Clinical Development of Chimp Adenovirus Vectors

本项目旨在追求两个复制缺陷黑猩猩（黑猩猩）的临床开发 腺病毒（Ad）载体，称为AdC 6和AdC 7。我们开发了黑猩猩Ad载体来规避先前存在的 中和抗体，其通常在人类中发现，针对腺病毒的人类血清型 并降低相应Ad载体的摄取，从而降低其诱导转基因的能力 产品特异性免疫反应。AdC 6和AdC 7的中和抗体在人类中是罕见的， 在美国或亚洲，撒哈拉以南非洲人的抗体低于目前在非洲的其他Ad载体。 试验.表达HIV-1或SIV抗原的AdC 6和AdC 7载体诱导有效和持续的T细胞 介导的免疫应答，其在连续使用两种载体时增加 在初免加强方案中。在用AdC 7载体或人的Ad载体致敏的恒河猴中， 血清型5（AdHuS），然后用SHIV89.6P攻击，AdC 7引发的NHP显示出更好的病毒控制， 与用AdHuS载体致敏的动物相比，CD 4 + T细胞的负载和更少的损失。与AdHuS类似， AdC 6和AdC 7载体是遗传稳定的，表现出合适的生长特性，并且生产和 已建立了媒介的质量控制。我们建议开发AdC 6和AdC 7载体， 表达HIV-1进化枝B gag（AdCGHIVgag，AdC 7 HIVgag）的初始早期人类临床试验。 基于AdHuS的HIV-1 gag疫苗的临床数据是可用的，这将允许与 黑猩猩Ad载体。表达另外的腺病毒的AdC 6和AdC 7载体的临床前开发和测试 项目2将继续研究HIV-1的序列，以便在未来的大规模临床试验中发挥潜在作用。 在本申请中，我们计划启动两项I期试验，这两项试验将解决安全性和 在人类志愿者中的单独剂量递增试验中，AdC 6和AdC 7载体的耐受性。此外，本发明还提供了一种方法， 因为我们并不期望单剂量的疫苗，如可以在I期试验中测试的，将导致 令人印象深刻的HIV-1抗原特异性免疫反应，我们提出了一个IIA期试验，其中两个 在初免加强方案中测试黑猩猩Ad载体，在人类中在4剂量方案中使用每种载体两次 志愿者我们将通过HVTN进行临床试验，HVTN最适合招募和招募人类 志愿者，按照药物临床试验质量管理规范（GCP）的伦理行为指南进行试验 涉及人类受试者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， 美国药品监督管理局（FDA）和美国国立卫生研究院（NIH），确保试验依从性，并评估 疫苗的安全性和免疫原性。HVTN的研究将是 作为补充，项目3的研究将在人类志愿者中评估疫苗诱导的免疫应答的质量。 gag特异性T细胞应答与对疫苗载体的预先存在的免疫力的关系。

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.