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 有效的疫苗将补充其他公共卫生措施，并且可能对于结束这种情况至关重要 不幸的是，大多数疟疾疫苗已进入后期临床阶段。 通过一些低收入和中等收入国家的发展，已显示出一定的效果。 研究表明，在不同国家和地区使用时，疫苗功效有 20% 到 100% 不等。 即使在同一人群中，也迫切需要更好地了解影响这种变化的因素。 国家农村和城市地区的疫苗功效存在显着差异。 除了遗传决定因素之外，环境因素的暴露也起着重要作用。 环境暴露会影响免疫特征，进而影响对疫苗的反应吗？ 当前提案将解决“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，包括此类平台。 转录组学正越来越多地应用于了解疫苗反应，并取得了有希望的结果。 然而，对于疟疾疫苗，没有统一的方法来询问免疫反应和 尽管其对公共卫生的重要性和队列的可用性，跨队列的途径已经被开发出来 评估临床相关结果（预防感染或疾病）的工作就更少了。 关于综合“组学”，比较生活在不同地理位置的人口及其 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针对一种环境因素。 我们建议解决这个问题，不仅评估疟疾疫苗队列的相关性，而且解决 我们将利用现有的知识来了解疫苗（低）反应的机制。 可能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完善和丰富 有关疟疾疫苗（低）反应性的问题此外，通过使用人原代肝细胞。 感染恶性疟原虫后，我们将使研究更接近组织特异性反应的机制 推断红细胞前对肝脏中疟疾的免疫力，这对于前红细胞来说特别重要。 红细胞疫苗，其中组织驻留反应可以发挥重要作用。 通过生成同一个体的数据，用于高维中介的数据集成方法 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 该信息可用于提高疟疾疫苗的功效以及 有证据表明，它可以确定哪些人不会从迄今为止使用的疫苗方案中受益。 基于方式，改变疫苗接种剂量、间隔时间和佐剂。