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

SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效

• 批准号: 10370480
• 负责人: KOEN K VAN ROMPAY
• 金额: $ 21.76万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370480
• 关键词: 2019-nCoV; AIDS/HIV problem; Achievement; Adjuvant; Adolescence; Adolescent; Adult; Age; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Autologous; B-Lymphocytes; Cell Communication; Cell Lineage; Cells; Childhood; Clinical Research; Collaborations; Development; Dose; Epidemic; Evolution; Funding; Future; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Human; Human Milk; Immune; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Immunologics; Immunology; Infant; Infection; Infrastructure; Life; Macaca mulatta; Mediating; Messenger RNA; Microbiology; Modeling; Molecular; Monkeys; Passive Immunization; Pathway interactions; Plasma; Population; Prevention; Proteins; RNA vaccine; Regimen; Rhesus; Risk; Sexual Transmission; System; Systems Biology; Target Populations; Testing; Time; Translations; Vaccination; Vaccine Clinical Trial; Vaccine Design; Vaccines; Vertical Disease Transmission; Virus; Woman; Work; Youth; age group; design; immunogenicity; infancy; insight; lipid nanoparticle; microbial; microbial signature; microbiome; microbiota; microorganism interaction; neutralizing antibody; nonhuman primate; novel; preadolescence; preclinical study; predictive signature; prevent; programs; response; sexual debut; simian human immunodeficiency virus; transcriptome; transcriptomics; transmission process; vaccination strategy; vaccine candidate; vaccine response; vaccine-induced antibodies; young adult

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.

摘要-总体 每年有近60万新的艾滋病毒感染发生在青少年/年轻人（15 - 24岁）中， 艾滋病毒感染人数继续上升。只有实现消除艾滋病毒/艾滋病的目标， 当一种有效的疫苗方案可以在青春期前，在性行为之前， 出道然而，即使是最有前途的HIV包膜（Env）疫苗平台也未能诱导高度- 在临床前和临床研究中对成人的保护性免疫。有趣的是，最近的研究表明， HIV感染后的持久、多功能和广泛中和抗体（bnAb）反应发生率更高， 通常，与成人相比，在婴儿中的效力相等或更强。然而，在我们的 了解与快速诱导HIV bnAb和效应物相关的免疫学机制 抗体在婴儿免疫系统中发挥作用。 这种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HIV免疫。这项工作建立在我们目前的HIVRAD计划的基础上， 开发HIV Env疫苗方案以预防婴儿感染HIV。我们定义了最优的 在婴儿免疫系统中达到最大免疫原性的疫苗间隔、佐剂和剂量，以及 确定同时进行被动bnAb-主动HIV Env免疫不会损害疫苗诱导的 免疫反应。在这个更新的HIVRAD计划中，我们假设HIV Env疫苗平台 在生命早期给予并在青春期前加强，将获得更持久，更广泛和多功能的 免疫反应，预防性传播比开始免疫更有效 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 候选物，bnAb生殖系靶向SOSIP三聚体（项目1）和脂质纳米颗粒mRNA疫苗（项目 2)在婴儿期开始接种，在整个儿童期加强接种， 恒河猴模型（非人灵长类（NHP）核心），并测试它们对直肠内同源 和异源性SHIV感染。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（综合系统免疫学核心（ISIC））。的 行政核心为科学、财政和其他方案提供全方位的支持。 管理和监督。通过利用疫苗诱导应答成熟的延长窗口， 并确定了早期免疫接种对有效抗艾滋病毒反应的机制优势， 该计划将告知目标人群和艾滋病毒Env疫苗的设计， 保护