Antibodies against the central repeat of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP) inhibit parasite activity and correlate with protection from malaria. However, the humoral response to the PfCSP C terminus (C-PfCSP) is less well characterized. Here, we describe B cell responses to C-PfCSP from European donors who underwent immunization with live Pf sporozoites (PfSPZ Challenge) under chloroquine prophylaxis (PfSPZ-CVac), and were protected against controlled human malaria infection. Out of 215 PfCSP-reactive monoclonal antibodies, only two unique antibodies were specific for C-PfCSP, highlighting the rare occurrence of C-PfCSP–reactive B cells in PfSPZ-CVac–induced protective immunity. These two antibodies showed poor sporozoite binding and weak inhibition of parasite traversal and development, and did not protect mice from infection with PfCSP transgenic Plasmodium berghei sporozoites. Structural analyses demonstrated that one antibody interacts with a polymorphic region overlapping two T cell epitopes, suggesting that variability in C-PfCSP may benefit parasite escape from humoral and cellular immunity. Our data identify important features underlying C-PfCSP shortcomings as a vaccine target.

对抗恶性疟原虫中央重复的抗体（Pf）环子孢子蛋白（CSP）抑制了寄生虫的活动，并与疟疾的防护相关。但是，对PfCSP C末端（C-PfCSP）的体液反应的特征较差。在这里，我们描述了来自欧洲捐献者的B细胞对C-PfCSP的反应，这些捐献者在氯喹预防（PfSPZ-CVac）下接受了活的Pf子孢子（PfSPZ-CVac）的免疫接种，并得到了预防人类疟疾感染的保护。在215种PfCSP反应性单克隆抗体中，只有两种独特的抗体对C-PfCSP具有特异性，这突显了PfSPZ-CVac诱导的保护性免疫中很少发生C-PfCSP反应性B细胞。这两种抗体表现出差的子孢子结合和弱的寄生虫遍历和发展的抑制作用，并不能保护小鼠免受PfCSP转基因的感染伯氏疟原虫子孢子。结构分析表明，一种抗体与重叠两个T细胞表位的多态性区域相互作用，表明C-PfCSP的变异性可能有益于寄生虫从体液和细胞免疫中逃逸。我们的数据确定了作为疫苗目标的C-PfCSP缺陷的潜在重要特征。