Basic and Applied Studies in Development of an AIDS Vacc

我们正在寻求一种复制能力腺病毒（Ad）重组引物/亚基增强方法作为HIV/AIDS的预防性疫苗。研究表明，该疫苗方案在非人类灵长类动物模型中引起体液、细胞和粘膜免疫，并具有显著的保护作用，已将该方法推向I期人体试验。与此同时，进一步的临床前研究正在评估编码其他病毒基因的重组体的效用，研究新的联合方案，并探索免疫途径，以获得最佳的免疫反应和保护效果。在此之前，我们报道了用多基因Ad-SIV重组启动，然后用gp120或代表包膜蛋白CD4结合位点的肽聚合物增强，在39%的免疫猕猴中获得了有效的保护。在最近的后续研究中，我们证明了这种保护的持久性，73%的受保护猕猴在没有额外免疫的情况下，在第一次接触后一年内抵抗了第二次SIV攻击。这种持久的保护作用与siv特异性CD8+ T细胞有关。然而，我们也表明，ad重组引物/蛋白质增强方案引发高滴度的抗包膜抗体，包括介导抗体依赖性细胞毒性（ADCC）的抗体。疫苗诱导的ADCC活性与减少急性期病毒血症相关。随后，我们证明了一种Ad-HIV重组引物/包膜蛋白增强方案诱导了高滴度抗体，介导了广泛的ADCC活性，这对于未来必须保护全球范围的HIV毒株的疫苗来说是一个重要的发现。对其他联合疫苗方案的研究表明，与基于单独或多基因方法的方案相比，给药编码HIVenv和HIVtat的Ad-HIV重组体，然后增强HIV Env和Tat蛋白，可增强对SHIV89.6P攻击的保护效果。增强的保护作用与对Tat和Env的抗体反应有关。目前正在调查与这种加强保护有关的机制。由于粘膜免疫对HIV疫苗至关重要，最近我们探索了粘膜免疫途径，并表明连续鼻内/口服注射Ad-SIV重组物比连续两次口服给药更具有免疫原性。前一方案也导致粘膜SIV攻击后急性病毒血症的更大减少。正在进行的研究正在调查将编码细胞因子的DNA疫苗添加到我们的疫苗策略中的价值，并评估新型包膜亚单位疫苗作为加强免疫的价值。重要的是，这些临床前研究有助于确定保护的免疫相关因素，并开发新的联合策略，诱导协同免疫和保护效果。这一新知识将为未来的疫苗设计提供信息，并确定值得在临床试验中进行测试的疫苗方案。

We are pursuing a replication-competent Adenovirus (Ad)-recombinant priming/subunit boosting approach as a prophylactic vaccine for HIV/AIDS. Studies showing that the vaccine regimen elicits humoral, cellular, and mucosal immunity together with significant protection in non-human primate models have moved this approach towards Phase I human trials. At the same time, further pre-clinical studies are evaluating the utility of recombinants encoding additional viral genes, investigating new combination regimens, and exploring routes of immunization for optimal elicitation of immune responses and protective efficacy. Previously, we reported that priming with multigenic Ad-SIV recombinants followed by boosting with either gp120 or a peptide polymer representing the CD4 binding site of the envelope protein elicited potent protection in 39% of immunized macaques. In recent follow-up studies we have demonstrated durability of the protection, as 73% of the protected macaques resisted a second SIV challenge one year following the first exposure with no additional immunizations. This durable protection was associated with SIV-specific CD8+ T cells. However, we have also shown that the Ad-recombinant prime/protein boost regimen elicits high titered anti-envelope antibodies, including those that mediate antibody-dependent cellular cytotoxicity (ADCC). Vaccine-induced ADCC activity correlated with reduced acute phase viremia. Subsequently, we demonstrated that an Ad-HIV recombinant prime/envelope protein boost regimen induced high titer antibodies that mediated broad ADCC activity across HIV clades, a significant finding for future vaccines that must protect against the global spectrum of HIV strains. Investigation of additional combination vaccine regimens have shown that administration of Ad-HIV recombinants encoding HIVenv and HIVtat, followed by boosting with HIV Env and Tat proteins elicits enhanced protective efficacy against a SHIV89.6P challenge in comparison to regimens based on Tat alone or multigenic approaches. The enhanced protection was associated with antibody responses to both Tat and Env. Mechanisms associated with this enhanced protection are under investigation. As mucosal immunity is critical for an HIV vaccine, more recently we have explored mucosal routes of immunization and have shown that sequential intranasal/oral administration of Ad-SIV recombinants is more immunogenic than a regimen based on two sequential oral administrations. The former regimen has also resulted in greater reduction of acute viremia following a mucosal SIV challenge. On-gong studies are investigating the value of adding DNA vaccine encoding cytokines into our vaccine strategy and evaluating novel envelope subunit vaccines as booster immunizations. Importantly, these pre-clinical studies contribute to identification of immune correlates of protection, and development of new combination strategies that induce synergistic immunity and protective efficacy. This new knowledge will inform future vaccine design and define vaccine regimens that will merit testing in clinical trials.