Structural Vaccinology Lab, Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Sci Rep. 2021 Mar 5;11(1):5318. doi: 10.1038/s41598-021-84622-x.
Plasmodium falciparum malaria contributes to a significant global disease burden. Circumsporozoite protein (CSP), the most abundant sporozoite stage antigen, is a prime vaccine candidate. Inhibitory monoclonal antibodies (mAbs) against CSP map to either a short junctional sequence or the central (NPNA) repeat region. We compared in vitro and in vivo activities of six CSP-specific mAbs derived from human recipients of a recombinant CSP vaccine RTS,S/AS01 (mAbs 317 and 311); an irradiated whole sporozoite vaccine PfSPZ (mAbs CIS43 and MGG4); or individuals exposed to malaria (mAbs 580 and 663). RTS,S mAb 317 that specifically binds the (NPNA) epitope, had the highest affinity and it elicited the best sterile protection in mice. The most potent inhibitor of sporozoite invasion in vitro was mAb CIS43 which shows dual-specific binding to the junctional sequence and (NPNA). In vivo mouse protection was associated with the mAb reactivity to the NANPx6 peptide, the in vitro inhibition of sporozoite invasion activity, and kinetic parameters measured using intact mAbs or their Fab fragments. Buried surface area between mAb and its target epitope was also associated with in vivo protection. Association and disconnects between in vitro and in vivo readouts has important implications for the design and down-selection of the next generation of CSP based interventions.
恶性疟原虫疟疾对全球疾病负担造成了重大影响。环子孢子蛋白（CSP）是最丰富的子孢子阶段抗原，是主要的疫苗候选物。针对 CSP 的抑制性单克隆抗体（mAbs）要么针对短连接序列，要么针对中央（NPNA）重复区。我们比较了六种源自接受重组 CSP 疫苗 RTS,S/AS01 （mAbs 317 和 311）的人类受体的 CSP 特异性 mAbs、来自辐照全子孢子疫苗 PfSPZ 的 mAbs（CIS43 和 MGG4），或暴露于疟疾的个体（mAbs 580 和 663）的体外和体内活性。专门结合（NPNA）表位的 RTS,S mAb 317 具有最高的亲和力，在小鼠中引起最佳的无菌保护。体外抑制子孢子入侵最有效的抑制剂是 mAb CIS43，它对子孢子的连接序列和（NPNA）都具有双重特异性。体内保护与 mAb 对 NANPx6 肽的反应性、对体外入侵活性的抑制、以及使用完整 mAbs 或其 Fab 片段测量的动力学参数相关。mAb 与其目标表位之间的埋藏表面积也与体内保护相关。体外和体内读数之间的关联和不相关对基于 CSP 的下一代干预措施的设计和选择具有重要意义。
