HIV-1 Vaccine Based on Chimp Serotypes of Adenovirus

基于黑猩猩腺病毒血清型的 HIV-1 疫苗

• 批准号: 7268595
• 负责人: Hildegund C. J. Ertl
• 金额: $ 256.94万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268595
• 关键词: HIV; Vaccine; Based; Chimp; Serotypes

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.

描述（由申请人提供）：该项目重点关注基于两种复制缺陷型黑猩猩腺病毒（Ad）载体（称为AdC 6和AdC 7）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进行表达HIV-1 gag的AdC 6和AdC 7载体的临床开发，以测试每种载体在剂量递增I期试验中的安全性，并评估在IIA期试验中在异源初免加强方案中组合的两种载体的免疫原性。临床试验将在NIAID赞助的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AdC 6和AdC 7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AdC 6/AdC 7初免加强方案的T细胞应答的质量。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应答的程度，而且影响其质量，并且这种质量实质上影响HIV-1感染向疾病的进展。疫苗诱导的对HIV-1相关疾病的保护相关性仍然定义不清，这使得难以比较被认为是候选HIV疫苗平台的载体的临床潜力。我们的目标是仔细定义相关的特性引起的黑猩猩Ad载体的初免加强方案在临床前模型中的细胞免疫应答，以及如何保护这些特性与模型病原体的挑战。我们的第四个目标是阐明预先存在的T细胞对Ads保守抗原对黑猩猩Ad载体作为疫苗载体的性能的影响。这些T细胞的流行率将在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。动物有效免疫应答的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中所追求的免疫保护相关性的理解。 项目1：CHIMP AD载体的临床开发（ERTL，H.） 项目1描述（由申请人提供）：该项目旨在进行两种复制缺陷型黑猩猩腺病毒（Ad）载体（称为AdC 6和AdC 7）的临床开发。我们开发了黑猩猩Ad载体以规避预先存在的中和抗体，所述中和抗体通常在人类中发现，针对腺病毒的人类血清型，并且减少相应Ad载体的摄取，从而减少其诱导转基因产物特异性免疫应答的能力。AdC 6和AdC 7的中和抗体在居住在美国或亚洲的人类中很少见，在撒哈拉以南非洲地区的中和抗体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AdC 6和AdC 7载体在实验动物中诱导有效和持续的T细胞介导的免疫应答，其在初免加强方案中连续使用两种载体时增加。在用AdC 7载体或人血清型5的Ad载体（AdHu 5）致敏然后用SHIV89.6P攻击的恒河猴中，与用AdHu 5载体致敏的动物相比，AdC 7致敏的NHP显示出更好的病毒载量控制和更少的CD 4 + T细胞损失。与AdHu 5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，并且已经建立了载体的生产和质量控制。我们建议开发AdC 6和AdC 7载体，用于最初的早期人类临床试验，表达HIV-1进化枝B的gag（AdC 6 HIVgag，AdC 7 HIVgag）。基于AdHu 5的HIV-1 gag疫苗的临床数据是可用的，这将允许与黑猩猩Ad载体进行比较。本申请的项目2将继续进行表达HIV-1额外序列的AdC 6和AdC 7载体的临床前开发和测试，以用于其在未来大规模临床试验中的潜在用途。在本申请中，我们计划启动两个I期试验，其将在人类志愿者中的单独剂量递增试验中解决AdC 6和AdC 7载体的安全性和耐受性。此外，由于我们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抗原特异性免疫应答，因此我们提出了IIA期试验，其中两种黑猩猩Ad载体在初免加强方案中进行测试，在人类志愿者的4剂量方案中使用每种载体两次。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，按照涉及人类受试者的研究伦理行为的药物临床试验质量管理规范（GCP）指南以及美国食品药品监督管理局（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，并使用复杂且经过验证的检测方法评估疫苗的安全性和免疫原性。HVTN的研究将得到项目3研究的补充，项目3将在人类志愿者中评估疫苗诱导的gag特异性T细胞应答的质量与对疫苗载体的既存免疫力的关系。