HIV-1 Vaccine Based on Chimp Serotypes of Adenovirus

描述(由申请者提供)：该计划基于两个复制缺陷的黑猩猩(黑猩猩)腺病毒(Ad)载体，命名为AdC6和AdC7，专注于HIV-1疫苗候选。该计划有四个相互关联的目标。我们的第一个目标是进行表达HIV-1 Gag的AdC6和AdC7载体的临床开发，以在剂量递增I阶段试验中测试每个载体的安全性，并在IIA阶段试验中评估这两个载体在异种主要增强方案中的免疫原性。临床试验将在NIAID赞助的艾滋病毒疫苗试验网络(HVTN)的赞助下进行。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 PRIME Boost方案的T细胞应答质量。越来越多的证据表明，不同的疫苗方案不仅影响随后的细胞免疫反应的大小和质量，而且这种质量在很大程度上影响艾滋病毒-1感染向疾病的进展。疫苗诱导的预防HIV-1相关疾病的相关性仍然不明确，这使得比较被认为是候选HIV疫苗平台的载体的临床潜力变得困难。我们的目标是在临床前模型中仔细定义黑猩猩Ad载体Prime Boost方案诱导的细胞免疫反应的相关特征，以及这些特征如何与抵抗模型病原体攻击的保护相关。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细胞的流行率将在来自美国和非洲的人类队列中确定。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。动物有效免疫反应特征的定义与人类疫苗接受者的比较研究将促进我们对未来艾滋病疫苗开发工作中免疫保护相关因素的理解。 项目1：黑猩猩AD载体的临床发展(Ertl，H.) 项目1描述(申请人提供)：该项目旨在进行两个复制缺陷黑猩猩(黑猩猩)腺病毒(Ad)载体的临床开发，命名为AdC6和AdC7。我们开发黑猩猩Ad载体是为了避开先前存在的中和抗体，这种中和抗体普遍存在于人类对人类血清型腺病毒的中和抗体中，这些抗体降低了对相应Ad载体的摄取，从而降低了它们诱导转基因产物特异性免疫反应的能力。AdC6和AdC7的中和抗体在居住在美国或亚洲的人类中很少见，在撒哈拉以南非洲人中低于目前正在测试的其他Ad载体的抗体。表达HIV-1或SIV抗原的AdC6和AdC7载体在实验动物体内诱导强大而持久的T细胞介导的免疫应答，在初始增强方案中连续使用这两种载体会增加免疫应答。在用AdC7载体或人血清5型Ad载体(AdHu5)预置后再用SHIV89.6P攻击的恒河猴中，AdC7预置的NHP与AdHu5载体预置的恒河猴相比，显示出更好的病毒载量控制和更少的CD4+T细胞损失。与AdHu5类似，AdC6和AdC7载体具有遗传稳定性，表现出适宜的生长特性，并且已经建立了载体的生产和质量控制。我们建议开发AdC6和AdC7载体，用于早期人类临床试验，表达HIV-1分支B的Gag(AdC6HIVgag，AdC7HIVgag)。基于AdHu5的HIV-1 Gag疫苗的临床数据已经可用，这将允许与黑猩猩Ad载体进行比较。本申请的项目2将继续进行AdC6和AdC7载体的临床前开发和测试，以表达更多的HIV-1序列，以便在未来的大规模临床试验中使用。在这项应用中，我们计划启动两个I期试验，在人体志愿者的单独剂量递增试验中解决AdC6和AdC7载体的安全性和耐受性问题。此外，由于我们不期望单剂疫苗(可以在I期试验中测试)会导致令人印象深刻的HIV-1抗原特异性免疫反应，我们提议进行IIA期试验，其中两个黑猩猩Ad载体在主要的Boost方案中进行测试，在人类志愿者中以4剂方案使用每个载体两次。我们将通过最适合招募和招募人类志愿者的HVTN进行临床试验，按照涉及人类受试者的研究道德行为的良好临床实践(GCP)指南以及美国食品和药物管理局(FDA)和美国国立卫生研究院(NIH)的必要标准和报告要求进行试验，确保试验合规性，并使用复杂和有效的分析方法评估疫苗安全性和免疫原性。HVTN的研究将得到项目3的研究的补充，该项目将在人类志愿者中评估疫苗诱导的GAG特异性T细胞反应的质量与疫苗载体先前存在的免疫之间的关系。

DESCRIPTION (provided by applicant): 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. PROJECT 1: CLINICAL DEVELOPMENT OF CHIMP AD VECTORS (ERTL, H.) PROJECT 1 DESCRIPTION (provided by applicant): This Project is designed to pursue clinical development of two replication-defective chimpanzee (chimp) adenovirus (Ad) vectors, termed AdC6 and AdC7. We developed the chimp Ad vectors to circumvent preexisting neutralizing antibodies, which are commonly found in humans to human serotypes of adenoviruses and which reduce uptake of the corresponding Ad vectors and hence their ability to induce transgene product-specific immune responses. Neutralizing antibodies to AdC6 and AdC7 are rare in humans residing in the US or Asia, and lower in Sub-Saharan Africans than antibodies against other Ad vectors currently in testing. AdC6 and AdC7 vectors expressing antigens of HIV-1 or SIV induce potent and sustained T cell mediated immune responses in experimental animals, which increase upon sequential use of the two vectors in prime boost regimens. In rhesus macaques primed with AdC7 vectors or Ad vectors of the human serotype 5 (AdHu5) and then challenged with SHIV89.6P, AdC7 primed NHPs showed better control of viral load and less loss of CD4+ T cells compared to animals primed with the AdHu5 vectors. Similar to AdHu5, AdC6 and AdC7 vectors are genetically stable, exhibit suitable growth characteristics, and production and quality control of vectors have been established. We are proposing to develop AdC6 and AdC7 vectors for initial early phase human clinical trials that express gag of HIV-1 clade B (AdC6HIVgag, AdC7HIVgag). Clinical data on AdHu5 based HIV-1 gag vaccines are available and this will allow for a comparison with the chimp Ad vectors. Pre-clinical development and testing of AdC6 and AdC7 vectors expressing additional sequences of HIV-1 for their potential use in future large scale clinical trials will be pursued by Project 2 of this application. In this application we plan to initiate two phase I trials which will address the safety and tolerability of the AdC6 and AdC7 vectors in separate dose escalation trials in human volunteers. In addition, since we do not expect that a single dose of a vaccine, as can be tested in the phase I trials, will result in impressive HIV-1 antigen-specific immune responses, we are proposing a phase IIA trial in which the two chimp Ad vectors are tested in a prime boost regimen, using each vector twice in a 4-dose regimen in human volunteers. We will conduct the clinical trials through HVTN, which is best poised to recruit and enroll human volunteers, conduct the trial in adherence to Good Clinical Practice (GCP) guidelines for ethical conduct of research involving human subjects and requisite standards and reporting requirements of U.S. Food and Drug Administration (FDA) and National Institutes of Health (NIH), ensure trial compliance, and assess vaccine safety and immunogenicity using sophisticated and validated assays. Studies by HVTN will be complemented by studies of Project 3, which will assess in human volunteers the quality of vaccine-induced gag-specific T cell responses in relationship to pre-existing immunity to the vaccine carrier.