atgaagaacc gcaatagaaa tgaagaagac aagagtcaac tatccttgta cataaaaaca catatatttg ctccaacatc ttgaccataa aaatggatcc aaggtgttat atcttaaaaa atcttaaaaa aattagaaga ctgaacaaat gtgatgtaaa agcccaacaa tactttcggc atcaaaatat ctccatcatg aatatcgatc gtggttttca aaatcacaac taaatgtttg ggctgagatg tactgaaatt tgtctttaat tgctaaataa gtcacacttt tattaagtaa gtgagctata ttataaagac cagtgggcaa gggaacctat caatatctca aattactaca ttatagtaat aagccaaaaa cattcagcaa aatcccaaat cacatcatgc aagtatcaca tatgtcgcga atgtcactac cttcatgtta aagtggagct agagagttac taaacttctt caattcacct aaacaacaag aataaagaac tgtgaatgat gtatatcatc tattacaatt atgaaattca ttaacatccc cgactctatg cattattaat ctctttttca tgattacacc actaactata accaacttat tgctacaact ggtgtacgcc taattcaggt tgtggaaaac cactatcaaa gttaatacac aaatgaggta gtttatttta tactacttac cttaattact tggattcaat atttcataat tctaaacata catcacagat attagacaag atttcttaaa ttttctcttc 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 8580 8640 8700 8760 8820 8880 8940 9000 9060 9120 9180 9240 9300 9360 9420 9480 9540 9600 9660 9720 9780 WO 99/49017 WO 9949017PCTIUS99/06225 agaatctttg tgtaatgaaa tatagaatca attgtcctac gaaatcacag ctgcctaaaa gatctaatat gaacatgaaa ttgagagata ctcaacaact agaatgtttg atagctgaaa cttcaaaaga aactacaaca gcatttagat caatctctgt agacatgcac agtggattat attgaagcta ctgataaatg cagacccatg gagtatgcag cagttcatga gtcctgagag tctataggca atatttagga tgtaacaata aatcttgata ggtggtgatc gaagctatag aagctccagg gataaaaatc gaaaggcaag atagccccaa ctaaatgaca gaaagtttac ataactaata gatatgatga gacaaaagag agagaaagat acaatgaaca aatgttaata acgcaggaga gaccaaatag gaattcatgg ttgtttccac tgtgaattcc cctatcaatc gacatccaat ctaagttcta taaaagggtt ctctaagatg aaaatgattt aagtggatct ggactagttt agttgaagtt ataaattcaa ctaatcacgt ctatgcaacc atattttaca tattagaatt attatatcag atgaaacatc tctcttggtt ctcctttcat acagatatca tatcattatt gtgataatca cacaag caga gt at aggc ca gcaaaacaat taggtccatg gcttaacaca acatttggtt agctatattt gcattgatat ctaatttgtt tacattcagt at ctt ccaga ccaatgccga ctaaaattac acaaaatatt ttatgcaaaa ctttttataa tacttgaaaa ggaaaaatat agttattaag cttggtcatt ttaaatatac gtttaactcg aaaaaacaat atttattagc aagaactgag aatatctaag ctgcatcaat atgtattaac ggtcgatgaa cttattaagt tgtaaatacc gttaaactac gattatttta tgaaatgata tcctagaaat ctctgaaagc tgaatgcgat ggtatcacta aggtatgtt t attcttccct aaaagcagga taaatgttct atgtatctgc gcatttaaca aaaggatcat tatgggtggt agatctaata gtcaattgat ttatttgtta taagcttaag ccagcacaat gataaacacg ggagttagaa atacaatcaa agatatattg ggc tttat ca atatcgaagc gtttgtgttg tgatagactg gtttgtaaca tagtgagatt ttctaaaagt tatagaacca agcagaaaaa aacatcagca aactttactt tttagaaaat atccaatata aactagcact tggtgaaaga gccagtgtac aaaattagac tactggaaca tgtcaattat accagcttat agaaaagtat agacaagcaa agtctaagta tacaacagat tataaactta tcaggattgc ataaatgaca tacatgccat gacagatcga ctatacaatt actggtaaag aggc aaat cc gagagtttga ataagcaaca atcattacag agtgatgtat atacctcttg gttgttaatc attgagggct tctctcaaag ataagcaaac gcattaaata ggaacagaga ggagtgtact atacttgatg tacagaggag attgctttgc aaagtattaa ttgtatatga ttttatagga agctattata aacaaattct ttgatgaggg aatagattag gcacaacatt acttaccctc atagttaatc atagatacaa ataaggatac cttagtataa gtaggagtaa atagccagtg ggac cc ac ca aacagacaag tgggtatatg cttggactgt ttacaccgtt agaacaacaa ggagatgaag tggattctgt cattaagagg ggc Ccacct t atacttatcc ggttctatcg aagccatttc cacatataca gaagagtact gtgtagtcaa aaagagagct aaatcttagc caagatatgg agtcaaatcg atcttagcaa tagatgaact tcacaataat ttaatgaggt ggtgtcaaaa ggaaattctc cagttagact gccttaaatt cctatatatc atccagccag attttaaagt aaagcttatt aactccgaaa aacacttaaa atttgcctat gaactccaga ctggtcacga tgacatgtgt at ccacaggc cagtaacaga atactaccac atggattaag ttatatcagg ctgatattaa ttccactaga ctgaattaag catcgccaag gtataataat agccatgggt ttttaaccaa cat cca taga catatgaaaa taacagtcag attatcattt atatcgacat aagaattaac tgctttcatt aaggaatgct atctctactt tgagtttcat acctccaaaa aaattatata agagtattac tcaaagctat cagtgtaggt agagaaaatg tgatctagag ttataatgat at tcaa tcag gcatggagta atgtacatat tgatgaacaa actgtggacc tatcacagct tatagagggt gttatataaa ccgagatatg tatcaaaaaa tagtttagaa atgcagttta tcatgcatta aacttttttt gctgtttggt cttccttaca tttacaagat catcacattt tttagggtct agtcttaagt tgagattgat agttgtttat aacaaaatcc tagggctact ttgtaacaaa caagtatgta tattatgttC agaaaaatat aggctcatcc aaagcaaaga caacaaagat agccaaaaag tagtagacca tgatactagt tgtgtttcaa 9840 9900 9960 10020 10080 10140 10200 10260 10320 10380 10440 10500 10560 10620 10680 10740 10800 10860 10920 10980 11040 11100 11160 11220 11280 11340 11400 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 WO 99/49017 WO 9949017PCTIUS99/06225 aattgcataa cctaatagaa t ttacaggag ctaccagata aaatctggat cataatgctt atgaaagatt atgttcatta aaaggttatg ttggagttaa gtcataaaat tttaagttgt gttaacatag agaatggggt gaattttaca ctaacaaaac cacccaaccc aacaaaccta agtaaaatgc ttgtacaatt gcaaaatcta gcatcacttt tccacaggat agttgtatag cttcatccag cctattgaat accattcctg gcagaaccta aaaattataa agatgcattt attactatat ttaatcctta aaattgatac atcgatgcaa attaagactt atagctggac ctaaaatggc tacatgatag gagctcaaga tagtttaaaa tagttattaa ttttagtctt acacaacgag gttttggtct ttattctcat atgttgatat aaataagttt ctcacatcaa atattttaag caaaaggtat atttgaatgt gtaaagcaaa tagacagtag acatagtcaa ggtttttaaa attatcaccc taataaatgt catcaaatct aaataagaat cagaaacttt aattttgtat atattaaatc tatttccaat accaacttta attgcatgct gcaagatcag cattcatagg acataagata ttctaaggtt ctacagatgc ttagcatctt ttgaatggag taattgcaaa taaaaactta caataggccc tttcaagaac atattaaaag cattgtcaaa gtaatgaagt tagatcatgt agtccacata agctgattaa tatcattaac agaatataca aaggggttaa acattagttt tagcctgatg accgaagctg catcaagttg aacccaatat ctctaattta tactaattta ttttgaaaaa tttctttaat attagaatgt ctactggaaa tcaagacaca acgccttaat aacacacatg agataaatta cttttacatt tgctaattca agaaaatatg aagtggaaat ttccactgtt tgttgtgata caccaccact tccttggcat tatagagtat tgaaggagct catttacaga atacaacggg aactaataac tgtctgcgat taagcatgta atatcatgct cgtgtgccta tgcaaatata taaaaatttc cttaatacct attgaagagt attcagcaac tttaaatttt tccttactta aataacaggt aagtttggtc aacttttcaa ataaaagtct ttgacacttt tcggttgtgg aatgagatac aagcaagtga gtagaattat atattagtac gctggacat t gattggggag gcttataaga gatatgaaca tctatgtcta agtttgcgta aatgctaaat aaagctatat accattaaaa agttataact gaattagaag tcattaattc accgaatcta accacaagat gacaagatta tcacatcaga catgtcaata attttaaaag ggtaact tat agtttaaaag catataaaca attcattggt gctgaattac agaaagtgca caagatgaca ggtagcaagt cttcctgttt attatgccta ttcctttgtt gtagttaatg aagcttataa agatcagctg agtgaattgt agtgtgctat aaatttagat taatttagca aaaactaaca ttttCtcgt aacaattcac att tgatgaa tacaaaagca tcttaagtaa ataaaatgtc ggattctgat aggggtacat cttatttgct cttcagatct aagttttcct gaataaaagg ttaccgtatg tatcttacat ataaaaacaa tttcagacaa ataattataa ctgttaaaag tgatgatgtc tcaattatag tagatcattc catctttagt gatttaactt atcttaagat tattacgtac attgcaatga tagattatgg cttatttaca ctgttacagc agtactgttc ttgatttcaa taaaaggat c ttgatgttgt aaaaaactga accctataac gagatatatt accacaagca aacttaatta taaatagttt acaaccttcc gctaacacat tattgattcc attatacatg aaacatatgt acctcctata gcacatgttc caaagcactt tgattatttt tattcaactt aactgatcat atgttttcat tctttgtgtt agaacaaaaa ctgtcacagt cccttgggtt agatttagtt attcaatgat cactcatttg caaactatat taataatagt aacattctct caaacaagac aggtaataca aaggaatagt tgtatttagt taaggacccc ggtagtagaa tcatagttta tgagaattta tataaaattt caattggagt ttctgtaaat attagataac tgaagtttac acaaaatgct caaggaatct aaaaaaagga atcatattct tatgaatatc caatcattta aacaaccaat caacgaacag cattatatta aaaattatca tgcattcaca 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15219 <210> 14 <211> 15219 <212> DNA <213> respiratory syncytial virus WO 99/49017 WO 9949017PCT[US99/06225 <400> 14 acgggaaaaa ttgataagtg atgataaagg acatgttata acaattaaat gataacaata tacatatggg aattgtgaaa caaatatctg tagacatgtg aataaactca gattgatgat aagaaatcat ttgatgaaag aagtagggag ccatgcctat aacacactcc cccaaccaaa cattttagta tggctcttag gcaaatacac aaaaacacct tcacaggatt agatacttaa gtcaagatat cagaaataca agatgggaga tgtgtatagc cagtaattag taccaaagga atgttttcgt gaatctttgc gagttttagc tggagcaagt accatatatt caagtgtggt caagaaacca gagtaataaa aactcaaccc agtcaacatg caaattccta tagcatAata tggcaccaac ctacccaaga ttctaagttg ct ca tatgaa aatgcgtact ctatttaagt ttagattaca ctgataaatt taaacggcat ttgtagtgaa aattgattga tcaaattttc acttacttgg tttattacca cctaatcaat cacagacatg cacacacaaa acaagctaca taccaaatac atttatcaat tataatatac ccaaactatt attaaaaata caaagtcaag tattcaacgt aaacaaacta aataggtatg agatgctgga aaatggaaag agtcaatat t agtggctcca tgcacttgtg gagggcaaac tatagctaac gcac t ttggc aggattgttt Sa-aa t ctgt a tgtggaagtc gaacaatcca cc taggcaa t ggatctttat ctacagtgta caaagaagat gagaagtttg gaatcaataa tctgttaact atcatcaatc aaacccctag tacaaggaaa gagataaatg acaaacttgc ctaacctttt aaatttattt aattcttctg agtttttata atctaacttt gttgacacac taaaagacta gcttgatctc ttttagttaa caaaccatga agacccctgt ttcatatact tttacattct aaaaaataca cacggcgggt aaatatgacc cctcaaacaa aaagtaaagc ttgaatgata agtacaggag tgtggtatgc ttatatgcta tatcatgtta gaaatgaaat gagatagaat gaatataggc ataaccaaat aatgtcttaa agtttttatg attgcacaat atgaatgcct aaaaatatca tatgagtatg aaagcatcat gcagcaggtc gatgcagcta ttagacttaa gatgtagagc cacctgaatt agggcaagtt caatagatat caacaagtga taagcttcaa caatagaaac atcaaacaaa acattcgaaa caatcagaaa gacaatgacg accaatgcat catgttataa acaacaatgc tgctctcaat agtgactcag aattcatgaa tataaaaact gcactacaaa caatggattc tgataaacaa tagtcaatta ctgaatataa ttctagaatg tcaacccgtg cagtgctcaa caataacata cattaaataa ataatattga tattaatcac tgtccaggtt aagctaatgg tcgaagtatt ctagaaagtc atgattctcc tagcagcagg aaaacgaaa t aagtgtttga catccacaag atggttcagg tgctaggaca cacagaagt t tgctgtcatt taggcataat aagcatatgc cagcagaaga tt taagttaa tcatggagaa cgcatcatcc agaagtaact agccgacagt agaagatctc atttgataac tgacaacatt aaaatggggc tggggtgcaa aagtagcatt tagccaaagc caagcagtga caatactaca taaacggttt taatgactaa ttatgtttag catcaaaggg tgacaacact aataataaca tgaatgtatt tgagatgaag tacaaaatat tattggcatt aattccaaca tagttaagaa aattggggca ggatcagctg cactcccaat tgaagatgca aggaagggaa agtagatata aacattatca ctacaaaaaa agactgtggg agac agat ca aaaacgatac aaaacaccct agggggtagt gcaagtaatg tgctagtgtc gggaggagaa aactcaattt gggagagtat agagcaactc attggaagcc caaaaaatac gatgcaaata aaagatccta aaagagagcc accccagaaa accccaagtg aatgaagaag acagcaagac aaataagaac ttcactgagc gttaaaaata agcaatacat agtgtgccct aaatggagga aatggatgat ttatatgaat tctaattcaa aaatggggca actatgcaaa tctcttacca gtaagaaaac ctactgcaca ggcactttcc aagcctacaa aaaaaaccaa ggagctaatc aatacaaaga ctgtcatcca tatgatgtgc aatcataaat gacactataa acaacatatc agcttgacat atgctaaaag atgataatac ggt cttacag aagggcctca catcttatag agagttgaag o taagatggg caggcagaaa gctggattct cccaacttct agaggtacac aaagaaaatg ataaagcatc ggggcaaata acaaagctac agaagaaaga cgataacatc caaaagccaa acaacccttt aatctagcta tagatagaat 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 WO 99/49017 WO 9949017PCTIUS99/06225 tgatgaaaaa acccacttca agaaaaaata taggaatgag aacttccaaa tgatgatttt tcaatccatt ccaatcaatc aaaagaacaa atacacagca aatatgggtg aagcatcaat gat taact ca tgtatcatta agcatgcagt catgaagaca gacatcaaaa tctgaactca aattattcct caaatatatc gagcatatat actagaggat acacactata ccactcaaaa aaataaaacc catttatacc acaatagaat ctaatctttt cataaagcat agttctacca ctt ct cacag tatttaaaaa aatgcaacca gatactctta atagcacaaa gccataatat acaataaaaa agggttagtt acatcaccca accacttcaa aaagatgatt Caactttgca atcaaaccca gccaaaacga acagaaagag acagtccaac acacccacag tagttattca ttaagtgaaa gctcgcgatg agagcggaag gaaagcgaaa aaattgagtg tgat cagcga gaatcaactg aaccaattga gatggggcaa gctgttcagt cctatgttcc atactagtga agaagtgctg gatgaaagaa ctaacatgct ttcaacccca agagtaataa ctagaaaata tatgcaggat aaaccacaga tatgtgacta taaacttaat tccaaacatc tccaaaatca aaaatatggg gccaattcaa tcacaagcaa tactaattat tctgtaacaa ttatgctgtg agtcatggtg ttaacataat tgtccaaaca atcatctaat tagcactatc tcatcatctc accacactga catccaagca atacaaaatc cacagaccaa accattttga aatccatctg caaacaaacc cgaaaaaaga acaccagcac agcaatccct catccgagcc aaaactacat tattaggaat gaataagaga cattaatgac aaatggcaaa acttgttgga tcaactcact ccagaccgaa tcaatcagca atatggaaac acaatgttct agtcatctgt agcagatctc tgctggctca gcaaattagc taaaagtaaa ctcatgagat taccaaccta tagcaaccac tagtgttagt gtcaatttat ctaattggaa tatcaacact ataaacatct ctaccagcca gtaaatagac cacatatact attttggccc aatcactatt aactcttgaa tcaaattata tcgcaaaacc gatgaattgt caagaatcaa tgtaatatcc agttttggca tgccaatcac aaaaaacatc acccacaacc agaaacacac caagccaagc agtgt tcaac caaaacaata aaccaccaaa aactaccacc Ctcacaatcc cctctcaacc ctccacacca cttagcagag gctccataca tgctatggtt caatgatagg agacacctca agacaacgat cagcaatcaa caaacaaacg acccgacaaa atacqtgaac agaaaaagat gccagcagac tacgcccaaa aatgcctagt atatgatgta aagtatgtta cattgctcta tctaagatca cgaattcaaa tatcacagtt agtagatctt gcatacagct gaatgacagg acactacaca ctatctgcta attagttaga ataaatctta tattttacac atgattgcaa ctaggacaga atcctgtata acgctaacta tagtatgaga cgcactgcca tcttgtttat atgataatct aaagttacac accacctacc acatcaccaa catacaacag acaaaaccac ttcgttccct ccaagcaaca accacaaaca aacccaacaa actgcactcg acccccgaaa aactccaccc aaccgtgatc ttagtagttg gqtctaagag ttagaggcta gatgaagtgt agtgacaatg caacatcaat tccatcagta attaacaata aagcttcacg gatgatcctg ttgctcataa ggaC ct tca C aatttcatca actacacctt actacagtca tgtgaatttg attagtgtca aatgctatca actgacaata gg tg CCta cc acacgttttt tccacatata cttcatcaca gacctagagt gttcaatcaa aaatgggaaa taatacatat tactaaataa tgtatcaaat tataaacaaa tcatggtagc tcaaaaacaa ggactctaga acagattaaa caacctctct taacaacggt c tact caagt tccacacaag cacaaaccaa gtccaaaaaa gcagtatatg aaccaaagaa aaagagaccc aaaaactaac acacaaccac acacacccaa aaaaaaccca tatcaagcaa caagtgCagg aagagatgat tggcaagact ctcttaatcc atctatcact aaaacagaca gaaccaccaa tagtaacaaa aaggctccac catcactaac aagaacttgc tacgagtcac taagcgcaaa gtgaaatcaa aagatcttac aaaatattat agaacaagga ccaatgcaaa aaggagcatt tagaaaaaga caatcaaacc tcctcaaact caaaccaatc gcgaataggt tcttaacaac tacatccatc gatcttaact gctaagtgaa caacacatag caaatccaat atagagtagt cattggggca aaagacctgg tttaaaatct cataattgca cacagttcaa ctcaccagaa ttcagctaca aggcagaacc tccaccaaaa tggcaacaat gaaaccaacc aaaaacacca cctcaagacc attaaaacac ctccacacaa gccacatgct gaacgaaatt 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 WO 99/49017 WO 9949017PCTIUS99/06225 aaacctgggg tcttgctatt atcgacatgt tagtgtcata taaagtaaaa gctacttatg tatgaactac acgaagattt atcaaaagtt aaacaaagct tctcaagaat ctccaacatt cagagaattt cagtgagtta gtcaagcaat agaagtcctt gaaattgcac aacaaggac t ggctgacact attaccaagt aattatgaca gtcatgctat attttctaat cactttatac aataaattac agtcaatgaa taatgtaaat cattgtagta cacaccagtt ataga caaaa caacttacaa tacccacata atcaaccact agaaatcctt agtcataatt aacaagatac gctgaactgg ataggatcta attgagatca aagataagag caaaccatcc acattagata caaaatgacc catattgatc taaccataac ttggacacct tgaagatata t cat ccaac c caaataacca aatgcattgt agtgcagtta acaatagaat cttatgaaac caaaacacac acaatcaata ctaggcttct ctacaccttg gtagtcagtt tacataaata gaaacagtta agtgtcaatg ctatcattaa gttcagatag gcatatgttg acat cgc ct c gatagaggat tgtaaagtac gaagtcagcc tcaaaaacag ggtaaaacta ggttgtgact tatgtaaaca tatgaccctc aaaatcaatc actggcaaat ttgttatcat acactaagca aaccacctga caaatatttc actaagctag aaatcaacac gtaaatttga actttgaatg tcaagtcaat atagaacaga taaacaacat atagtgatga tgtacaatac atctgctcaa tccacaaaag aaaccaaaaa tcaagtgaaa tatttggata aaaaacttat tatacagtat ataaaactat tggagttgat acctcacctc gcagaggtta taagtaatat aagaattaga cagctgtcaa ccactaaaaa tgttaggtgt aaggagaagt tatcaaatgg accaattatt tagaattcca caggtgtaac tcaatgatat taaggcaaca tacagctgcc tatgcactac ggtattgtga agtccaatcg tttgtaacac acataagcag aatgcactgc atgtgtcaaa agctggaagg tagtgtttcc aaagtttagc ctactacaaa taatagctat aagaccaact tcatgtttca aacatcacag atccttaact atcattcaca gattagaggt gcctcctcat ggacaaaagc agaatatgct aacaaaacaa cattaaaaag tgttatatca gagactacca cataaccata taatgatatt gcatggttgc accaccagcg tagatgccac atatattagt tttgataagg gatccacaag aagtcagaac ttttagtgct aaaagaaac c taagtataag caaccgggcc cctaaatgta gggatctgca gaacaagatc ggtcagtgtt acccatagta gcagaagaac aacaccttta gcctataaca aagttattcc tatctatggt caacatcaaa taatgcagga agtattttgt tgacatattc ctcagtaatt atccaacaaa caaaggagta caagaacctt ttctgatgag ttttattcgt tattatgata tggtttactg aagtggaatc acaacaatct tacaggctga tatagttaca aaattaacag cattgcttga gcattactag atagacactt cttggtatag tcagcatgtg cttagagata tacattgaga gcagacgtgc agcaatccaa accggataaa tacattcaat tttattaaat tcaacaattt gtcataatgc ttatgggaca tcaagtgcaa ataactgagg ttaagaacag aaatgcaatg aatgcagtaa agaagagaag tcaataagca atagcaagtg aaaaatgctt ttaaccagca aatcaacaga agcagattgt agcacttaca aatgatcaga atcatgtcta gtaatagata gaaggatcaa tcagtatcct gacactatga aattccaagt acttctcttg aatcgtggga gatactgtgt tatgtaaaag tttgatgcat agatctgatg actacaatta ttgtattgta aataatattg gctgaccacc atcatttcct taaaaacctc ctggggcaaa atggtagaag tgaggcaaaa tgtctgaaat ttggagtgc t ttgctatgag atgaagaacc gcaatagaaa tgaagaagac aagagtcaac tatccttgta cataaaaaca catatatttg ctccaacatc ttgaccataa aaatggatcc tcttcctaac agttttacca gttggtatac gaactgacac cagaattaca caccacagta agaagaggaa gtatagctgt tgttgtctac aagtgttaga gctgtcgcat tggaaa tca c tgttgacaaa aaaaattaat taataaagga caccttgctg atatttgttt tctttccaca acagtttgac atgactgcaa gagctatagt ttataaagac cagtgggcaa gggaacctat caatatctca aattactaca ttatagtaat aagccaaaaa cattcagcaa aatcccaaat cacatcatgc aagtatcaca tatgtcgcga atgtcactac cttcatgtta aagtggagct agagagttac taaacttctt caattcacct aaacaacaag aataaagaac tgtgaatgat gtatatcatc tattacaatt atgaaattca ttaacatccc cgactctatg cattattaat 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6420 6480 6540 6600 6660 6720 6780 6840 6900 6960 7020 7080 7140 7200 7260 7320 7380 7440 7500 7560 7620 7680 7740 7800 7860 7920 7980 8040 8100 8160 8220 8280 8340 8400 8460 8520 WO 99/49017 WO 9949017PCTIUS99/06225 ggaaactctg gagtgtaatg aacttaatta acacagtcat ttccagtcat aacttactta atcttgaata gatgaaaact aatcaatcat acaacactct tggttcaatt aaaagtcatg aatcaatatg aatcaatttt tggataagta aatgttgtgt gaaggcttct acagaagaag gcagctatta acagtgtctg ttgattaagc agaatctttg tgtaatgaaa tatagaatca attgtcctac gaaatcacag ctgcctaaaa gatctaatat gaacatgaaa ttgagagata ctcaacaact agaatgt ttg atagctgaaa cttcaaaaga aactacaaca gcatttagat caatctctgt agacatgcac agtggattat attgaagcta ctgataaatg cagacccatg gagtatgcag cagttcatga gtcctgagag tctataggca atatttagga tgtaacaata ctaatqtgta ctttagggag gtagacaaag taatatctag tacttatgac aaaaaataat aactaggatt cagtacttac atacaaattc tgaaaaaatt tatatacaaa ggtttatatt gttgtatcgt tgacatggaa attgtttaaa tatcacaatt acataataaa atcaatttag aggc t caaaa ataatatcat ttgcaggtga gacatccaat ctaagttcta taaaagggtt ctctaagatg aaaatgattt aagtggatct ggactagttt agttgaagtt ataaattcaa ctaatcacgt ctatgcaacc atattttaca tattagaatt attatatcag atgaaacatc tctcttggtt ctcctttcat acagatatca tatcattatt gtgataatca cacaagcaga gtataggcca gcaaaacaat taggtccatg gcttaacaca acatttggtt agctatattt tctaactgat ttatcttttt cccactacta atatcataaa atataaaagt acgaagagcc aaaggaaaag aactataatt agacaaaagt gatgtgttca attaaataac aatagataat ttatcataaa agacatcagc tacattaaac atttctttat agaagtagag gaaacgattt ggacctacta aaatggtaaa taataatctc ggtcgatgaa cttattaagt tgtaaatacc gttaaactac gattatttta tgaaatgata tcctagaaat ctctgaaagc tgaatgcgat ggtatcacta aggtatgttt attcttccct aaaagcagga taaatgttct atgtatctgc gcatttaaca aaaggatcat tatgggtggt agatctaata gtcaattgat ttatttgtta taagcttaag ccagcacaat gataaacacg ggagttagaa atacaatcaa agatatattg agttatttaa aacggccctt gagcatatga ggtgaactga atgtcctcgt atagaaataa gacagagtta aaagatgata cactcagtaa atgcaacatc atattaacac caaactttaa ggactcaaaa cttagcagat aaaagcttag ggagattgta ggatttatta tataatagca tcaagagtat tgg ataa tC C aataacttga agacaagcaa agtctaagta t acaacaga t tataaactta tcaggattgc ataaatgaca tacatgccat gacagatcga ctatacaatt actggtaaag aggcaaatcc gagagtttga ataagcaaca atcattacag agtgatgtat atacctcttg gttgttaatc attgagggct tctctcaaag ataagcaaac gcattaaata ggaacagaga ggagtgtact atacttgatg tacagaggag attgctttgc aaagtattaa aaggtgttat atcttaaaaa atcttaaaaa aattagaaga ctgaacaaat gtgatgtaaa agcccaacaa tactttcggc atcaaaatat ctccatcatg aatatcgatc qtggttttca aaatcacaac taaatgtttg ggctgagatg tactgaaatt tgtctttaat tgctaaataa gtcacacttt tattaagtaa gtgagctata tggattctgt cattaagagg ggcccacctt atacttatcc ggttctat cg aagccatttc cacatataca gaagagtact gtgtagtcaa aaagagagct aaatcttagc caagatatgg agtcaaatcg atcttagcaa tagatgaact tcacaataat ttaatgaggt ggtgtcaaaa ggaaattctc cagttagact gccttaaatt cctatatatc atccagccag attttaaagt aaagcttatt aactccgaaa aacacttaaa ctctttttca 8580 tgattacacc 8640 actaactata 8700 accaacttat 8760 tgctacaact 8820 ggtgtacgcc 8880 taattcaggt 8940 tgtggaaaac 9000 cactatcaaa 9060 gttaatacac 9120 aaatgaggta 9180 gtttatttta 9240 tactacttac 9300 cttaattact 9360 tggattcaat 9420 atttcataat 9480 tctaaacata 9540 catcacagat 9600 attagacaag 9660 atttcttaaa 9720 ttttctcttc 9780 aagaattaac 9840 tgctttcatt 9900 aaggaatgct 9960 atctctactt 10020 tgagtttcat 10080 acctccaaaa 10140 aaattatata 10200 agagtattac 10260 tcaaagctat 10320 cagtgtaggt 10380 agagaaaatg 10440 tgatctagag 10500 ttataatgat 10560 attcaatcag 10620 gcatggagta 10680 atgtacatat 10740 tgatgaacaa 10800 actgtggacc 10860 tatcacagct 10920 tatagagggt 10980 gttatataaa 11040 ccgagatatg 11100 tatcaaaaaa 11160 tagtttagaa 11220 atgcagttta 11280 tcatgcatta 11340 aacttttttt 11400 WO 99/49017 WO 9949017PCTIUS99/06225 aatcttgata ggtggtgatc gaagctatag aagctccagg gataaaaatc gaaaggcaag atagccccaa ctaaatgaca gaaagtttac ataactaata gatatgatga gacaaaagag agagaaagat acaatggaca aatgttaata acgcaggaga gaccaaatag gaattcatgg ttgtttccac tgtgaattcc cctatcaatc aattgcataa cctaatagaa tttacaggag ct accagata aaatctggat cataatgctt atgaaagatt atgttcatta aaaggttatg ttggagttaa gtcataaaat tttaagttgt gttaacatag agaatggggt gaattttaca ctaacaaaac cacccaaccc aacaaaccta agtaaaatgc ttgtacaatt gcaaaatcta gcatcacttt tccacaggat agttgtatag cttcatccag cctattgaat accattcctg gcattgatat ctaatttgtt tacattcagt atcttccaga ccaatgccga ctaaaattac acaaaatatt ttatgcaaaa ctttttataa tacttgaaaa ggaaaaatat agttattaag cttggtcatt ttaaatatac gtttaactcg aaaaaacaat atttattagc aagaactgag aatatctaag ctgcatcaat atgtattaac gttttggtct ttattctcat atgttgatat aaataagttt ctcacatcaa atattttaag caaaaggtat atttgaatgt gtaaagcaaa tagacagtag acatagtcaa ggtttttaaa attatcaccc taataaatgt catcaaatct aaataagaat cagaaacttt aattttgtat atattaaatc tatttccaat accaacttta attgcatgct gcaagatcag catt catagg acataagata tt ctaaggt t ctacagatgc ggctttatca atatcgaagc gtttgtgttg tgatagactg gtttgtaaca tagtgagatt ttctaaaagt tatagaacca agcagaaaaa aacatcagca aactttactt tttagaaaat atccaatata aactagcact tggtgaaaga gccagtgtac aaaattagac tactggaaca tgtcaattat accagcttat agaaaagtat tagcctgatg accgaagctg catcaagttg aacccaatat ctctaattta tactaattta ttttgaaaaa tttctttaat attagaatgt ctactggaaa tcaagacaca acgccttgat aacacacatg aga taaat ta cttttacatt tgctaattca agaaaatatg aagtggaaat ttccactqtt tgttgtgata caccaccact tccttggcat tatagagtat tgaaggagct catttacaga atacaacggg aactaataac ttgtatatga ttttatagga agctattata aacaaattct ttgatgaggg aatagattag gcacaacatt acttaccctc atagttaatc atagatacaa ataaggatac cttagtataa gtaggagtaa atagccagtg ggacccacca aacagacaag tgggtatatg cttggactgt ttacaccgtt agaacaacaa ggagatgaag tcggttgtgg aatgagatac aagcaagtga gtagaattat atattagtac gctggacatt gattggggag gcttataaga gatatgaaca tctatgtcta agtttgcgta aatgctaaat aaagctatat accattaaaa agttataact gaattagaag tcattaattc accgaatcta accacaagat gacaagatta tcacatcaga catgtcaata attttaaaag ggtaacttat agtttaaaag catataaaca attcattggt atttgcctat gaactccaga ctggtcacga tgacatgtgt atccacaggc cagtaacaga atactaccac atggattaag ttatatcagg ctgatattaa ttccactaga ctgaattaag catcgccaag gtataataat agccatgggt ttttaaccaa catccataga catatgaaaa taacagtcag attatcattt atatcgacat aacaattcac atttgatgaa tacaaaagca tcttaagtaa ataaaatgtc ggattctgat aggggtacat cttatttgct cttcagatct aagttttcct gaataaaagg ttaccgtatg tatcttacat ataaaaacaa tttcagacaa ataattataa ctgttaaaag tgatgatgtc tcaattatag tagatcattc catctttagt gatttaactt atcttaagat tattacgtac attgcaatga tagattatgg cttatttaca gctgtttggt cttccttaca tttacaagat catcacattt tttagggtct agtcttaagt tgagattgat agttgtttat aacaaaatcc tagggctact ttgtaacaaa caagtatgta tattatgttc agaaaaatat aggctcatcc aaagcaaaga caacaaagat agccaaaaag tagtagacca tgatactagt tgtgtttcaa aaacatatgt acctcctata gcacatgttc caaagcactt tgattatttt tattcaactt aactgatcat atgttttcat tctttgtgtt agaacaaaaa ctgtcacagt cccttgggtt agatttagtt attcaatgat cactcatttg caaactatat taataatagt aacattctct caaacaagac aggtaataca aaggaatagt tgtatttagt taaggacccc ggtagtagaa tcatagttta tgagaattta tataaaattt 11460 11520 11580 11640 11700 11760 11820 11880 11940 12000 12060 12120 12180 12240 12300 12360 12420 12480 12540 12600 12660 12720 12780 12840 12900 12960 13020 13080 13140 13200 13260 13320 13380 13440 13500 13560 13620 13680 13740 13800 13860 13920 13980 14040 14100 14160 14220 14280 WO 99/49017 WO 9949017PCTIUS99/06225 gcagaaccta aaaattataa agatgcattt attactatat ttaatcctta aaattgatac atcgatgcag attaagactt atagctggac ctaaaatggc tacatgatag gagctcaaga tagtttaaaa tagttattaa ttttagtctt acacaacgag ttagcatctt ttgaatggag taattgcaaa taaaaactta caataggccc tttcaagaac ttattaaaag cattgtcaaa gtaatgaagt tagatcatgt agtccacata agctgattaa tatcattaac aaaatataca aaggggttaa acattagttt tgtctgcgat taagcatgta atatcatgct cgtgtgccta tgcaaatata taaaaatttc cttaatacct at tgaagagt attcagcaac tttaaatttt tccttactta aataacaggt aagtttggtc aacttttcaa ataaaagtct ttgacacttt gctgaattac agaaagtgca caagatgaca ggtagcaagt cttcctgttt attatgccta ttcctttgtt gtagttaatg aagcttataa agatcagctg agtgaattgt agtgtgctat aaatttagat taatttagca aaaactaaca ttttctcgt ctgttacagc agtactgttc ttgatttcaa taaaaggatc ttgatgttgt aaaaaactga accctataac gagatatatt accacaagca aacttaatta taaatagttt acaaccttcc gctaacacat tattgattcc attatacatg caattggagt ttctgtaaat attagataac tgaagtttac acaaaatgct caaggaatct aaaaaaagga atcatattct tatgaatatc caatcattta aacaaccaat caacgaacag cattatatta aaaattatca tgcattcaca 14340 14400 14460 14520 14580 14640 14700 14760 14820 14880 14940 15000 15060 15120 15180 15219 <210> <211> 24 <212> DNA <213> Measles virus <400> catatcactc actctgggat ggag <210> <211> <212> <213> 16

DNA

Measles virus <400> 16 tcagaacatc aagcaccgcc <210> 17 <211> <212> DNA <213> Measles virus <400> 17 acagtcaaga ctgagatgag <210> <211> <212> <213> 18

DNA

Measles virus <400> 18 aagagtcaga tacatgtgga WO 99/49017 WO 9949017PCT/US99/06225 <210> 19 <211> <212> DNA <213> Measles virus <400> 19 acatgaatca gcctaaagtc <210> <211> <212> DNA <213> Measles virus <400> ccgaaagagt tcctgcgtta cgacc <210> 21 <211> <212> DNA <213> Measles virus <400> 21 cagtccacac aagtaccagg <210> 22 <211> <212> DNA <213> Measles virus <400> 22 gtcagaagct gtggaccatc <210> 23 <211> <212> DNA <213> Measles virus <400> 23 aatattgcta caacaatggc <210> 24 <211> <212> DNA <213> Measles virus <400> 24 actcttcatt cctagactgg WO 99/49017 WO 9949017PCTIUS99/06225 <210> <211> <212> DNA <213> Measles virus <400> gtccaattat gactatgaac <210> 26 <211> <212> DNA <213> Measles virus <400> 26 agaacagaca tgaagcttgc <210> 27 <211> <212> DNA <213> Measles virus <400> 27 ccaacaagga atgcttctag <210> 28 <211> <212> DNA <213> Measles virus <400> 28 acagcactat ctatgattga cctgg <210> 29 <211> <212> DNA <213> Measles virus <400> 29 gcaacatggt ttacqcatgc <210> <211> <212> DNA <213> Measles virus <400> agattgagag ttgatccagg WO 99/49017 WO 9949017PCTIUS99/06225 <210> 31 <211> <212> DNA <213> Measles virus <400> 31 aggagatact taaactaagc <210> 32 <211> <212> DNA <213> Measles virus <400> 32 taagcttatg cctttcagcg <210> 33 <211> <212> DNA <213> Measles virus <400> 33 ttaacggacc taagctgtgc <210> 34 <211> <212> DNA <213> Measles virus <400> 34 gaaacagatt attatgacgg <210> <211> 24 <212> DNA <213> Measles virus <400> cgggctatct aggtgaactt cagg 24 <210> 36 <211> <212> DNA <213> Measles virus <400> 36 atttggatat ggaatatgag WO 99/49017 WO 9949017PCT/US99/06225 <210> 37 <211> <212> DNA <213> Measles virus <400> 37 actcaactga actaccagtg <210> 38 <211> <212> DNA <213> Measles virus <400> 38 aagaacatca tgtatttcag <210> 39 <211> <212> DNA <213> Measles virus <400> 39 ttatcaacgc actgcticatg <210> <211> <212> DNA <213> Measles virus <400> attttcagca atcacttggc atgcc <210> 41 <211> <212> DNA <213> Measles virus <400> 41 gcctctgtgc aaacaagctg <210> 42 <211> <212> DNA <213> Measles virus <400> 42 tctctagtta ctctagcagc WO 99/49017 WO 9949017PCT/US99/06225 <210> 43 <211> <212> DNA <213> Measles virus <400> 43 aggtcgttgt ttgtgaggag <210> 44 <211> <212> DNA <213> Measles virus <400> 44 tCgtcctctt ctttactgtc <210> <211> <212> DNA <213> Measles virus <400> ccgtcctcga gctagcctcg <210> 46 <211> <212> DNA <213> Measles virus <400> 46 ctcctccagg ctcacattgg <210> 47 <211> <212> DNA <213> Measles virus <400> 47 gggttggtac atagctctgc <210> 48 <211> <212> DNA <213> Measles virus <400> 48 cacccatctg atatttccct gatgg WO 99/49017 WO 9949017PCTIUS99/06225 <210> 49 <211> <212> DNA <213> Measles virus <400> 49 tggttgacag tacaaatctg <210> <211> <212> DNA <213> Measles virus <400> ctgaaatggg aagattgtgc <210> 51 <211> <212> DNA <213> Measles virus <400> 51 agcaatctac actgcctacc <210> 52 <211> <212> DNA <213> Measles virus <400> 52 tcacagatga ttcaattatc <210> 53 <211> <212> DNA <213> Measles virus <400> 53 gatcctagat ataagttctc <210> 54 <211> 21 <212> DNA <213> Measles virus <400> 54 accaaacaaa gttgggtaag g 21 WO 99/49017 WO 9949017PCTIUS99/06225 <210> <211> 32 <212> DNA <213> Measles virus <400> gggggatcca tccctaatcc tgctcttgtc cc 32 <210> 56 <211> <212> DNA <213> Measles virus <400> 56 gattcctctg atggctccac <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

Claims (32)

1. An isolated, recombinantly-generated, attenuated measles virus having one or more attenuating mutations selected from the group consisting of: for the N gene, nucleotide changes which produce a changes in the amino acid residue 479 (serine threonine); for the C gene, nucleotide changes which produce a change in the amino acid residue 104 (methionine -4threonine); and for the F gene-end signal, the change at nucleotide 7243 (T C), where these nucleotides are presented in positive strand, antigenornic, message sense.

2. The measles virus of Claim I which further comprises: at least one attenuating mutation in the 3 genornic promoter region selected from the group consisting of nucleotide 26 (A nucleotide 42 (A T or A C) and nucleotide 96 (G where these p S. 000 0 0000 00 @000 One S 0 0 S 0 @0 S. S 0 *500 @5 S. S SS@S 9 *5 0 0 0059 SSSOOS 0 LR LEDUU]02677.doc jin COMS ID No: SMBI-00416777 Received by IP Australia: Time 10:08 Date 2003-09-16 WO 99/49017 PCT/US99/06225 74 nucleotides are presented in positive strand, antigenomic, message sense; and at least one attenuating mutation in the RNA polymerase gene selected from the group consisting of nucleotide changes which produce changes in an amino acid selected from the group consisting of 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).

3. An isolated, recombinantly-generated, attenuated human respiratory syncytial virus (RSV) subgroup B having an attenuating mutation in the M gene-end signal at nucleotide 4199 (T where these nucleotides are presented in positive strand, antigenomic, message sense.

4. The RSV subgroup B of Claim 3 which further comprises: at least one attenuating mutation in the 3' genomic promoter region selected from the group consisting of nucleotide 4 (C G) and the insertion of an additional A in the stretch of A's at nucleotides

6-11, where these nucleotides are presented in positive strand, antigenomic, message sense; and at least one attenuating mutation in the RNA polymerase gene selected from the group consisting of nucleotide changes which produce changes in an amino acid WO 99/49017 PCT/US99/06225 75 selected from the group consisting of residues 353 (arginine lysine), 451 (lysine arginine), 1229 (aspartic acid asparagine), 2029 (threonine isoleucine) and 2050 (asparagine -4 aspartic acid). The RSV subgroup B of Claim 4 which includes the insertion of an additional A in the stretch of A's at nucleotides 6-11, such that the attenuating mutation in the M gene-end signal (T C) is at nucleotide 4200, where these nucleotides are presented in positive strand, antigenomic, message sense. 6. A vaccine comprising an isolated, recombinantly-generated, attenuated measles virus according to Claim 1 and a physiologically acceptable carrier.

7. The vaccine of Claim 6 comprising a measles virus according to Claim 2 and a physiologically acceptable carrier.

8. A vaccine comprising an isolated, recombinantly-generated, attenuated RSV subgroup B according to Claim 3 and a physiologically acceptable carrier.

9. The vaccine of Claim 8 comprising an RSV subgroup B according to Claim 4 and a physiologically acceptable carrier. The vaccine of Claim 8 comprising an RSV subgroup B according to Claim 5 and a physiologically acceptable carrier.

11. A method for immunizing an individual to induce protection against measles virus which comprises administering to the individual the vaccine of Claim 6. WO 99/49017 PCT/US99/06225 76

12. The method of Claim 11 wherein the vaccine is the vaccine of Claim 7.

13. A method for immunizing an individual to induce protection against RSV subgroup B which comprises administering to the individual the vaccine of Claim 8.

14. The method of Claim 13 wherein the vaccine is the vaccine of Claim 9. The method of Claim 13 wherein the vaccine is the vaccine of Claim

16. A composition which comprises a transcription vector comprising an isolated nucleic acid molecule encoding a genome or antigenome of a measles virus according to Claim i, together with at least one expression vector which comprises at least one isolated nucleic acid molecule encoding the trans- acting proteins N, P and L necessary for encapsidation, transcription and replication, whereby upon expression an infectious attenuated virus is produced.

17. The composition of Claim 16 wherein the transcription vector comprises an isolated nucleic acid molecule which encodes a measles virus according to Claim 2.

18. A composition which comprises a transcription vector comprising an isolated nucleic acid molecule encoding a genome or antigenome of an RSV subgroup B according to Claim 3, together with at least one expression vector which comprises at least one isolated nucleic acid molecule encoding the trans- acting proteins N, P, L and M2 necessary for encapsidation, transcription and replication, whereby upon expression an infectious attenuated RSV subgroup B is produced. WO 99/49017 PCT/US99/06225 77

19. The composition of Claim 18 wherein the transcription vector comprises an isolated nucleic acid molecule which encodes an RSV subgroup B according to Claim 4. The composition of Claim 18 wherein the transcription vector comprises an isolated nucleic acid molecule which encodes an RSV subgroup B according to Claim

21. A method for producing infectious attenuated measles virus which comprises transforming or transfecting host cells with the at least two vectors of Claim 16 and culturing the host cells under conditions which permit the co-expression of these vectors so as to produce the infectious attenuated measles virus.

22. The method of Claim 21 wherein the virus is the measles virus of Claim 2.

23. A method for producing infectious attenuated RSV subgroup B which comprises transforming or transfecting host cells with the at least two vectors of Claim 18 and culturing the host cells under conditions which permit the co-expression of these vectors so as to produce the infectious attenuated RSV subgroup B.

24. The method of Claim 23 wherein the virus is the RSV subgroup B of Claim 4. The method of Claim 23 wherein the virus is the RSV subgroup B of Claim 16, SEP. 2003 10:04 SPRUSON FERGUSON 61 2 92615486 NO. 5932 P. 16/16 -78-

26. An isolated, recombinantly-generated, attenuated measles virus substantially as hereinbefore described with reference to Example 1.

27. A method for producing infectious attenuated measles virus, said method substantially as hereinbefore described with reference to Example 1. 18. Infectious attenuated measles virus produced by the method according to any one of claims 21, 22 or 27.

29. A vaccine comprising the virus according to claim 26 or claim 28 and a physiologically acceptable carrier. Use of the virus according to any one of claims 1, 2, 26 or 28 for the preparation of a vaccine.

31. A vaccine according to any one of claims 6, 7 or 29 when used in vaccinating an individual to induce protection against measles virus.

32. A method of vaccinating an individual against measles virus, which method comprises administering to said individual an immunologically effective amount of a Is vaccine according to claim 29.

33. An isolated, recombinantly-generated, attenuated RSV type B substantially as hereinbefore described with reference to Example 2.

34. A method for producing an infectious, attenuated RSV subgroup B substantially as hereinbefore described with reference to Example 2.

35- Infectious attenuated RSV subgroup B produced by the method according to any one of claims 23 to 25 or 34.

36. A vaccine comprising the virus according to claim 33 or claim 35 and a "physiologically acceptable carrier.

37. Use of the virus according to any one of claims 3 to 5, 33 or 35 for the preparation of a vaccine.

38. A vaccine according to any one of claims 8 to 10 or 36 when used in vaccinating an individual to induce protection against RSV subgroup B.

39. A method of vaccinating an individual against RSV subgroup B, which method comprises administering to said individual an immunologically effective amount of a vaccine according to claim 36. @9 0 9669 Dated 15 September 2003 e American Cyanamid Company 35 Patent Attorneys for the Applicant/Nominated Person S.o. SPRUSON FERGUSON 4 (RALIBLIJ'1]02677 doc:ji COMS ID No: SMBI-00416777 Received by IP Australia: Time 10:08 Date 2003-09-16