HIV-1 Vaccine Based on Chimp Serotypes of Adenovirus

该项目重点研究基于两种复制缺陷黑猩猩腺病毒（Ad）载体AdC6和AdC7的HIV-1候选疫苗。该计划有四个相互关联的目标。我们的第一个目标是寻求表达HIV-1 gag的AdC6和AdC7载体的临床开发，以在剂量递增的I期试验中测试每种载体的安全性，并在IIA期试验中评估两种载体在异种初始增强方案中联合使用的免疫原性。临床试验将在niaid资助的HIV疫苗试验网络（HVTN）的主持下进行。我们的第二个目标是进一步优化AdC6和AdC7载体，用于后期临床试验。我们的第三个目标是确定实验动物和人类疫苗接受者对AdC6/AdC7主要增强方案的T细胞反应的质量。越来越多的证据表明，不同的疫苗方案不仅会影响细胞免疫反应的强度，还会影响细胞免疫反应的质量，而这种质量实质上会影响HIV-1感染的进展。疫苗诱导的预防艾滋病毒-1相关疾病的相关性仍然不明确，这使得难以比较作为候选艾滋病毒疫苗平台的媒介的临床潜力。我们的目标是仔细定义临床前模型中黑猩猩Ad载体初始增强方案引发的细胞免疫反应的相关特征，以及这些特征如何与模型病原体的攻击保护相关。我们的第四个目标是阐明预先存在的T细胞对Ad的保守抗原对黑猩猩Ad载体作为疫苗载体的性能的影响。这种T细胞的流行程度将在美国和非洲的人群中确定。它们对疫苗诱导的T细胞反应的影响将首先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。定义动物体内有效免疫反应的特征，并与人类疫苗接种者进行比较研究，将促进我们对未来艾滋病疫苗开发中所追求的免疫保护相关关系的理解。

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.