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Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques

Nature Medicine volume 19, pages 1313–1317 (2013)Cite this article

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Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) is of global concern: the virus has caused severe respiratory illness, with 111 confirmed cases and 52 deaths1 at the time of this article's publication. Therapeutic interventions have not been evaluated in vivo; thus, patient management relies exclusively on supportive care, which, given the high case-fatality rate, is not highly effective. The rhesus macaque is the only known model organism for MERS-CoV infection, developing an acute localized to widespread pneumonia with transient clinical disease2,3 that recapitulates mild to moderate human MERS-CoV cases4,5. The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro6; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs. Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.

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Figure 1: Schedule of treatment and selected clinical laboratory parameters.
Figure 2: Radiographic alterations.
Figure 3: Pathology and viral loads in selected tissue samples.
Figure 4: Transcriptional signatures.

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Acknowledgements

We would like to thank B. Haagmans and R. Fouchier, Erasmus Medical Center, for providing MERS-CoV (isolate hCoV-EMC/2012). We also thank all the members of the Rocky Mountain Veterinary Branch (Division of Intramural Research, NIAID, US National Institutes of Health (NIH)) for their assistance, especially K. Cordova, J. Faris, K. Hardcastle, R. LaCasse, D. Long, K. Meade-White, R. Rosenke, T. Thomas and A. Weidow. A. Mora and A. Athman assisted with editing the figures.

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Authors and Affiliations

  1. Division of Intramural Research, Disease Modeling and Transmission Unit, Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA

    Darryl Falzarano, Emmie de Wit, Cynthia Martellaro, Laura Baseler & Heinz Feldmann

  2. Department of Microbiology, University of Washington, Seattle, Washington, USA

    Angela L Rasmussen, Atsushi Okumura, Arndt G Benecke & Michael G Katze

  3. Division of Intramural Research, Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA

    Friederike Feldmann, Dana P Scott & Doug Brining

  4. Division of Intramural Research, Virus Ecology Unit, Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA

    Trenton Bushmaker & Vincent J Munster

  5. Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, USA

    Laura Baseler

  6. Université Pierre et Marie Curie, Centre National de la Recherche Scientifique, Paris, UMR7224, France

    Arndt G Benecke

  7. Washington National Primate Research Center, University of Washington, Seattle, Washington, USA

    Michael G Katze

  8. Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada

    Heinz Feldmann

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  1. Darryl Falzarano
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Contributions

D.F., E.d.W., V.J.M. and H.F. conceived of and designed the study. D.F., E.d.W., A.L.R., F.F., A.O., D.P.S., T.B., C.M. and D.B. performed the experiments. D.F., E.d.W., A.L.R., A.O., D.P.S., L.B., A.G.B., V.J.M., M.G.K. and H.F. analyzed the data. D.F., A.L.R., M.G.K. and H.F. wrote the manuscript. This work was supported in part by the Intramural Research Program, NIAID, NIH, in addition to the NIAID Regional Centers of Excellence (U54 AI081680), Systems Virology (NIH/NIAID contract number HHSN272200800060C) and Washington National Primate Research Center (P51OD010425) to M.G.K.

Corresponding author

Correspondence to Heinz Feldmann.

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Falzarano, D., de Wit, E., Rasmussen, A. et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques. Nat Med 19, 1313–1317 (2013). https://doi.org/10.1038/nm.3362

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