Li Yan, Chen Zhihai, Wu Lili, Dai Lianpan, Qi Jianxun, Chai Yan, Li Shihua, Wang Qihui, Tong Zhou, Ma Sufang, Duan Xiaomin, Ren Shuning, Song Rui, Liang Mifang, Liu Wenjun, Yan Jinghua, Gao George F
CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China.
Innovation (Camb). 2022 Sep 15;3(6):100323. doi: 10.1016/j.xinn.2022.100323. eCollection 2022 Nov 8.
The yellow fever virus (YFV) is a life-threatening human pathogen. Owing to the lack of available therapeutics, non-vaccinated individuals are at risk. Here, we isolated eight human monoclonal antibodies that neutralize YFV infection. Five recognized overlapping epitopes and exhibited potent neutralizing activity. Two (YD6 and YD73) were ultra-potent and conferred complete protection against the lethal challenge of YFV as both prophylactics and therapeutics in a mouse model. Crystal structures revealed that YD6 engaged the YFV envelope protein in both pre- and post-fusion states, suggesting viral inhibition by a "double-lock" mechanism. The recognition determinants for YD6 and YD73 are clustered at the premembrane (prM)-binding site. Notably, antibodies targeting this site were present in minute traces in YFV-infected individuals but contributed significantly to neutralization, suggesting a vulnerable supersite of YFV. We provide two promising candidates for immunotherapy against YFV, and the supersite represents an ideal target for epitope-based vaccine design.
黄热病病毒（YFV）是一种危及生命的人类病原体。由于缺乏有效的治疗方法，未接种疫苗的个体面临风险。在此，我们分离出了八种可中和YFV感染的人源单克隆抗体。其中五种识别重叠表位并表现出强大的中和活性。两种（YD6和YD73）具有超强效力，在小鼠模型中作为预防和治疗药物，对YFV的致死性攻击均能提供完全保护。晶体结构显示，YD6在融合前和融合后状态均与YFV包膜蛋白结合，提示其通过“双锁”机制抑制病毒。YD6和YD73的识别决定簇聚集在膜前体（prM）结合位点。值得注意的是，靶向该位点的抗体在YFV感染个体中微量存在，但对中和作用有显著贡献，提示YFV存在一个易损超位点。我们提供了两种有前景的抗YFV免疫治疗候选药物，且该超位点是基于表位的疫苗设计的理想靶点。
