Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets
Robert M Cox, Josef D Wolf, Richard K Plemper, Robert M Cox, Josef D Wolf, Richard K Plemper
Abstract
The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.
Conflict of interest statement
Competing interests
The authors declare no competing interests.
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References
- Rodriguez Mega E COVID has killed more than one million people. How many more will die? Nature, doi:10.1038/d41586-020-02762-y (2020).
- Martinot M et al. Remdesivir failure with SARS-CoV-2 RNA-dependent RNA-polymerase mutation in a B-cell immunodeficient patient with protracted Covid-19. Clin. Infect. Dis, doi:10.1093/cid/ciaa1474 (2020).
- Humeniuk R et al. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin. Transl. Sci 13, 896–906, doi:10.1111/cts.12840 (2020).
- Toots M et al. Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia. Sci. Transl. Med 11, doi:10.1126/scitranslmed.aax5866 (2019).
- Toots M & Plemper RK Next-generation direct-acting influenza therapeutics. Transl. Res, doi:10.1016/j.trsl.2020.01.005 (2020).
- Salajegheh Tazerji S et al. Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to animals: an updated review. J. Transl. Med 18, 358, doi:10.1186/s12967-020-02534-2 (2020).
- Oreshkova N et al. SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020. Euro Surveill. 25, doi:10.2807/1560-7917.ES.2020.25.23.2001005 (2020).
- Enserink M Coronavirus rips through Dutch mink farms, triggering culls. Science 368, 1169, doi:10.1126/science.368.6496.1169 (2020).
- Oude Munnink BB et al. Jumping back and forth: anthropozoonotic and zoonotic transmission of SARS-CoV-2 on mink farms. bioRxiv, 2020.2009.2001.277152, doi:10.1101/2020.09.01.277152 (2020).
- Toots M et al. Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl. Res 218, 16–28, doi:10.1016/j.trsl.2019.12.002 (2020).
- Yoon JJ et al. Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses. Antimicrob. Agents Chemother 62, doi:10.1128/AAC.00766-18 (2018).
- Urakova N et al. beta-d-N (4)-Hydroxycytidine Is a Potent Anti-alphavirus Compound That Induces a High Level of Mutations in the Viral Genome. J. Virol 92, doi:10.1128/JVI.01965-17 (2018).
- Sheahan TP et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med 12, doi:10.1126/scitranslmed.abb5883 (2020).
- Han K et al. Lung Expression of Human ACE2 Sensitizes the Mouse to SARS-CoV-2 Infection. Am. J. Respir. Cell Mol. Biol, doi:10.1165/rcmb.2020-0354OC (2020).
- Bruschke C (ed Nature and Food Quality Ministry of Agriculture) (2020).
- Schlottau K et al. SARS-CoV-2 in fruit bats, ferrets, pigs, and chickens: an experimental transmission study. Lancet Microbe 1, e218–e225, doi:10.1016/S2666-5247(20)30089-6 (2020).
- Richard M et al. SARS-CoV-2 is transmitted via contact and via the air between ferrets. Nat Commun 11, 3496, doi:10.1038/s41467-020-17367-2 (2020).
- Davies NG et al. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat. Med 26, 1205–1211, doi:10.1038/s41591-020-0962-9 (2020).
- Agostini ML et al. Small-Molecule Antiviral beta-d-N (4)-Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. J. Virol 93, doi:10.1128/JVI.01348-19 (2019).
- Shi J et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science 368, 1016–1020, doi:10.1126/science.abb7015 (2020).
- Park SJ et al. Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets. mBio 11, doi:10.1128/mBio.01114-20 (2020).
- Kutter JS et al. SARS-CoV and SARS-CoV-2 are transmitted through the air between ferrets over more than one meter distance. bioRxiv, 2020.2010.2019.345363, doi:10.1101/2020.10.19.345363 (2020).
- in GEN Genetic Engineering & Biotechnology News (2020).
- Painter GR et al. The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection. Antiviral Res. 171, 104597, doi:10.1016/j.antiviral.2019.104597 (2019).
- Les A, Adamowicz L & Rode W Structure and conformation of N4-hydroxycytosine and N4-hydroxy-5-fluorocytosine. A theoretical ab initio study. Biochim. Biophys. Acta 1173, 39–48, doi:10.1016/0167-4781(93)90240-e (1993).
- Crotty S, Cameron CE & Andino R RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sci. U. S. A 98, 6895–6900, doi:10.1073/pnas.111085598 (2001).
- Desmyter J, Melnick JL & Rawls WE Defectiveness of interferon production and of rubella virus interference in a line of African green monkey kidney cells (Vero). J. Virol 2, 955–961, doi:10.1128/JVI.2.10.955-961.1968 (1968).
- Cox RM et al. Orally efficacious broad-spectrum allosteric inhibitor of paramyxovirus polymerase. Nat Microbiol, doi:10.1038/s41564-020-0752-7 (2020).
- Wolfel R et al. Virological assessment of hospitalized patients with COVID-2019. Nature 581, 465–469, doi:10.1038/s41586-020-2196-x (2020).
Source: PubMed