高度保守的恶性疟原虫富含半胱氨酸的保护性抗原(PfCyRPA)是针对血液阶段疟疾的下一代疫苗的关键靶标。PfCyRPA构成三元复合物的核心,包括网织红细胞结合样同源蛋白5(PfRh5)和Rh5相互作用蛋白(PfRipr),是裂殖子侵入红细胞的基础。在这项研究中,我们表明,对PfCyRPA具有特异性的单克隆抗体(mAb)可以中和加纳野外分离株以及许多实验室适应的寄生虫系的体外生长。我们鉴定了具有中和活性的mAb的子集,其与PfCyRPA上的不同位点结合并且组合增强中和作用。由于针对多种裂殖子入侵蛋白的抗体反应被认为可以提高血液阶段疫苗的功效,我们还证明了PfCyRPA-和PfRh5特异性mAb的组合协同作用以中和寄生虫的生长。然而,我们确定了突出的菌株依赖性中和效力,我们的结果表明PfCyRPA表达水平和多态性是独立的,证明在评估血液阶段候选疫苗时解决功能转换的重要性。最后,我们的结果表明,通过将抗体应答导向多种寄生虫抗原上确定的保护性表位,可以提高血液阶段疫苗的效力.
The highly conserved Plasmodium falciparum cysteine-rich protective antigen (PfCyRPA) is a key target for next-generation vaccines against blood-stage malaria. PfCyRPA constitute the core of a ternary complex, including the reticulocyte binding-like homologous protein 5 (PfRh5) and the Rh5-interacting protein (PfRipr), and is fundamental for merozoite invasion of erythrocytes. In this study, we show that monoclonal antibodies (mAbs) specific to PfCyRPA neutralize the in vitro growth of Ghanaian field isolates as well as numerous laboratory-adapted parasite lines. We identified subsets of mAbs with neutralizing activity that bind to distinct sites on PfCyRPA and that in combination potentiate the neutralizing effect. As antibody responses against multiple merozoite invasion proteins are thought to improve the efficacy of blood-stage vaccines, we also demonstrated that combinations of PfCyRPA- and PfRh5 specific mAbs act synergistically to neutralize parasite growth. Yet, we identified prominent strain-dependent neutralization potencies, which our results suggest is independent of PfCyRPA expression level and polymorphism, demonstrating the importance of addressing functional converseness when evaluating blood-stage vaccine candidates. Finally, our results suggest that blood-stage vaccine efficacy can be improved by directing the antibody response towards defined protective epitopes on multiple parasite antigens.