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

非洲儿童疫苗接种引起的保护性免疫力的系统生物学评估

• 批准号: 10553671
• 负责人: James Beeson
• 金额: $ 80万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553671
• 关键词: ATAC-seq; Address; Africa; African; Antibodies; Antibody Response; Biological Markers; Cells; Cellular Assay; Cessation of life; Child; Childhood; Clinical; Collaborations; Computer Models; Coupled; Cytometry; Data; Data Analyses; Data Set; Epigenetic Process; Falciparum Malaria; Future; Goals; Government; Herpes zoster disease; Human; Immune response; Immunity; Immunoglobulin G; Immunologic Epidemiology; Immunologic Monitoring; Immunologics; Immunology; Incidence; Innate Immune Response; Longitudinal cohort; Malaria; Malaria Vaccines; Malawi; Measurement; Measures; Molecular; Molecular Profiling; Nature; Plasma; Plasmodium falciparum; Population; Research; Secondary Immunization; Serum; System; Systems Analysis; Systems Biology; T-Lymphocyte; Time; Vaccination; Vaccine Design; Vaccines; Work; World Health Organization; Yellow Fever; adaptive immune response; biological systems; booster vaccine; cohort; computational pipelines; cytokine; effectiveness study; epigenetic profiling; global health; gut microbiota; immunogenicity; implementation study; insight; international center; malaria infection; malaria transmission; metabolomics; multidisciplinary; multiple omics; predictive signature; prevent; response; seasonal influenza; single-cell RNA sequencing; tool; transcriptome sequencing; transcriptomics; vaccine candidate; vaccine efficacy; vaccine immunogenicity; vaccine-induced immunity

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.

项目摘要/摘要 最先进的疟疾疫苗候选者RTS，S仅提供针对临床疟疾的部分功效 发作时发作时。此外，疫苗接种后12-18个月内疗效降低， 由于许多儿童的幅度较低和/或迅速减弱的免疫反应，并且增强剂量为 只有部分有效。免疫反应下层状和减弱的免疫机制 疫苗功效尚不清楚。我们建议利用多摩普的系统生物学方法 定义基线和疫苗诱导的特征，以预测免疫原性和保护 RTS，在马拉维的幼儿疫苗接种。这个项目将利用一个非凡的 在年轻人中全面研究基线和疫苗诱导的RT的免疫反应的机会 通过与马拉维国际疟疾卓越研究中心合作的儿童 （ICEMR）。马拉维ICEMR正在研究RTS的有效性，以防止疟疾感染和 作为世界卫生组织赞助的一部分，在纵向儿童的纵向队列中传播 实施研究。通过利用我们良好特征的队列，详细的免疫学特征 主机响应和最先进的免疫计算模型，我们将在AIM 1中执行系统 分析预测免疫原性和保护免受一次疫苗接种的基线特征 反对PF。我们将使用大量RNA-seq，血清代谢组学，细胞术，通过 表观遗传分析（Epitof）和单细胞表观遗传分析的飞行时间 在初级RTS之前的签名，300名马拉维儿童的疫苗接种。我们的目标是执行 这些正交数据集的集成分析，以定义可用于预测的基线签名 RTS的免疫原性和功效，S疫苗接种。在AIM 2中，我们将对 疫苗诱导的特征，可预测免疫原性和保护原发和助推器 针对PF的疫苗接种。我们将使用大量RNA-seq，血清代谢组学使用多词方法， 血清细胞因子和CSP特异性T细胞测定的多重分析，以全面概况疫苗 - 在RTS之后引起的签名，马拉维儿童的疫苗接种。我们将进行综合分析 这些数据集用于定义疫苗诱导的特征，这些特征可用于预测免疫原性和 RTS的功效，S疫苗接种。这些目标的成功完成将为您深入了解 对RT，S疫苗接种和疫苗的生物标志物的次优度免疫的分子机制 诱导的免疫力和保护。