HIV-1 Vaccine Based on Chimp Serotypes of Adenovirus

描述（由申请人提供）：该项目侧重于基于两种复制缺陷黑猩猩（黑猩猩）腺病毒（Ad）载体的HIV-1候选疫苗，称为AdC6和AdC7。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。

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.