Schmitz: Second Generation rBCG Immunogens
An effective AIDS vaccine must elicit robust cellular and humoral immune responses to HIV-1, and theseresponses must be active in mucosal tissues. These complementing arms of the immune system have important anti-HIV-1 activity and should synergize to block the establishment of an infection upon mucosal exposure to the virus.
CD4+ T lymphocytes play a central and important role in HIV-1 control, by providing critical help for the induction and maintenance of both virus-specific CD8+ T lymphocyte and antibody responses. Previous work accomplished by the consortium led by Dr. Letvin, resulted in the development of a novel recombinant BCG prime/recombinant NYVAC boost strategy that induces CD8+ T lymphocyte responses as well as mucosal CD4+ T lymphocyte responses to the SIV Gag transgene. These 2nd generation rBCG immunogens generated robust CD4+ T cell responses with properties that should make them better priming immunogens than some of the other currently available vaccine modalities. This grant will extend that work and add in a protein boosting component in an effort to optimize antibody responses.
Vaccine candidates developed in this grant will be candidates for future testing in phase I clinical trials, with the goal of eventually advancing them to larger trials. As immune correlates data from the RV144 trial is further described and understood, this information will be used to evaluate and optimize the rBCG/protein prime-boost regimen to the greatest extent possible.
1. Create, optimize and evaluate QC-produced rBCG and rBCG auxotrophic vaccine strains in mice and support SHIV stocks generation for challenge studies in primates
2. Choose formulation and route of vaccine administration to optimize CD8+ and CD4+ T cell responses and antibody induction
3. Explore impact of pre-existing anti-vector immunity on efficacy of rBCG vectors
4. Evaluate final versions of mycobacterial vaccine constructs as priming immunogens in primates