title: Immune responses to the nonglycosylated ectodomain of respiratory syncytial virus attachment glycoprotein mediate pulmonary eosinophilia in inbred strains of mice with different MHC haplotypes.
abstract: Development of subunit vaccines against respiratory syncytial virus (RSV) for naive human infants is hindered by concerns that immunization with the fusion or attachment (G) proteins will elicit polarized Type 2 T cell responses and cause immunopotentiation upon subsequent natural infection. We investigated the regions of G protein responsible for inducing a Type 2 T cell phenotype in inbred mice of different MHC haplotype toward development of vaccines with improved safety. As demonstrated by IL-5-dependent pulmonary eosinophilia after challenge and serum anti-G protein IgG1 to IgG2 ratios, highly purified native G protein sensitized all strains for a Type 2 T cell phenotype. Stimulation of G protein-primed splenocytes with synthetic overlapping peptides indicated that the nonglycosylated ectodomain was primarily responsible. Respectively the recall responses of BALB/c (H2(d)), C57BL/6 (H-2(b)), SJL (H-2(s)), and C3H/HeJ (H-2(k)) mice were directed against epitopes within peptides spanning amino acids 184-198 (pep(184-198)), 168-181 (pep(168-181)) or 171-185 (pep(171-185)), 176-190 (pep(176-190)), and 104-118 (pep(104-118)) or 159-173 (pep(159-173)). Injection of pep(184-198) conjugated to KLH (pep(184-198)-KLH) primed H2(d) [BALB/c, B6.C-H2(d)/bBy], but not H-2(b) [C57Bl/6, C.B10-H2(b)/LiMcd] mice for pulmonary eosinophilia. Sensitization with a peptide-KLH conjugate encompassing amino acids 149-200 (pep(149-200)-KLH) further confirmed that Type 2 T cell responses in BALB/c, C57BL/6 and SJL, but not C3H/HeJ mice were induced by the nonglycosylated ectodomain of G protein. These data are important for design of safe and efficacious subunit and attenuated vaccines for RSV.
authors.affiliation: Department of Immunology Research, Wyeth Vaccines, West Henrietta, New York 14586-9728, USA. hancocg@wyeth.com
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Hancock
authors.forename: Paul W
authors.initials: PW
authors.lastname: Tebbey
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Scheuer
authors.forename: Karin S
authors.initials: KS
authors.lastname: Pryharski
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Heers
authors.forename: Natisha A
authors.initials: NA
authors.lastname: LaPierre
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D004802:Eosinophilia; D018604:Epitope Mapping; D006031:Glycosylation; D006183:H-2 Antigens / Q000235:genetics; D006239:Haplotypes; D016056:Immunodominant Epitopes; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D010455:Peptides; D010641:Phenotype; D011657:Pulmonary Eosinophilia / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000517:prevention & control; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology; D014764:Viral Proteins / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D014765:Viral Vaccines / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D006183:H-2 Antigens; D016056:Immunodominant Epitopes; D010455:Peptides; D014613:Vaccines, Attenuated; D014764:Viral Proteins; D014765:Viral Vaccines