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.

疟疾寄生虫抗原多样性由获得的免疫力驱动，并由功能界定 约束。这些力之间的相互作用（如果更好地理解）可以加速疫苗 发展。恶性疟原虫的基因组，这是导致最大的真核寄生虫 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标志。 虽然大多数基因组的人口多样性低，但编码抗原的数百个基因 免疫介导的平衡选择引起的蛋白质具有很高的变异水平。 人类不会形成对恶性疟原虫感染的免疫力，而是发展 通过复发性感染自然获得的免疫力（NAI），可降低血液中的寄生虫密度， 因此发病和死亡率。为了自然选择以维持寄生虫的抗原变异性 种群，它必须赋予健身优势，以使携带某些变体的寄生虫喜欢 成功传输到另一个人类宿主的可能性提高了。我们最近产生了PCR- 基于来自5000多个临床样本的下一代测序数据，以证明 RTS疫苗接种S/AS01疟疾疫苗，一种针对蛋白质亚基疫苗 割孢子虫蛋白（CSP）导致随后的血液阶段感染减少 CSP基因型与疫苗菌株相同。这表明疫苗赋予的免疫力为 在某些个体中暂时消毒，但以特定于等位基因的方式进行消毒。探索nai是否 结构抗原多样性的方式类似于RTS，S疫苗在更大的集合上 抗原以及一些观察到的变体是否损害了抗原功能，我们提出了遗传 来自不同年龄段的血液样本中的轮廓寄生虫抗原，深入收集 传输季节和整个马里传输季节的纵向，使用全基因组 测序调查。使用数学模型，我们将阐明机械力结构 抗原多样性通过产生所有疟疾感染的详细分子流行病学特征 在一个传输季节内多个年龄组（AIM 1），在多个传输季节 （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/抑制测定法（AIM 3）。这项工作将为排名提供新的方法 与现有排名相辅相成的疫苗目标，并为多价开发提供信息 现有疫苗靶标的策略已知具有特定于等位基因保护的保护。我们的发现将澄清 与许多传染病系统和疫苗开发有关的基本现象 努力。