Current efforts to protect hosts against bacterial infection through the development of vaccines suffer from an absence of fundamental information about detailed immune responses. Host factors leading to the development of protective antibodies such as the antibody isotype, subclass and affinity largely are uncharacterized. The chemical characterization of what constitutes an immunogenic determinant on the bacterial surface has not been defined. In this grant we propose to analyze chemically and immunologically host and parasite factors which mediate protective immunity and will serve as the basis for developing a new class of bacterial vaccines, oligasaccharide protein conjugates. Our attention over the past several years has focused on the immunochemistry of group B Streptococcus GBS type specific polysaccharides. The proposed study is a fundamental investigation into specific interactions between oligosaccharide haptens derived from GBS polysaccharides and immunoglobulins. Critical to our study will be the preparation of oligosaccharides from type III specific polysaccharide. These oligosaccharides will be characterized chemically and modified structurally to produce a series of oligosaccharide fragments which will serve as haptens. These oligosaccharides will differ in critical structures which will facilitate determination of immunospecificity. Using thes oligosaccharides coupled to protein carriers, specific antibodies will be purified by affinity chromatography. Physical-chemical and immunological studies of the interactions of oligosaccharides and monoclonal antibodies will be performed. These studies will define the immunodeterminants on oligosaccharide utilizing monoclonal antibodies. We will characterize the isotype, subclass and affinity of protective antibodies in human sera from naturally acquired infection and following vaccination. Thes oligosaccharide-protein conjugates will be studied for immunogenicity and protection in an animal model of type III GBS infection. Conjugate vaccines will be constructed to determine optimal carbohydrate chain length and density of coupling. The knowledge gained will be essential in developing bacterial vaccines in the future.
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