Clinical Evaluation of Novel Adenovirus Prime-Boost HIV-1 Vaccine

目前基于重组腺病毒血清5型(RAd5)载体的HIV-1候选疫苗有 有希望，但可能被证明是有限的，因为先前存在的抗Ad5免疫在发展中的高流行率 世界。为了克服这一问题，我们构建了一系列新的血清型和嵌合体Rad 有效规避抗Ad5免疫的载体。我们还证明了异源Rad 使用两个血清学上不同的Rad载体的Prime-Boost方案诱导显著有效的免疫 应答，特别是包括rAd26启动和rAd5或rAd5HVR48增强的方案。此外，我们 已经构建了表达最佳C分支、M一致和M马赛克HIV-1抗原的Rad载体 旨在最大限度地减少遗传距离并优化全球HIV-1中T细胞表位的覆盖率 序列。 因此，我们建议开发一种实用的、两次注射的异源rAd26启动子， RAd5HVR48 Boost方案作为一种新的候选方案表达针对全球覆盖优化的抗原 HIV-1疫苗。项目2的目标是在阶段1研究中定义最佳Rad向量组合 并将这种新的HIV-1候选疫苗推进到扩大的国际2a阶段研究中 与艾滋病毒疫苗试验网络(HVTN)合作。项目2中的临床研究将建立在 项目1中的临床前研究和项目3中的制造计划。 在项目2中，我们假设异源rAd26 Prime，rAd5HVR48 Boost方案 将在美国和撒哈拉以南非洲的人类身上证明是安全的和高度免疫原性的。 我们进一步假设，这个HIV-1候选疫苗不会被预先存在的反载体抑制 免疫，将是一个有希望的候选者进一步发展到高级阶段 在本项目期结束前进行临床试验。为了探索这些假设，我们提出了以下建议 三个具体目标： 1.进行第一阶段研究，评估rAd26和rAd5HVR48的安全性和免疫原性 美国的HIV-1疫苗方案； 2.进行第一阶段研究，评估rAd26和rAd5HVR48的安全性和免疫原性 南非的艾滋病毒-1疫苗方案；以及 3.进行国际2a期研究，评估扩大的安全性和免疫原性 异源rAd26Prime、rAd5HVR48 Boost HIV-1疫苗方案。

Current HIV-1 vaccine candidates based on recombinant adenovirus serotype 5 (rAd5) vectors are promising but may prove limited by the high prevalence of pre-existing anti-Ad5 immunity in the developing world. To overcome this problem, we have constructed a series of novel serotype and novel chimeric rAd vectors that effectively circumvent anti-Ad5 immunity. We have also demonstrated that heterologous rAd prime-boost regimens utilizing two serologically distinct rAd vectors elicit remarkably potent immune responses, particularly regimens involving rAd26 priming and rAd5 or rAd5HVR48 boosting. In addition, we have generated rAd vectors expressing optimal C clade, M consensus, and M mosaic HIV-1 antigens designed to minimize genetic distance and to optimize T cell epitope coverage among global HIV-1 sequences. We therefore propose to develop a practical, two-injection, heterologous rAd26 prime, rAd5HVR48 boost regimen expressing antigens optimized for global coverage as a novel candidate HIV-1 vaccine. The goals of Project 2 are to define the optimal rAd vector combination in phase 1 studies and to advance this novel HIV-1 vaccine candidate into expanded international phase 2a studies in collaboration with the HIV Vaccine Trials Network (HVTN). The clinical studies in Project 2 will build on the preclinical studies in Project 1 and the manufacturing program in Project 3. In Project 2, we hypothesize that the heterologous rAd26 prime, rAd5HVR48 boost regimen will prove safe and highly immunogenic in humans in both the United States and sub-Saharan Africa. We further hypothesize that this HIV-1 vaccine candidate will not be suppressed by pre-existing antivector immunity and will be a promising candidate for further development into advanced phase clinical trials by the end of this project period. To explore these hypotheses, we propose the following three Specific Aims: 1. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in the United States; 2. To perform a phase 1 study assessing the safety and immunogenicity of rAd26 and rAd5HVR48 HIV-1 vaccine regimens in South Africa; and 3. To perform an international phase 2a study evaluating expanded safety and immunogenicity of the heterologous rAd26 prime, rAd5HVR48 boost HIV-1 vaccine regimen.