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

影响流行地区红细胞前疟疾疫苗（低）反应性的基线宿主和环境因素

• 批准号: 10586094
• 负责人: Maria Yazdanbakhsh
• 金额: $ 65万
• 依托单位: LEIDEN UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-08 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586094
• 关键词: Address; Adjuvant; Affect; Africa; African; American; Antibodies; Antigen Presentation; Area; Attenuated; B-Lymphocytes; Bayesian Modeling; Biological; Biological Assay; Cell physiology; Cells; Chemoprophylaxis; Complement; Country; Cytometry; Data; Data Analytics; Data Engineering; Disease; Dose; Ebola; Environmental Exposure; Environmental Risk Factor; Erythrocytes; Europe; European; Exposure to; Falciparum Malaria; Foundations; Gabon; Genetic; Genetic Determinism; Geographic Locations; Hepatocyte; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Income; Individual; Infection prevention; Inflammation; Influenza; Integration Host Factors; Knowledge; Link; Liver; Lymphocyte; Malaria; Malaria Vaccines; Measures; Mediation; Metabolic; Methodology; Molecular; Myelogenous; Nature; North America; Outcome; Parasites; Pathway interactions; Phenotype; Plasmodium falciparum; Plasmodium falciparum vaccine; Play; Population; Process; Public Health; Recording of previous events; Regimen; Reporting; Research; Role; Rural; Safety; Sampling; Secure; Shapes; Sporozoites; Subunit Vaccines; T-Lymphocyte; Technology; Testing; Tetanus Vaccine; Time; Tissues; Vaccination; Vaccines; Variant; Whole Organism; Yellow Fever; acquired immunity; clinical development; clinically relevant; cohort; data integration; data management; evidence base; experimental study; global health; glycosylated IgG; high dimensionality; immune activation; immunogenicity; immunoregulation; improved; influenza virus vaccine; innovation; insight; low and middle-income countries; microorganism; multiple omics; response; rural area; transcriptome sequencing; transcriptomics; urban area; vaccine efficacy; vaccine response; vaccine trial; vaccine-induced immunity

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.

抽象的 一种有效的疫苗将完成其他公共卫生措施，可能对结束 全球疟疾的高负担。不幸的是，大多数进入晚期临床的疟疾疫苗 开发显示了低收入国家和中低收入国家的现代效率。通过多个 研究疫苗效率显示在不同国家使用时从20％到100％不等 人群。迫切需要更好地理解影响这种变异的因素。甚至在一个 国家存在疫苗效率和城市地区的疫苗效率显着差异。这意味着这一点 除了遗传确定剂以外，暴露于环境因素还起着重要作用。如何以及在多大程度上 环境暴露会影响免疫学特征，进而影响对疫苗的反应吗？这 当前提案将解决问题。 “ OMIC”平台中的技术进步具有 提高了我们以更公正的方式检查免疫系统的能力。这样的平台，涉及 转录组学，越来越多地应用于了解疫苗反应，并有希望的结果。 然而，对于疟疾疫苗，没有统一的审问免疫反应性和 跨人群的途径已经开发了目的地 评估临床相关结果（预防感染或疾病）。甚至少了 关于综合的“ OMIC”，比较生活在不同地理位置及其的人口 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 免疫系统的变化和如果有的话，研究通常一次解决一个环境因素。 我们建议解决这个问题，而不仅要解决疟疾疫苗队列中的评估相关性，而且还解决 疫苗（HYPO）反应性的机制。我们将基于可用知识 可以影响疟疾疫苗反应的免疫过程，并使用同类的样品 高维细胞术和RNASEQ和抗体审查将有助于完善和丰富 有关疟疾疫苗（HYPO）反应性的问题。另外，使用人类原发性肝细胞 被恶性疟原虫感染，我们将使研究更接近组织特异性反应的机制和 为了推断肝脏中疟疾前的肠细胞免疫。这对于预审查至关重要 红细胞疫苗，组织居民反应可以发挥重要作用。 通过生成同一个人的数据，数据集成方法用于高维中介 分析将用于查明导致疟疾的特定免疫途径和机制 疫苗（低调）反应性。这些信息可用于提高疟疾疫苗效率，也可以 确定那些不会从迄今为止使用的疫苗方案中受益的人。它可以指导，以证据 基于疫苗接种剂量的改变，间隔和调节器。