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: 10370481
• 负责人: Sallie R. Permar
• 金额: $ 3.55万
• 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/10370481
• 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; 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 近60万新的艾滋病毒感染每年发生在青少年/年轻人（15-24岁）中，唯一 艾滋病毒感染继续增加的人群。艾滋病毒/艾滋病流行的终结只会成功 当有效的疫苗方案可以在性行为之前引起长期保护的免疫力 首次亮相。然而，即使是最有前途的艾滋病毒信封（ENV）疫苗平台也未能高度诱导 临床前和临床研究成人的保护性免疫学。有趣的是，最近的研究表明 HIV感染后，耐用，多功能和广泛的中和抗体（BNAB）反应发生了更多 与成年人相比，婴儿经常具有相等或更多的潜力。但是，我们的 了解与HIV BNAB快速诱导和效应子相关的免疫机制 婴儿免疫景观中的抗体功能。 此Hivrad更新的总体目标是利用早期免疫系统的独特品质 疫苗引起受保护的HIV免疫。这项工作以我们当前的Hivrad计划为基础 HIV INV疫苗方案的开发用于预防婴儿HIV获取。我们定义了最佳 疫苗间隔，调节剂和剂量以实现婴儿免疫系统中的最大免疫原性，并且 确定并发的被动性BNAB活性HIV ENV免疫抑制不会损害疫苗引起的疫苗 免疫反应。在此更新Hivrad计划中，我们假设HIV Env疫苗平台 在早期生命中进行管理并在前期促进，将实现更耐用，宽阔和多功能 免疫反应和预防性传播方面的效率比免疫倡议更有效 在前青年中。我们将比较疫苗的反应与两个最有前途的HIV ENV疫苗 候选者，bnab系生殖线sosip三聚体（项目1）和脂质纳米粒子mRNA疫苗（项目 2）启动婴儿期，在整个童年时期都提高了疫苗接种的疫苗接种。 恒河猴模型（非人类灵长类动物（NHP）核心），并测试其直肠内同源的效率 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，转录组和微生物学特征 BNAB前体的功能和诱导（集成系统免疫学核心（ISIC））。这 行政核心为科学，财政和其他计划提供了全面的支持 管理和监督。通过利用扩展窗口以成熟疫苗诱导的反应 并确定早期生命免疫的机械优势以进行有效的抗HIV反应，这是 计划将告知目标人群和艾滋病毒环境疫苗的设计，该疫苗将提供终身 保护。