Shigellosis, or bacillary dysentery, caused by the non-capsulated enteroinvasive bacteria Shigella, is a major burden especially in developing countries. It remains one of the top four diarrheal diseases in children under five. Species and serotype diversity, added to their geographical distribution, strongly support the need for a multivalent vaccine. With regard to endemic shigellosis, special attention is paid to S. flexneri and S. sonnei. Protection against re-infection is thought to be achieved, to a large extent, by antibodies specific for the O-antigen moiety of the lipopolysaccharide. In this context, a multidisciplinary strategy toward vaccine candidates encompassing synthetic oligosaccharides mimicking the “protective” determinants carried by the O-antigen of selected serotypes was undertaken. The two-step process under development aims first at identifying sets of “protective” epitopes, and second at designing conjugates thereof acting as strong immunogens. With a vaccine candidate in hand for the most prevalent Shigella serotype, this presentation will first highlight our strategy for broadening vaccine coverage against S. flexneri, which comprises some 15 serotypes. Most known repeating units from S. flexneri O-antigens encompass a common tetrasaccharide backbone, itself a linear combination of three L-rhamnose residues and a N-acetyl-D-glucosamine. Diversity and serotype specificity are related, in part, to the occurrence of α-D-glucosylation and/or acetylation at specific hydroxyl groups of the basic tetrasaccharide. The possible impact of these substitutions on vaccine development will be discussed. Then, the influence of these same substitutions on glycoconjugate synthesis and properties will be exemplified in the case of S. flexneri serotype 3a. In particular, the presentation will report the synthesis and antigenicity data for a panel of oligosaccharides representative of fragments from the corresponding O-antigen. Moreover, the immunogenicity in mice of selected S. flexneri 3a glycoconjugates differing in terms of hapten length and composition will be discussed.

Toward a bivalent synthetic carbohydrate-based vaccine candidate against shigellosis

254th National Meeting (2017)

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