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

摘要 一种有效的疫苗将补充其他公共卫生措施，并可能对结束艾滋病至关重要。 全球疟疾的高负担。不幸的是，大多数进入后期临床阶段的疟疾疫苗 在低收入和中等收入国家，通过若干 研究表明，在不同国家使用时，疫苗的有效性从20%到100%不等， 人口。迫切需要更好地了解影响这种变化的因素。甚至在 农村和城市地区的疫苗效力存在显著差异。这意味着 除了遗传因素外，环境因素也起着重要作用。如何以及在何种程度上 环境暴露会影响免疫状况，进而影响对疫苗的反应？这 这个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。这些平台，包括 转录组学正越来越多地应用于了解疫苗反应，并取得了可喜的成果。 然而，对于疟疾疫苗，没有统一的方法来询问免疫反应性， 尽管队列的公共卫生重要性和队列的可用性， 评估临床相关结局（预防感染或疾病）。做的更少 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，如果可行的话，这些研究通常一次解决一个环境因素。 我们建议解决这一问题，不仅评估疟疾疫苗队列的相关性， 疫苗（低）反应性的机制。我们将利用现有的知识， 免疫过程，可以影响疟疾疫苗的反应，并使用样本的队列，其中 高维细胞计数和RNASeq和抗体询问将有助于完善和丰富 关于疟疾疫苗（低）反应性的问题。此外，通过使用人原代肝细胞， 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， 推断肝脏中的红细胞前免疫力与疟疾有关。这对前期工作尤为重要。 红细胞疫苗，其中组织驻留应答可以发挥重要作用。 通过在相同的个体上生成数据， 分析，将用于查明导致疟疾的特定免疫途径和机制， 疫苗（低）反应性。这些信息可用于提高疟疾疫苗的效力， 确定那些不能从迄今为止使用的疫苗方案中获益的人。它可以直接，在一个证据， 根据不同的接种方式，改变疫苗接种剂量、间隔和佐剂。

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.