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.

项目概要/摘要 最先进的候选疟疾疫苗 RTS,S 对临床疟疾仅提供部分功效 给幼儿时会出现发作。此外，疫苗接种后 12-18 个月内功效减弱， 许多儿童的免疫反应强度较低和/或迅速减弱，因此需要加强剂量 仅部分有效。免疫反应欠佳和减弱的免疫机制 和疫苗的功效仍不清楚。我们建议利用多组学、系统生物学方法 定义预测免疫原性和保护的基线和疫苗诱导的特征，如下 马拉维幼儿的 RTS,S 疫苗接种。该项目将利用非凡的优势 有机会全面研究年轻人对 RTS,S 的基线和疫苗诱导的免疫反应 通过与马拉维国际疟疾研究卓越中心合作，为儿童提供帮助 （ICEMR）。马拉维 ICEMR 正在研究 RTS,S 预防疟疾感染和 作为世界卫生组织资助的一项儿童纵向队列的传播 实施研究。通过利用我们充分表征的队列，详细的免疫学特征 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 分析预测免疫原性和初次疫苗接种保护的基线特征 反对Pf。我们将使用多组学方法，使用批量 RNA 测序、血清代谢组学、细胞计数法 表观遗传分析 (EpiTOF) 的飞行时间和单细胞表观遗传分析以分析基线 300 名马拉维儿童在初次 RTS,S 疫苗接种前签名。我们的目标是执行 对这些正交数据集进行综合分析，以定义可用于预测的基线特征 RTS,S 疫苗接种的免疫原性和功效。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以及对初级和加​​强免疫的保护 接种 Pf 疫苗。我们将使用多组学方法，使用批量 RNA 测序、血清代谢组学、 血清细胞因子和 CSP 特异性 T 细胞检测的多重分析，以全面分析疫苗- 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 这些数据集来定义疫苗诱导的特征，可用于预测免疫原性和 RTS,S 疫苗接种的功效。这些目标的成功完成将提供对 RTS、S 疫苗接种次优免疫的分子机制，并产生疫苗的生物标志物 诱导免疫和保护。