Baseline host and environmental factors that impact pre-erythrocytic malaria vaccine (hypo)responsiveness in endemic regions

摘要 一种有效的疫苗将与其他公共卫生措施相辅相成，并可能对杜绝 世界范围内疟疾的沉重负担。不幸的是，大多数进入临床晚期的疟疾疫苗 发展，在低收入和中等收入国家显示出中等效果。通过多项 研究表明，在不同的国家和地区使用疫苗时，效力从20%到100%不等 人口。迫切需要更好地了解影响这种变异的因素。即使在一个 农村和城市地区的疫苗效力存在显着差异。这意味着 除了遗传决定因素外，暴露在环境因素中也起着重要作用。如何以及在何种程度上 环境暴露会影响免疫模式，进而影响对疫苗的反应吗？这 这一问题将在目前的提案中得到解决。“组学”平台的技术进步 提高了我们以更公正的方式检查免疫系统的能力。这类平台，涉及 转录学，正被越来越多地应用于理解疫苗反应，取得了令人振奋的结果。 然而，对于疟疾疫苗，没有统一的方法来询问免疫反应性和 尽管队列对公共卫生的重要性和队列的可用性，但已经开发了跨队列的路径 评估临床上相关的结果(预防感染或疾病)。所做的事情更少 关于综合“组学”，比较生活在不同地理位置的人口及其 对疫苗的反应。此外，很少有数据将环境暴露与深度联系起来 免疫系统的变化，如果有的话，这些研究通常一次只解决一个环境因素。 我们建议解决这一问题，不仅评估疟疾疫苗队列中的相关性，而且还应解决 疫苗(低效)反应的潜在机制。我们将建立在现有知识的基础上 可以影响疟疾疫苗反应的免疫过程，并使用来自队列的样本 高维细胞术、RNAseq和抗体询问将有助于提炼和丰富 关于疟疾疫苗(低效)反应性的问题。此外，通过使用人类原代肝细胞 感染恶性疟原虫，我们将使研究更接近组织特异性反应的机制和 推断肝脏对疟疾的红细胞前免疫功能。这一点对Pre-Rate特别重要 红细胞疫苗，其中组织驻留反应可以发挥重要作用。 通过生成关于相同个人的数据，数据集成方法可用于高维调解 分析，将用于确定导致疟疾的特定免疫途径和机制 疫苗(次)反应性。这些信息可用于提高疟疾疫苗的效力，也可用于 确定不会从迄今使用的疫苗方案中受益的个人。它可以指导，在证据中 基于方式、疫苗接种剂量、间隔和佐剂的改变。

ABSTRACT An effective vaccine would complement other public health measures and is likely essential for putting an end to the high burden of malaria worldwide. Unfortunately, most malaria vaccines that entered late-stage clinical development, have shown moderate efficacy in low and middle income countries. Through a number of studies vaccine efficacy was shown to vary from 20% to 100% when used in different countries and populations. Better understanding of factors that influence this variation is urgently needed. Even within a country significant differences in vaccine efficacy in rural and urban areas are present. This implies that exposure to environmental factors plays a major role besides genetic determinants. How and to what extent environmental exposures can influence immune profiles and in turn affect responses to vaccines? This question will be addressed in the current proposal. Technological advances in “omics” platforms have improved our ability to examine the immune system in a more unbiased manner. Such platforms, involving transcriptomics, are being increasingly applied to understand vaccine responses, with promising results. However, for malaria vaccines, no harmonized approach to interrogate immunological reactivities and pathways across cohorts has been developed despite its public health importance and availability of cohorts assessed for a clinically relevant outcome (prevention of infection or disease). Even less has been done regarding integrated “omics”, comparing populations living in different geographical locations and their response to vaccines. Moreover, there are very little data that link environmental exposures to in depth changes in the immune system and if available, the studies often address one environmental factor at a time. We propose to address this and not only assess correlations in malaria vaccine cohorts, but also to address the mechanisms underlying vaccine (hypo)responsiveness. We will build on available knowledge of immunological processes that can affect malaria vaccine responses, and use samples from the cohorts where high dimensional cytometry and RNASeq and antibody interrogations will help to refine and enrich the questions regarding malaria vaccine (hypo)responsiveness. In addition, by using human primary hepatocytes infected with P. falciparum, we will bring the research closer to mechanisms of tissue-specific responses and to extrapolate pre-erythrocytic immunity to malaria in the liver. This is of particular importance for pre- erythrocytic vaccines, where tissue-resident responses can play an important role. By generating data on the same individuals, data integration approaches for high dimensional mediation analysis, will be used to pinpoint the specific immunological pathways and mechanisms that result in malaria vaccine (hypo) responsiveness. This information can be used to improve malaria vaccine efficacy and also to identify individuals who will not benefit from the vaccine regimens used so far. It can direct, in an evidence based manner, alterations to the vaccination dose, intervals and adjuvants.