PEPTIDE MIMETICS OF STREPTOCOCCAL CARBOHYDRATE ANTIGENS

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DESCRIPTION (Adapted from applicant's abstract): Group B streptococcal (GBS) infections are a major cause of neonatal morbidity and mortality. It is known that the presence of maternal antibody protects against the development of infection in newborns and the development of a GBS vaccine is considered an important public health priority. GBS antigens that elicit protective antibodies are found on the capsular polysaccharide. Because microbial polysaccharides are notoriously poor immunogens, GBS capsular carbohydrates have been conjugated to carrier proteins in an effort to produce efficacious vaccines. In this application, a novel approach to this problem is proposed. Peptides that mimic the structure of GBS antigens have been identified and shown to elicit anti-GBS antibodies. Using the peptides that mimic the major protective epitope on group B streptococcal (GBS) type III capsular polysaccharide, these studies will address the hypothesis that peptides which simulate the conformation of protective carbohydrate epitopes will reliably induce protective antibody responses of greater magnitude and of the IgG isotype than will immunogens based upon the microbial carbohydrate. Monoclonal anti-GBS antibodies have been used to select a peptide-display phage library to identify peptides that mimic GBS carbohydrate antigens. The peptides bind to the selecting antibodies and inhibit antibody binding to GBS in a specific manner. Immunization with a mimetic peptide results in the production of anti-GBS antibody. Studies proposed here will explore the utility of carbohydrate-mimetic peptides to enhance the immunogenicity of GBS vaccines. The following specific aims are proposed: 1) A series of immunogens will be constructed using mimetic peptides, a carrier protein, and GBS capsular polysaccharide. 2) These conjugates will be compared for their ability to induce antibody that binds to GBS and functionally opsonizes the bacteria. 3) The ability of the conjugates to induce protective immunity will be compared in two animal models: clearance of GBS from immune adult mice and a neonatal challenge model where maternal mice have been immunized. These studies may lead to the development of better maternal vaccines for the prevention of neonatal GBS infection. The techniques developed here may also be applied to other microbial polysaccharide antigens of limited immunogenicity.