Collective Responses to Malaria Vaccination

对疟疾疫苗接种的集体反应

• 批准号: 10569619
• 负责人: KENNETH D STUART
• 金额: $ 70万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569619
• 关键词: Antibodies; Antibody Response; Antibody Specificity; Antigen Presentation; Antigen Receptors; Antigens; Attenuated; B-Cell Antigen Receptor; B-Lymphocytes; Base Sequence; Benchmarking; Bioinformatics; Biological Assay; Biophysics; Blood; Cell physiology; Cells; Characteristics; Clinical Trials; Complex; Cytometry; Data; Epitopes; Erythrocytes; Gene Expression; Gene Expression Profile; Genes; Goals; Immune; Immune response; Immunity; Immunologics; Immunology; In Vitro; Infection; Informatics; Infrastructure; Innate Immune Response; Joints; Kinetics; Knowledge; Link; Liver; Malaria; Malaria Vaccines; Mediating; Metadata; Methods; Molecular; Monoclonal Antibodies; Parasites; Peptide/MHC Complex; Peptides; Persons; Phenotype; Plasmodium falciparum; Population; Process; Resources; Role; Sampling; Sequence Analysis; Sorting; Specificity; Sporozoites; Stains; System; T Chain; T-Lymphocyte; T-cell receptor repertoire; United States National Institutes of Health; Vaccination; Vaccine Antigen; Vaccines; Yeasts; adaptive immune response; analytical tool; antigen-specific T cells; biophysical properties; cytokine; data portal; data sharing; experience; family structure; immune function; insight; longitudinal analysis; multiple omics; novel; novel vaccines; protein expression; prototype; response; single cell sequencing; transcriptomics; vaccine development; vaccine efficacy; vaccine evaluation; vaccine-induced antibodies

SUMMARY The overall project goal is to identify key characteristics of immune responses to vaccination with attenuated Plasmodium falciparum sporozoites (aPfSPZs) which results in sterilizing immunity. We hypothesize that this immunity is due to cellular and humoral responses to specific to Pf antigens (Ags) that are presented during the liver stage (LS) of infection. We propose a detailed longitudinal analysis of innate and adaptive immune responses using cutting-edge immunological analyses, associated informatics, and systems immunology. We will identify aSPZ vaccine-induced cellular and humoral responses that correlate with protection in malaria naïve and malaria experienced subjects. Complementary orthogonal analytical tools and approaches will identify relevant immune cell subsets, Ag receptor (AR) repertoires, lineages, and specificities to protective Ags. The functional characteristics of the immune cells and products, including antibodies, that correlate with protection will be identified and validated. This will be accomplished by: Aim 1: Identifying aSPZ vaccine induced cellular and humoral responses that are associated with protection. Unbiased and Ag specific cellular profiling will characterize the kinetics of protection associated responses to vaccination and CHMI. Follow-on analyses will profile identified Ag-specific adaptive and innate cellular responses by mass cytometry (CyTOF), multiplexed pMHC/Ag multimer staining, and multi-omic single cell sequencing to determine protection- associated gene and protein expression signatures and functional antibody responses, which will be extended in later aims. Aim 2: Identify protection associated T and B cell Ag receptor (AR) repertoires at key times after vaccinations and CHMI. Natively paired and single ARs chains from T and B cells will be sequenced to determine repertoire attributes and identify vaccine induced Pf Ag specific ARs. Cellular transcriptomic profiles and Ag specificities will be linked by joint single cell and TCR/BCR sequence analyses. Novel AR-Ag and antibody specificities will be identified by yeast display methods. This aim will identify T and B cell ARs and antibody Ag specificities that are correlated with protection. Aim 3: Identifying functional characteristics of cellular and antibody responses that confer protection. Sorted reactive T cells will be assayed by Ag-specific CyTOF-based intracellular cytokine staining (ICS), activation-induce marker (AIM), and single-cell sequence based multi-omics analyses. The biophysical and functional analyses of monoclonal antibodies will be used to assess B cell roles in protection. The comprehensive project data will undergo integrated multi-factorial bioinformatic analysis, curation and sharing using established platforms. Overall, this project will identify key characteristics of the intricate immune responses to the complex antigenic composition of aSPZ Pf vaccination and the effector processes that correlate with protection and provide a set of immune correlates of protective immunity against malaria to guide vaccine development.

概括 总体项目目标是识别免疫复杂的关键特征，以便疫苗接种 恶性疟原虫孢子岩（APFSPZ）导致免疫史进行消毒。我们假设这是 免疫力是由于对PF抗原（AG）（AG）的细胞和体液反应引起的 感染的肝阶段（LS）。我们提出了对先天和适应性免疫的详细纵向分析 使用前沿免疫学分析，相关信息和系统免疫学的反应。我们 将识别ASPZ疫苗诱导的细胞和体液反应，与疟疾的保护相关 幼稚和疟疾经历了学科。互补的正交分析工具和方法将 确定相关的免疫细胞子集，Ag受体（AR）曲目，谱系和规格以保护 AGS。免疫细胞和产品（包括抗体）的功能特性与 保护将被识别和验证。这将通过：AIM 1：识别ASPZ疫苗 与保护相关的诱导细胞和体液反应。公正和AG特异性细胞 分析将表征与疫苗接种和CHMI相关反应的动力学。跟进 分析将通过质量细胞术（Cytof），鉴定出AG特异性的自适应和先天细胞反应， 多路复用PMHC/AG多聚机存储和多摩尼克单细胞测序，以确定保护 相关的基因和蛋白质表达特征和功能抗体反应，将扩展 在以后的目标中。 AIM 2：在关键时间确定相关的T和B细胞Ag受体（AR）曲目 疫苗接种和CHMI。来自T和B细胞的本机配对和单个AR链将被测序 确定曲目属性并识别疫苗诱导的PF Ag特异性AR。细胞转录组轮廓 AG规格将通过关节单细胞和TCR/BCR序列分析链接。新颖的Ar-ag和 抗体规格将通过酵母显示方法确定。这个目标将确定T和B细胞ARS，并且 与保护相关的抗体AG规格。目标3：确定功能特征 会议保护的细胞和抗体反应。排序的反应性T细胞将通过Ag特异性分配 基于细胞的细胞内细胞因子染色（ICS），激活诱导的标记（AIM）和单细胞序列 基于多媒体分析。单克隆抗体的生物物理和功能分析将用于 评估B细胞在保护中的作用。全面的项目数据将进行集成的多因素 使用既定平台的生物信息学分析，策展和共享。总体而言，该项目将确定关键 对ASPZ PF疫苗接种的复杂抗原组成的复杂免疫反应的特征 以及与保护并提供一组受保护的免疫复合物的效应过程 防止疟疾的免疫力指导​​疫苗开发。