Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
2000-05-08
2004-05-04
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S204100, C435S069300, C435S320100, C435S325000, C435S173300, C435S236000, C530S403000
Reexamination Certificate
active
06730305
ABSTRACT:
1. INTRODUCTION
The present invention relates to recombinant DNA molecules which encode bovine respiratory syncytial (BRS) virus proteins as well as corresponding BRS virus proteins and peptides derived therefrom. It is based, in part, on the cloning of full length cDNAs encoding a number of bovine respiratory syncytial virus proteins, including, F, G, and N. DNAs encoding the G and F proteins have been inserted into vaccinia virus vectors, and these vectors have been used to express the G and F proteins in culture and G protein encoding vectors have been used to induce an anti-bovine respiratory syncytial virus immune response. The molecules of the invention may be used to produce safe and effective bovine respiratory syncytial virus vaccines.
2. BACKGROUND OF THE INVENTION
2.1. Bovine Respiratory Syncytial Virus
Bovine respiratory syncytial (BRS) virus strain 391-2 was isolated from an outbreak of respiratory syncytial virus in cattle in North Carolina during the winter of 1984 to 1985. The outbreak involved five dairy herds, a beef calf and cow operation, and a dairy and steer feeder operation (Fetrow et al., North Carolina State University Agric. Extension Service Vet. Newsl.).
Respiratory syncytial virus, an enveloped, single-stranded, negative-sense RNA virus (Huang and Wertz, 1982, J. Virol. 43:150-157; Kingsbury et al., 1978, Intervirology 10:137-153), was originally isolated from a chimpanzee (Morris, et al., 1956, Proc. Soc. Exp. Biol. Med. 92:544-549). Subsequently, respiratory syncytial virus has been isolated from humans, cattle, sheep and goats (Chanock et al. 1957, Am. J. Hyg. 66:281-290; Evermann et al., 1985, AM. J. Vet. Res. 46:947-951; Lehmkuhl et al., 1980, Arch. Virol. 65:269-276; Lewis, F. A., et al., 1961, Med. J. Aust. 48:932-33; Paccaud and Jacquier, 1970, Arch. Gesamte Virusforsch 30:327-342). Human respiratory syncytial (HRS) virus is a major cause of severe lower respiratory tract infections in children during their first year of life, and epidemics occur annually (Stott and Taylor, 1985, Arch. Virol. 84:1-52). Similarly, BRS virus causes bronchiolitis and pneumonia in cattle, and there are annual winter epidemics of economic significance to the beef industry (Bohlender et al., 1982, Mod. Vet. Pract. 63:613-618; Stott and Taylor, 1985, Arch. Virol. 84:1-52; Stott et al., 1980, J. Hyg. 85:257-270). The highest incidence of severe BRS virus-caused disease is usually in cattle between 2 and 4.5 months old. The outbreak of BRS virus strain 391-2 was atypical in that the majority of adult cows were affected, resulting in a 50% drop in milk production for one dairy herd and causing the death of some animals, while the young of the herds were only mildly affected (Fetrow et al., 1985, North Carolina State University Agric. Extension Service Vet. Newsl.).
BRS virus was first isolated in 1970 (Paccaud and Jacquier, 1970, Arch. Gesamte Virusforsch. 30:327-342), and research has focused on the clinical (van Nieuwstadt, A. P. et al., 1982, Proc. 12th World Congr. Dis. Cattle 1:124-130; Verhoeff et al., 1984, Vet. Rec. 114:288-293) and pathological effects of the viral infection on the host (Baker et al., 1986, J. Am. Vet. Med. Assoc. 189:66-70; Castleman et al., 1985, Am. J. Vet. Res. 46:554-560; Castleman et al. 1985, Am. J. Vet. Res. 46:547-553) and on serological studies (Baker et al., 1985, Am. J. Vet. Res. 46:891-892; Kimman et al., 1987, J. Clin. Microbiol. 25:1097-1106; Stott et al., 1980, J. Hyg. 85:257-270). The virus has not been described in molecular detail. Only one study has compared the proteins found in BRS virus-infected cells with the proteins found in HRS virus-infected cells (Cash et. al., 1977, Virology 82:369-379). In contrast, a detailed molecular analysis of HRS virus has been undertaken. cDNA clones to the HRS virus mRNAs have been prepared and used to identify 10 virus-specific mRNAs which code for 10 unique polypeptides, and the complete nucleotide sequences for 9 of the 10 genes are available (Collins, P. L., et al., 1986, in “Concepts in Viral Pathogenesis II,” Springer-Verlag., New York; Stott and Taylor, 1985, Arch. Virol. 84:1-52).
Two lines of evidence suggest that HRS virus and BRS virus belong in distinct respiratory syncytial virus subgroups. First, BRS virus and HRS virus differ in their abilities to infect tissue culture cells of different species (Paccaud and Jacquier, 1970, Arch. Gesamte Virusforsch. 30:327-342). With one exception, studies have shown that BRS virus exhibits a narrower host range than HRS virus. Matumoto et al. (1974, Arch. Gesamte Virusforsch. 44:280-290) reported that the NMK7 strain of BRS virus has a larger host range than the Long strain of HRS virus. Others have been unable to repeat this with other BRS strains (Paccaud and Jacquier, 1970, Arch. Gesamte Virusforsch. 30:327-342; Pringle and Crass, 1978, Nature (London) 276:501-502). The second line of evidence indicating that BRS virus differs from HRS virus comes from the demonstration of antigenic differences in the major glycoprotein, G, of BRS virus and HRS virus (Orvell et al., 1987, J. Gen. Virol. 68:3125-3135). Studies using monoclonal antibodies have grouped HRS virus strains into two subgroups on the basis of relatedness of the G glycoprotein (Anderson 1985, J. Infect. Dis. 151:626-633; Mufson, et al., 1985, J. Gen. Virol. 66:2111-2124). The G protein of BRS virus strains included in these studies did not react with monoclonal antibodies generated against viruses from either HRS virus subgroup (Orvell et al., 1987, J. Gen. Virol. 68:3125-3135).
BRS virus provides an opportunity to study the role of the major glycoprotein, G, in attachment, the possible host range restrictions of BRS virus compared to HRS virus, and the roles of the individual viral antigens necessary to elicit a protective immune response in the natural host, which is something that cannot be done easily for HRS virus at present.
2.2. The G Protein
Previous work has shown that there is no cross reactivity between the attachment surface glycoproteins, G, of BRS virus and HRS virus, whereas there is cross antigenic reactivity between the other transmembrane glycoprotein, the fusion, F, protein and the major structural proteins, N, P, and M (Lerch et al., 1989, J. Virol. 63:833-840; Orville et al., 1987, J. Gen. Virol. 68:3125-3135). Available evidence indicates that BRS virus has a more narrow host restriction, infecting only cattle and bovine cells in culture, whereas HRS virus can infect a variety of cell types and experimental animals (Jacobs and Edington, 1975, Res. Vet. Sci. 18:299-306; Mohanty et al., 1976, J. Inf. Dis. 134:409-413; Paccaud and Jacquier, 1970, Arch. Gesamte Virusforsch 30:327-342). Since the G protein of HRS virus is the viral attachment protein (Levine et al., 1987, J. Gen. Virol. 68:2521-2524), this observation suggested that the differences in the BRS virus and HRS virus G proteins may be responsible for the differences in attachment and host range observed between BRS virus and HRS virus.
Based on sequence analysis of the HRS virus G mRNA, the G protein is proposed to have three domains; an internal or cytoplasmic domain, a transmembrane domain, and an external domain which comprises three quarters of the polypeptide (Satake et al., 1985, Nucl. Acids Res: 13:7795-7812; Wertz et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:4075-4079). Evidence suggests that the respiratory syncytial virus G protein is oriented with its amino terminus internal, and its carboxy terminus external, to the virion (Olmsted et al., 1989, J. Viral. 13:7795-7812; Vijaya et al., 1988, Mol. Cell. Biol. 8:1709-1714; Wertz et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:4075-4079). Unlike the other Paramyxovirus attachment proteins, the respiratory syncytial virus G protein lacks both neuraminidase and hemagglutinating activity (Gruber and Levine, 1983, J. Gen. Virol. 64:825-832; Richman et al., 1971, Appl. Microbiol. 21:1099). The mature G protein, found in virions and infected cells, has an estimated molecular weight of 80-90 kDa based on migration in SDS-polyacrylamide gels (Dub
Lerch Robert
Wertz Gail W.
Gifford, Krass, Groh Sprinkle, Anderson & Citkowski, P.C.
Scheiner Laurie
The UAB Research Foundation
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