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Toll-like receptor 2 dependent immunogenicity of glycoconjugate vaccines containing chemically derived zwitterionic polysaccharides

Gallorini, Simona, Berti, Francesco, Mancuso, Giuseppe, Cozzi, Roberta, Tortoli, Marco, Volpini, Gianfranco, Telford, John L., Beninati, Concetta, Maione, Domenico, Wack, Andreas
Proceedings of the National Academy of Sciences of the United States of America 2009 v.106 no.41 pp. 17481-17486
Streptococcus agalactiae, T-lymphocytes, Toll-like receptor 2, adjuvants, antibodies, antigens, dendritic cells, glycoconjugates, humans, immune response, knockout mutants, mice, mothers, neonates, polysaccharides, progeny, protective effect, tetanus, vaccination, vaccine development, vaccines, zwitterions
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.