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.

项目概要/摘要 有效的疟疾疫苗将为消除疟疾运动带来变革，这是消除疟疾运动面临的一项重大挑战。 疟疾疫苗的开发是大多数免疫原性寄生虫抗原也表现出极高的免疫原性 因此，单价疫苗对错配变异的功效较低。 此外，还有自然获得的保护性免疫的特征，即不完善的交叉保护性免疫。 告知疫苗设计，在大多数实地研究中都不清楚，其中寄生虫多样性的背景 终生累积的暴露可能会掩盖暴露生物标志物中的功能反应。 了解自然暴露于蛋白质变体如何提供保护对于设计疫苗至关重要 可以克服寄生虫多样性并提供强有力的保护。 携带变异单倍型以应对针对这些特定变异表位的后续免疫反应 支持这一结论，并可以识别交叉反应性或交叉保护模式并告知多价 疫苗靶点筛选和设计。寄生虫抗原变异和变异特异性宿主的并行分析。 对一致队列进行的多年纵向研究中的抗体反应提供了前所未有的机会 对多态性疟疾抗原内有助于保护性的变异位置和表位进行三角测量 我将利用密集采样的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 资助的正在进行的队列研究的一部分收集的样本，并将这些丰富的 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 具体来说，我将：（1）将保护性临床再感染关联起来。 表型与恶性疟原虫 CSP C 末端氨基酸位置和表位在计算机中的比较，(2) 比较 累积寄生虫单倍型暴露曲线对针对现场的位置和表位特异性血清反应性 衍生的 CSP 序列，以及 (3) 测量和比较非 CSP 候选抗原所赋予的保护作用 以及自然暴露人群中的变异。完成这些目标后，我将开发出新的数据。 科学驱动的方法用于筛选多态性抗原的表位和疫苗靶标，这可以 为消灭疟疾运动提供合理的疫苗设计。拟议的工作建立在 PI 的基础上。 疟疾分子流行病学和血清学方面的优势，并作为计算机疫苗学的桥梁。 现有的合作、资源和支持性制度环境。 职业发展计划提供流行病学、免疫学、信息学和 转化研究，这将使 PI 能够开展独立的职业生涯，旨在减轻负担 疟疾的研究并在血清流行病学和分子流行病学的交叉领域培训下一代科学家， 生物分析化学和数据科学。