Annual and Interim Progress Report Summaries
Principal Investigator: Norman Letvin
Project: Novel Recombinant Adenovirus & Mycobacteria Vector-Based Vaccines for HIV-1
Submitted August 1, 2009
The Letvin VDC is developing novel, recombinant adenovirus (rAd) and mycobacteria (rMyco) vectors to elicit durable systemic and mucosal immune responses against HIV-1 by three approaches: (1) The Barouch group has two parallel projects: in studying critical aspects of anti-Ad5 immunity following the results of the STEP trial, they have contributed substantially to our understanding of the biology of rAd vectors. In developing novel Ad vectors that evade pre-existing anti-Ad5 immunity, they have made substantial progress in generating both replication non-competent chimeric rAd vectors and replication competent rare serotype rAd26 vectors. (2) The Nabel team focuses on rAd vectors that target the intestinal mucosa for use in prime-boost vaccine combinations. Based on their small animal studies, they have identified rare serotype Ad28 as their lead candidate vector, and with the Letvin group, they are testing a set of nonreplicating rAd28 vectors in nonhuman primate (NHP) studies to assess the efficacy of this prime-boost regimen in an SIV challenge model. (3) The first generation rBCG-SIV vectors provided effective priming for a heterologous rAd5-SIV boost in a pilot NHP study. To optimize vector immunogenicity, the rMyco team employed genome-wide screens to identify BCG genes that affect the host’s immune responses, and molecular biology to increase transgene expression and secretion by BCG. The team is on target in generating more immunogenic second generation rBCG vectors with a streamlined roadmap towards clinical vectors production. The lead candidate rBCG-SIV vectors are on track to be tested in NHP studies in Year 4.