Preclinical Evaluation of Novel Ad/MVA and Ad/Protein HIV-1 Vaccines

新型 Ad/MVA 和 Ad/蛋白 HIV-1 疫苗的临床前评价

• 批准号: 8393795
• 负责人: Dan H. Barouch
• 金额: $ 103.43万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-13 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393795
• 关键词: Adenovirus Vector; Adoptive Transfer; Africa South of the Sahara; Antibodies; Antibody Formation; Antigens; Binding; Cavia; Clinical; Clinical Trials; Collaborations; Data; Development; Drug Formulations; Failure; Gagging; Grant; HIV Envelope Protein gp120; HIV-1; Health Priorities; Immune; Immune response; Infection; Instruction; Laboratories; Lead; Macaca mulatta; Phase; Phenotype; Program Development; Proteins; Regimen; Resistance; SIV; Safety; Serotyping; Testing; Tropism; Vaccines; base; global health; immunogenicity; in vivo; monomer; neutralizing antibody; novel; novel vaccines; pre-clinical; preclinical evaluation; preclinical study; programs; protective efficacy; receptor; response; vaccine candidate; vector; vector vaccine

PROJECT SUMMARY (See instructions): Adenovirus vectors have proven highly potent for inducing both humoral and cellular immune responses. The failure of an Ad5-Gag/Pol/Nef vaccine in the Step study has led to the development of novel serotype Ad vectors, which are biologically very different and arguably substantially superior to Ad5 in terms of seroepidemiology, cellular receptor usage, in vivo tropism, innate immune responses, transcriptional profiles, adaptive immune phenotypes, and protective efficacy against SIV in rhesus monkeys. Moreover, the inclusion of Env may be critical for an HIV-1 vaccine. Based on our preclinical and clinical preliminary data, we have prioritized Ad26/MVA and Ad26/Protein regimens for further development. In Project 1, we will conduct the key preclinical studies to inform the clinical development program described in Project 2. These studies will help define the lead vaccine candidate and will help determine the mechanism of protection afforded by our optimal vaccine regimen. Specifically, we will test the hypothesis that adding a gp140 trimer protein boost will augment the partial protection afforded by our optimal vaccine vectors against acquisition of highly stringent, heterologous SIV challenges. We will also test the hypothesis that vaccine-elicited Env-specific antibodies are critical for this protection. To evaluate these hypotheses, we propose the following two Specific Aims: 1. To compare the immunogenicity and protective efficacy of Ad26/Ad26 and Ad26/MVA vector regimens with and without a gp140 trimer protein boost against repetitive, heterologous, neutralization-resistant, intrarectal SIV challenges in rhesus monkeys; and 2. To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys.

项目总结（见说明）： 腺病毒载体已被证明在诱导体液和细胞免疫应答方面具有高度效力。步骤研究中Ad 5-Gag/Pol/Nef疫苗的失败导致了新型血清型Ad载体的开发，其在生物学上非常不同，并且可以说在血清流行病学、细胞受体使用、体内嗜性、先天免疫应答、转录谱、适应性免疫表型和恒河猴中针对SIV的保护功效方面实质上上级Ad 5。此外，包含Env可能对HIV-1疫苗至关重要。根据我们的临床前和临床初步数据，我们优先考虑Ad 26/MVA和Ad 26/蛋白方案进行进一步开发。 在项目1中，我们将进行关键临床前研究，以告知项目2中描述的临床开发项目。这些研究将有助于确定主要的候选疫苗，并将有助于确定我们的最佳疫苗方案所提供的保护机制。具体地说，我们将测试这样的假设，即添加gp 140三聚体蛋白加强将增强我们的最佳疫苗载体针对获得高度严格的异源SIV挑战所提供的部分保护。我们 还将检验疫苗引发的Env特异性抗体对于这种保护至关重要的假设。为了评估这些假设，我们提出了以下两个具体目标： 1.在恒河猴中比较有和没有gp 140三聚体蛋白加强的Ad 26/Ad 26和Ad 26/MVA载体方案针对重复的、异源的、中和抗性的直肠内SIV攻击的免疫原性和保护功效;以及 2.通过在恒河猴中进行抗原配制和过继转移研究，确定阻断获得严格SIV攻毒的机制。