Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques

摘要--总体 每年有近60万新的艾滋病毒感染发生在青少年/青壮年(15-24岁)中，这是唯一 艾滋病毒感染持续上升的人口。艾滋病毒/艾滋病流行病的结束只能是可以实现的 当一种有效的疫苗方案可以在青春期前、性行为之前诱导长期保护性免疫时 首次亮相。然而，即使是最有希望的HIV包膜(Env)疫苗平台也未能诱导高度... 临床前和临床研究中成人的保护性免疫。有趣的是，最近的研究表明 HIV感染后的持久、多功能和广谱中和抗体(BNab)反应更多 通常，与成人相比，婴儿的能力相当或更强。然而，我们的差距仍然存在 对HIV bNab及其效应器快速诱导的免疫学机制的理解 抗体在婴儿免疫系统中发挥作用。 此次HIVRAD更新的总体目标是利用早期生命免疫系统的独特品质 HIV保护性免疫的疫苗激发。这项工作建立在我们当前的HIVRAD计划基础上，重点是 制定预防婴儿感染艾滋病毒的HIV env疫苗方案。我们定义了最优的 在婴儿免疫系统中实现最大免疫原性的疫苗间隔、佐剂和剂量，以及 确定同时被动的bNab主动HIV Env免疫不会损害疫苗引发的 免疫反应。在这一更新的HIVRAD计划中，我们假设HIV Env疫苗平台 在生命早期使用并在青春期前加强使用将获得更持久、更广泛和更多功能的效果 免疫应答，在防止性传播方面比免疫接种更有效 在青春期前。我们将比较两种最有希望的HIV Env疫苗的疫苗反应 候选的bNab种系靶向SOSIP三聚体(项目1)和脂质纳米颗粒mRNA疫苗(项目 2)从婴儿期开始，从整个童年到青春期前开始接种疫苗 恒河猴模型(非人灵长类(NHP)核心)，并测试其对直肠内同种异体动物的疗效 和异源SIV挑战青春期。我们将应用系统免疫学来定义 与HIV Env疫苗抗体相关的免疫学、转录学和微生物学特征 BNab前体的功能和诱导(综合系统免疫学核心(ISIC))。这个 管理核心为科学、财政和其他规划提供全方位的支持 管理和监督。通过利用疫苗诱导的反应成熟的延长窗口 并确定了早期生命免疫对有效的抗艾滋病毒反应的机制优势，这 该计划将向目标人群提供信息，并设计一种艾滋病毒环境疫苗，将提供终身 保护。

ABSTRACT – Overall Nearly 600,000 new HIV infections occur yearly in adolescents/young adults (ages 15-24 years), the only population in which HIV infections continue to rise. The end of the HIV/AIDS epidemic will be achievable only when an effective vaccine regimen can elicit long-term protective immunity in preadolescence, prior to sexual debut. Yet, even the most promising HIV envelope (Env) vaccine platforms have failed to induce highly- protective immunity in adults in preclinical and clinical studies. Interestingly, recent studies indicate that durable, polyfunctional, and broad neutralizing antibody (bnAb) responses following HIV infection occur more frequently and are equal or more potent in infants compared to that of adults. Yet, there remains a gap in our understanding of the immunologic mechanisms associated with the rapid induction of HIV bnAb and effector antibody functions within the infant immune landscape. The overall goal of this HIVRAD renewal is to harness the unique qualities of the early life immune system for vaccine elicitation of protective HIV immunity. This work builds on our current HIVRAD Program focusing on the development of HIV Env vaccine regimens for prevention of infant HIV acquisition. We defined the optimal vaccine intervals, adjuvants, and doses to achieve maximal immunogenicity in the infant immune system, and determined that concurrent passive bnAb-active HIV Env immunization does not impair vaccine-elicited immune responses. In this renewal HIVRAD Program, we hypothesize that HIV Env vaccine platforms administered in early life and boosted in preadolescence will achieve more durable, broad, and polyfunctional immune responses and be more efficacious at prevention of sexual transmission than initiation of immunization in preadolescence. We will compare vaccine responses to two of the most promising HIV Env vaccine candidates, bnAb germline-targeting SOSIP trimers (Project 1) and lipid nanoparticle mRNA vaccines (Project 2) initiated in infancy with boosting throughout childhood to that of initiation of vaccination in preadolescence in the rhesus model (Nonhuman Primate (NHP) Core), and test their efficacy against intrarectal homologous and heterologous SHIV challenge in adolescence. We will apply systems immunology to define the immunologic, transcriptomic, and microbiologic signatures associated with the HIV Env vaccine antibody function and induction of bnAb precursors (Integrated Systems Immunology Core (ISIC)). The Administrative Core provides the full range of support for scientific, fiscal, and other programmatic management and oversight. By leveraging the extended window for maturation of vaccine-induced responses and defining the mechanistic advantages of early life immunization for effective anti-HIV responses, this Program will inform the target population and design of an HIV Env vaccine that will provide life-long protection.