Project 2: RNA vaccination in early life to induce potent and broad HIV Env-specific antibody responses

摘要-项目2 2017年，全球约有60万年轻人(15-24岁)感染了艾滋病毒-1。年轻女性 15-19岁是受影响最大的年龄段，这一年龄段的艾滋病毒感染率继续上升。因此，一种疫苗可以 预防年轻人感染艾滋病毒仍然是当务之急，需要在首次性行为之前有效。 诱导广谱中和抗体(BNAbs)是HIV疫苗设计的一个主要目标。然而，所以 到目前为止，临床前疫苗试验在诱导bNAbs方面只产生了有限的结果。因此，新的疫苗策略 都是需要的。在这里，我们建议使用HIV Env mRNA疫苗，并在生命早期开始接种疫苗 为发展bNAbs留出必要的时间。我们的理论基础是基于数据，在艾滋病毒感染者中使用bNAbs 与感染艾滋病毒的成年人相比，婴儿发育得更早，频率也更高。此外，艾滋病毒中的bNAbs- 与成人相比，受感染的婴儿表现出较低的躯体超突变，并且更频繁地被定向 对抗多个表位。这些发现表明，婴儿的免疫状况可能会更好地 用于发展bNAbs。事实上，婴儿的滤泡辅助性T细胞(TFH)频率更高， 在驱动生发中心B细胞反应中起关键作用。我们的信使核糖核酸疫苗将包装在脂质纳米粒中。 (LNPs)对TFH具有强大的佐剂活性并允许持续的抗原释放；这两个标准都 一直与中和的广度有关。我们的初步数据证实了一种核苷修饰的HIV环境 Gp160mRNA-LNPs可诱导TFH和GC反应，并促进TILE1和TILE2的诱导 成年恒河猴(RMS)中的NAB。基于这个前提，我们假设HIV环境gp160 在生命早期接种mRNA-LNP疫苗使疫苗诱导的抗体有时间成熟 具有广泛的中和和/或Fc介导的效应器功能的反应，可以在儿童时期增强， 在青春期预防艾滋病毒感染的效果优于#年接种疫苗 青春期前。我们将通过比较相同HIV疫苗的免疫原性来检验这一假设 对婴幼儿或青春期前的RMS，并确定其对直肠内颤动的保护效果 青春期习得(目标1)。通过应用几种系统生物学方法和生物信息学 通过管道，我们将确定导致bNab反应的发育途径。我们将使用系统 免疫学方法表征伴随有效的分子和微生物特征 在每个年龄段内接种疫苗，进一步完善疫苗战略，包括佐剂设计 (目标2和3)。为了加强我们的NHP研究的翻译潜力，我们将进行以下分析 乙肝疫苗在恒河猴和人类婴儿中平行诱导B细胞反应。这些数据是预期的 告知最佳年龄、间隔、加强次数以及免疫细胞和微生物之间必须 通过疫苗接种和佐剂选择产生，实现保护性免疫。

ABSTRACT – Project 2 Globally, about 600,000 young adults (15-24 years of age) became infected with HIV-1 in 2017. Young women age 15-19 years are most affected, and HIV-infection in this age group continue to rise. Therefore, a vaccine to prevent HIV acquisition in young adults remains a top priority and needs to be effective prior to sexual debut. The induction of broadly neutralizing antibodies (bnAbs) represents a major goal in HIV vaccine design. Yet, so far, preclinical vaccine trials have only yielded modest results in eliciting bnAbs. Thus, novel vaccine strategies are needed. Here, we propose to employ an HIV Env mRNA vaccine and to start vaccination in early life to allow for the necessary time to develop bnAbs. Our rationale is based on data that bnAbs in HIV-infected infants develop earlier and at higher frequencies compared to HIV-infected adults. Furthermore, bnAbs in HIV- infected infants exhibit lower somatic hypermutation and, in contrast to adults, are more frequently directed against multiple epitopes. These findings suggest that the infant immune landscape might be better equipped for the development of bnAbs. Indeed, infants have higher frequencies of follicular T helper (TFH) cells that are critical in driving germinal center B cell responses. Our mRNA vaccines will be packaged in lipid nanoparticles (LNPs) that exert potent adjuvant activity for TFH and allow for sustained antigen release; both criteria have been associated with neutralization breadth. Our preliminary data confirm that a nucleoside-modified HIV Env gp160 mRNA-LNPs can induce potent TFH and GC responses and promote the induction of tier 1 and tier 2 nAbs in adult rhesus macaques (RMs). Based on this premise, we hypothesize that an HIV Env gp160 mRNA-LNP vaccine administered in early life allows for the time to mature vaccine-induced antibody responses with broadly neutralizing and/or Fc-mediated effector functions that can be boosted in childhood, and that protection against HIV acquisition in adolescence is superior to that achieved by vaccination in preadolescence. We will test this hypothesis by comparing the immunogenicity of the same HIV vaccine given either to infant or to preadolescent RMs and determine the protective efficacy against intrarectal SHIV acquisition in adolescence (Aim 1). By applying several systems biology approaches and bioinformatic pipelines, we will identify the developmental pathways resulting in bnAb responses. We will use system immunology approaches to characterize the molecular and microbial signatures that accompany effective vaccination within each of the age groups, further refining the vaccine strategies, including adjuvant design (Aims 2 and 3). To enhance the translational potential of our NHP studies, we will perform an analysis of Hepatitis B vaccine-induced B cell responses in rhesus and human infants in parallel. These data are expected to inform the optimal age, intervals, number of boosts, and immune cell and microbial interactions that must be generated through vaccination and adjuvant selection to achieve protective immunity.