title: A synthetic carbohydrate-protein conjugate vaccine candidate against Shigella flexneri 2a infection.
abstract: The protective Ag of Shigella, the Gram-negative enteroinvasive bacterium causing bacillary dysentery, or shigellosis, is its O-specific polysaccharide (O-SP) domain of the LPS, the major bacterial surface component. As an alternative to the development of detoxified LPS-based conjugate vaccines, recent effort was put into the investigation of neoglycoproteins encompassing synthetic oligosaccharides mimicking the protective Ags of the O-SP. We previously reported that when coupled to tetanus toxoid via single point attachment, a synthetic pentadecasaccharide representing three biological repeating units of the O-SP of Shigella flexneri 2a (SF2a), one of the most common Shigella serotypes, elicits a better serum anti-LPS 2a Ab response in mice than shorter synthetic O-SP sequences. In this study, we show that the pentadecasaccharide-induced anti-LPS 2a Abs protect passively administered naive mice from Shigella infection. Therefore, this three repeating units sequence, which is recognized by anti-SF2a sera from infected patients, acts as a functional mimic of the native polysaccharide Ag. Analyses of parameters influencing immunogenicity revealed that an investigational SF2a vaccine displaying a pentadecasaccharide:tetanus toxoid molar loading of 14:1 triggers a high and sustained anti-LPS Ab response, without inducing anti-linker Ab, when administered four times at a dose corresponding to 1 mug of carbohydrate. In addition, the profile of the anti-LPS Ab response, dominated by IgG1 production (Th2-type response), mimics that observed in human upon natural SF2a infection. This synthetic carbohydrate-based conjugate may be a candidate for a SF2a vaccine.
authors.affiliation: Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Phalipon
authors.forename: Myriam
authors.initials: M
authors.lastname: Tanguy
authors.forename: Cyrille
authors.initials: C
authors.lastname: Grandjean
authors.forename: Catherine
authors.initials: C
authors.lastname: Guerreiro
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bélot
authors.forename: Dani
authors.initials: D
authors.lastname: Cohen
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Mulard
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D004405:Dysentery, Bacillary / Q000276:immunology / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019081:O Antigens / Q000276:immunology*; D012763:Shigella flexneri / Q000276:immunology; D018074:Vaccines, Conjugate / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001428:Bacterial Vaccines; D008070:Lipopolysaccharides; D019081:O Antigens; D018074:Vaccines, Conjugate