Synthesizing immunoinformatics and genetic epidemiology to identify signatures of natural functional immunity to malaria parasites

综合免疫信息学和遗传流行病学，以确定对疟疾寄生虫的天然功能免疫特征

• 批准号: 10642330
• 负责人: Christine Markwalter
• 金额: $ 12.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642330
• 关键词: Age; Amino Acid Sequence; Amino Acids; Antibodies; Antibody Response; Antigen Targeting; Antigenic Variation; Antigens; Biological Markers; C-terminal; Catalogs; Chemistry; Child; Clinical; Cohort Studies; Collaborations; Combinatorics; Data; Data Science; Data Set; Development Plans; Discipline; Environment; Epidemiology; Epitopes; Exhibits; Exposure to; Face; Funding; Future; Genetic Polymorphism; Genotype; Goals; Haplotypes; Immune Targeting; Immune response; Immunity; Immunology; Incidence; Individual; Infection; Informatics; Institution; Kenya; Link; Longitudinal Studies; Malaria; Malaria Vaccines; Measurement; Measures; Mentors; Molecular Epidemiology; National Institute of Allergy and Infectious Disease; Nature; Parasites; Participant; Pattern; Peptides; Phenotype; Plasmodium; Plasmodium falciparum; Population; Positioning Attribute; Preventive vaccine; Proteins; Protocols documentation; Recording of previous events; Resources; Sampling; Scientist; Serology; Structure; Time; Training; Translational Research; United States National Institutes of Health; Vaccine Design; Vaccines; Variant; Work; career; career development; circumsporozoite protein; cohort; combinatorial; cross immunity; cross reactivity; deep sequencing; design; field study; genetic epidemiology; high dimensionality; immunogenic; improved; in silico; mortality; next generation; rational design; response; screening; seropositive; training opportunity; vaccine candidate; vaccine development; vaccinology

PROJECT SUMMARY/ABSTRACT An effective malaria vaccine would be transformative for malaria elimination campaigns. A major challenge to malaria vaccine development is that most immunogenic parasite antigens also exhibit extremely high polymorphism. As a consequence, monovalent vaccines have lower efficacy against mismatched variants due to imperfect cross-protective immunity. Additionally, signatures of naturally-acquired protective immunity, which inform vaccine design, are not clearly legible in most field studies, where the background of parasite diversity and accumulated lifetime exposure can bury functional responses among biomarkers of exposure. Understanding how natural exposure to protein variants confers protection is essential for designing vaccines that can overcome parasite diversity and provide robust protection. Additionally, linking infections with parasites harboring variant haplotypes to subsequent immune responses against those specific variant epitopes would support this conclusion and could identify cross-reactivity or cross-protection patterns and inform multivalent vaccine target screening and design. Parallel analysis of parasite antigenic variation and variant-specific host antibody responses in a multi-year longitudinal study of a consistent cohort offers an unprecedented opportunity to triangulate variant positions and epitopes within polymorphic malaria antigens that contribute to protective immunity. I will leverage densely-sampled longitudinal parasite genotype data (36 months of observation in over 500 participants) and samples collected as part of an ongoing, NIH-funded cohort study and combine this rich sampling structure with high-dimensional serological measurements, molecular epidemiology, and data science to develop in silico approaches for epitope screening. Specifically, I will: (1) correlate protective clinical reinfection phenotypes with P. falciparum CSP C-terminal amino acid positions and epitopes in silico, (2) compare cumulative parasite haplotype exposure profiles to position- and epitope-specific seroreactivity against field- derived CSP sequences, and (3) measure and compare protection conferred by non-CSP antigen candidates and variants in a naturally-exposed population. Upon completion of these aims, I will have developed new data science-driven approaches for screening polymorphic antigens for epitopes and vaccine targets, which could inform rational vaccine design for malaria elimination campaigns. The proposed work builds upon the PI’s strengths in malaria molecular epidemiology and serology and serves as a bridge to in silico vaccinology. It builds on existing collaborations, resources, and a supportive institutional environment. The proposed projects and career development plan offer extensive training opportunities in epidemiology, immunology, informatics, and translational research, which will position the PI to launch an independent career aimed at reducing the burden of malaria and training the next generation of scientists at the intersection of sero- and molecular epidemiology, bioanalytical chemistry, and data science.

项目摘要/摘要 有效的疟疾疫苗将是消除疟疾运动的变革。对 疟疾疫苗的发育是，大多数免疫原性抗原也暴露了极高的 多态性。结果，单价疫苗的效率较低 不完美的跨保护免疫史。此外，自然获得的保护性免疫史的签名，这是 在大多数现场研究中，在寄生虫多样性背景的情况下，告知疫苗设计并不清楚 累积的终生暴露会掩埋在暴露的生物标志物之间的功能反应。 了解自然暴露于蛋白质变异的保护是如何设计疫苗的必不可少的 这可以克服寄生虫的多样性并提供强大的保护。另外，将感染与寄生虫联系起来 携带变异单倍型以随后针对那些特定变异表位的免疫反应将 支持此结论，并可以识别交叉反应性或交叉保护模式并为多价提供信息 疫苗目标筛查和设计。寄生虫抗原变异和特异性宿主的平行分析 一致队列的多年纵向研究中的抗体反应提供了前所未有的机会 三角变异位置和多态性疟疾抗原中有助于保护的变体位置和表位 免疫。我将利用纵向寄生虫基因型数据（超过36个月的观察 500名参与者）和作为NIH资助的同类研究的一部分收集的样品，并结合了这一富裕 具有高维血清学测量，分子流行病学和数据科学的采样结构 在硅方法中开发表位筛选。具体来说，我将：（1）相关的保护性临床再感染 具有恶性疟原虫CSP C末端氨基酸位置和硅中的表位的表型，（2）比较 累积的寄生虫单倍型暴露概况，以对现场的位置和表位特异性呼吸反应性 派生的CSP序列，（3）测量和比较非CSP抗原候选者提供的保护 和自然曝光人群中的变体。完成这些目标后，我将开发新数据 科学驱动的方法用于筛选表位和疫苗靶标的多态性抗原 疟疾消除运动的信息理性疫苗设计。拟议的工作建立在PI的 疟疾分子流行病学和血清学的优势是硅疫苗学的桥梁。它建立 关于现有的合作，资源和支持的机构环境。拟议的项目以及 职业发展计划为流行病学，免疫学，信息信息和信息提供了广泛的培训机会 转化研究，该研究将定位PI启动旨在减少燃烧的独立职业 疟疾和在血清和分子流行病学的交集中训练下一代科学家， 生物分析化学和数据科学。