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

摘要-项目1 目前迫切需要通过制定预防艾滋病毒感染的措施， 一种在初次性行为之前增强保护性免疫力的早期生命疫苗策略。然而，迄今为止， 开发一种可以引发保护性广泛中和抗体（bnAb）的疫苗， 通过生殖系B细胞受体对bnAb表位的有限接合和体细胞超突变水平 实现bnAb所需的时间，以及可能需要长期加强和几年的时间， 使B细胞应答向广泛中和发展。最近的两项研究结果表明， 在母乳喂养和首次性行为之间的时期获得可能提供独特的窗口和免疫 疫苗诱导的bnAb生产的前景：1）儿科免疫系统的高能力超过了 在HIV感染期间，成人的bnAb反应的发展，和2）显着低的体细胞 从HIV感染儿童中分离的bnAbs的高突变水平，这可能提供了指导 通过疫苗接种开发bnAb B细胞克隆。然而，在我们的理解中有一个差距， 早期生命免疫系统相对于成人免疫系统在通过接种诱导bnAb方面的潜在优势。 因此，项目1建议将免疫应答与bnAb种系长期免疫进行比较- 靶向天然样HIV Env三聚体：婴儿期启动的BG 505 GT1.1 SOSIP三聚体免疫原与 青春期前（以及与项目2中BG 505 Env mRNA婴儿疫苗接种的比较）。 具体来说，本项目的目标1将测试假设，即生命早期免疫的独特灵活性 系统和差异B细胞耐受机制将允许增强B细胞的接合和进化 克隆通过bnAb生殖系靶向SOSIP免疫相比，在老年猴。目标2将 检验以下假设：与青春期前相比，在生命早期开始接种HIV B细胞谱系疫苗 将导致抗体成熟，这将转化为针对HIV的增强的保护性疫苗效力 在初次性行为之前获得。最后，目标3将检验生命早期免疫和 微生物特征预测SOSIP疫苗接种后HIV中和反应的发展， 与该计划的综合系统免疫学核心合作，评估转录组学和 与bnAb前体诱导和2级病毒中和相关的微生物组特征 应答此外，为了建立可翻译性，我们将比较疫苗引起的免疫应答的总体动力学。 美国和马拉维婴儿的体细胞超突变与幼猴的体细胞超突变相比。综合来看， 本项目将提供有关年龄特异性疫苗引起的免疫应答的关键信息， 完善艾滋病毒Env疫苗战略，利用免疫发展，如目标人群， 疫苗时间表、新型佐剂和长期加强，以实现高水平的bnAb 在人群中诱导。

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.