Optimization of novel prime-boost strategies based on chimpanzee-origin adenovirus vaccine vectors

Human Immunodeficiency Virus Type 1 (HIV-1) is responsible for significant morbidity and mortality in the human population. Current therapies, although effective, are complicated by high cost, side effects, and the emergence of drug-resistant viruses. Therefore, development of novel therapies to treat or prevent HIV-1 is essential. Much has been gleaned regarding HIV-1 pathogenesis from studying the closely related simian immunodeficiency virus (SIV) in non-human primates but preclinical vaccine studies utilizing SIV have not mirrored results in human clinical trials, which have thus far been underwhelming. The Merck STEP trial, a phase IIb clinical trial which tested the efficacy of a homologous adenovirus (Ad) prime-boost regimen solely designed to induce anti-HIV-1 cytotoxic T cell responses, was halted early due to lack of efficacy. The more recent RV144 trial, which tested a heterologous prime-boost regimen designed to elicit both B and T cell responses against HIV-1, was the first to achieve statistically significant, albeit modest, efficacy. We hypothesized that an effective HIV-1 vaccine should induce potent humoral and cellular mediated immunity to either reduce viral transmission or induce sustained post-infection virological control. To this end, we developed and tested heterologous prime-boost regimens designed to generate more effective immune responses than the previous clinically tested vaccine candidates. Prior to testing our vaccine candidates, we attempted to understand the lack of efficacy in the STEP trial by testing a CTL-inducing Ad prime-boost strategy in non-human primates. We compared the Ad regimen to a live, attenuated SIV vaccine (SIVΔNef), which has repeatedly been shown to be protective in rhesus macaques. Gene profiling revealed that many more genes were significantly affected by SIVΔnef immunization versus Ad immunization. In addition, we show that SIVΔNef immunization confers only partial protection against low dose SIVmac251 challenge while Ad vaccination is not protective. This result supported utilizing this challenge model in future SIV vaccine studies. We conducted another study utilizing Ad vectors derived from chimpanzee serotypes (AdC), to which neutralizing antibodies are rare. To assess the effect of neutralizing antibodies to human Ads (AdHu) on prime-boost regimens designed to elicit both B and T cell responses, rhesus macaques were pre-exposed to AdHu5 and AdHu26 and received prime-boost regimens consisting of either AdHu or AdC vectors. We show that vaccination elicited both potent B and T cell responses and we demonstrate vaccine control of virus replication to undetectable levels in a majority of immunized animals. In contrast, all control animals became infected and developed higher and more sustained peak and set viral loads. Whereas AdHu vaccine efficacy was linked to controller genotypes, AdC vectors immunization led to significant protection even in animals with non-controller genotypes. After reaffirming AdC vectors as a viable HIV-1 vaccine platform, we sought to further optimize immunogenicity. Since the majority of HIV-1 transmission occurs at mucosal sites, we sought to identify a mucosal adjuvant to use as part of an AdC vaccine strategy. We show that co-immunization of AdC with all trans retinoic acid leads to enhanced mucosal and systemic immune responses after priming. We further show that humoral responses elicited by AdC vectors expressing HIV-1 Env can be boosted with two novel Env immunogens