Scientific Project 1: Malaria Immune Responses to Pre-erythrocytic Malaria Vaccination or Infection

科学项目 1：对红细胞前疟疾疫苗或感染的疟疾免疫反应

• 批准号: 10631098
• 负责人: KENNETH D STUART
• 金额: $ 40.37万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631098
• 关键词: Adaptive Immune System; Affect; Antibodies; Antibody Response; Antigen Receptors; Antigens; Attenuated; B-Lymphocytes; Benchmarking; Biological Assay; Cell Lineage; Cell physiology; Cells; Characteristics; Development; Erythrocytes; Evaluation; Event; Falciparum Malaria; Fingerprint; Future; Generations; Genetic; Genetic Programming; Genetic Transcription; Goals; HIV; Human; Human Characteristics; Immune; Immune response; Immunity; Immunization; Immunologics; Immunology; Infection; Innate Immune System; Lead; Malaria; Malaria Vaccines; Mediating; Mediator; Methods; Molecular; Monoclonal Antibodies; Multiparametric Analysis; Outcome; Pathway interactions; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Plasmodium falciparum; Population; Process; SARS-CoV-2 infection; Sampling; Serum; Signal Transduction; Sorting; Sporozoites; Stains; System; Systems Biology; T cell response; T-Lymphocyte; Testing; Vaccination; Vaccines; Variant; adaptive immunity; cytokine; high dimensionality; improved; insight; malaria infection; monocyte; multiple omics; response; single cell sequencing; therapy development; vaccine development; vaccine efficacy; vaccine response; vaccine trial

Scientific Project 1: Immune Responses to Pre-erythrocytic Malaria Vaccination or Infection Abstract This project will identify and characterize key characteristics of human immune responses to the pre-erythrocytic (PE) falciparum malaria infection and vaccination that targets this stage with a focus on responses that correlate with protection or infection. We hypothesize that responses by protected vs. not protected, and infected subjects will identify the relevant immune constituents and processes. We will use complementary immunological analyses and systems immunology approaches and characterize responses in the innate and adaptive immune compartments to identify cellular and humoral responses that correlate with protection or infection. We will: 1. Define cellular and soluble mediators of early innate responses and test the hypothesis that innate response variations affect adaptive responses and are predictive of protective immunity development. We will also analyze the influence of prior malaria exposure on vaccine efficacy. 2. Define the stimulation and temporal programming of vaccine-elicited protective adaptive immune cells with a focus on the stimulation, signaling, and programming of T and B cells and which pathways lead to protective phenotypes. We hypothesize that key signaling and maturation pathways lead to protective adaptive immunity. Details of antigen receptor usage, cell lineages, transcriptional programming, and phenotypic changes will be integrated with innate signaling events to define events that shepherd cells through recall and maturation during immunization. 3. Connect protective phenotypes with adaptive immune functional activity to identify functional characteristics of cellular and humoral responses that correlate with protection. Antigen specific reactive T cell responses will be analyzed by cytometric, functional, single-cell sequencing, and multi-omics methods. B functions will be analyzed by deep multi-parametric analysis of sera and monoclonal antibodies. This will identify key functional characteristics of cell populations and antibodies that are associated with immune protection. Integration of cell phenotypes and functional activities of multiple immune compartments will give insights into immune signatures and processes that define protective responses to malaria vaccines and provide benchmarks to guide vaccine development. Overall, our integrated immunological and systems biology analyses of samples from malaria vaccine trials will identify immune signatures during critical stages following vaccination which correlate with protection against malaria or result from its infection and advance understanding of factors that impact development of elicited protective immune responses.

科学项目 1：对红细胞前疟疾疫苗或感染的免疫反应 抽象的 该项目将识别和表征人类对前红细胞免疫反应的关键特征 (PE) 恶性疟疾感染和针对此阶段的疫苗接种，重点是相关的反应 具有保护或感染作用。我们假设受保护与不受保护以及受感染受试者的反应 将识别相关的免疫成分和过程。我们将使用补充免疫学 分析和系统免疫学方法并表征先天性和适应性免疫的反应 区室来识别与保护或感染相关的细胞和体液反应。我们将： 1. 定义早期先天反应的细胞和可溶性介质，并检验先天反应的假设 变异影响适应性反应，并可预测保护性免疫的发展。我们还将分析 既往疟疾暴露对疫苗功效的影响。 2. 定义刺激和时间编程 疫苗引发的保护性适应性免疫细胞，重点是刺激、信号传导和编程 T 细胞和 B 细胞的组成以及哪些途径导致保护性表型。我们假设关键信号和 成熟途径导致保护性适应性免疫。抗原受体用途、细胞谱系的详细信息， 转录编程和表型变化将与先天信号事件整合以定义 在免疫过程中引导细胞回忆和成熟的事件。 3. 连接保护表型 具有适应性免疫功能活性，可识别细胞和体液的功能特征 与保护相关的反应。抗原特异性反应性 T 细胞反应将通过以下方式进行分析： 细胞计数、功能、单细胞测序和多组学方法。 B 函数将被分析为 血清和单克隆抗体的深度多参数分析。这将确定关键的功能特征 与免疫保护相关的细胞群和抗体。细胞表型的整合和 多个免疫区室的功能活动将深入了解免疫特征和过程 定义了对疟疾疫苗的保护性反应，并提供了指导疫苗开发的基准。 总体而言，我们对疟疾疫苗试验样本的综合免疫学和系统生物学分析将 在疫苗接种后的关键阶段识别与预防相关的免疫特征 疟疾或其感染引起的疾病，并加深对影响其发展的因素的了解 保护性免疫反应。