Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection

Emmie de Wit; Friederike Feldmann; Jacqueline Cronin; Robert Jordan; Atsushi Okumura; Tina Thomas; Dana Scott; Tomas Cihlar; Heinz Feldmann

doi:10.1073/pnas.1922083117

New Research In

Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved February 7, 2020 (received for review December 16, 2019)

Significance

Middle East Respiratory Syndrome, caused by the MERS coronavirus (MERS-CoV), continues to cause severe respiratory disease with a high case fatality rate. To date, potential antiviral treatments for MERS-CoV have shown limited efficacy in animal studies. Here, we tested the efficacy of the broad-acting antiviral remdesivir in the rhesus macaque model of MERS-CoV infection. Remdesivir reduced the severity of disease, virus replication, and damage to the lungs when administered either before or after animals were infected with MERS-CoV. Our data show that remdesivir is a promising antiviral treatment against MERS that could be considered for implementation in clinical trials. It may also have utility for related coronaviruses such as the novel coronavirus 2019-nCoV emerging from Wuhan, China.

Abstract

The continued emergence of Middle East Respiratory Syndrome (MERS) cases with a high case fatality rate stresses the need for the availability of effective antiviral treatments. Remdesivir (GS-5734) effectively inhibited MERS coronavirus (MERS-CoV) replication in vitro, and showed efficacy against Severe Acute Respiratory Syndrome (SARS)-CoV in a mouse model. Here, we tested the efficacy of prophylactic and therapeutic remdesivir treatment in a nonhuman primate model of MERS-CoV infection, the rhesus macaque. Prophylactic remdesivir treatment initiated 24 h prior to inoculation completely prevented MERS-CoV−induced clinical disease, strongly inhibited MERS-CoV replication in respiratory tissues, and prevented the formation of lung lesions. Therapeutic remdesivir treatment initiated 12 h postinoculation also provided a clear clinical benefit, with a reduction in clinical signs, reduced virus replication in the lungs, and decreased presence and severity of lung lesions. The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.

Footnotes

↵¹To whom correspondence may be addressed. Email: Emmie.deWit{at}nih.gov.

Author contributions: E.d.W., R.J., and H.F. designed research; E.d.W., F.F., J.C., A.O., T.T., and D.S. performed research; T.C. contributed new reagents/analytic tools; E.d.W., A.O., and D.S. analyzed data; E.d.W. and H.F. wrote the paper; and F.F., J.C., R.J., A.O., T.T., D.S., and T.C. read and approved the manuscript.
Competing interest statement: The authors affiliated with Gilead Sciences are employees of the company and may own company stock; R.J. holds a patent on the use of remdesivir to treat Filovirus infections. The authors affiliated with NIH have no conflict of interest to report.
This article is a PNAS Direct Submission.
Data deposition: All data discussed here will be made available to readers upon request.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1922083117/-/DCSupplemental.

This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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