Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV
Timothy P Sheahan, Amy C Sims, Sarah R Leist, Alexandra Schäfer, John Won, Ariane J Brown, Stephanie A Montgomery, Alison Hogg, Darius Babusis, Michael O Clarke, Jamie E Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y Feng, Tomas Cihlar, Robert Jordan, Mark R Denison, Ralph S Baric, Timothy P Sheahan, Amy C Sims, Sarah R Leist, Alexandra Schäfer, John Won, Ariane J Brown, Stephanie A Montgomery, Alison Hogg, Darius Babusis, Michael O Clarke, Jamie E Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y Feng, Tomas Cihlar, Robert Jordan, Mark R Denison, Ralph S Baric
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is the causative agent of a severe respiratory disease associated with more than 2468 human infections and over 851 deaths in 27 countries since 2012. There are no approved treatments for MERS-CoV infection although a combination of lopinavir, ritonavir and interferon beta (LPV/RTV-IFNb) is currently being evaluated in humans in the Kingdom of Saudi Arabia. Here, we show that remdesivir (RDV) and IFNb have superior antiviral activity to LPV and RTV in vitro. In mice, both prophylactic and therapeutic RDV improve pulmonary function and reduce lung viral loads and severe lung pathology. In contrast, prophylactic LPV/RTV-IFNb slightly reduces viral loads without impacting other disease parameters. Therapeutic LPV/RTV-IFNb improves pulmonary function but does not reduce virus replication or severe lung pathology. Thus, we provide in vivo evidence of the potential for RDV to treat MERS-CoV infections.
Conflict of interest statement
A.C.S. received a contract from Gilead Sciences to support the in vitro and in vivo efficacy studies reported herein. These authors are employees of Gilead Sciences and hold stock in Gilead Sciences: Alison Hogg, Darius Babusis, Michael O. Clarke, Jamie E. Spahn, Laura Bauer, Scott Sellers, Danielle Porter, Joy Y. Feng, Tomas Cihlar, and Robert Jordan.
Figures
References
- de Wit E, van Doremalen N, Falzarano D, Munster VJ. SARS and MERS: recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 2016;14:523–534. doi: 10.1038/nrmicro.2016.81.
- Muller MA, et al. Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study. Lancet Infect. Dis. 2015;15:629. doi: 10.1016/S1473-3099(15)70090-3.
- Dudas, G., Carvalho, L. M., Rambaut, A. & Bedford, T. MERS-CoV spillover at the camel-human interface. eLife7, e31257 (2018).
- Morra ME, et al. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis. Rev. Med Virol. 2018;28:e1977. doi: 10.1002/rmv.1977.
- WHO. Middle East respiratory syndrome coronavirus (MERS-CoV). (2018).
- Cho SY, et al. MERS-CoV outbreak following a single patient exposure in an emergency room in South Korea: an epidemiological outbreak study. Lancet. 2016;388:994–1001. doi: 10.1016/S0140-6736(16)30623-7.
- Kaletra. Highlights of Prescribing Information. (2017).
- Chan JF, et al. Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J. Infect. 2013;67:606–616. doi: 10.1016/j.jinf.2013.09.029.
- de Wilde AH, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 2014;58:4875–4884. doi: 10.1128/AAC.03011-14.
- Hart BJ, et al. Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J. Gen. Virol. 2014;95:571–577. doi: 10.1099/vir.0.061911-0.
- Chan JF, et al. Treatment with lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J. Infect. Dis. 2015;212:1904–1913. doi: 10.1093/infdis/jiv392.
- Kim UJ, Won EJ, Kee SJ, Jung SI, Jang HC. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-alpha for Middle East respiratory syndrome. Antivir. Ther. 2016;21:455–459. doi: 10.3851/IMP3002.
- Spanakis N, et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J. Antimicrob. Agents. 2014;44:528–532. doi: 10.1016/j.ijantimicag.2014.07.026.
- Arabi YM, et al. Treatment of Middle East respiratory syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018;19:81. doi: 10.1186/s13063-017-2427-0.
- Arabi, Y. M. Twitter account for MIRACLE Trial. (2019).
- Lo MK, et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci. Rep. 2017;7:43395. doi: 10.1038/srep43395.
- Sheahan Timothy P., Sims Amy C., Graham Rachel L., Menachery Vineet D., Gralinski Lisa E., Case James B., Leist Sarah R., Pyrc Krzysztof, Feng Joy Y., Trantcheva Iva, Bannister Roy, Park Yeojin, Babusis Darius, Clarke Michael O., Mackman Richard L., Spahn Jamie E., Palmiotti Christopher A., Siegel Dustin, Ray Adrian S., Cihlar Tomas, Jordan Robert, Denison Mark R., Baric Ralph S. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine. 2017;9(396):eaal3653. doi: 10.1126/scitranslmed.aal3653.
- Warren TK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–385. doi: 10.1038/nature17180.
- Jordan PC, et al. Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase. PLoS Pathog. 2018;14:e1006889. doi: 10.1371/journal.ppat.1006889.
- Tchesnokov, E. P., Feng, J. Y., Porter, D. P. & Gotte, M. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses11, 326 (2019).
- Brown AJ, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antivir. Res. 2019;169:104541. doi: 10.1016/j.antiviral.2019.104541.
- Cockrell AS, et al. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat. Microbiol. 2016;2:16226. doi: 10.1038/nmicrobiol.2016.226.
- Mo H, et al. Estimation of inhibitory quotient using a comparative equilibrium dialysis assay for prediction of viral response to hepatitis C virus inhibitors. J. Viral Hepat. 2011;18:338–348. doi: 10.1111/j.1365-2893.2010.01314.x.
- Douglas MG, Kocher JF, Scobey T, Baric RS, Cockrell AS. Adaptive evolution influences the infectious dose of MERS-CoV necessary to achieve severe respiratory disease. Virology. 2018;517:98–107. doi: 10.1016/j.virol.2017.12.006.
- Fukushi M, et al. Serial histopathological examination of the lungs of mice infected with influenza A virus PR8 strain. PLoS One. 2011;6:e21207. doi: 10.1371/journal.pone.0021207.
- Matute-Bello G, et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am. J. Respir. Cell Mol. Biol. 2011;44:725–738. doi: 10.1165/rcmb.2009-0210ST.
- Arabi, Y. M. MERS-CoV infection treated with a combination of lopinavir/ritonavir and interferon beta-1b (MIRACLE). (2016).
- Menachery VD, Gralinski LE, Baric RS, Ferris MT. New metrics for evaluating viral respiratory pathogenesis. PLoS One. 2015;10:e0131451. doi: 10.1371/journal.pone.0131451.
- Schmidt ME, et al. Memory CD8 T cells mediate severe immunopathology following respiratory syncytial virus infection. PLoS Pathog. 2018;14:e1006810. doi: 10.1371/journal.ppat.1006810.
- Lossi, L., Castagna, C. & Merighi, A. Caspase-3 mediated cell death in the normal development of the mammalian cerebellum. Int. J. Mol. Sci.19, 3999 (2018).
- Ge XY, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013;503:535–538. doi: 10.1038/nature12711.
- Woo PC, et al. Molecular diversity of coronaviruses in bats. Virology. 2006;351:180–187. doi: 10.1016/j.virol.2006.02.041.
- Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses—drug discovery and therapeutic options. Nat. Rev. Drug Disco. 2016;15:327–347. doi: 10.1038/nrd.2015.37.
- Lambert JS, et al. Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy. HIV Med. 2011;12:166–173. doi: 10.1111/j.1468-1293.2010.00865.x.
- Friedman RM. Clinical uses of interferons. Br. J. Clin. Pharm. 2008;65:158–162. doi: 10.1111/j.1365-2125.2007.03055.x.
- Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc. R. Soc. Lond. B Biol. Sci. 1957;147:258–267. doi: 10.1098/rspb.1957.0048.
- Falzarano D, et al. Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat. Med. 2013;19:1313–1317. doi: 10.1038/nm.3362.
- Zhao J, et al. Rapid generation of a mouse model for Middle East respiratory syndrome. Proc. Natl Acad. Sci. USA. 2014;111:4970–4975. doi: 10.1073/pnas.1323279111.
- Channappanavar R, et al. Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J. Infect. Dis. 2015;212:1894–1903. doi: 10.1093/infdis/jiv325.
- Li K, et al. Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J. Infect. Dis. 2016;213:712–722. doi: 10.1093/infdis/jiv499.
- Falzarano D, et al. Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLoS Pathog. 2014;10:e1004250. doi: 10.1371/journal.ppat.1004250.
- Johnson RF, et al. Intratracheal exposure of common marmosets to MERS-CoV Jordan-n3/2012 or MERS-CoV EMC/2012 isolates does not result in lethal disease. Virology. 2015;485:422–430. doi: 10.1016/j.virol.2015.07.013.
- Davidson S, et al. IFNlambda is a potent anti-influenza therapeutic without the inflammatory side effects of IFNalpha treatment. EMBO Mol. Med. 2016;8:1099–1112. doi: 10.15252/emmm.201606413.
- Galani IE, et al. Interferon-lambda mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity. 2017;46:875–890 e876. doi: 10.1016/j.immuni.2017.04.025.
- Kim S, et al. The Superiority of IFN-lambda as a therapeutic candidate to control acute influenza viral lung infection. Am. J. Respir. Cell Mol. Biol. 2017;56:202–212. doi: 10.1165/rcmb.2016-0373OC.
- Aeffner F, Bolon B, Davis IC. Mouse models of acute respiratory distress syndrome: a review of analytical approaches, pathologic features, and common measurements. Toxicol. Pathol. 2015;43:1074–1092. doi: 10.1177/0192623315598399.
- National Institute of Allergy and Infectious Diseases (NIAID). Center, N.I.o.H.C. Investigational Therapeutics for the Treatment of People With Ebola Virus Disease NCT03719586. (2019).
- National Institute of Allergy and Infectious Diseases (NIAID). Center, N.I.o.H.C. GS-5734 to Assess the Antiviral Activity, Longer-Term Clearance of Ebola Virus, and Safety in Male Ebola Survivors With Evidence of Ebola Virus Persistence in Semen NCT02818582. (2019).
- Choi WS, et al. Clinical presentation and outcomes of Middle East respiratory syndrome in the Republic of Korea. Infect. Chemother. 2016;48:118–126. doi: 10.3947/ic.2016.48.2.118.
- Oh MD, et al. Viral load kinetics of MERS coronavirus infection. N. Engl. J. Med. 2016;375:1303–1305. doi: 10.1056/NEJMc1511695.
- de Wit E, et al. Prophylactic and therapeutic efficacy of mAb treatment against MERS-CoV in common marmosets. Antivir. Res. 2018;156:64–71. doi: 10.1016/j.antiviral.2018.06.006.
- Agostini, M. L. et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio9, e00221-18(2018).
- Scobey T, et al. Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc. Natl Acad. Sci. USA. 2013;110:16157–16162. doi: 10.1073/pnas.1311542110.
- Betaseron. Highlights of Prescribing Information. (2015).
- Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 2016;7:27–31. doi: 10.4103/0976-0105.177703.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262.
Source: PubMed