Exploring the roles of acquired immunity and functional constraint in sculpting malaria antigenic diversity in a longitudinal cohort

探索获得性免疫和功能限制在纵向队列中塑造疟疾抗原多样性中的作用

• 批准号: 10465075
• 负责人: Daniel E Neafsey
• 金额: $ 29.04万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-25 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465075
• 关键词: Adult; Age; Alleles; Amino Acids; Antigen Targeting; Antigenic Diversity; Antigenic Variation; Antigens; Biological Assay; Biological Process; Blood; Blood specimen; CRISPR/Cas technology; Child; Clinical; Communicable Diseases; Complement; Data; Development; Disadvantaged; Ecology; Epidemiology; Equilibrium; Erythrocytes; Evolution; Exhibits; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Geographic Locations; Growth; Haplotypes; Human; Immune; Immunity; Immunoglobulin G; Immunologics; Impairment; In Vitro; Individual; Infection; Linkage Disequilibrium; Longitudinal cohort; Malaria; Malaria Vaccines; Mali; Measures; Mediating; Modeling; Molecular; Molecular Epidemiology; Morbidity - disease rate; Natural Selections; Parasites; Participant; Plasma; Plasmodium falciparum; Plasmodium falciparum genome; Population; Population Heterogeneity; Positioning Attribute; Probability; Protein Subunits; Proteins; Role; Sampling; Seasons; Signal Transduction; Structure; Subunit Vaccines; Surveys; Systems Development; Testing; Vaccination; Vaccines; Variant; Work; acquired immunity; age group; age stratification; base; circumsporozoite protein; cohort; cross immunity; density; design; epidemiological model; fitness; genome sequencing; genome-wide; genomic data; infancy; malaria infection; malaria transmission; mathematical model; mortality; next generation sequencing; pathogen; pressure; protein function; recurrent infection; transmission process; vaccine development; whole genome

Malaria parasite antigenic diversity is driven by acquired immunity and bounded by functional constraints. The interplay between these forces, if better understood, could accelerate vaccine development. The genome of Plasmodium falciparum, the eukaryotic parasite that causes the most lethal form of human malaria, exhibits a strong signature of evolutionary interaction with human hosts. While most of the genome exhibits low population diversity, several hundred genes encoding antigenic proteins harbor very high levels of variation resulting from immune-mediated balancing selection. Humans do not develop sterilizing immunity to infection with P. falciparum parasites, but develop naturally acquired immunity (NAI) through recurrent infection that reduces parasite density in the blood, and thus morbidity and mortality. For natural selection to maintain antigenic variability in parasite populations, it must confer a fitness advantage, such that parasites harboring certain variants enjoy enhanced probability of successful transmission to another human host. We recently generated PCR- based next-generation sequencing data from more than 5000 clinical samples to demonstrate that vaccination with the RTS,S/AS01 malaria vaccine, a protein subunit vaccine targeting the circumsporozoite protein (CSP), results in a reduction of subsequent blood-stage infections harboring a CSP genotype identical to the vaccine strain. This indicates that immunity conferred by the vaccine was transiently sterilizing in some individuals, but in an allele-specific manner. To explore whether NAI structures antigenic diversity in a manner similar to the RTS,S vaccine on a much larger set of antigens, and whether some observed variants impair antigen function, we propose to genetically profile parasite antigens in blood samples from different age groups, collected deeply within a single transmission season and longitudinally across transmission seasons in Mali, using whole-genome sequencing surveys. Using mathematical models, we will elucidate the mechanistic forces structuring antigenic diversity by generating detailed molecular epidemiological profiles of all malaria infections in multiple age groups within one transmission season (AIM 1), across multiple transmission seasons (AIM 2), and we will evaluate the functional constraints on malaria parasite antigen polymorphism through growth efficiency/inhibition assays (AIM 3). This work will provide a new means of ranking vaccine targets that is complementary to existing rankings, and inform polyvalent development strategies for existing vaccine targets known to exhibit allele-specific protection. Our findings will clarify a fundamental phenomenon relevant to many infectious disease systems and vaccine development efforts.

疟原虫抗原多样性是由获得性免疫驱动的，并受功能性免疫的限制。 限制。如果更好地理解这些力量之间的相互作用，可能会加速疫苗的开发 发展。恶性疟原虫的基因组，这种真核寄生虫是造成最多人死亡的真核寄生虫。 人类疟疾的致命形式，表现出与人类宿主进化相互作用的强烈特征。 虽然大多数基因组表现出较低的群体多样性，但编码抗原的数百个基因 蛋白质由于免疫介导的平衡选择而具有非常高水平的变异。 人类不会对恶性疟原虫感染产生杀菌免疫力，但会发展 通过反复感染自然获得免疫（NAI），降低血液中的寄生虫密度， 从而导致发病率和死亡率。用于自然选择以维持寄生虫的抗原变异性 种群，它必须赋予适应性优势，以便携带某些变体的寄生虫享受 提高成功传播到另一个人类宿主的可能性。我们最近生成了 PCR- 基于来自 5000 多个临床样本的下一代测序数据来证明 接种 RTS,S/AS01 疟疾疫苗，这是一种针对疟疾的蛋白质亚单位疫苗 环子孢子蛋白（CSP），导致随后的血液阶段感染减少 CSP 基因型与疫苗株相同。这表明疫苗所赋予的免疫力是 在某些个体中短暂绝育，但以等位基因特异性方式。探讨 NAI 是否 以类似于 RTS,S 疫苗的方式在更大的一组上构建抗原多样性 抗原，以及某些观察到的变异是否会损害抗原功能，我们建议从基因角度 对来自不同年龄组的血液样本中的寄生虫抗原进行分析，这些样本是在单个样本中深度收集的 使用全基因组研究马里的传播季节和纵向跨传播季节 排序调查。使用数学模型，我们将阐明机械力的结构 通过生成所有疟疾感染的详细分子流行病学特征来确定抗原多样性 一个传播季节内的多个年龄组 (AIM 1)，跨多个传播季节 （AIM 2），我们将评估疟原虫抗原多态性的功能限制 通过生长效率/抑制测定（AIM 3）。这项工作将提供一种新的排名方式 疫苗目标是对现有排名的补充，并为多价开发提供信息 针对已知具有等位基因特异性保护的现有疫苗靶标的策略。我们的研究结果将澄清 与许多传染病系统和疫苗开发相关的基本现象 努力。