Abstract

Little is known about the specificities and neutralization breadth of the H7-reactive antibody repertoire induced by natural H7N9 infection in humans. We have isolated and characterized 73 H7-reactive monoclonal antibodies from peripheral B cells from four donors infected in 2013 and 2014. Of these, 45 antibodies were H7-specific, and 17 of these neutralized the virus, albeit with few somatic mutations in their variable domain sequences. An additional set of 28 antibodies, isolated from younger donors born after 1968, cross-reacted between H7 and H3 haemagglutinins in binding assays, and had accumulated significantly more somatic mutations, but were predominantly non-neutralizing in vitro. Crystal structures of three neutralizing and protective antibodies in complex with the H7 haemagglutinin revealed that they recognize overlapping residues surrounding the receptor-binding site of haemagglutinin. One of the antibodies, L4A-14, bound into the sialic acid binding site and made contacts with haemagglutinin residues that were conserved in the great majority of 2016–2017 H7N9 isolates. However, only 3 of the 17 neutralizing antibodies retained activity for the Yangtze River Delta lineage viruses isolated in 2016–2017 that have undergone antigenic change, which emphasizes the need for updated H7N9 vaccines.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon request. Atomic coordinates for the H7-FabL4A-14, H7-FabL4B-18 and H7-FabL3A-44 complex as well as structure factors have been deposited to the Protein Data Bank under accession codes 6II4, 6II8 and 6II9.

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Acknowledgements

The authors acknowledge support from the laboratories that provided the sequences of reference antibody MEDI885221 for the comparisons in the tables and figures. The authors also acknowledge the BD FACSAria cell sorter service provided by the Core Instrument Center of Chang Gung University, and C. Waugh for FACS sorting B cells and MDCK-SIAT1 cell lines at WIMM Oxford. These studies were funded by the Townsend-Jeantet Charitable Trust (registered charity no. 1011770), the Emergency Technology Research Issue on Prevention and Control for Human infection with A (H7N9) Avian Influenza Virus (10600100000015001206), the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) (XDB29010000), the National Science and Technology Major Project (2018ZX10101004), the Human Immunology Unit (MRC), Oxford University, Chang Gung Medical Research Program (CMRPG3G0921, CMRPG3G0922) and the Ministry of Science and Technology of Taiwan (MOST 104-2320-B-182A-002-MY2, MOST 105-2320-B-182A-008- and MOST 107-2321-B-182A-003-). G.F.G. is supported partly as a leading principal investigator of the NSFC Innovative Research Group (81621091). Y.S. is supported by the Excellent Young Scientist Program from the National Natural Science Foundation of China (81622031), the Excellent Young Scientist Program of CAS and the Youth Innovation Promotion Association CAS (2015078).

Author information

Author notes

  1. These authors contributed equally: Kuan-Ying A. Huang, Pramila Rijal, Haihai Jiang, Beibei Wang.

Affiliations

  1. Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    • Kuan-Ying A. Huang
    •  & Tzou-Yien Lin
  2. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    • Kuan-Ying A. Huang
    •  & Tzou-Yien Lin
  3. Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    • Pramila Rijal
    • , Lisa Schimanski
    • , Tao Dong
    • , Timothy J. Powell
    •  & Alain R. Townsend
  4. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China

    • Haihai Jiang
    • , Jianxun Qi
    • , George F. Gao
    •  & Yi Shi
  5. College of Veterinary Medicine, China Agricultural University, Beijing, China

    • Haihai Jiang
  6. Center for translational Immunology, Chinese Academy of Medical Science Oxford Institute, Nuffield Department of Medicine, Oxford University, Oxford, UK

    • Beibei Wang
    • , Tao Dong
    •  & Alain R. Townsend
  7. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China

    • Beibei Wang
    •  & Ang Li
  8. Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China

    • Beibei Wang
    • , Zhihai Chen
    • , Rui Song
    •  & Ang Li
  9. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    • Yo-Min Liu
    • , Jia-Tsrong Jan
    •  & Che Ma
  10. The Pirbright Institute, Pirbright, Woking, UK

    • Pengxiang Chang
    •  & Munir Iqbal
  11. Department of Cardiovascular Surgery, Min-Sheng General Hospital, Taoyuan, Taiwan

    • Mu-Chun Wang
  12. Clinical and Research Center of Infectious Diseases, The National Clinical Key Department of Infectious Disease, Beijing Ditan Hospital, Capital Medical University, Beijing, China

    • Zhihai Chen
    •  & Rui Song
  13. Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    • Chung-Chi Huang
  14. Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    • Jeng-How Yang
  15. Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China

    • George F. Gao
    •  & Yi Shi
  16. Center for Influenza Research and Early-Warning, Chinese Academy of Sciences, Beijing, China

    • George F. Gao
    •  & Yi Shi

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Contributions

K.-Y.A.H., G.F.G., Y.S. and A.R.T. conceived and designed the study. K.-Y.A.H., P.R., H.J., B.W., L.S., T.D., Y.-M.L., P.C., M.I., M.-C.W., Z.C., R.S., C.-C.H., J.-H.Y., J.Q., T.-Y.L., A.L., T.J.P., J.-T.J., C.M., G.F.G., Y.S. and A.R.T. carried out the experiments. K.-Y.A.H., P.R., H.J., B.W., L.S., T.D., Y.-M.L., J.-T.J., C.M., G.F.G., Y.S. and A.R.T. performed data analysis and figure/table preparation. K.-Y.A.H., P.R., G.F.G., Y.S. and A.R.T. wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Kuan-Ying A. Huang or George F. Gao or Yi Shi or Alain R. Townsend.

Supplementary information

  1. Supplementary Information

    Supplementary Figures 1–8, Supplementary Tables 1–6.

  2. Reporting Summary

  3. Supplementary Table 1

    Binding and neutralizing activities of of 73 H7-reactive monoclonal antibodies isolated from donors.

  4. Supplementary table 2

    Details of 73 H7-reactive monoclonal antibodies variable domain sequences isolated from donors.

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DOI

https://doi.org/10.1038/s41564-018-0303-7