Annual and Interim Progress Report Summaries
Principal Investigator: Norman Letvin
Project: Novel Recombinant Adenovirus & Mycobacteria Vector-Based Vaccines for HIV-1
The Letvin VDC was funded originally to develop replication-incompetent recombinant adenovirus (rAd) and live recombinant mycobacteria (rMyco) vectors as candidate HIV-1 vaccines; a large portfolio of rAd and rMyco vectors has been constructed and evaluated. Priorities were modified in light of the failed Merck STEP trial and the modest success of the RV144 Thai trial. The rAd program continues with a two-pronged approach: the Barouch group pursues work aimed at advancing prototype replication competent Ad26 and Ad35 (rcAd26, rcAd35) constructs expressing HIV-1 antigens for clinical production; the Nabel team uses the existing portfolio of rAd vectors to develop and optimize strategies for inducing and assessing mucosal immune responses in nonhuman primates (NHPs). The Barouch group has completed a large international Ad seroprevalence study, and continued preclinical studies on the mucosal and innate responses induced by replication-incompetent rAd vectors. They have established vector systems with improved replication efficiency, which support the development and optimization of rcAd vectors. They have also begun a program to manufacture rcAd vectors for Phase I clinical studies. The Nabel team focuses efforts on generating mucosal immunity and testing its contribution to protection in NHP models, using RV144-like (pox vector prime/protein boost) regimens. The goal is to understand (i) the quality of mucosal immune responses generated with combination regimens and the contribution of mucosal immunity to protection in SIV challenge models, and (ii) to define superior combination regimens utilizing pox vector (NYVAC or MVA or ALVAC) and protein or other gene-based boosting to generate mucosal immune responses in an SIV challenge model to inform the design of next generation HIV-1 vaccines. They compared in mice the efficacy of various combination regimens to RV144-like regimens in stimulating immune responses and have identified the most potent regimen. The Nabel team has shown that a mucosal prime/systemic boost regimen stimulated both mucosal and systemic immune responses in mice, and they are evaluating this strategy in NHP models. The rMyco team of investigators from the Haynes, Lee, Jacobs, Letvin, and Porcelli laboratories has created the first generation rBCG-SIV vectors, which effectively primed for a heterologous rAd5-SIV boost in NHPs. Using strategies to select mutants with increased transgene expression/secretion, with impaired immune evasion and apoptopic-blocking effecter phenotypes, and with increased MHC class I presentation, the team has generated panels of novel BCG strains. These second generation rBCG vectors elicit enhanced immune responses in mice. Following the roadmap established for selecting candidate BCG vectors for clinical development, the team has begun testing the first group of lead candidate rBCG mutants as priming immunogens in NHPs. They found that early after priming, monkeys immunized with the two lead-candidate rBCG-SIV Gag vectors have enhanced levels of polyfunctional Gag-specific CD4+ T cells expressing mucosal homing markers. The rBCG-primed animals have just been boosted with rNYVAC-SIV Gag vectors (Sanofi Pasteur), and the vaccine-elicited immune responses are being monitored. With enhanced immune responses in mice, the rMyco team has also begun to evaluate the potential efficacy of lipid-adjuvanting of live mycobacteria in NHPs.