Project 1: Age-related impact on early life B cell lineage-designed SOSIP HIV Env vaccination

项目 1：年龄相关对早期生命的影响 B 细胞谱系设计的 SOSIP HIV Env 疫苗接种

• 批准号: 10379077
• 负责人: Sallie R. Permar
• 金额: $ 34.4万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379077
• 关键词: Achievement; Adjuvant; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affect; Age; Antibodies; Antigens; B-Cell Antigen Receptor; B-Lymphocytes; Birth; Breast Feeding; Cell Lineage; Cells; Child; Childhood; Clinical Trials; Clone Cells; Development; Epitopes; Evaluation; Evolution; Frequencies; Gene Expression Regulation; HIV; HIV Infections; HIV immunization; HIV vaccine; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin Somatic Hypermutation; Immunologics; Immunology; Infant; Infusion procedures; Kinetics; Life; Macaca mulatta; Messenger RNA; Microbiology; Monkeys; Mutation; Newborn Infant; Pathway interactions; Patients; Plasma; Population; Probability; Production; RNA vaccination; Risk; Schedule; Sexual Transmission; Somatic Cell; Specificity; System; T cell response; Target Populations; Testing; Time; Translating; Vaccination; Vaccines; Virus; age related; comparative efficacy; design; efficacy study; flexibility; follow-up; immunogenicity; individual variation; infancy; infant infection; mature animal; microbial; microbiome; microbiome signature; neutralizing antibody; nonhuman primate; novel; pediatric human immunodeficiency virus; preadolescence; predictive signature; prevent; programs; protective effect; rational design; rectal; response; sexual debut; simian human immunodeficiency virus; transcriptome; transcriptomics; trial design; vaccination strategy; vaccine development; vaccine efficacy; vaccine response; vaccine strategy; vaccine trial

ABSTRACT – Project 1 There is a critical need to protect adolescents and young adults from HIV infection through the development of an early life vaccine strategy that elicits protective immunity prior to sexual debut. However, to date, efforts to develop a vaccine that can elicit protective broadly neutralizing antibodies (bnAbs) have been challenged both by limited engagement of bnAb epitopes by germline B cell receptors and levels of somatic hypermutation needed for achievement of bnAb, as well as the likely need for long term boosting and several years time to evolve the B cell responses towards broad neutralization. Two recent findings suggest that the low risk of HIV acquisition in the period between breastfeeding and sexual debut might provide unique window and immune landscape for vaccine-induced bnAb production: 1) the high capacity of the pediatric immune system over that of adults for the development of bnAb responses during HIV infection, and 2) the remarkably low somatic hypermutation level in bnAbs isolated from HIV-infected children, which may provide the opportunity to direct development of bnAb B cell clones through vaccination. Yet, there is a gap in our understanding of the potential advantages of the early life immune system over that of adults for induction of bnAbs via vaccination. Thus, Project 1 proposes to compare immune response to long-term immunization with the bnAb germline- targeting native-like HIV Env trimer: BG505 GT1.1 SOSIP trimer immunogen initiated in infancy compared to that of pre-adolescents (as well as comparison to BG505 Env mRNA infant vaccination in Project 2). Specifically, Aim 1 of this project will test the hypothesis that the unique flexibility of the early life immune system and differential B cell tolerance mechanisms will allow enhanced engagement and evolution of B cell clones through bnAb germline-targeting SOSIP immunization compared to that in older monkeys. Aim 2 will test the hypothesis that the initiation of HIV B cell lineage vaccination in early life compared to preadolescence will result in antibody maturation that will translate into enhanced protective vaccine efficacy against HIV acquisition prior to sexual debut. Finally, Aim 3 will test the hypothesis that early life immunologic and microbiologic signatures predict the development of HIV-neutralizing responses to SOSIP vaccination by working with the Program's Integrated Systems Immunology Core, to assess the transcriptomic and microbiome signatures that associated with the induction of bnAb precursor and tier 2 virus neutralization responses. Furthermore, to establish translatability, we will compare the overall kinetics of vaccine-elicited somatic hypermutation in U.S and Malawian infants to that of infant monkeys. Taken together, the results of this Project will provide critical information about age-specific vaccine-elicited immune responses relevant to refining HIV Env vaccine strategies that take advantage of immune development, such as target population, vaccine schedule, novel adjuvants, and long term boosting that will be needed to achieve a high level of bnAb induction in human populations.

摘要 - 项目1 通过开发，保护青少年和年轻人免受艾滋病毒感染的迫切需要 一种早期生命疫苗策略，在性首次亮相之前引起保护性免疫学。但是，迄今为止，努力 开发一种可以引起受保护的广泛中和抗体（BNAB）的疫苗已受到挑战 通过生殖线B细胞受体的BNAB表位和体细胞超突变的水平有限 实现BNAB所需的需要，以及可能需要长期提升的需求以及数年的时间 进化B细胞对广泛神经化的反应。最近的两个发现表明艾滋病毒的风险很低 在母乳喂养和性行会之间的收购时期获取可能会提供独特的窗口和免疫力 疫苗引起的BNAB生产的景观：1）小儿免疫系统的高容量 在HIV感染期间开发BNAB反应的成年人，以及2）非常低的体细胞 与感染HIV感染的儿童分离的BNAB中的超称水平，这可能提供了指导的机会 通过疫苗开发BNAB B细胞克隆。然而，我们对 早期生命免疫系统比成年人通过疫苗诱导BNAB的潜在优势。 这是项目1的提案，将对长期免疫的免疫反应与BNAB种系的免疫反应进行比较 针对天然样的HIV ENV触发：BG505 GT1.1 SOSIP三聚体免疫原在婴儿期开始 预种植者（以及项目2中的BG505 Env mRNA婴儿疫苗的比较）。 具体而言，该项目的目标1将检验以下假设：早期生命免疫的独特灵活性 系统和差异B细胞耐受机制将允许增强B细胞的参与度和演变 与老猴子相比，克隆通过BNAB种系靶向SOSIP免疫。 AIM 2意志 检验以下假设，即早期艾滋病毒B细胞谱系疫苗的倡议与前期疫苗相比 将导致抗体成熟，将转化为对HIV的保护性疫苗效率的增强 在性首次亮相之前获取。最后，AIM 3将检验以下假设，即早期的免疫学和 微生物学特征可以预测HIV中和反应对SOSIP疫苗接种的反应的发展 与该计划的集成系统免疫学核心合作，以评估转录组和 与诱导BNAB前体和第2层病毒神经元化相关的微生物组特征 回答。此外，为了建立可翻译性，我们将比较疫苗吸收的整体动力学 在美国和马拉维婴儿的体细胞超数与婴儿猴子的婴儿。总之，结果 该项目将提供有关特异性疫苗引起的免疫反应的关键信息 精炼利用免疫发育的HIV Env疫苗策略，例如目标人群 疫苗时间表，新颖的调节器和长期提升，将需要获得高水平的BNAB 人口的归纳。