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

摘要——总体 每年有近 600,000 例新的艾滋病毒感染发生在青少年/年轻人（15-24 岁）中，这是唯一 艾滋病毒感染人数持续上升。只有实现艾滋病毒/艾滋病流行的终结 当有效的疫苗方案可以在青春期前、性行为之前引发长期保护性免疫力时 首次亮相。然而，即使是最有前途的 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 感染后发生持久、多功能和广泛的中和抗体 (bnAb) 反应的情况更多 频繁发生，并且与成人相比，对婴儿的作用相同或更有效。然而，我们仍然存在差距 了解与快速诱导 HIV bnAb 和效应物相关的免疫机制 抗体在婴儿免疫环境中发挥作用。 HIVRAD 更新的总体目标是利用生命早期免疫系统的独特品质 疫苗激发保护性艾滋病毒免疫力。这项工作建立在我们当前的 HIVRAD 计划的基础上，重点关注 开发 HIV Env 疫苗方案以预防婴儿感染艾滋病毒。我们定义了最优的 疫苗间隔、佐剂和剂量，以在婴儿免疫系统中实现最大免疫原性，以及 确定同时被动 bnAb 主动 HIV Env 免疫不会损害疫苗诱发 免疫反应。在这个更新的 HIVRAD 计划中，我们假设 HIV Env 疫苗平台 在生命早期进行管理并在青春期前加强将实现更持久、更广泛和多功能 免疫反应，在预防性传播方面比开始免疫更有效 在青春期前。我们将比较两种最有前途的 HIV Env 疫苗的疫苗反应 候选药物、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) 从婴儿期开始接种，并在整个儿童期加强接种，直至青春期前开始接种 恒河猴模型（非人类灵长类动物（NHP）核心），并测试其针对直肠内同源物的功效 和青春期异源 SHIV 挑战。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、转录组学和微生物学特征 bnAb 前体的功能和诱导（集成系统免疫学核心 (ISIC)）。的 行政核心为科学、财政和其他计划提供全方位的支持 管理和监督。利用延长的窗口期使疫苗诱导的反应成熟 并确定生命早期免疫对于有效抗艾滋病毒反应的机制优势，这 该计划将告知目标人群和 HIV 包膜疫苗的设计，该疫苗将提供终身保护 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.