Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1997-02-25
2000-06-20
Mosher, Mary E.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
530324, 5303879, 5303883, 5303894, 4241921, 4241931, 4242111, 435 5, A61K 39155, C07K 1410, C07K 14115, C12Q 170
Patent
active
060775114
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to the fields of peptide-based diagnostics and vaccines in connection with diseases caused by or related with respiratory syncytial virus (RSV) infection.
The invention involves a so far unidentified small, independently folding, globular protein module between mucin-like regions in the attachment protein G of RSV, and its use. More specifically, the invention relates to the design of an antigenic substance, preferably peptide-based, corresponding to said protein module in the attachment protein G of RSV, that can be used as a basis for e.g. a diagnostic assay. Peptides corresponding to this independently folding globular protein can also be incorporated in vaccines along with other peptides to induce protective immune responses to the virus.
BACKGROUND OF THE INVENTION
RSV infections are a major cause of respiratory tract disease in humans, cattle, sheep and goats (Stott and Taylor, 1985). The virus is classified within the Pneumovirus genus of the Paramyxoviridae. Human respiratory syncytial virus (HRSV) is the most important causative agent of bronchiolitis and pneumonia in infants and young children. Approximately 100,000 children are hospitalized each year in the USA as a result of RSV infection. A vaccine against the virus is not available and development of a vaccine is third--subsequent to Malaria and Human Immunodeficiency Virus--on the priority list of the World Health Organization. In cattle, respiratory disease is one of the most frequently recorded diseases. Recent reports indicate that respiratory disease can account for up to 60% of morbidity and for around 60% of mortality in feedlot cattle (Healy et al., 1993, Edwards, 1989). Bovine respiratory syncytial virus (BRSV) infections are the major cause of respiratory disease in calves resulting in high economic losses.
Because different antigenic subgroups are described for HRSV and BRSV (Johnson et al., 1987, Furze et al., 1994), it is important to monitor the prevailing subgroups in a population to choose a candidate vaccine of the right subgroup(s)
The virus has two major surface glycoproteins: the attachment protein G and the fusion protein F. The G protein is unique for RSV, it is highly variable between HRSV subgroups (53% amino acid homology; Johnson et al., 1987), or between HRSV and ungulate RSV (30% amino acid homology; Lerch et al., 1990). However, within the subgroups the amino acid homology is much larger (80% or more within several HRSV-A strains; Cane et al., 1991), 90% or more within several HRSV-B strains (Sullender et al., 1991) and 90% or more within four BRSV strains (Mallipeddi and Samal, 1993a). The G protein shares neither sequence nor structural homology with other attachment proteins of other Paramyxoviruses (Satake et al., 1985, Wertz et al., 1985). In contrast to the attachment proteins of other paramyxoviruses, G is shorter and lacks hemagglutination or neuraminidase activity. RSV-G is a type II membrane protein and contains about 60% carbohydrate by weight. Approximately 20% of the carbohydrate moieties are N-linked carbohydrates and 80% are O-linked carbohydrates which are linked to the unusually high number of hydroxy amino acids in the protein.
A number of diagnostic assays (reviewed by Welliver, 1988) are available for the detection of RSV. However, these assays are based on whole virus or complete proteins that do not (effectively) discriminate between subgroups of HRSV nor between different RSV types. Because the F protein is highly conserved between all RSV types, a discriminating assay is hard to design based on protein F and should therefore include at least a part of the more variable G protein.
Empirical methods to determine the immunodominant site on BRSV-G and HRSV-G showed that the immunodominant site of the peptide was located within the C-terminal half of this peptide (residues 174-188; Norrby et al., 1987). It has been suggested that a 15-residue peptide (residues 174-188) could be used for subtype-specific site-directed serology (Akerlind-Stopner et
REFERENCES:
Norrby, E. et al. Proceedings of the National Academy of Sciences (USA), vol. 84, pp. 6572-6576, 1987.
.ANG.kerlind-Stopner et al., "A Subgroup-Specific Antigenic Site in the G Protein of Respiratory Syncytial Virus Forms a Disulfide-Bonded Loop," Journal of Virology, vol. 64, No. 10, pp. 5143-5148, Oct. 1990.
Cane et al., "Identification of variable domains of the attachment (G) protein of subgroup A respiratory syncytial viruses," Journal of General Virology, vol. 72, pp. 2091-2096, 1991.
Edwards, Alvin J., "The Effect of Stressors Like Rumen Overload and Induced Abortion on BRD in Feedlot Cattle," Agri-Practice, vol. 10, No. 2, pp. 10-15, Mar./Apr. 1989.
Felsenstein, J., "PHYLIP--Phylogeny Inference Package (Version 3.2)", Cladistics, 5, pp. 164-166, 1989.
Fields et al., "HBTU Activation for Automated Fmoc Solid-Phase Peptide Synthesis," Peptide Research, vol. 4, No. 2, pp. 95-101, 1991.
Furze et al., "Antigenic heterogeneity of the attachment protein of bovine respiratory syncytial virus," Journal of General Virology, vol. 75, pp. 363-370, 1994.
Healy et al., "Morbidity and Mortality in a Large Irish Feedlot; Microbiological and Serological Findings in Cattle with Acute Respiratory Disease," British Veterinary Journal, vol. 149, No. 6, pp. 549-560, 1993.
Jentoft, Neil, "Why are proteins O-glycosylated?," TIBS, vol. 15, pp. 291-294, Aug. 1990.
Johnson et al., "The G glycoprotein of human respiratory syncytial viruses of subgroups A and B: Extensive sequence divergence between antigenically related proteins," Proc. Natl. Acad. Sci. USA, vol. 84, pp. 5625-5629, Aug. 1987.
Lerch et al., "Nucleotide Sequence Analysis and Expression from Recombinant Vectors Demonstrate That the Attachment Protein G of Bovine Respiratory Syncytial Virus is Distinct from that of Human Respiratory Syncytial Virus," Journal of Virology, vol. 64, No. 11, pp. 5559-5569, Nov. 1990.
Mallipeddi et al., "Analysis of the ovine respiratory syncytial virus (RSV) G glycoprotein gene defines a subgroup of ungulate RSV," Journal of General Virology, vol. 74, pp. 2787-2791, 1993.
Mallipeddi et al., "Sequence variability of the glycoprotein gene of bovine respiratory syncytial virus," Journal of General Virology, vol. 74, pp. 2001-2004, 1993.
Norrby et al., "Site-directed serology with synthetic peptides representing the large glycoprotein G of respiratory syncytial virus," Proc. Natl. Acad. Sci. USA, vol. 84, pp. 6572-6576, Sep. 1987.
Saitou et al, "The Neighbor-joining Method: A New Method for Reconstructing Phylogenetic Trees," Mol.Biol. Evol., vol. 4, No. 4, pp. 406-425, 1987.
Satake et al., "Respiratory syncytial virus envelope glycoprotein (G) has a novel structure," Nucleic Acids Research, vol. 13, No. 21, pp. 7795-7812, 1985.
Sullender et al., "Genetic Diversity of the Attachment Protein of Subgroup B Respiratory Syncytial Viruses," Journal of Virology, vol. 65, No. 10, pp. 5425-5434, Oct. 1991.
Van der Poel et al., "Dynamics of bovine respiratory syncytial virus infections: a longitudinal epidemiological study in dairy herds," Archives of Virology, vol. 133, pp. 309-321, 1993.
Welliver, Robert C., "Detection, Pathogenesis, and Therapy of Respiratory Syncytial Virus Infections," Clinical Microbiology Reviews, vol. 1, No. 1, pp. 27-39, Jan. 1988.
Wensvoort et al., "Production of Monoclonal Antibodies Against Swine Fever Virus and Their Use in Laboratory Diagnosis", Veterinary Microbiology, vol. 12, pp. 101-108, 1986.
Wertz et al., "Nucleotide sequence of the G protein gene of human respiratory syncytial virus reveals an unusual type of viral membrane protein," Proc. Natl. Acad. Sci. USA, vol. 82, pp. 4075-4079, Jun. 1985.
Westenbrink et al., "Comparison of a newly developed enzyme-linked immunosorbent assay with complement fixation and neutralisation tests for serology of bovine respiratory syncytial virus infections", Res. Vet. Sci., vol. 38, pp. 334-340, 1985.
Stott et al., "Respiratory Syncytial Virus: Brief Review", Arch. Virol., 84, pp. 1-52, 1985.
Instituut voor Dierhouderij en Diergezondheid
Mosher Mary E.
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