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.

摘要