title: A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design.
abstract: Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein-derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4(+) T cell clones to produce interleukins 2 and 4-cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50-100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4(+) T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Fikri Y
authors.initials: FY
authors.lastname: Avci
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.forename: Moriya
authors.initials: M
authors.lastname: Tsuji
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kasper
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006001:Glycoconjugates / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011135:Polysaccharides, Bacterial / Q000378:metabolism; D014612:Vaccines / Q000138:chemical synthesis*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006001:Glycoconjugates; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007376:Interleukin-2; D011135:Polysaccharides, Bacterial; D014612:Vaccines; C032263:streptococcal polysaccharide type III group B; D015847:Interleukin-4
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