DEVELOPMENT OF THE HBCAG AS A VACCINE CARRIER PLATFORM

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The recent ability to map neutralizing B cell epitopes on protein antigens has created much interest in the potential use of these "hapten-like" antigens in vaccine development. However, peptide antigens often require conjugation to an immunogenic carrier for efficient immunogenicity. An optimal protein carrier moiety suitable for human immunization is not available. The objective of the proposal is to exploit the potential of the hepatitis B nucleocapsid to function as a multi-valent carrier platform to enhance the immune response to weak peptide antigens. We recently used the HBcAg as a carrier for rodent (i.e., P. berghei, P. yoelii) and human (i.e., P. falciparum) malarial vaccine development. The rodent vaccines are 90-100% protective and the human candidate vaccine elicits unprecedented levels of sporozoite-neutralizing antibody in mice. A number of unique immunologic characteristics of the native HBCAG and the success achieved with the hybrid HBcAg-malaria candidate vaccines suggest that this particulate protein will be useful as a means of delivering a variety of antigens to the immune system. Three specific projects are proposed. (1) Examine basic immunologic mechanisms responsible for the enhanced immunogenicity of HBcAg- malaria hybrid particles. Understanding the cellular m4echanisms regulating the enhanced immune response to HBcAg-CS hybrid particles will enable future rational vaccine design. This will be accomplished in mice and involve examination of B cell recognition (i.e., T cell- independence, induction of co-stimulatory molecules) and Th cell recognition (i.e., fine specificity, genetic restriction, cytokine production, Th cell subset distribution) of HBcAg-hybrid particles as well as the antigen presentation and processing of hybrid particles. (2) Optimization of the HBcAg as a vaccine carrier platform. Variables to be examine: the optimal number of B cell/Th cell inserts, the insertion sites within HBcAg that best accommodate B cell as well as Th cell epitopes, the importance of particle stability, the effects of inclusion of unmethylated CpG dinucleotides, and the potential for multiple or combination vaccine design. Chemical conjugation of protein antigens to the HBCAG will also be explored. (3) Application of the HBcAg platform technology to other epitopes in addition to P. falciparum. We anticipate that the experience and information gained during the development of malaria candidate vaccines will be applicable to other vaccines which may benefit from the use of HBcAg as a platform. Specifically, selected epitopes (B and Th) cell from pathogens such as Influenza, P. vivax, FMDV, HCV and HIV-1 will be incorporated into hybrid HBcAg particles to determine the general applicability of the HBcAg carrier system.