Synthetic Vaccine Against Human Pathogenic Bacteria

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Human pathogenic bacteria frequently express surface-exposed glycans such as lipopolysaccharides, capsular polysaccharides, and glycolipids. These materials may serve both as virulence factors and as protective antigens. There is evidence that oligosaccharides smaller than the native polysaccharides may also induce protective IgG antibodies after their covalent attachment to immunogenic proteins. The proteins in the conjugates can convert the T-independent carbohydrate haptens into T cell-dependent immunogens. Our projects focus on vaccines against, E. coli O148, and Borrelia burgdorferi. Synthetic glycoconjugates as experimental vaccines E. coli O148 is a human enteropathogen that, similar to Shigella dysenteriae type 1, can cause shigellosis, a serious gastrointestinal disease found in both developed and developing countries. The O-specific polysaccharide of E. coli O148 is similar to that of S. dysenteriae type 1. Both are composed of tetrasaccharide repeating units. The only difference between them is that the glucose residue in the former is replaced by a galactose residue in the latter. The component monosaccharides are connected at the same positions in the identical anomeric stereochemistry. Because of this similarity, we hypothesized the existence of cross-reactivity between their O-specific polysaccharides and, that as a consequence, antibodies against one of them would offer protection against both these bacteria. To demonstrate cross-reactivity we designed chemical synthetic routes to fragments of the O-specific polysaccharide of E. coli O148, ranging from mono- to dodecasaccharides. As a continuation of earlier work, we optimized the synthetic methodology so that the targeted oligosaccharides can be obtained in high yields, reproducibly. We found that antisera to the oligosaccharide-protein conjugates reacted with the homologous O-specific polysaccharides and the homologous lipopolysaccharides and also with the heterologous ones. No cross-reaction occurred with the monosaccharides glucose and galactose. Our findings confirm evidence for the cross-reactivity in both directions and supports the view that an O-specific oligosaccharide-based vaccine against one of the organisms will offer protection against both bacteria. Borrelia burgdorferi is the causative agent of Lyme disease that afflicts a large number of people of all ages, including children, in large areas of the US, predominantly in the northeastern and north central parts of the country. There is no vaccine against this organism. B. burgdorferi expresses two groups of glycolipids on its surface termed BBGL-1 and BBGL-2. We surmised that ant-BBGL antibodies would offer protection against this bacterium. Earlier we synthesized protein conjugates where the point of attachment of the linker on BBGL-1 was at the terminus of the fatty acid moiety. Currently we have designed a synthetic route to protein conjugates of BBGL-1 where the attachment point is at carbon no. 27 in the cholesterol moiety. In such a conjugate both the saccharide and the fatty acid remain unchanged, thus allowing a better mimicking of the native structure. Accordingly, we designed synthetic routes and have synthesized an advanced intermediate that will allow the synthesis of the targeted conjugate.