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Neutralization mechanism of human monoclonal antibodies against Rift Valley fever virus

Nature Microbiology volume 4, pages 1231–1241 (2019) Cite this article

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Abstract

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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Fig. 1: Binding characteristics of RVFV monoclonal antibodies.
The alternative text for this image may have been generated using AI.
Fig. 2: Protection potency of monoclonal antibodies against RVFV infection in vitro and in vivo.
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Fig. 3: Interference of Gn–cell and RVFV–cell interactions by Gn monoclonal antibodies.
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Fig. 4: Molecular determinants of four human neutralizing Gn monoclonal antibodies.
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Fig. 5: The detailed atomic interaction at the Gn/monoclonal antibody interface.
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Fig. 6: Identification of neutralizing hotspots located on Gn DI.
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Data availability

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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Acknowledgements

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).

Author information

Author notes

  1. These authors contributed equally: Qihui Wang, Tong Ma, Yan Wu, Zhihai Chen.

Authors and Affiliations

  1. CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Qihui Wang, Tong Ma, Zhou Tong, Huabing Yang, Lili Wu, Rui Shi, Mi Yang & Jinghua Yan

  2. Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China

    Qihui Wang, Yan Wu, Yi Shi, George F. Gao & Jinghua Yan

  3. Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA

    Qihui Wang & Zhiqiang An

  4. Institute of Physical Science and Information, Anhui University, Hefei, China

    Tong Ma, Huabing Yang & Jinghua Yan

  5. Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China

    Yan Wu & George F. Gao

  6. Center of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China

    Zhihai Chen

  7. Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China

    Hui Zeng

  8. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China

    Feng Gao

  9. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Jianxun Qi, Zhennan Zhao, Yan Chai, Yuhai Bi, Jian Song, Haihai Jiang, Yi Shi, George F. Gao & Jinghua Yan

  10. Département de Microbiologie-Infectiologie et d’Immunologie, Université Laval, Quebec, Quebec, Canada

    Gary Wong

  11. Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Gary Wong

  12. College of Veterinary Medicine, China Agricultural University, Beijing, China

    Haihai Jiang & George F. Gao

  13. Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, Beijing, China

    Junzhi Wang

  14. International Laboratory of Molecular Biology for Tropical Disease Agents, School of Veterinary Medicine, University of California, Davis, Davis, CA, USA

    Tilahun D. Yilma

  15. Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, USA

    Tilahun D. Yilma

  16. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China

    Yi Shi & George F. Gao

  17. National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing, China

    William J. Liu, Mifang Liang & George F. Gao

  18. Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Institute of Medical Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China

    Chuan Qin

  19. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China

    George F. Gao

  20. College of Life Science, University of Chinese Academy of Sciences, Beijing, China

    Jinghua Yan

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  1. Qihui Wang
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Contributions

Q.W., Z.T., G.F.G. and J.Y. initiated and coordinated the project. Q.W., Y.W., Z.T., G.F.G. and J.Y. designed the experiments. Q.W., T.M., Y.W., Z.T. and H.Y. conducted the experiments with the assistance of Z.Z., L.W., R.S. and M.Y. F.G., J.Q. and Y.C. collected the crystallographic data and solved the structures. Z.C. and H.Z. coordinated the isolation of peripheral blood mononuclear cells from the RVFV patient. M.L., C.Q., G.F.G. and J.Y. coordinated the viral experiments. T.M. and G.W. manipulated the viruses with the help of Y.B., J.S. and H.J. Q.W., Y.W., Z.T., Z.A., Y.S., G.F.G. and J.Y. analysed the data. Q.W. wrote the manuscript. Y.W., G.W., Z.A., J.W., T.D.Y., Y.S., W.J.L., G.F.G. and J.Y. helped revise the manuscript.

Corresponding authors

Correspondence to George F. Gao or Jinghua Yan.

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Wang, Q., Ma, T., Wu, Y. et al. Neutralization mechanism of human monoclonal antibodies against Rift Valley fever virus. Nat Microbiol 4, 1231–1241 (2019). https://doi.org/10.1038/s41564-019-0411-z

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