Characterization of Functional Oligosaccharide Mimics of the Shigella flexneri Serotype 2a O-Antigen: Implications for the Development of a Chemically Defined Glycoconjugate Vaccine

• Published in: Journal of Immunology Vol. 176; no. 3; pp. 1686 - 1694
• Main Authors: Phalipon, Armelle, Costachel, Corina, Grandjean, Cyrille, Thuizat, Audrey, Guerreiro, Catherine, Tanguy, Myriam, Nato, Farida, Vulliez-Le Normand, Brigitte, Belot, Frederic, Wright, Karen, Marcel-Peyre, Veronique, Sansonetti, Philippe J, Mulard, Laurence A
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.02.2006; Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists
• Subjects: Amino Acid Sequence; Animals; Carbohydrate Sequence; Chemical Sciences; Drug Design; Dysentery, Bacillary; Dysentery, Bacillary - immunology; Dysentery, Bacillary - prevention & control; Glycoconjugates; Glycoconjugates - chemistry; Glycoconjugates - immunology; Immunoglobulin G; Immunoglobulin G - genetics; Life Sciences; Medicinal Chemistry; Mice; Mice, Inbred BALB C; Microbiology and Parasitology; Molecular Mimicry; Molecular Mimicry - immunology; Molecular Sequence Data; O Antigens; O Antigens - chemistry; O Antigens - immunology; Oligosaccharides; Oligosaccharides - chemistry; Oligosaccharides - immunology; Serotyping; Shigella flexneri; Shigella flexneri - chemistry; Shigella flexneri - classification; Shigella flexneri - immunology; Shigella Vaccines; Shigella Vaccines - chemical synthesis; Shigella Vaccines - immunology; Vaccines, Conjugate - chemistry; Vaccines, Conjugate - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.176.3.1686

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.