Clinical Evaluation of Novel Adenovirus Vectors

开发HIV-1疫苗的一个关键障碍是我们目前无法有效地将HIV-1抗原传递到免疫系统，并启动人类可预测的高频免疫反应。基于Ad5载体的重组疫苗在临床前研究中已经引起了有效的免疫反应。然而，发展中国家高频率的抗Ad5免疫可能会极大地限制rAd5疫苗的免疫原性和临床应用。因此，我们建议开发新的、复制不能的、基于Rad载体的HIV-1疫苗。在IPCAVD赠款的项目1中，将评估几种新型Rad疫苗在具有抗Ad5免疫的恒河猴身上的免疫原性，最优载体组合将进入该项目所述的临床研究。我们预测，最具免疫原性的Rad疫苗方案将包括两个在人类群体中都很罕见的异源Rad载体，它们来自不同的Ad亚家族，具有最佳的免疫原性，与Ad5截然不同。我们假设这将是rAd35k5-rAd49素数增强方案。将制造临床级别的疫苗载体，并通过媒介核心设施(核心B)获得监管批准。在这个项目中，我们建议研究这样一个假设，即最优异源Rad PrimeBoost 事实证明，该方案在美国和美国的个体中都是安全的和高度免疫原性的 发展中世界。我们进一步假设，这些疫苗的免疫原性不会因人类人群中存在的抗媒介免疫而实质上受到抑制。为了研究这些假设，我们提出了以下三个具体目标：1.进行I期剂量递增研究，以评估rAd35k5疫苗在美国健康个体中的安全性和免疫原性；2.进行I期剂量递增研究，以评估rAd49疫苗在美国健康个体中的安全性和免疫原性；以及3.进行II期研究，以评估异源rAd35k5-rAd49 Prime-Boost方案在发展中国家健康个体中的安全性和免疫原性。

A critical roadblock in the development of an HIV-1 vaccine is our current inability to deliver HIV-1 antigens efficiently to the immune system and to prime predictable, high frequency immune responses in humans. Recombinant Ad5 vector-based vaccines have elicited potent immune responses in preclinical studies. However, the high frequency of anti-Ad5 immunity in the developing world will likely substantially limit the immunogenicity and clinical utility of rAd5 vaccines. We therefore propose the development of novel, replication-incompetent rAd vector-based vaccines for HIV-1. The immunogenicity of several novel rAd vaccines will be assessed in rhesus monkeys with anti-Ad5 immunity in Project 1 of this IPCAVD grant, and the optimal vector combination will be advanced into the clinical studies described in this project. We predict that the most immunogenic rAd vaccine regimen will involve two heterologous rAd vectors that are both rare in human populations, engineered for optimal immunogenicity, derived from different Ad subfamilies, and distinct from Ad5. We assume that this will be the rAd35k5-rAd49 prime-boost regimen. Clinical-grade vaccine vectors will be manufactured and regulatory approvals will be obtained through the Vector Core Facility (Core B). In this project, we propose to investigate the hypothesis that the optimal heterologous rAd primeboost regimen will prove safe and highly immunogenic in individuals both in the United States and in the developing world. We further hypothesize that the immunogenicity of these vaccines will not be substantially suppressed by anti-vector immunity present in human populations. To investigate these hypotheses, we propose the following three Specific Aims: 1. To perform a phase I dose-escalation study to assess the safety and immunogenicity of the rAd35k5 vaccine in healthy individuals in the United States; 2. To perform a phase I dose-escalation study to assess the safety and immunogenicity of the rAd49 vaccine in healthy individuals in the United States; and 3. To perform a phase II study to assess the safety and immunogenicity of the heterologous rAd35k5-rAd49 prime-boost regimen in healthy individuals in the developing world.