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* Institut Pasteur, Unité de Pathogénie Microbienne Moléculaire, Paris, France;
Institut National de la Santé et de la Recherche Médicale, Institut Pasteur, Paris, France;
Institut Pasteur, Unité de Chimie Organique, Paris, France;
Institut Pasteur, Unité de Chimie des Biomolécules, Paris, France; and
¶ Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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 µg 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The authors thank the Bourse Roux Foundation (fellowship to F.B.), the Institut Pasteur (Grant PTR 99, fellowship to C.G.), and the Agence Nationale pour la Recherche (A.N.R., Grant EMPB-013-02) for financial support.
2 Current address: Laboratoire des Glucides, Université de Picardie Jules Verne, Amiens, France.
3 Address correspondence and reprint requests to Dr. Laurence Mulard, Institut Pasteur, Unité de Chimie des Biomolécules, 28 rue du Dr Roux, F-75015 Paris, France. E-mail address: laurence.mulard{at}pasteur.fr
4 Abbreviations used in this paper: SF2a, Shigella flexneri 2a; i.n., intranasal; mIgG, monoclonal IgG; RU, repeating unit; OS, oligosaccharides; O-SP, O-specific polysaccharide; TT, tetanus toxoid.
5 The online version of this article contains supplemental materail.
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