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.

摘要