SYNTHETIC VACCINE AGAINST SHIGELLOSIS

点击翻译按钮获取中文摘要

Shigellosis caused by Shiqella dysenteriae type 1 continues to be a major enteric disease worldwide and most strains are now antibiotic resistant. Although the need for vaccines to control this disease has been documented by the WHO, there is no licenced vaccine against shigellosis. Following the discovery by Robbins and coworkers that serum antibodies against the O-specific polysaccharide (OSP) of Shigella sonnei immunity to disease caused by this pathogen in humans, we hypothesized that extended fragments of the OSP may also be suitable for the induction of protective antibodies when coupled to immunogenic proteins, provided that the conformational ensemble of such saccharides approaches that of the conformational determinant of the native polysaccharide. The use of synthetic saccharides of defined structure instead of native polysaccharides of complex architecture is likely to offer advantages including enhanced uniformity of conjugates and elimination of the analytical difficulties associated with the established, polysaccharide- protein vaccines. Based on this hypothesis we are developing synthetic oligo- and poly-saccharide-based immunogens of well -defined characteristics. We designed a strategy to prepare fragments of the OSP of S. dysenteriae type 1. The OSP consists of a tetrasaccharide repeating unit that is composed of D-galactose, N-acetyl-D-glucosamine, and L-rhamnose. Starting from monosaccharide building blocks that carry orthogonal protecting and activating groups, a tetrasaccharide donor/acceptor molecule was assembled. Iterative combination of this building block afforded di-, tri- and tetramers of the repeating unit corresponding to octa-, dodeca- and hexadeca-saccharides. The dodeca- and the hexadeca-saccharides exhibit a high degree of conformational similarity to the native O-SP by NMR. The first conjugate of a tetra- repeating unit has been synthesized. In vitro experiments showed that the synthetic saccharides inhibit the binding of the OSP to homologous monoclonal antibodies.