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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural basis of antigenic escape of a malaria vaccine candidate
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Structural basis of antigenic escape of a malaria vaccine candidate

机译：疟疾疫苗候选者抗原逃逸的结构基础

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Antibodies against the malaria vaccine candidate apical membrane antigen-1 (AMA-1) can inhibit invasion of merozoites into RBC, but antigenic diversity can compromise vaccine efficacy. We hypothesize that polymorphic sites located within inhibitory epitopes function as antigenic escape residues (AER). By using an in vitro model of antigenic escape, the inhibitory contribution of 24 polymorphic sites of the 3D7 AMA-1 vaccine was determined. An AER cluster of 13 polymorphisms, located within domain 1, had the highest inhibitory contribution. Within this AER cluster, antibodies primarily targeted five polymorphic residues situated on an α-helical loop. A second important AER cluster was localized to domain 2. Domain 3 polymorphisms enhanced the inhibitory contribution of the domain 2 AER cluster. Importantly, the AER clusters could be split, such that chimeras containing domain 1 of FVO and domain 2 + 3 of 3D7 generated antisera that showed similarly high level inhibition of the two vaccine strains. Antibodies to this chimeric protein also inhibited unrelated strains of the parasite. Interstrain AER chimeras can be a way to incorporate inhibitory epitopes of two AMA-1 strains into a single protein. The AER clusters map in close proximity to conserved structural elements: the hydrophobic trough and the C-terminal proteolytic processing site. This finding led us to hypothesize that a conserved structural basis of antigenic escape from anti-AMA-1 exists. Genotyping high-impact AER may be useful for classifying AMA-1 strains into inhibition groups and to detect allelic effects of an AMA-1 vaccine in the field.
机译：针对疟疾疫苗候选顶膜抗原1（AMA-1）的抗体可以抑制裂殖子侵入RBC，但是抗原多样性可能会损害疫苗的功效。我们假设位于抑制性表位内的多态性位点起着抗原逃逸残基（AER）的作用。通过使用抗原逃逸的体外模型，确定了3D7 AMA-1疫苗的24个多态性位点的抑制作用。位于域1内的具有13个多态性的AER簇具有最高的抑制作用。在这个AER簇中，抗体主要靶向位于α螺旋环上的五个多态残基。第二个重要的AER簇位于域2。域3多态性增强了域2的AER簇的抑制作用。重要的是，可以拆分AER簇，以使包含FVO结构域1和3D7的结构域2 + 3的嵌合体产生抗血清，该抗血清显示出对两种疫苗菌株的相似高水平抑制作用。该嵌合蛋白的抗体也抑制了该寄生虫的无关菌株。株间AER嵌合体可以是将两个AMA-1株的抑制性表位整合到单个蛋白中的一种方法。 AER簇的位置非常接近保守的结构元素：疏水槽和C端蛋白水解加工位点。该发现使我们假设存在从抗AMA-1抗原逃逸的保守结构基础。对高影响力AER进行基因分型对于将AMA-1菌株分为抑制组和检测AMA-1疫苗的等位基因效应可能很有用。

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