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

疟疾寄生虫抗原多样性由获得性免疫驱动，并受功能限制 约束条件。这些力量之间的相互作用，如果得到更好的理解，可能会加速疫苗 发展。恶性疟原虫的基因组，这种真核寄生虫造成了最大的 致命的人类疟疾，表现出与人类宿主进化互动的强烈特征。 虽然大多数基因组显示出较低的种群多样性，但数百个编码抗原的基因 由于免疫调节的平衡选择，蛋白质具有非常高的变异水平。 人类不会对感染恶性疟原虫产生无菌免疫力，但会发展成 通过反复感染降低血液中寄生虫密度的自然获得性免疫(NAI)， 从而导致发病率和死亡率。为了保持寄生虫的抗原性而进行自然选择 种群，它必须赋予健康优势，这样携带某些变异的寄生虫就能享受 提高了成功传输到另一个人类主机的概率。我们最近产生了聚合酶链式反应- 基于5000多个临床样本的下一代测序数据来证明 用RTS疫苗接种S/AS01疟疾疫苗，一种针对日本血吸虫病患者的蛋白质亚单位疫苗 环子孢子蛋白(CSP)，可减少随后的血液期感染 与疫苗株相同的CSP基因。这表明疫苗赋予的免疫力是 在一些个体中暂时不育，但以等位基因特有的方式。探索NAI是否 结构抗原多样性的方式类似于RTS，S疫苗上的集合要大得多 抗原，以及一些观察到的变异是否会损害抗原功能，我们建议从基因上 来自不同年龄段的血液样本中的寄生虫抗原图谱，在单个 使用全基因组在马里传播季节和纵向传播季节 排序调查。利用数学模型，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概况来实现抗原多样性 一个传播季节(AIM 1)内的多个年龄段，跨越多个传播季节 (目标2)，我们将评估疟疾寄生虫抗原多态性的功能限制 通过生长效率/抑制试验(AIM 3)。这项工作将提供一种新的排名手段 疫苗目标是对现有排名的补充，并为多价疫苗的发展提供信息 已知具有等位基因特异性保护作用的现有疫苗靶点的策略。我们的发现将澄清 与许多传染病系统和疫苗开发相关的基本现象 努力。

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.