A continuing long-term goal of the research conducted under this grant is to develop a dental caries vaccine that mediates protection via the mucosal immune system. The patterns of infection and initial human responses to mutans streptococcal antigens have revealed parameters of time and specificity for potential pediatric application of dental caries vaccines, and have suggested novel pathways for vaccine therapy. A direct result of this study has been the identification of Streptococcus mutans glucan binding protein (GBP59) as a new mutans streptococcal target for vaccine therapy. This discovery permits a broader based approach to immunologically mediated control of dental caries than previously possible. Preliminary studies with novel mucosal adjuvants and bioadhesive microparticles have suggested new, or more refined, methods of enhancing the induction of immunity to mucosally applied antigens such as GBP59. To build on these important discoveries, the investigators will explore the molecular characteristics of S. mutans GBP59 by cloning and sequencing the gene responsible for its synthesis. Epitopes associated with caries protection will then be identified using deduced sequence homologies with functionally important regions of other proteins, and by using immunologic probes. The potential use of these epitopes in subunit vaccines will then be tested in a rodent caries model. Also, the presence of human T and B Iymphocyte responsiveness to these epitopes will be explored. The success of mucosal-based vaccines is dependent, not only on inclusion of appropriate epitopes, but also on the ability to induce an adequate immune response. Thus, the investigators propose to explore the potential for Clostridium difficile toxin A (TxA) to serve as a novel mucosal adjuvant for important caries vaccine antigens, such as GBP59, as well as its potential to contribute epitopes to which caries-protective antibody may be induced. Targeted delivery of antigen to appropriate lymphatic sites can also contribute to the success of mucosal vaccines. Hence, the proposed studies will investigate the ability of a novel bioadhesive microparticle system to deliver immunogenic doses of these antigenic constructs to inductive sites in the GALT and BALT, and to induce protective immune responses, alone, and in combination with TxA.
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