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

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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

Authors

1. Estefania Fernandez
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2. Wanwisa Dejnirattisai
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3. Bin Cao
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4. Suzanne M Scheaffer
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5. Piyada Supasa
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6. Wiyada Wongwiwat
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7. Prabagaran Esakky
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8. Andrea Drury
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9. Juthathip Mongkolsapaya
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10. Kelle H Moley
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11. Indira U Mysorekar
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12. Gavin R Screaton
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13. 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.

Corresponding authors

Correspondence toGavin 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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• Received: 07 August 2017
• Accepted: 01 September 2017
• Published: 25 September 2017
• Issue Date: 01 November 2017
• DOI: https://doi.org/10.1038/ni.3849