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: 10570273
• 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/10570273
• 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; Exhibits; Goals; Human; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunization; Immunologic Markers; Immunologics; Immunology; Immunosuppression; Incidence; Individual; Infection; Infection prevention; Inflammation; Inflammatory; Innate Immune Response; Laboratories; 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-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; disorder control; efficacy trial; experience; exposed human population; human data; immunogenicity; immunoregulation; insight; inter-institutional; malaria infection; model building; mouse model; nonhuman primate; novel; peripheral blood; response; tissue resident memory T cell; 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 肺炎前（PE）疟疾疫苗完全阻止疟疾非内态区域感染 在内在区域进行测试时，通常无法获得同样高级的保护。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。活动或以前 疟原虫感染在这些因素中很高，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调查。我们假设以前的疟疾暴露是 在内在区域的PE疫苗临床试验中观察到的次级免疫学的主要驱动力。但是， 全面评估这种情况如何影响芽孢杆菌的免疫回避，这在很大程度上缺乏 因为由于组织居民记忆T细胞而存在许多受保护的免疫恐惧症。 在人类临床试验中无法访问的肝脏中。在这里，我们建议解决这个疟疾问题 通过对先前感染的疫苗研究进行疫苗研究，在流行地区的疫苗不足。 幼稚的非人类隐私（NHP），我们可以研究对单个细胞的组织特异性反应 水平并将其与来自类似疫苗接种人类临床试验的外周血样本的数据集成在一起 流行和非内在地区的参与者。我们在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，建立模型和制定混凝土假设，然后可以在多个多个 临床试验样品的总体目标是阐明图案或生物标志物，这些模式或生物标志物绘制的保护/缺乏 保护和免疫原性/缺乏疟疾和经验的志愿者中的免疫原性。那，我们 目的是：1）在单细胞水平上定义受保护的肝脏居住的PE免疫； 2）通过 以前的疟疾暴露会影响基线和先天免疫； 3）建立综合体的模型 基线，先天和适应性免疫之间的相互作用； 4）使用这些来确定克服的策略 内在地区对PE疫苗的反应不足。这个U01项目结合了一个机构间的， 来自疟疾内外的基本，翻译和临床科学家的纪律团队，他们独特 专业知识，资源和协作风格将创建有关这种高度复杂尚未的突破性见解 至关重要的疫苗挑战。