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HIV-1。年轻女性 15-19岁年龄组受影响最大，这一年龄组的艾滋病毒感染继续上升。因此，疫苗 预防年轻人感染艾滋病毒仍然是首要任务，需要在初次性行为之前有效。 广泛中和抗体（bnAb）的诱导代表HIV疫苗设计的主要目标。然而， 到目前为止，临床前疫苗试验在诱导bnAb方面只取得了适度的结果。因此，新的疫苗策略 是必要的。在这里，我们建议使用HIV Env mRNA疫苗，并在生命早期开始接种， 为开发bnAb留出必要的时间。我们的理论基础是基于HIV感染者中的bnAb 与感染艾滋病毒的成年人相比，婴儿发病更早，发病率更高。此外，艾滋病毒中的bnAbs- 感染的婴儿表现出较低的体细胞超突变，与成人相比， 针对多个表位。这些发现表明，婴儿的免疫状况可能更好地装备 用于bnAb的开发。事实上，婴儿有更高频率的滤泡性T辅助细胞（TFH）， 在驱动生发中心B细胞反应中至关重要。我们的mRNA疫苗将被包装在脂质纳米颗粒中 （LNP），其对TFH发挥有效的佐剂活性并允许持续的抗原释放;两个标准都具有 与中和宽度有关。我们的初步数据证实，核苷修饰的HIV Env gp 160 mRNA-LNP可诱导有效的TFH和GC应答，并促进第1层和第2层的诱导。 成年恒河猴（RM）中的nAb。基于这一前提，我们假设HIV Env gp 160 在生命早期给予mRNA-LNP疫苗允许有时间使疫苗诱导的抗体成熟 具有广泛中和和/或Fc介导的效应子功能的应答，其可在儿童期加强， 在青春期预防艾滋病毒感染上级接种疫苗， 青春期前我们将通过比较给予的相同HIV疫苗的免疫原性来检验这一假设。 对婴儿或青春期前RM的保护作用，并确定对直肠内SHIV的保护作用 青春期的学习（Aim 1）通过应用几种系统生物学方法和生物信息学 管道，我们将确定导致bnAb反应的发展途径。我们将使用系统 免疫学方法来表征分子和微生物的签名，伴随着有效的 在每个年龄组内进行疫苗接种，进一步完善疫苗策略，包括佐剂设计 (Aims 2和3）。为了提高我们的NHP研究的翻译潜力，我们将进行分析， B型肝炎疫苗在恒河猴和人类婴儿中诱导的B细胞应答平行。这些数据预计 以告知最佳年龄，间隔，加强次数，以及免疫细胞和微生物的相互作用， 通过疫苗接种和佐剂选择产生保护性免疫。

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.