title: Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides.
abstract: Group B Streptococcus (GBS) causes serious infection in neonates and is an important target of vaccine development. Zwitterionic polysaccharides (ZPS), obtained through chemical introduction of positive charges into anionic polysaccharides (PS) from GBS, have the ability to activate human and mouse antigen presenting cells (APCs) through toll-like receptor 2 (TLR2). To generate a polysaccharide vaccine with antigen (Ag) and adjuvant properties in one molecule, we have conjugated ZPS with a carrier protein. ZPS-glycoconjugates induce higher T-cell and Ab responses to carrier and PS, respectively, compared to control PS-glycoconjugates made with the native polysaccharide form. The increased immunogenicity of ZPS-conjugates correlates with their ability to activate dendritic cells (DCs). Moreover, protection of mothers or neonate offspring from lethal GBS challenge is better when mothers are immunized with ZPS-conjugates compared to immunization with PS-conjugates. In TLR2 knockout mice, ZPS-conjugates lose both their increased immunogenicity and protective effect after vaccination. When ZPS are coadministered as adjuvants with unconjugated tetanus toxoid (TT), they have the ability to increase the TT-specific antibody titer. In conclusion, glycoconjugates containing ZPS are potent vaccines. They target Ag to TLR2-expressing APCs and activate these APCs, leading to better T-cell priming and ultimately to higher protective Ab titers. Thus, rational chemical design can generate potent PS-adjuvants with wide application, including glycoconjugates and coadministration with unrelated protein Ags.
authors.affiliation: Novartis Vaccines Research Center, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Gallorini
authors.forename: Francesco
authors.initials: F
authors.lastname: Berti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancuso
authors.forename: Roberta
authors.initials: R
authors.lastname: Cozzi
authors.forename: Marco
authors.initials: M
authors.lastname: Tortoli
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Volpini
authors.forename: John L
authors.initials: JL
authors.lastname: Telford
authors.forename: Concetta
authors.initials: C
authors.lastname: Beninati
authors.forename: Domenico
authors.initials: D
authors.lastname: Maione
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000627:therapeutic use; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D018074:Vaccines, Conjugate / Q000737:chemistry*
chemical_list: D001428:Bacterial Vaccines; D011134:Polysaccharides; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D018074:Vaccines, Conjugate