The major approach to the prevention of infection by encapsulated bacteria has been the use of vaccines consisting primarily of the polysaccharide capsules of these bacteria. The group B Streptococcus (GBS) is the most serious pathogen for the neonatal age group. Antibody to the capsular polysaccharides of GBS has been shown to be protective. Attempts to induce protective immunity to GBS utilizing polysaccharide capsules have met with only modest success due to the overall poor immunogenicity of these polysaccharide antigens in humans. The most effective approach to overcoming the problem of poor immunogenicity of polysaccharides has been covalent coupling to carrier proteins to produce conjugate vaccines, which have significantly enhanced immunogenicity. While it is clear that induction of T cell help is one important aspect of the enhanced immunogenicity of these conjugates, another factor, which we believe to be important, is the effect of conjugation on the polysaccharide epitope presentation and expression. Our studies of GBS polysaccharides have defined a unique system that allows the determination of how specific physicochemical characteristics, such as antigen conformation, affect the host recognition of polysaccharide antigens. Antibodies directed against these polysaccharides appear to recognize a conformational epitope that is fully expressed in higher-molecular-weight forms of the polysaccharide. Although a conjugate vaccine is likely to enhance the immune response by eliciting T cell help, conjugate designs that stabilize the conformational epitope may also increase the immune response by enhancing expression of this epitope. In this proposal we present a program to rigorously define model conjugate vaccines that allow the differentiation of the effects of conjugation in modifying polysaccharide epitope expression as distinct from the T cell dependent effects. Conjugation may modify particular structural features of the polysaccharide making it more immunogenic by changing the interaction of the polysaccharide and immune system. There are five specific aims in this proposal.
In Specific Aims 1 and 2, oligosaccharides of differing length will be conjugated either at the reducing end or at multiple sites along the chain to determine what effect conformational stability has on the chain-length dependent epitope. The effect of single versus multisite coupling on T cell dependence will be studied.
In Specific Aim 3, the effect on T cell dependence of the degree of cross-linking between the full length polysaccharide and the carrier protein molecules in a conjugate vaccine will be studied.
In Specific Aims 4 and 5, specific chemical parameters which define conformation, NMR spectroscopy, and X-ray crystallography will define precisely how conformationally dependent polysaccharide epitopes interact directly with antibody.
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