ORAL CANDIDASIS: ANTIGEN STRUCTURE AND VACCINE DESIGN

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The goal of this proposal is to develop and evaluate the efficacy of anti-Candida vaccines for use in the treatment of oropharyngeal Candidiasis (OPC). To achieve optimal design, the applicants will take a purely synthetic approach to vaccine synthesis. The immunogenic core of the vaccine is based on recently discovered peptides that are able to elicit protective anti-Candida responses in mice. These peptides were found by screening antibodies, raised against the cell surface polysaccharides of C. albicans, against a phage-displayed peptide library. To enhance the immunogenicity of the peptides, they will be covalently linked to a branched dendrimer, which will also contain a linked lipid adjuvant. This approach will enable the applicants to precisely vary the valency of the vaccine molecules and thereby optimize their immunogenicity. The details of the mechanism through which the immunogenic peptides are able to mimic the endogenous carbohydrate epitope are unknown. This mimicry is not an isolated example. Several peptides have now been reported that are capable of mimicking carbohydrates from a variety of sources. In general, this mimicry can be both immunological and structural. To date, however, very little is known about the physical nature of this mimicry. In order to exploit fully the peptide mimetics in the design of a vaccine, it is essential to better understand the structures of the peptides and the mechanism of the molecular mimicry. Therefore, concurrent with the chemical synthesis and immunological evaluations, they will attempt to determine the 3-dimensional structures of the free and antibody-bound forms of the carbohydrate epitope and the peptide mimetics. The structural information will be provided by three complementary techniques, namely, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction analysis, and molecular modeling. Insight into the antigenic conformations of the peptides and endogenous antigens will provide a model for the further design and optimization of anti-Candida vaccines.