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

摘要 在疟疾非流行地区完全预防感染的红细胞前（PE）疟疾疫苗， 当在流行地区进行测试时，往往不能达到同样高水平的保护。动物模型数据 人类已经发现了可能导致这种差异的某些因素。活动或既往 疟原虫感染在这些因素中排名很高，因为已知感染会显著影响 先天性和适应性免疫反应的疟疾疫苗。我们假设先前的疟疾暴露是 在流行地区PE疫苗临床试验中观察到的次优免疫力的关键驱动因素。但 对这些疾病如何影响红细胞前免疫应答的全面评估在很大程度上缺乏 因为大部分针对PE疟疾的保护性免疫库以组织驻留记忆T细胞的形式存在 在人类临床试验中无法达到的肝脏中。在此，我们提议解决疟疾问题， 通过在既往感染者与 幼稚的非人类灵长类动物（NHP），我们可以研究组织特异性反应，直到单细胞 将这些数据与来自类似疫苗接种人类临床试验的外周血样本的数据进行水平整合 流行和非流行地区的参与者。我们在NHP的详尽研究将具体指导 通过直接从人类数据中得出的假设。新出现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，然后可以在一些验证 临床试验样本，总体目标是阐明与保护/缺乏相关的模式或生物标志物。 未患疟疾和有疟疾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 目的：1）在单细胞水平上定义保护性肝脏驻留PE免疫; 2）通过以下方式确定机制： 以前的疟疾暴露影响基线和先天免疫; 3）建立复杂的模型 基线，先天性和适应性免疫之间的相互作用; 4）使用这些来确定克服 流行区PE疫苗的低反应性。该U 01项目结合了机构间、 来自疟疾内外的基础、转化和临床科学家组成的学科团队， 专业知识、资源和协作方式将为这一高度复杂但 疫苗的重大挑战。

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.