We propose to continue our existing National Cooperative Vaccine Development Group (NCVDG) and retain the goal of developing novel vaccination approaches to the induction of mucosal and systemic immune responses to protect against the sexual transmission of HIV. This proposal is responsive to the growing body of evidence that the mucosal immune system is a critical element in HIV pathogenesis and host defense which is understudied. The Birmingham NCVDG represents a natural outgrowth of the research strengths in mucosal immunology at the University of Alabama at Birmingham (UAB), in molecular virology at UAB and Emory University, in microencapsulation technology at the Southern Research Institute, and primate retrovirology at UAB and the New Mexico State University Primate Research Laboratory. This NCVDG will develop, characterize and test in murine and primate model systems novel recombinant poliovirus-based live vectors and microencapsulated antigens and DNA expression vectors for their ability to induce concurrent systemic and mucosal immunity to HIV/SIV. The murine model will be employed to develop, characterize and select the most promising approaches for testing in non-human primates. Rhesus and chimpanzee immunization and challenge studies will provide objective measures of humoral and cellular immune responses, viremia, clinical and laboratory defined immunodeficiency and death. The NCVDG will consist of six highly interactive projects that will carry prototype HIV and SIV vaccines from concept through animal testing for efficacy. (Compans) will develop HIV and SIV virus-like particles, DNA expression vectors, and recombinant Salmonella for use as vaccines. (Morrow) will develop recombinant poliovirus live vectors to target HIV and SIV antigens to mucosal tissues. (Eldridge, Gilley) will develop microencapsulated immunogens and characterize the immune responses elicited by the various immunization approaches. (Marx) will evaluate SIV immunogens in macaque immunization/genital challenge experiments. (Fultz) will evaluate HIV immunogens in chimpanzee immunization/genital challenge experiments. (Mestecky) will characterize human genital immune responses to vaccines to provide the information necessary to apply the immunization approaches in man. Thus, the Birmingham NCVDG will develop and characterize several innovative approaches to immunizing both the systemic and mucosal immune compartments against HIV, will provide proof of concept in relevant animal challenge models, and will set the stage for human testing.
