Characterization of functional oligosaccharide mimics of the Shigella flexneri serotype 2a O-antigen: implications for the development of a chemically defined glycoconjugate vaccine.
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.
Phalipon
Armelle
A
Unité de Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale Unité 389. phalipon@pasteur.fr
Costachel
Corina
C
Grandjean
Cyrille
C
Thuizat
Audrey
A
Guerreiro
Catherine
C
Tanguy
Myriam
M
Nato
Farida
F
Vulliez-Le Normand
Brigitte
B
Bélot
Frédéric
F
Wright
Karen
K
Marcel-Peyre
Véronique
V
Sansonetti
Philippe J
PJ
Mulard
Laurence A
LA
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
D006001:Glycoconjugates; D007074:Immunoglobulin G; D019081:O Antigens; D009844:Oligosaccharides; D022281:Shigella Vaccines; D018074:Vaccines, Conjugate