title: Characterization of functional oligosaccharide mimics of the Shigella flexneri serotype 2a O-antigen: implications for the development of a chemically defined glycoconjugate vaccine.
abstract: Protection against reinfection with noncapsulated Gram-negative bacteria, such as Shigella, an enteroinvasive bacterium responsible for bacillary dysentery, is mainly achieved by Abs specific for the O-Ag, the polysaccharide part of the LPS, the major bacterial surface Ag. The use of chemically defined glycoconjugates encompassing oligosaccharides mimicking the protective determinants carried by the O-Ag, thus expected to induce an efficient anti-LPS Ab response, has been considered an alternative to detoxified LPS-protein conjugate vaccines. The aim of this study was to identify such functional oligosaccharide mimics of the S. flexneri serotype 2a O-Ag. Using protective murine mAbs specific for S. flexneri serotype 2a and synthetic oligosaccharides designed to analyze the contribution of each sugar residue of the branched pentasaccharide repeating unit of the O-Ag, we demonstrated that the O-Ag exhibited an immunodominant serotype-specific determinant. We also showed that elongating the oligosaccharide sequence improved Ab recognition. From these antigenicity data, selected synthetic oligosaccharides were assessed for their potential to mimic the O-Ag by analyzing their immunogenicity in mice when coupled to tetanus toxoid via single point attachment. Our results demonstrated that induction of an efficient serotype 2a-specific anti-O-Ag Ab response was dependent on the length of the oligosaccharide sequence. A pentadecasaccharide representing three biological repeating units was identified as a potential candidate for further development of a chemically defined glycoconjugate vaccine against S. flexneri 2a infection.
authors.affiliation: Unité de Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale Unité 389. phalipon@pasteur.fr
authors.forename: Armelle
authors.initials: A
authors.lastname: Phalipon
authors.forename: Corina
authors.initials: C
authors.lastname: Costachel
authors.forename: Cyrille
authors.initials: C
authors.lastname: Grandjean
authors.forename: Audrey
authors.initials: A
authors.lastname: Thuizat
authors.forename: Catherine
authors.initials: C
authors.lastname: Guerreiro
authors.forename: Myriam
authors.initials: M
authors.lastname: Tanguy
authors.forename: Farida
authors.initials: F
authors.lastname: Nato
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vulliez-Le Normand
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bélot
authors.forename: Karen
authors.initials: K
authors.lastname: Wright
authors.forename: Véronique
authors.initials: V
authors.lastname: Marcel-Peyre
authors.forename: Philippe J
authors.initials: PJ
authors.lastname: Sansonetti
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Mulard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002240:Carbohydrate Sequence; D015195:Drug Design; D004405:Dysentery, Bacillary / Q000276:immunology / Q000517:prevention & control*; D006001:Glycoconjugates / Q000737:chemistry / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D019081:O Antigens / Q000737:chemistry* / Q000276:immunology; D009844:Oligosaccharides / Q000737:chemistry* / Q000276:immunology; D012703:Serotyping; D022281:Shigella Vaccines / Q000138:chemical synthesis* / Q000276:immunology; D012763:Shigella flexneri / Q000737:chemistry / Q000145:classification* / Q000276:immunology; D018074:Vaccines, Conjugate / Q000737:chemistry / Q000276:immunology
chemical_list: D006001:Glycoconjugates; D007074:Immunoglobulin G; D019081:O Antigens; D009844:Oligosaccharides; D022281:Shigella Vaccines; D018074:Vaccines, Conjugate