Clinical Evaluation of Novel Adenovirus Vectors

开发HIV-1疫苗的一个关键障碍是，我们目前无法将HIV-1抗原有效地递送到免疫系统，并在人体中引发可预测的高频免疫反应。在临床前研究中，重组Ad5载体疫苗已经引起了强有力的免疫反应。然而，发展中国家抗ad5免疫的高频率可能会大大限制rAd5疫苗的免疫原性和临床应用。因此，我们建议开发一种新的、复制能力不强的基于rAd载体的HIV-1疫苗。IPCAVD项目1将在具有抗ad5免疫的恒河猴中评估几种新型rAd疫苗的免疫原性，并将最佳载体组合推进本项目所述的临床研究。我们预测，最具免疫原性的rAd疫苗方案将涉及两种异种rAd载体，这两种载体在人群中都是罕见的，经过优化的免疫原性，来自不同的Ad亚家族，与Ad5不同。我们假设这将是rAd35k5-rAd49的初始增强方案。将生产临床级疫苗载体，并通过载体核心设施（Core B）获得监管部门的批准。在这个项目中，我们提出了一个假设，即最优的异种rAd初始增益

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.