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)-重组启动/亚单位增强方法作为艾滋病毒/艾滋病的预防性疫苗。研究表明，疫苗方案在非人类灵长类动物模型中诱导体液、细胞和粘膜免疫以及显著保护，已将这种方法推向第一阶段人类试验。与此同时，进一步的临床前研究正在评估编码更多病毒基因的重组体的实用性，研究新的组合方案，并探索免疫途径，以最佳地激发免疫反应和保护效果。此前，我们曾报道，用多基因Ad-SIV重组体启动，然后用gp120或代表包膜蛋白结合位点的多肽聚合物加强免疫，可在39%的免疫猕猴中产生有效的保护作用。在最近的后续研究中，我们证明了这种保护的持久性，因为73%的受保护猕猴在没有额外免疫的情况下，在第一次接触SIV一年后抵抗了第二次SIV挑战。这种持久的保护与SIV特异性CD8+T细胞有关。然而，我们也表明，Ad-重组Prime/Protein Boost方案诱导了高滴度的抗包膜抗体，包括那些介导抗体依赖的细胞细胞毒(ADCC)的抗体。疫苗诱导的ADCC活性与急性期病毒血症的减少相关。随后，我们证明了Ad-HIV重组主蛋白/包膜蛋白Boost方案诱导了高滴度抗体，该抗体介导了HIV分支中广泛的ADCC活性，这对未来必须保护全球HIV毒株谱的疫苗来说是一个重大发现。对其他组合疫苗方案的研究表明，与单独使用TAT或多基因方案相比，接种编码HIVenv和HIVtat的重组腺病毒，然后用HIV env和Tat蛋白加强免疫，可以增强对SHIV89.6P攻击的保护效果。这种增强的保护作用与对TAT和Env的抗体反应有关。与这种加强保护相关的机制正在调查中。由于粘膜免疫是HIV疫苗的关键，最近我们探索了粘膜免疫途径，并表明连续鼻腔/口服Ad-SIV重组体比基于两次连续口服的方案更具免疫原性。前一种方案也大大减少了黏膜SIV挑战后的急性病毒血症。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，并评估新的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，以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.