Systems biological assessment of vaccination-induced protective immunity in African children

项目总结/摘要 最先进的疟疾候选疫苗RTS，S对临床疟疾仅提供部分效力 当给年幼的孩子。此外，效力在接种后12-18个月内减弱， 许多儿童的免疫应答强度较低和/或迅速减弱， 只是部分有效。免疫应答的次优和减弱的免疫学机制 疫苗的有效性尚不清楚。我们建议利用多组学，系统生物学方法， 定义基线，以及预测免疫原性和保护的疫苗诱导特征， 在马拉维为幼儿接种RTS、S疫苗。这个项目将利用一个非凡的 有机会全面研究基线和疫苗诱导的免疫反应RTS，S在年轻 通过与马拉维国际疟疾研究卓越中心合作， （ICEMR）。马拉维ICEMR正在研究RTS，S预防疟疾感染的有效性， 作为世界卫生组织赞助的一项研究的一部分， 执行研究。通过利用我们充分表征的队列，详细的免疫学表征 宿主反应和最先进的免疫计算模型，我们将在目标1中执行一个系统 预测免疫原性和初次接种保护的基线特征分析 我们将使用多组学方法，使用批量RNA-seq，血清代谢组学，细胞计数， 飞行时间表观遗传学分析（EpiTOF）和单细胞表观遗传学分析基线 在300名马拉维儿童中进行RTS，S初次接种前签名。我们的目标是 这些正交数据集的综合分析，以定义可用于预测 RTS，S疫苗免疫原性和效力。在目标2中，我们将进行系统分析， 疫苗诱导的特征，可预测免疫原性和对初次和加强免疫的保护 我们将使用多组学方法，使用批量RNA-seq，血清代谢组学， 血清细胞因子和CSP特异性T细胞测定的多重分析，以全面描述疫苗- 在马拉维儿童接种RTS，S疫苗后诱导的特征。我们将进行综合分析 定义疫苗诱导的特征，可用于预测免疫原性， RTS，S疫苗的效力。这些目标的成功实现将使人们对 RTS，S疫苗接种的次优免疫力的分子机制，以及疫苗的生物标志物产量- 诱导免疫和保护。

PROJECT SUMMARY/ABSTRACT The most advanced malaria vaccine candidate, RTS,S, provides only partial efficacy against clinical malaria episodes when given to young children. Furthermore, efficacy wanes within 12-18 months post vaccination, with many children having low magnitude and/or rapidly waning immune responses, and booster doses are only partially efficacious. The immunologic mechanisms underlying sub-optimal and waning immune responses and vaccine efficacy remain unclear. We propose to utilize a multi-omics, systems biology approach to define baseline, and vaccine-induced signatures that predict immunogenicity and protection, following RTS,S vaccination of young children in Malawi. This project will take advantage of an extraordinary opportunity to comprehensively study baseline and vaccine-induced immune responses to RTS,S in young children through a collaboration with the Malawi International Centers of Excellence in Malaria Research (ICEMR). The Malawi ICEMR is studying the effectiveness of RTS,S to prevent malaria infection and transmission in a longitudinal cohort of children as part of a World Health Organization-sponsored implementation study. By leveraging our well-characterized cohort, detailed immunological characterization of host responses, and state-of-the-art computational models of immunity, we will in Aim 1 perform a systems analysis of baseline signatures that predict immunogenicity and protection from primary vaccination against Pf. We will use a multi-omics approach, using bulk RNA-seq, metabolomics of serum, cytometry by time of flight with epigenetic profiling (EpiTOF), and single cell epigenetic profiling to profile baseline signatures prior to primary RTS,S vaccination in 300 Malawian children. Our goal will be to perform an integrated analysis of these orthogonal datasets to define a baseline signature that can be used to predict the immunogenicity and efficacy of RTS,S vaccination. In Aim 2, we will perform a systems analysis of vaccine-induced signatures that predict immunogenicity and protection from primary and booster vaccination against Pf. We will use a multi-omics approach, using bulk RNA-seq, metabolomics of serum, multiplex analysis of serum cytokines and CSP-specific T cell assays, to comprehensively profile vaccine- induced signatures following RTS,S vaccination in Malawian children. We will perform an integrated analysis of these datasets to define vaccine-induced signatures that can be used to predict the immunogenicity and efficacy of RTS,S vaccination. The successful completion of these aims will provide deep insight into the molecular mechanisms underlying suboptimal immunity to RTS,S vaccination, and yield biomarkers of vaccine- induced immunity and protection.