Discovery and characterization of potent broadly neutralizing antibodies from human survivors of severe fever with thrombocytopenia syndromeResearch in context
Shuo Zhang,
Hang Shang,
Shuo Han,
Jiachen Li,
Xuefang Peng,
Yongxiang Wu,
Xin Yang,
Yu Leng,
Fengze Wang,
Ning Cui,
Lingjie Xu,
Hongkai Zhang,
Yu Guo,
Xiaoyu Xu,
Nan Zhang,
Wei Liu,
Hao Li
Affiliations
Shuo Zhang
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China; College of Biological Science and Food Engineering, Southwest Forestry University, Kunming, 650224, PR China
Hang Shang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, PR China
Shuo Han
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Jiachen Li
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Xuefang Peng
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Yongxiang Wu
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Xin Yang
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Yu Leng
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China
Fengze Wang
Vazyme Biotech Co., Ltd, Nanjing, 210046, PR China
Ning Cui
The 154th Hospital, Xinyang, Henan, 464000, PR China
Lingjie Xu
Vazyme Biotech Co., Ltd, Nanjing, 210046, PR China
Hongkai Zhang
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, PR China
Yu Guo
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, PR China
State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, 300071, PR China; Corresponding author.
Wei Liu
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China; College of Biological Science and Food Engineering, Southwest Forestry University, Kunming, 650224, PR China; Corresponding author.
Hao Li
State Key Laboratory of Pathogen and Biosecurity, Academy of Military Medical Sciences, Beijing, 100071, PR China; Corresponding author.
Summary: Background: Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne phlebovirus that causes viral hemorrhagic fever. Pandemic concerns have arisen due to the increased human-to-human transmission and high mortality rate, highlighting the urgent need for specific therapeutics. Methods: Our observational study characterized the memory B cell response to natural SFTSV infection in four survivors. Monoclonal antibodies (mAbs) targeting the SFTSV glycoprotein N (Gn) were isolated and tested for in vitro neutralizing activities and effects on virus binding. Structural analysis was performed to identify neutralizing epitopes recognized by the mAbs. Prophylactical and therapeutical protections were evaluated using a lethal SFTSV infection model. Findings: The selected mAbs exhibiting neutralizing activity primarily originate from the IGHV5-51 and IGHV3-30 germlines and target four distinct antigenic sites on SFTSV Gn. These elite mAbs effectively blocked the interaction between Gn and the cell receptor, preventing infections from five phylogenetically distinct SFTSV clades. Structural analysis revealed a novel neutralizing epitope located within SFTSV Gn domain I recognized by the elite mAbs. In mice of lethal infections with different SFTSV strains, administering a low dose of elite mAbs significantly improved survival rates in both prophylactic and therapeutic settings. Interpretation: This study identifies potent broadly neutralizing antibodies that holds promise for use in humans against SFTSV infection and highlights inhibition of receptor binding as a crucial mechanism for effective antibody-mediated neutralization against phleboviruses. Funding: The National Key Research and Development Plan of China (2018YFE0200401, 2022YFC2303300), National Natural Science Foundation of China (81825019), China Postdoctoral Science Foundation (2023M741824).
