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.

疟原虫抗原多样性受获得性免疫驱动，受功能限制