Integrating human and non-human primate data to understand the acquisition of pre-erythrocytic immunity in the face of previous malaria exposure

整合人类和非人类灵长类动物数据，以了解在面对先前的疟疾暴露时获得红细胞前免疫力

• 批准号: 10343399
• 负责人: Sean C Murphy
• 金额: $ 102.86万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343399
• 关键词: Acute; Address; Affect; Africa South of the Sahara; Age; Animal Model; Animals; Antigen-Antibody Complex; Area; Biological Markers; Blood; Blood specimen; Bone Marrow; CD8-Positive T-Lymphocytes; Cells; Chronic; Clinical; Clinical Trials; Complex; Data; Disease; Erythrocytes; Europe; Evolution; Exhibits; Goals; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunization; Immunologic Markers; Immunologics; Immunology; Immunosuppression; Incidence; Individual; Infection; Infection prevention; Inflammation; Laboratories; Lead; Liver; Macaca mulatta; Macaca nemestrina; Malaria; Malaria Vaccines; Maps; Measures; Modeling; Natural Immunity; Parasitemia; Parasites; Pattern; Performance; Peripheral; Persons; Plasmodium; Primates; Publishing; Resources; Sampling; Scientist; Site; Sporozoites; Symptoms; T memory cell; T-Lymphocyte; Testing; Tissue Sample; Tissues; Vaccinated; Vaccination; Vaccines; acute infection; adaptive immune response; adaptive immunity; animal data; base; chronic infection; circumsporozoite protein; clinical trial participant; density; design; efficacy trial; exhaustion; experience; exposed human population; human data; immunogenicity; immunoregulation; insight; inter-institutional; malaria infection; mouse model; nonhuman primate; novel; peripheral blood; preclinical trial; response; transmission process; vaccine candidate; vaccine efficacy; vaccine trial; volunteer

ABSTRACT Pre-erythrocytic (PE) malaria vaccines that completely prevent infection in malaria non-endemic regions have often failed to achieve equally high-level protection when tested in endemic regions. Data from animal models and humans has identified certain factors that may be contributing to this difference. Active or previous Plasmodium infections rank highly amongst these factors because infection is known to significantly impact innate and adaptive immune responses to malaria vaccines. We hypothesize that previous malaria exposure is a key driver of the suboptimal immunity observed in clinical trials of PE vaccines in endemic areas. However, a full assessment of how such conditions affect pre-erythrocytic immune responses is lacking in large part because much of the protective immune repertoire against PE malaria exists as tissue resident memory T cells in the liver, which is inaccessible in human clinical trials. Here, we propose to address this question of malaria vaccine hyporesponsiveness in endemic regions by performing vaccine studies in previously-infected versus naïve non-human primates (NHP) where we can study the tissue-specific response down to the single cell level and integrate these with data from peripheral blood samples from similarly-vaccinated human clinical trial participants in endemic and non-endemic regions. Our exhaustive studies in NHPs will be specifically guided by hypotheses derived directly from human data. The emerging high-density data will then be used to identify mechanisms, build models and formulate concrete hypotheses that can then be validated across a number of clinical trial samples with the overall goal of elucidating patterns or biomarkers that map with protection/lack of protection and immunogenicity/lack of immunogenicity in malaria-naïve and -experienced volunteers. Thus, we aim to: 1) define protective liver-resident PE immunity at the single cell level; 2) identify the mechanisms by which previous malaria exposure impacts baseline and innate immunity; 3) build models of the complex interplay between baseline, innate, and adaptive immunity and; 4) use these to identify strategies to overcome hyporesponsiveness to PE vaccines in endemic areas. This U01 project combines an inter-institutional, inter- disciplinary team of basic, translational, and clinical scientists from within and outside malaria whose unique expertise, resources, and collaborative style will create breakthroughs insights about this highly complex yet critically important vaccine challenge.

抽象的 完全预防疟疾非流行地区感染的前红细胞（PE）疟疾疫苗 在流行地区进行测试时，往往无法实现同等高水平的保护。来自动物模型的数据 人类已经确定了可能导致这种差异的某些因素。活跃或以前 疟原虫感染在这些因素中排名靠前，因为已知感染会显着影响 对疟疾疫苗的先天和适应性免疫反应。我们假设以前接触过疟疾 这是流行地区 PE 疫苗临床试验中观察到的免疫欠佳的关键驱动因素。然而，一个 很大程度上缺乏对此类情况如何影响红细胞前免疫反应的全面评估 因为针对 PE 疟疾的大部分保护性免疫组库以组织驻留记忆 T 细胞的形式存在 在肝脏中，这是人体临床试验中无法达到的。在这里，我们建议解决疟疾问题 通过在既往感染者和已感染者中进行疫苗研究来了解流行地区的疫苗反应低下 幼稚的非人类灵长类动物 (NHP)，我们可以研究单个细胞的组织特异性反应 将这些数据与来自类似疫苗接种的人类临床试验的外周血样本的数据进行整合 流行区和非流行区的参与者。我们对 NHP 的详尽研究将得到专门指导 通过直接从人类数据得出的假设。然后，新兴的高密度数据将用于识别 机制，建立模型并制定具体的假设，然后可以在多个方面进行验证 临床试验样本的总体目标是阐明与保护/缺乏相关的模式或生物标志物 未接触过疟疾和有经验的志愿者中的保护和免疫原性/缺乏免疫原性。因此，我们 目标是： 1) 在单细胞水平上定义保护性肝脏驻留 PE 免疫； 2）确定机制 以前接触过哪些疟疾会影响基线和先天免疫力； 3）建立复杂的模型 基线免疫、先天免疫和适应性免疫之间的相互作用； 4）利用这些来确定克服的策略 流行地区对 PE 疫苗反应低下。这个 U01 项目结合了跨机构、跨 由来自疟疾内外的基础科学家、转化科学家和临床科学家组成的学科团队，其独特的 专业知识、资源和协作方式将为这个高度复杂的领域带来突破性的见解 至关重要的疫苗挑战。