Antibodies against the NANP repeat of circumsporozoite protein (CSP), the major surface antigen of Plasmodium falciparum (Pf) sporozoites, can protect from malaria in animal models but protective humoral immunity is difficult to induce in humans. Here we cloned and characterized rare affinity-matured human NANP-reactive memory B cell antibodies elicited by natural Pf exposure that potently inhibited parasite transmission and development in vivo. We unveiled the molecular details of antibody binding to two distinct protective epitopes within the NANP repeat. NANP repeat recognition was largely mediated by germline encoded and immunoglobulin (Ig) heavy-chain complementarity determining region 3 (HCDR3) residues, whereas affinity maturation contributed predominantly to stabilizing the antigen-binding site conformation. Combined, our findings illustrate the power of exploring human anti-CSP antibody responses to develop tools for malaria control in the mammalian and the mosquito vector and provide a molecular basis for the structure-based design of next-generation CSP malaria vaccines.

抗环子孢子蛋白（CSP）（恶性疟原虫（Pf）子孢子的主要表面抗原）的NANP重复序列的抗体可以在动物模型中预防疟疾，但是很难在人体内诱导出保护性体液免疫。在这里，我们克隆并鉴定了天然Pf暴露引起的罕见的亲和力成熟的人NANP反应性记忆B细胞抗体，该抗体有效抑制了体内的寄生虫传播和发育。。我们揭示了与NANP重复序列内两个不同的保护性表位结合的抗体的分子细节。NANP重复识别主要由种系编码和免疫球蛋白（Ig）重链互补决定区3（HCDR3）残基介导，而亲和力成熟则主要是稳定抗原结合位点构象。结合起来，我们的发现说明了探索人类抗CSP抗体反应的能力，从而开发了用于控制哺乳动物和蚊媒疟疾的工具，并为下一代CSP疟疾疫苗的基于结构的设计提供了分子基础。