Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

Dinesh Kumar, N.; Ter Ellen, B.; Bouma, E. M.; Troost, B.; van de Pol, D. P. I.; van der Ende-Metselaar, H. H.; van Gosliga, D.; Apperloo, L.; Carpaij, O. A.; van den Berge, M.; Nawijn, M. C.; Stienstra, Y.; Rodenhuis-Zybert, I. A.; Smit, J.

doi:10.1101/2021.05.17.444467

bioRxiv · 10.1101/2021.05.17.444467

Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

Dinesh Kumar, N.·Ter Ellen, B.·Bouma, E. M.·Troost, B.·van de Pol, D. P. I.·van der Ende-Metselaar, H. H.·van Gosliga, D.·Apperloo, L.·Carpaij, O. A.·van den Berge, M.·Nawijn, M. C.·Stienstra, Y.·Rodenhuis-Zybert, I. A.·Smit, J.

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Abstract

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 {micro}M. These in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: "the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive". It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and a structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 {micro}M. These disappointing results calls for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

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Dinesh Kumar, N., Ter Ellen, B., Bouma, E. M., Troost, B., van de Pol, D. P. I., van der Ende-Metselaar, H. H., van Gosliga, D., Apperloo, L., Carpaij, O. A., van den Berge, M., Nawijn, M. C., Stienstra, Y., Rodenhuis-Zybert, I. A., Smit, J.. 2021-05-17. Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells. https://doi.org/10.1101/2021.05.17.444467

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