Rift Valley fever virus (RVFV) is a mosquito-borne pathogen that causes substantial morbidity and mortality in livestock and humans. To date, there are no licensed human vaccines or therapeutics available. Here, we report the isolation of monoclonal antibodies from a convalescent patient, targeting the RVFV envelope proteins Gn and Gc. The Gn-specific monoclonal antibodies exhibited much higher neutralizing activities in vitro and protection efficacies in mice against RVFV infection, compared to the Gc-specific monoclonal antibodies. The Gn monoclonal antibodies were found to interfere with soluble Gn binding to cells and prevent infection by blocking the attachment of virions to host cells. Structural analysis of Gn complexed with four Gn-specific monoclonal antibodies resulted in the definition of three antigenic patches (A, B and C) on Gn domain I. Both patches A and B are major neutralizing epitopes. Our results highlight the potential of antibody-based therapeutics and provide a structure-based rationale for designing vaccines against RVFV.
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The crystal structures of Gn complexed with the Fab form of the monoclonal antibodies R12, R13 and R15 and the scFv of R17 have been deposited in the Protein Data Bank under accession codes 6IEK, 6IEA, 6IEB and 6IEC, respectively. The data that support the findings of this study are available from the corresponding author upon request.
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We thank G. Salazar (University of Texas Health Science Center at Houston) for her critical editing of the manuscript. We acknowledge L. Zhang and Q. Zhang (Comprehensive AIDS Research Center, and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University) for their instruction and help with isolating single B cells. We thank the staff of the BL19U1 beamline at Shanghai Synchrotron Radiation Facility (Shanghai, People’s Republic of China) for assistance during data collection. We are grateful to J. Jia (Institute of Biophysics, Chinese Academy of Sciences) for technical support of BDAria II manipulation and Y. Chen and Z. Yang (Institute of Biophysics, Chinese Academy of Sciences) for technical help with BIAcore experiments. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB29040201), the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (grant no. 2018ZX09711003-002-001), the National Science and Technology Major Project (grant nos. 2016ZX10004222-008 and 2018ZX10101004-001), the External Cooperation Program of CAS (153211KYSB20160001) and the National Natural Science Foundation of China (NSFC, grant nos. 31872745, 31502078 and 81502972). Y.S. is supported by the National Science and Technology Major Project (grant no. 2018ZX10101004-001). G.F.G. is also supported by the External Cooperation Program of CAS (grant no. 153211KYSB20160001). Q.W. is supported by Young Elite Scientist Sponsorship Program by China Association for Science and Technology (grant no. 2015QNRC001), the Youth Innovation Promotion Association CAS (grant no. 2018119) and the grant from China Scholarship Council (grant no. 201704910327). Y.W. is supported by the Youth Innovation Promotion Association CAS (grant no. 2016086). J.Y. and G.F.G. are supported by the foundation of the NSFC Innovative Research Group (grant no. 81621091).