Abstract

The Zika virus (ZIKV) epidemic has resulted in congenital abnormalities in fetuses and neonates. Although some cross-reactive dengue virus (DENV)-specific antibodies can enhance ZIKV infection in mice, those recognizing the DENV E-dimer epitope (EDE) can neutralize ZIKV infection in cell culture. We evaluated the therapeutic activity of human monoclonal antibodies to DENV EDE for their ability to control ZIKV infection in the brains, testes, placentas, and fetuses of mice. A single dose of the EDE1-B10 antibody given 3 d after ZIKV infection protected against lethality, reduced ZIKV levels in brains and testes, and preserved sperm counts. In pregnant mice, wild-type or engineered LALA variants of EDE1-B10, which cannot engage Fcg receptors, diminished ZIKV burden in maternal and fetal tissues, and protected against fetal demise. Because neutralizing antibodies to EDE have therapeutic potential against ZIKV, in addition to their established inhibitory effects against DENV, it may be possible to develop therapies that control disease caused by both viruses.

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Acknowledgements

We thank Haina Shin for advice on the intravaginal infection experiments, S. Whitehead (US National Institutes of Health (NIH)) for ZIKV-Brazil (Paraiba, 2015), S. Shresta(La Jolla Institute of Allergy and Immunology) for DENV-2 strain D2S20, P. Malasit and S. Noisakran (Mahidol University) for DENV-1, DENV-3, and DENV-4 isolates from patients, C. Simmons (University of Melbourne) for DENV-2 strain DF-699, A. Kohl, R.F. de Oliveira Freitas, and L.J. Pena (University of Glasgow) for ZIKV-Brazil PE243, and A. Sakuntabhai (Institut Pasteur) for ZIKV-Africa HD78788. Supported by grants and contracts from the NIH (R01 AI073755 (M.S.D.), R01 AI127828 (M.S.D.), R01 HD091218 (I.U.M. and M.S.D.), HHSN272201400018C (M.S.D.), T32 AI007163 (E.F.)), the Wellcome Trust (G.R.S.), MRC-NEWTON UK (J.M.), and the National Institute for Health Research Biomedical Research Centre funding scheme UK (G.R.S.).

Author information

Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Estefania Fernandez
    • , Indira U Mysorekar
    •  & Michael S Diamond
  2. Division of Immunology and Inflammation, Department of Medicine, Hammersmith Campus, Imperial College, London, UK.

    • Wanwisa Dejnirattisai
    • , Piyada Supasa
    • , Wiyada Wongwiwat
    • , Juthathip Mongkolsapaya
    •  & Gavin R Screaton
  3. Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Bin Cao
    • , Suzanne M Scheaffer
    • , Prabagaran Esakky
    • , Andrea Drury
    • , Kelle H Moley
    •  & Indira U Mysorekar
  4. Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Siriraj Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand.

    • Juthathip Mongkolsapaya
  5. Medical Sciences Divisional Office, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • Gavin R Screaton
  6. Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  7. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond
  8. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Michael S Diamond

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Contributions

E.F., J.M., W.D., S.M.S., B.C., G.R.S., and M.S.D. designed the experiments; E.F., W.D., S.M.S., B.C., P.S., and W.W. performed the experiments; E.F., J.M., W.D., S.M.S., B.C., P.E., A.D., I.U.M., K.H.M., G.R.S., and M.S.D. analyzed the data; E.F. and M.S.D. wrote the first draft of the paper; and all authors participated in editing the final version of the manuscript.

Competing interests

M.S.D. is a consultant for Inbios, Visterra, Aviana and Sanofi-Pasteur and is on the Scientific Advisory Boards of Moderna and OvaGene. G.R.S. is on the Vaccine Scientific Advisory Board of GlaxoSmithKline plc.

Corresponding authors

Correspondence to Gavin R Screaton or Michael S Diamond.

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https://doi.org/10.1038/ni.3849

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