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, Emmie de Wit, Friederike Feldmann, Jacqueline Cronin, Robert Jordan, Atsushi Okumura, Tina Thomas, Dana Scott, Tomas Cihlar, Heinz Feldmann
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.
Keywords: MERS-CoV; animal model; antiviral; remdesivir; therapy.
Conflict of interest statement
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.
Figures
References
- World Health Organization , Coronavirus infections. . Accessed 25 January 2020.
- Modjarrad K., et al. , A roadmap for MERS-CoV research and product development: Report from a World Health Organization consultation. Nat. Med. 22, 701–705 (2016).
- Brende B., et al. , CEPI-a new global R&D organisation for epidemic preparedness and response. Lancet 389, 233–235 (2017).
- Lo M. K., et al. , GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep. 7, 43395 (2017).
- Warren T. K., et al. , Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531, 381–385 (2016).
- Lo M. K., et al. , Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge. Sci. Transl. Med. 11, eaau9242 (2019).
- Sheahan T. P., et al. , Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 9, eaal3653 (2017).
- Sheahan T. P., et al. , Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 11, 222 (2020).
- Agostini M. L., et al. , Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio 9, e00221-18 (2018).
- de Wit E., et al. , Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc. Natl. Acad. Sci. U.S.A. 110, 16598–16603 (2013).
- Hui D. S., et al. , Middle East respiratory syndrome coronavirus: Risk factors and determinants of primary, household, and nosocomial transmission. Lancet Infect. Dis. 18, e217–e227 (2018).
- Assiri A., et al. , Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: A descriptive study. Lancet Infect. Dis. 13, 752–761 (2013).
- Chan J. F., et al. , Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J. Infect. Dis. 212, 1904–1913 (2015).
- Chen Z., et al. , Human neutralizing monoclonal antibody inhibition of Middle East respiratory syndrome coronavirus replication in the common marmoset. J. Infect. Dis. 215, 1807–1815 (2017).
- de Wit E., et al. , Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets. Antiviral Res. 156, 64–71 (2018).
- Falzarano D., et al. , Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat. Med. 19, 1313–1317 (2013).
- van Doremalen N., et al. , Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets. Antiviral Res. 143, 30–37 (2017).
- Al-Abdely H. M., et al. , Middle East respiratory syndrome coronavirus infection dynamics and antibody responses among clinically diverse patients, Saudi Arabia. Emerg. Infect. Dis. 25, 753–766 (2019).
- Bin S. Y., et al. , Environmental contamination and viral shedding in MERS patients during MERS-CoV outbreak in South Korea. Clin. Infect. Dis. 62, 755–760 (2016).
- Prescott J., et al. , Pathogenicity and viral shedding of MERS-CoV in immunocompromised rhesus macaques. Front. Immunol. 9, 205 (2018).
- Dörnemann J., et al. , First newborn baby to receive experimental therapies survives Ebola virus disease. J. Infect. Dis. 215, 171–174 (2017).
- Jacobs M., et al. , Late Ebola virus relapse causing meningoencephalitis: A case report. Lancet 388, 498–503 (2016).
- Mulangu S., et al. ; PALM Writing Group ; PALM Consortium Study Team , A randomized, controlled trial of Ebola virus disease therapeutics. N. Engl. J. Med. 381, 2293–2303 (2019).
- , GS-5734 to assess the antiviral activity, long-term clearance of Ebola virus and safety in male Ebola survivors with evidence of Ebola virus persistence in semen. . Accessed 25 January 2020.
- , Investigational therapeutics for the treatment of people with Ebola virus disease. . Accessed 25 January 2020.
- World Health Organization , Novel coronavirus (2019-nCoV). . Accessed 25 January 2020.
- Falzarano D., et al. , Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog. 10, e1004250 (2014).
- Brining D. L., et al. , Thoracic radiography as a refinement methodology for the study of H1N1 influenza in cynomologus macaques (Macaca fascicularis). Comp. Med. 60, 389–395 (2010).
- Corman V. M., et al. , Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Euro. Surveill. 17 20285 (2012).
Source: PubMed