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

Nilima Dinesh Kumar, Bram M. ter Ellen, Ellen M. Bouma, Berit Troost, Denise P. I. van de Pol, Heidi H. van der Ende-Metselaar, Djoke van Gosliga, Leonie Apperloo, Orestes A. Carpaij, Maarten van den Berge, Martijn C. Nawijn, Ymkje Stienstra, Izabela A Rodenhuis-Zybert, Jolanda M. Smit
doi: https://doi.org/10.1101/2021.05.17.444467
Nilima Dinesh Kumar
1Department of Biomedical Sciences of Cells & Systems, University of Groningen, University Medical Center Groningen, The Netherlands
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Bram M. ter Ellen
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Ellen M. Bouma
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Berit Troost
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Denise P. I. van de Pol
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Heidi H. van der Ende-Metselaar
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Djoke van Gosliga
4Department of Pediatrics, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, GRIAC Research Institute, 9700 RB Groningen, The Netherlands
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Leonie Apperloo
3Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, GRIAC Research Institute, 9700 RB Groningen, The Netherlands
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Orestes A. Carpaij
5Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, GRIAC Research Institute, 9700 RB Groningen, The Netherlands
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Maarten van den Berge
5Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, GRIAC Research Institute, 9700 RB Groningen, The Netherlands
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Martijn C. Nawijn
3Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, GRIAC Research Institute, 9700 RB Groningen, The Netherlands
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Ymkje Stienstra
6Department of Internal Medicine/Infectious Diseases, University of Groningen, University Medical Center Groningen, The Netherlands
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Izabela A Rodenhuis-Zybert
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Jolanda M. Smit
2Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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  • For correspondence: jolanda.smit@umcg.nl
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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 µM. 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 µM. 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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 21, 2021.
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Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells
Nilima Dinesh Kumar, Bram M. ter Ellen, Ellen M. Bouma, Berit Troost, Denise P. I. van de Pol, Heidi H. van der Ende-Metselaar, Djoke van Gosliga, Leonie Apperloo, Orestes A. Carpaij, Maarten van den Berge, Martijn C. Nawijn, Ymkje Stienstra, Izabela A Rodenhuis-Zybert, Jolanda M. Smit
bioRxiv 2021.05.17.444467; doi: https://doi.org/10.1101/2021.05.17.444467
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Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells
Nilima Dinesh Kumar, Bram M. ter Ellen, Ellen M. Bouma, Berit Troost, Denise P. I. van de Pol, Heidi H. van der Ende-Metselaar, Djoke van Gosliga, Leonie Apperloo, Orestes A. Carpaij, Maarten van den Berge, Martijn C. Nawijn, Ymkje Stienstra, Izabela A Rodenhuis-Zybert, Jolanda M. Smit
bioRxiv 2021.05.17.444467; doi: https://doi.org/10.1101/2021.05.17.444467

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