Clinical Development of Chimp Adenovirus Vectors

该项目旨在研究两种复制缺陷黑猩猩(黑猩猩)的临床开发。 腺病毒(Ad)载体，称为AdC6和AdC7。我们开发了黑猩猩广告载体来绕过先前存在的 中和抗体，在人类中常见的对腺病毒血清型的中和抗体 这降低了相应的Ad载体的摄取，从而降低了它们诱导转基因的能力 产品特定的免疫反应。AdC6和AdC7的中和抗体在居住的人类中很少见 在美国或亚洲，撒哈拉以南非洲人的抗体低于目前在 测试。表达HIV-1或SIV抗原的AdC6和AdC7载体诱导持续有效的T细胞 实验动物的介导性免疫反应，在连续使用这两个载体时增加 在最佳强化养生法中。用人的AdC7载体或Ad载体启动恒河猴 血清5型(AdHuS)再用SHIV89.6P攻击后，AdC7免疫的NHP显示出更好的病毒控制 与使用AdHuS载体的动物相比，CD4+T细胞的负载和损失更少。与AdHus类似， AdC6和AdC7载体遗传稳定，表现出合适的生长特性，生产和 已经建立了病媒的质量控制。我们建议开发AdC6和AdC7载体，用于 表达HIV-1分支B(AdCGHIVgag，AdC7HIVgag)Gag的早期人类临床试验。 基于AdHuS的HIV-1 Gag疫苗的临床数据现已可用，这将使我们能够与 黑猩猩广告媒介。AdC6和AdC7载体的临床前开发和检测 未来大规模临床试验中可能使用的HIV-1序列将由项目2进行 在本申请中，我们计划启动两个阶段的I期试验，以解决安全性和 不同剂量递增试验中AdC6和AdC7载体在人类志愿者中的耐受性。此外, 因为我们不期望单剂疫苗，就像可以在第一阶段试验中测试的那样，会导致 令人印象深刻的HIV-1抗原特异性免疫反应，我们提议进行一项IIA期试验，在这两项试验中， 黑猩猩Ad载体在主要的增强方案中进行测试，每个载体在4剂人体方案中使用两次 志愿者。我们将通过HVTN进行临床试验，它最适合招募和招募人类 志愿者，按照良好临床实践(GCP)的道德行为指南进行试验 涉及人体对象的研究以及美国食品和药物管理局的必要标准和报告要求 药品监督管理局(FDA)和美国国立卫生研究院(NIH)，确保试验合规性，并评估 疫苗的安全性和免疫原性使用复杂和有效的检测方法。由HVTN进行的研究将 作为补充，项目3的研究将在人类志愿者身上评估疫苗诱导的质量 GAG特异性T细胞反应与疫苗载体既往免疫的关系。

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 (AdHuS) 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 AdHuS vectors. Similar to AdHuS, 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 (AdCGHIVgag, AdC7HIVgag). Clinical data on AdHuS 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.