We have shown that plasmid constructs containing HIV env and rev genes are safe and immunogenic when administered to HIV-infected and HIV-naive subjects. We hypothesize that the use of this vaccine combined with a gag/pol construct will be safe and more stimulatory of HIV-1-specific immune responses in HIV-naive subjects than the env/rev vaccine alone. We further hypothesize that combining the optimal dose of the two HIV vaccines with a construct containing the gene for an immunostimulatory molecule such as IL-12 or B7-2 will enhance responses to the HIV vaccines. We propose a total of 3 clinical trials to test these hypotheses. First, we will perform a dose-escalation trial of the combined gag/pol and env/rev vaccines to determine optimal dose for safety and immune response. Second, we will compare the adjuvant effects of constructs containing either the IL-12 or B7-2 genes when co-administered with the optimized dose of the combined HIV vaccines. Finally, we will compare the more effective of the adjuvant constructs from trial 2 versus several additional immunostimulatory gene constructs derived from Projects 1 and 2 of this Proposal, to determine if any of the new products have a better adjuvant effect for the combined HIV vaccines. The long-term goal of the proposed research is to determine the optimal doses of the HIV-1 vaccines to be administered with the most effective adjuvant vaccine to employ in a large field trial of prophylactic efficacy and safety in HIV-naive subjects at risk of infection.
| Shedlock, Devon J; Talbott, Kendra T; Cress, Christina et al. (2011) A highly optimized DNA vaccine confers complete protective immunity against high-dose lethal lymphocytic choriomeningitis virus challenge. Vaccine 29:6755-62 |
| Yan, Jian; Corbitt, Natasha; Pankhong, Panyupa et al. (2011) Immunogenicity of a novel engineered HIV-1 clade C synthetic consensus-based envelope DNA vaccine. Vaccine 29:7173-81 |
| Ingolotti, Mariana; Kawalekar, Omkar; Shedlock, Devon J et al. (2010) DNA vaccines for targeting bacterial infections. Expert Rev Vaccines 9:747-63 |
| Muthumani, Karuppiah; Lankaraman, Katthikbabu M; Laddy, Dominick J et al. (2008) Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine 26:5128-34 |
| Edgeworth, Rebecca L; San, Juan Homero; Rosenzweig, Jason A et al. (2002) Vaccine development against HIV-1: current perspectives and future directions. Immunol Res 25:53-74 |
| Sin, J I; Kim, J; Chattergoon, M et al. (2000) Engineering of DNA vaccines using molecular adjuvant plasmids. Dev Biol (Basel) 104:187-98 |
