Basic and Applied Studies in Development of an AIDS Vacc

艾滋病疫苗开发的基础和应用研究

• 批准号: 7337903
• 负责人: Marjorie Robert-Guroff
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7337903
• 关键词: Basic; Applied; Studies; Development; AIDS

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.

我们正在寻求一种复制型腺病毒（Ad）重组引发/亚单位加强的方法作为艾滋病毒/艾滋病的预防性疫苗。研究表明，疫苗方案增强了体液、细胞和粘膜免疫力，并在非人灵长类动物模型中具有显著的保护作用，这一方法已进入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额外病毒基因的重组体的效用，研究新的组合方案，并探索免疫途径以最佳地引发免疫应答和保护效力。以前，我们报告说，引发与多基因的广告-SIV重组，然后加强与gp 120或肽聚合物代表的CD 4结合位点的包膜蛋白引起有效的保护，在39%的免疫猕猴。在最近的后续研究中，我们已经证明了保护的持久性，因为73%的受保护猕猴在第一次暴露后一年抵抗了第二次SIV攻击，没有额外的免疫接种。这种持久的保护作用与SIV特异性CD 8 + T细胞有关。然而，我们还表明，Ad-重组初免/蛋白加强方案激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活性与急性期病毒血症减少相关。随后，我们证明了Ad-HIV重组初免/包膜蛋白加强方案诱导了高滴度抗体，这些抗体介导了跨HIV进化枝的广泛ADCC活性，这是未来疫苗必须保护免受全球HIV毒株谱影响的重要发现。对其他组合疫苗方案的研究表明，与基于单独达特或多基因方法的方案相比，施用编码HIVenv和HIVtat的Ad-HIV重组体，随后用HIV Env和达特蛋白加强免疫增强了针对SHIV 89.6 P攻击的保护效力。增强的保护作用与对达特和Env的抗体应答有关。目前正在调查与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，并显示Ad-SIV重组体的连续鼻内/口服给药比基于两次连续口服给药的方案更具免疫原性。前一种方案也导致粘膜SIV攻击后急性病毒血症的更大减少。目前正在研究将编码细胞因子的DNA疫苗加入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鉴定保护的免疫相关性，并开发诱导协同免疫和保护功效的新组合策略。这些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。