HIV-1 Vaccine Based on Chimp Serotypes of Adenovirus

这个项目的重点是以两只复制缺陷的黑猩猩为基础的HIV-1疫苗候选 (黑猩猩)腺病毒(Ad)载体，称为AdC6和AdC7。该计划有四个相互关联的目标。我们的第一次 目的是追踪表达HIV-1 Gag的AdC6和AdC7载体的临床开发，以测试其安全性 在剂量递增I期试验中对每个载体进行比较，并评估两种载体组合的免疫原性 在IIA期试验中的异种主要增强方案。临床试验将在 NIAID赞助的艾滋病毒疫苗试验网络(HVTN)的赞助。我们的第二个目标是进一步优化 用于后期临床试验的AdC6和AdC7载体。我们的第三个目标是研究目标，以定义 实验动物和人对AdC6/AdC7初始增强方案的T细胞应答质量 疫苗接受者。越来越多的证据表明，不同的疫苗方案不仅影响病毒的大小 以及随后的细胞免疫反应的质量，这种质量在很大程度上影响着 HIV-1感染向疾病的进展。疫苗诱导的HIV-1保护性相关因素 相关疾病的定义仍然不明确，这使得很难比较 载体被认为是候选艾滋病毒疫苗的平台。我们的目标是仔细定义相关的 临床前黑猩猩Ad载体Prime Boost方案诱导的细胞免疫应答特征 模型，以及这些特征如何与模型的挑战保护相关联 病原体。我们的第四个目标是阐明预先存在的T细胞对ADS保守抗原的影响 黑猩猩Ad载体作为疫苗载体的性能。这种T细胞的流行率将被确定 在来自美国和非洲的人类队列中。它们对疫苗诱导的T细胞反应的影响首先是 在实验动物中进行评估，然后在人类疫苗接受者中进行评估。特征的定义 动物的有效免疫反应与人类疫苗接受者的比较研究将取得进展 我们对未来艾滋病疫苗免疫保护相关因素的理解 发展。

This program focuses on vaccine candidates for HIV-1 based on two replication-defective chimpanzee (chimp) adenovirus (Ad) vectors, termed AdC6 and AdC7. The program has four interlinked goals. Our first goal is to pursue clinical development of AdC6 and AdC7 vectors expressing gag of HIV-1 to test the safety of each vector in dose-escalation phase I trials, and to assess the immunogenicity of both vectors combined in a heterologous prime boost regimen in a phase IIA trial. Clinical trials will be conducted under the auspices of the NIAID-sponsored HIV Vaccine Trials Network (HVTN). Our second goal is to further optimize the AdC6 and AdC7 vectors for later stage clinical trials. Our third goal is a research objective to define the quality of T cell responses to AdC6/AdC7 prime boost regimens in both experimental animals and human vaccine recipients. Evidence is mounting that different vaccine regimens not only influence the magnitude but also the quality of the ensuing cellular immune responses, and that this quality substantially influences progression of HIV-1 infections toward disease. Vaccine-induced correlates of protection against HIV-1 associated illness remain poorly defined, which has made it difficult to compare the clinical potential of the vectors considered as platforms for a candidate HIV vaccine. We aim to carefully define pertinent characteristics of the cellular immune responses elicited by chimp Ad vector prime boost regimens in preclinical models, and how such characteristics correlate with protection against challenge with model pathogens. Our fourth goal is to elucidate the effect of pre-existing T cells to conserved antigens of Ads on the performance of chimp Ad vectors as vaccine carriers. The prevalence of such T cells will be determined in human cohorts from the US and Africa. Their effect on vaccine-induced T cell responses will first be assessed in experimental animals and then in human vaccine recipients. Definition of the characteristics of effective immune responses in animals with comparison studies in human vaccine recipients will advance our understanding of the correlates of immune protection to be pursued in future efforts of AIDS vaccine development.