Preclinical Development of Ad26/Env Vaccines for HIV

在我们目前的IPCAVD计划(U19AI096040)中，我们已经开发了另一种血清型腺病毒载体， 生物信息优化的HIV-1马赛克抗原，以及稳定的Env gp140蛋白免疫原。我们已经展示了 AD26-Env/Gag/Pol Prime，Env gp140 Protein Boost(AD26/Env)疫苗提供了前所未有的 恒河猴对异源SIVmac251攻击后感染的保护作用 猴子，以及针对SIV-SF162P3挑战的强大保护。相关保护 由系统血清学确定的多功能抗体反应。我们还推出了AD26/Env， AD26/MVA和AD26/MVA/Env马赛克疫苗进入1/2a期临床试验在美国、东非、 南非和泰国。在未来5年的IPCAVD计划中，我们建议定义范围和 我们的主要AD26/Env疫苗方案在恒河猴中实现保护的机制，以促进我们的 将疫苗方案带入2b/3期人类疗效研究，并开发改进的下一代 HIV-1疫苗候选。 在这个项目中，我们假设我们目前的AD26/Env马赛克疫苗以及简化疫苗 方案将通过一致的机制保护来自不同支系的SHIV，包括 多功能非中和抗体。我们进一步假设，下一代HIV-1疫苗 引起NAB幅度和广度增加的候选人将提高对 希沃克病毒在恒河猴身上的挑战。为了检验这些假设，我们提出了以下具体目标： 具体目的1.确定我们的AD26/Env嵌合体疫苗的保护效果和保护机制 以及针对恒河猴不同分支来源的SHIV的简化疫苗方案 特定目标2.开发一种改进的HIV-1疫苗策略，在恒河猴中引起增强的NAB反应 猴子

In our current IPCAVD program (U19 AI096040), we have developed alternative serotype adenovirus vectors, bioinformatically optimized HIV-1 mosaic antigens, and stable Env gp140 protein immunogens. We have shown that the Ad26-Env/Gag/Pol prime, Env gp140 protein boost (Ad26/Env) vaccine afforded unprecedented protective efficacy against acquisition of infection following heterologous SIVmac251 challenges in rhesus monkeys, as well as robust protection against SHIV-SF162P3 challenges. Protection correlated with polyfunctional antibody responses as determined by systems serology. We have also advanced the Ad26/Env, Ad26/MVA, and Ad26/MVA/Env mosaic vaccines into phase 1/2a clinical trials in the United States, East Africa, South Africa, and Thailand. Over the next 5 years of this IPCAVD program, we propose to define the extent and mechanism of protection achieved by our lead Ad26/Env vaccine regimen in rhesus monkeys, to advance our lead vaccine regimen into phase 2b/3 efficacy studies in humans, and to develop an improved next generation HIV-1 vaccine candidate. In this Project, we hypothesize that our current Ad26/Env mosaic vaccine as well as simplified vaccine regimens will protect against SHIVs derived from diverse clades by a consistent mechanism involving polyfunctional non-neutralizing antibodies. We further hypothesize that a next generation HIV-1 vaccine candidate that elicits augmented NAb magnitude and breadth will improve protective efficacy against SHIV challenges in rhesus monkeys. To test these hypotheses we propose the following Specific Aims: Specific Aim 1. To define the protective efficacy and protective mechanism of our Ad26/Env mosaic vaccine and simplified vaccine regimens against SHIVs derived from diverse clades in rhesus monkeys Specific Aim 2. To develop an improved HIV-1 vaccine strategy that elicits augmented NAb responses in rhesus monkeys