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 总体项目目标是确定因衰减而对疫苗接种的免疫反应的关键特征 恶性疟原虫孢子菌（APFSPZS）导致免疫力进行灭菌。 免疫力是由于Celarrar和对PF抗原（AG）（AGS）的体液反应引起的 感染的肝阶段（LS）。 使用尖端免疫分析，相关信息和系统免疫学的反应 将鉴定ASPZ疫苗 - 各个诱导的细胞和体液反应，与疟疾的保护相关 幼稚和疟疾经历了编译的正交分析工具和方法 确定相关的免疫细胞子集，AG受体（AR）曲目，谱系和特殊性 AGS。 保护和验证将通过：AIM 1：确定ASPZ疫苗 诱导的细胞和体液应对，与无偏的细胞相关。 分析将表征与疫苗接种和CHMI的保护动力学 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多聚合物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。 疫苗接种和CHMI。 确定曲目属性并鉴定疫苗诱导的PF AG特异性AR AG特异性将通过关节单细胞和TCR/BCR序列分析联系起来。 抗体特异性将通过酵母显示方法确定。 抗体特异性与保护相关。 赋予反应性T细胞的细胞抗体反应。 基于细胞的细胞内细胞因子染色（ICS），激活诱导标记（AIM）和单细胞序列 基于多摩尼克分析。 评估B细胞在保护中的角色。 使用既定平台的生物信息学分析，策展和共享。 对ASPZ PF疫苗接种的复杂抗原组成的不可接受反应的特征 以及与保护并提供一组免疫相关的效应器过程 防止疟疾的免疫力指导​​疫苗开发。