We propose to form a National Cooperative Vaccine Development Group (NCVDG) with a unifying goal of developing novel vaccine approaches for eliciting protective mucosal and systemic immunity to simian and human immunodeficiency viruses (SIV,HIV). This proposal is responsive to the growing recognition of the mucosal immune system as a critical element in HIV pathogenesis and host defense yet an area heretofore largely neglected. The Birmingham NCVDG represents a natural outgrowth of research strengths at UAB in molecular virology and mucosal immunology, at southern Research Institute in microencapsulation technology, and at the California Primate Research Center in primate retrovirology. This NCVDG will develop, characterize, and test in primate and murine model systems novel oral and systemic SIV MAC and HIV-1 vaccines derived from whole inactivated virus, recombinant viral proteins, and synthetic viral components. These immunogens will be formulated as microencapsulated products, as cholera toxin-conjugates, and as poliovirus-based recombinant viral vectors. Primate vaccination/challenge studies will be objective measures of humoral and cellular immune responses, viremia, clinical and laboratory defined immunodeficiency and death, whereas the murine model will be used to develop and characterize the different vaccine forms. The proposed NCVDG will consist of five highly interactive projects that will develop SIV and HIV vaccines from initial formulation through animal testing for efficacy. PROJECT 1 (Compans) will design, produce, and characterize SIV MAC and HIV- 1 antigens using recombinant virus expression systems for use as immunogens and will define important viral components to be used in vaccines. PROJECT 2 (Eldridge, Tice and Elson) will develop novel microencapsulated antigen delivery systems for SIVmac and HIV vaccines. PROJECT 3 (marx) will evaluate immunogens delivered orally and systemically in eliciting protective immunity to SIVmac in rhesus monkeys challenged by intravenous and transmucosal routes. PROJECT 4 (McGhee and Mestecky) will characterize the mucosal and systemic immune responses to micro-encapsulated vaccine preparations in rhesus monkeys. PROJECT 5, (Morrow) will develop recombinant poliovirus-based vectors for targeting SIV/HIV antigens to the gut mucosal immune system. Thus, the Birmingham NCVDG will develop three new approaches to SIV/HIV vaccination targeting both systemic and mucosal immune response, will define the immune response to these immunogens in two animal model systems, and will test for protection against illness and fatal disease in a new simian model in which fatal immunodeficiency can be routinely elicited by intravenous and transmucosal challenge with SIV MAC.
