Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors arepromising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developingworld. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAdvectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAdprime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immuneresponses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, wehave generated rAd vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigensdesigned to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1sequences.We therefore propose to develop a practical, two-injection, heterologous rAd26 prime,rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidateHIV-1 vaccine. The goals of Project 2 are to define the optimal rAd vector combination in phase 1 studiesand to advance this novel HIV-1 vaccine candidate into expanded international phase 2a studies incollaboration with the HIV Vaccine Trials Network (HVTN). The clinical studies in Project 2 will build on thepreclinical studies in Project 1 and the manufacturing program in Project 3.In Project 2, we hypothesize that the heterologous rAd26 prime, rAd5HVR48 boost regimenwill prove safe and highly immunogenic in humans in both the United States and sub-Saharan Africa.We further hypothesize that this HIV-1 vaccine candidate will not be suppressed by pre-existing antivectorimmunity and will be a promising candidate for further development into advanced phaseclinical trials by the end of this project period. To explore these hypotheses, we propose the followingthree Specific Aims:1. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48HIV-1 vaccine regimens in the United States;2. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48HIV-1 vaccine regimens in South Africa; and3. To perform an international phase 2a study evaluating expanded safety and immunogenicity of theheterologous rAd26 prime, rAd5HVR48 boost HIV-1 vaccine regimen.
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