Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Immunity. 2020 Oct 13;53(4):733-744.e8. doi: 10.1016/j.immuni.2020.08.014. Epub 2020 Sep 17.
Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.
发现针对疟原虫裂殖子表面蛋白（PfCSP）的有效人类单克隆抗体（mAbs），阐明其中和机制，将有助于被动预防，并有助于下一代疫苗的开发。在这里，我们分离到一种中和性的人源 mAb，L9，它优先与 PfCSP 的 NVDP 次要重复结合，具有高亲和力，同时与 NANP 主要重复发生交叉反应。L9 在介导抗蚊子叮咬的保护作用方面比六种已发表的中和性人类 PfCSP mAbs 更为有效。等温滴定量热法和多光子显微镜显示，L9 和其他最具保护性的 mAbs 通过两个结合事件与 PfCSP 结合，并通过杀死肝脏中的裂殖子和阻止它们从窦状隙逸出和穿过肝细胞来介导保护作用。这项研究将 PfCSP 的亚显性次要重复定义为中和表位，确定了裂殖子中和的体外生物物理相关性，并证明肝脏是抗体预防疟疾的重要部位。
