Preclinical Development of Ad26/Env Vaccines for HIV

在我们目前的IPCAVD项目（U19 AI 096040）中，我们已经开发了替代血清型腺病毒载体， 生物信息学优化的HIV-1嵌合抗原和稳定的Env gp 140蛋白免疫原。我们已经表明 Ad 26-Env/Gag/Pol prime，Env gp 140蛋白加强（Ad 26/Env）疫苗提供了前所未有的 恒河猴在异源SIVmac 251攻击后对获得性感染的保护效力 猴，以及对SHIV-SF 162 P3攻击的强大保护。保护与 通过系统血清学测定的多功能抗体应答。我们还改进了Ad 26/Env， Ad 26/MVA和Ad 26/MVA/Env嵌合体疫苗在美国、东非、非洲、 南非和泰国。在未来5年的IPCAVD计划中，我们建议定义 我们的主要Ad 26/Env疫苗方案在恒河猴中实现的保护机制，以推进我们的 将疫苗方案引入人体2b/3期疗效研究，并开发改进的下一代疫苗 HIV-1候选疫苗。 在这个项目中，我们假设我们目前的Ad 26/Env嵌合疫苗以及简化的疫苗， 方案将通过一致的机制保护来自不同分支的SHIV， 多功能非中和抗体。我们进一步假设下一代HIV-1疫苗 增强NAb幅度和宽度的候选物将提高对 恒河猴中的SHIV挑战。为了验证这些假设，我们提出以下具体目标： 具体目标1。目的探讨腺病毒26/Env嵌合体疫苗的免疫效果及免疫保护机制 以及针对恒河猴中来自不同分支的SHIV的简化疫苗方案 具体目标2。开发一种改进的HIV-1疫苗策略，增强恒河猴的NAb应答 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