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A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus

Nature Immunology volume 16, pages 170–177 (2015)Cite this article

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A Corrigendum to this article was published on 18 June 2015

A Corrigendum to this article was published on 21 April 2015

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Abstract

Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.

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Figure 1: Characterization of human mAbs to DENV.
Figure 2: Epitope mapping of anti-DENV.
Figure 3: mAbs to FLE versus mAbs to EDE in individual patients.
Figure 4: Antibodies to EDE are potent and highly crossreactive in neutralization assays.
Figure 5: EDE-specific antibodies have superior neutralizing activities.
Figure 6: Binding and neutralization of virus generated by insect cells and DCs.
Figure 7: Binding of antibody to viral particles in various states of maturation.
Figure 8: Reduced ADE with mAbs to EDE.

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  • 08 April 2015

    In the version of this article initially published, affiliation 3 was incomplete. The correct affiliation 3 is as follows: Graduate Program in Immunology, Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. The Acknowledgements section was also incomplete. The "Supported by" statement should end "...and the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (S.S. and J.M.)." The error has been corrected in the HTML and PDF versions of the article.

  • 27 February 2015

    In the version of this article initially published, the sixth author's surname is spelled incorrectly. The correct spelling is Rouvinski. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank the Armed Forces Research Institute of Medical Sciences of Thailand (AFRIMS), C. Puttikhunt (National Center for Genetic Engineering and Biotechnology, Thailand) and W. Kasinrerk (Chiang Mai University) for the mouse mAb 4G2 to DENV E protein and mAb 1H10 to DENV; E. Harris (University of California Berkeley School of Public Health) for mAb E1D8 to DENV NS3 protein; H. Wardemann (Max Planck Institute for Infection Biology) for expression vectors for IgG1 or immunoglobulin κ-chain or λ-chain; A Flanagan (University of Oxford) for recombinant soluble E protein; the staff at Oxford University Clinical Research Unit Viet Nam for sample collection; and N. Ferguson (Imperial College London) for statistical advice. We acknowledge the use of instruments at the Electron Imaging Center for Nanomachines, supported by University of California Los Angeles and the US National Institutes of Health (1S10OD018111 and NSF DBI-1338135). Supported by the Medical Research Council UK, the Wellcome Trust (G.R.S.), the National Institutes for Health Research Biomedical Research Centre, the US National Institutes of Health (GM071940 and AI094386), European Commission Seventh Framework Programme (FP7/2007-2013; DENFREE project, 282 378) and the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (S.S. and J.M.).

Author information

Author notes

  1. Wanwisa Dejnirattisai, Wiyada Wongwiwat and Sunpetchuda Supasa: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immunology and Inflammation, Department of Medicine, Faculty of Medicine, Hammersmith Campus, Imperial College, London, UK

    Wanwisa Dejnirattisai, Wiyada Wongwiwat, Sunpetchuda Supasa, Amonrat Jumnainsong, Carolyn Edwards, Juthathip Mongkolsapaya & Gavin R Screaton

  2. Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Sunpetchuda Supasa, Prida Malasit & Juthathip Mongkolsapaya

  3. Department of Immunology, Graduate Program in Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Sunpetchuda Supasa

  4. Département de Virologie, Institut Pasteur, Unité de Virologie Structurale, Paris, France

    Xiaokang Zhang, Alexander Rouvinski & Felix A Rey

  5. CNRS UMR 3569 Virologie, Paris, France

    Xiaokang Zhang, Alexander Rouvinski & Felix A Rey

  6. Department of Microbiology, Immunology and Molecular Genetics and California NanoSystems Institute, University of California Los Angeles, Los Angeles, California, USA

    Xinghong Dai & Z Hong Zhou

  7. The Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand

    Amonrat Jumnainsong

  8. Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Program, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam

    Nguyen Than Ha Quyen, Jeremy Farrar & Cameron P Simmons

  9. Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand

    Thaneeya Duangchinda & Prida Malasit

  10. Division of Structural Biology and Oxford Protein Production Facility, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Jonathan M Grimes

  11. Science Division, Diamond Light Source, Diamond House, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK

    Jonathan M Grimes

  12. Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA

    Wen-Yang Tsai, Chih-Yun Lai & Wei-Kung Wang

  13. Department of Microbiology and Immunology, University of Melbourne, Carlton, Victoria, Australia

    Cameron P Simmons

Authors
  1. Wanwisa Dejnirattisai
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Contributions

J.M. and G.R.S. conceived the experiments; Z.H.Z. and F.A.R. conceived the cryo-EM experiments; N.T.H.Q., J.F. and C.P.S. provided specimens; W.D., W.W., S.S., A.J., C.E. and T.D. generated human mAbs; W.D., S.S. and T.D. prepared viral stocks; W.D., S.S., A.J. and C.E. identified cross-reactivity and protein recognition of mAbs; W.D., S.S. and A.J. carried out neutralization, ADE and binding assay; P.M. provided reagents; W.D., S.S., W.W., J.M.G., W.-Y.T., C.-Y.L. and W.W. mapped epitopes; W.-K.W. mapped epitopes; A.R. produced Fab 747(4)B7; X.Z. and X.D. determined the cryo-EM structure; J.M., W.W. and C.E. analyzed antibody clonality; and W.D., J.M. and G.R.S. wrote the paper.

Corresponding authors

Correspondence to Juthathip Mongkolsapaya or Gavin R Screaton.

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Competing interests

The results from this paper form the basis for an application by G.S., J.M., F.R. and A.R. for a patent on the antibodies and epitope.

Integrated supplementary information

Supplementary Figure 1 DENV structure.

The lattice of 90 E dimers is illustrated in as a cryo electron microscopy reconstruction of the mature dengue virus particle taken from PDB accession no 3J27

Supplementary Figure 2 The cryo-EM of DENV2–Fab 747(4)B7.

The cryo-EM map of the DENV-2/Fab 747B7 complex (mesh) superposed onto the structure of the unbound mature DENV-2 virion, from the 3.5Å cryo-EM structure (PDB accession no 3J27), represented with the E proteins shown as surfaces. The three independent E polypeptides of the icosahedral asymmetric unit are displayed in different colors.

Supplementary Figure 3 The Fourier shell correlation function.

The Fourier shell correlation function (Harauz, G. and van Heel M. Optik 73, 146-156 (1986)) indicates a resolution of about 10 Å considering a 0.5 cutoff correlation value, and about 8Å if the 0.143 cutoff is used.

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Dejnirattisai, W., Wongwiwat, W., Supasa, S. et al. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat Immunol 16, 170–177 (2015). https://doi.org/10.1038/ni.3058

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