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: 10347973
• 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/10347973
• 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 Set; Epigenetic Process; Falciparum Malaria; Future; Goals; Government; 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; adaptive immune response; base; 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; 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 最先进的候选疟疾疫苗，S，对临床疟疾只有部分疗效 如果给幼儿看，就会出现一些小插曲。此外，接种疫苗后12-18个月内效力下降， 由于许多儿童的免疫反应程度低和/或迅速减弱，加强剂量是 只有部分有效。次优免疫应答和免疫应答减弱的免疫学机制 疫苗的效力仍不清楚。我们建议利用多组学、系统生物学的方法来 定义预测免疫原性和保护性的基线和疫苗诱导签名，如下 近日，S在马拉维为幼儿接种疫苗。这个项目将利用一个非同寻常的 综合研究基线和疫苗诱导的RTS免疫反应的机会，S，年轻人 儿童，与马拉维国际疟疾研究英才中心合作 (ICEMR)。马拉维ICEMR正在研究RTS、S预防疟疾感染和 作为世界卫生组织赞助的儿童纵向队列传播的一部分 实施研究。通过利用我们特征良好的队列，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中执行系统 预测免疫原性和对初次接种的保护的基线特征分析 对阵爱国阵线。我们将使用一种多组学方法，使用Bulk RNA-Seq，血清代谢组学，通过 飞行时间与表观遗传学图谱(EpiTOF)和单细胞表观遗传学图谱以图谱基线 签名在初选RTS前，S为300名马拉维儿童接种了疫苗。我们的目标将是执行一个 对这些正交数据集进行综合分析，以定义可用于预测 呼吸道合胞病毒的免疫原性和疗效，S疫苗。在目标2中，我们将执行系统分析 疫苗诱导的特征，预测免疫原性和对初免和加强免疫的保护 接种肺炎支原体疫苗。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细胞检测的多重分析，以全面描述疫苗- S在马拉维儿童接种RTS疫苗后诱导签名。我们将进行综合分析 以定义可用于预测免疫原性的疫苗诱导签名和 对RTS的疗效，S接种疫苗。这些目标的成功实现将为我们提供对 对RTS、S疫苗免疫次优的分子机制和疫苗生物标志物的产生 诱导免疫和保护。