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Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection

Nature Immunology volume 18, pages 1261–1269 (2017)Cite this article

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An Author Correction to this article was published on 30 January 2020

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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Figure 1: EDE1-B10 is a human mAb to DENV that cross-neutralizes ZIKV infection.
Figure 2: EDE1-B10 protects against ZIKV-induced lethality and viral burden.
Figure 3: EDE1-B10 protects against testis infection and injury.
Figure 4: EDE1-B10 protects Ifnar1−/− pregnant dams.
Figure 5: Therapeutic effect of EDE1-B10 in WT pregnant dams.
Figure 6: Treatment with EDE1-B10 prevents maternal and fetal ZIKV infection after intravaginal inoculation of pregnant dams.

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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.).

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Authors and 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.

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Correspondence to Gavin R Screaton or Michael S Diamond.

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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.

Integrated supplementary information

Supplementary Figure 1 EDE-specific mAbs protect against ZIKV-induced lethality.

Four to five week-old WT male mice were treated with anti-Ifnar1 mAb followed by subcutaneous infection with 103 FFU of mouse-adapted ZIKV-Dakar. Mice then were treated with isotype-control, EDE1-C8, or EDE2-A11 mAbs at day +1 (100 μg, left) or day +3 (250 μg, right). Data were pooled from two (isotype-control mAb) or three (EDE1-C8 and EDE2-A11) independent experiments (isotype-control mAb, n = 19; EDE1-C8, n = 10; EDE2-A11, n = 10). Statistical significance was analyzed (log-rank test: ****, P < 0.0001).

Supplementary Figure 2 Levels of EDE1-B10 mAb in tissues at day +5 after infection.

Eight to nine week old WT male mice were treated with a single dose of EDE1-B10 mAb at day +1 or +3 as described in Fig 2. a. At D+5, tissues were harvested and EDE1-B10 levels were assessed by ELISA using a standard curve. Bars indicate median values. Data were pooled from two independent experiments, and symbols correspond to individual mice (n = 8 per group). Statistical analysis was determined (Mann-Whitney test: **, P < 0.01; ***, P < 0.001).

Supplementary Figure 3 ISH and histological analysis of epididymis from mice treated with EDE1-B10.

Eight- to nine- week old male WT mice were treated with isotype control or EDE1-B10 mAb at day +1 (n=6 mice), day +3 (n=4 mice), day +5 (n=8 mice) after infection, as described in Figure 2. a. RNA in situ hybridization (ISH) staining of epididymis at day +21 using ZIKV-specific RNA probes. Low power (scale bar = 500 μm) and high power (scale bar = 20 μm) images are presented in sequence. The images in the panels are representative of sections from 4 to 6 mice. b. H & E staining of epididymis. Low power (scale bar = 500 μm) and high power (scale bar = 20 μm) images are shown in sequence. The images are representative of sections from 3 to 5 mice.

Supplementary Figure 4 Protection of pregnant mice with WT and LALA EDE1-C8 mAbs.

WT female mice were mated with WT sires. At E5.5, dams were treated with anti-Ifnar1 mAb. At E6.5, dams were infected subcutaneously with 103 FFU of mouse-adapted ZIKV-Dakar. At E7.5 (day +1), dams were treated with 250 μg of either isotype-control mAb or EDE1-C8 (wild-type or LALA variant). At E13.5, placentas and fetal heads were harvested, and viral RNA was assessed by qRT-PCR. Bars indicate median values. Data were pooled from two independent experiments, and symbols correspond to individual mice (isotype mAb, n = 16; EDE1-C8, n = 20; EDE1-C8 LALA, n = 12). Statistical significance was determined (Kruskal-Wallis test: ***, P < 0.001; ****, P < 0.0001). Dashed line indicates the limit of detection for the assay.

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Fernandez, E., Dejnirattisai, W., Cao, B. et al. Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection. Nat Immunol 18, 1261–1269 (2017). https://doi.org/10.1038/ni.3849

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