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Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine

View ORCID ProfileSuzanne JF Kaptein, Sofie Jacobs, Lana Langendries, Laura Seldeslachts, Sebastiaan ter Horst, Laurens Liesenborghs, Bart Hens, Valentijn Vergote, Elisabeth Heylen, Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants, Tina Van Buyten, Hendrik Jan Thibaut, Kai Dallmeier, Robbert Boudewijns, Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher Cawthorne, Birgit Weynand, View ORCID ProfilePieter Annaert, Isabel Spriet, View ORCID ProfileGreetje Vande Velde, View ORCID ProfileJohan Neyts, Joana Rocha-Pereira, View ORCID ProfileLeen Delang
doi: https://doi.org/10.1101/2020.06.19.159053
Suzanne JF Kaptein
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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  • ORCID record for Suzanne JF Kaptein
  • For correspondence: suzanne.kaptein@kuleuven.be johan.neyts@kuleuven.be joana.rochapereira@kuleuven.be leen.delang@kuleuven.be
Sofie Jacobs
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Lana Langendries
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Laura Seldeslachts
2KU Leuven Department of Imaging and Pathology, Biomedical MRI and MoSAIC, B-3000 Leuven, Belgium
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Sebastiaan ter Horst
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Laurens Liesenborghs
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Bart Hens
3KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery & Disposition, Box 921, 3000 Leuven, Belgium
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Valentijn Vergote
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Elisabeth Heylen
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Elke Maas
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Carolien De Keyzer
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Lindsey Bervoets
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Jasper Rymenants
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Tina Van Buyten
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Hendrik Jan Thibaut
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Kai Dallmeier
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Robbert Boudewijns
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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Jens Wouters
4KU Leuven Department of Imaging and Pathology, Molecular Small Animal Imaging Centre (MoSAIC), B-3000 Leuven, Belgium
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Patrick Augustijns
3KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery & Disposition, Box 921, 3000 Leuven, Belgium
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Nick Verougstraete
5Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
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Christopher Cawthorne
6KU Leuven, Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, B-3000 Leuven, Belgium
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Birgit Weynand
7KU Leuven Department of Imaging and Pathology, Translational Cell and Tissue Research, B-3000 Leuven, Belgium; Division of Translational Cell and Tissue Research
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Pieter Annaert
3KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery & Disposition, Box 921, 3000 Leuven, Belgium
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Isabel Spriet
8Pharmacy Dpt, University Hospitals Leuven and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven – University of Leuven, Belgium
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Greetje Vande Velde
2KU Leuven Department of Imaging and Pathology, Biomedical MRI and MoSAIC, B-3000 Leuven, Belgium
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Johan Neyts
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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  • For correspondence: suzanne.kaptein@kuleuven.be johan.neyts@kuleuven.be joana.rochapereira@kuleuven.be leen.delang@kuleuven.be
Joana Rocha-Pereira
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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  • For correspondence: suzanne.kaptein@kuleuven.be johan.neyts@kuleuven.be joana.rochapereira@kuleuven.be leen.delang@kuleuven.be
Leen Delang
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
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  • ORCID record for Leen Delang
  • For correspondence: suzanne.kaptein@kuleuven.be johan.neyts@kuleuven.be joana.rochapereira@kuleuven.be leen.delang@kuleuven.be
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Abstract

SARS-CoV-2 rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus was able to infect millions of people. To date, close to half a million patients succumbed to the viral disease, COVID-19. The high need for treatment options, together with the lack of small animal models of infection has led to clinical trials with repurposed drugs before any preclinical in vivo evidence attesting their efficacy was available. We used Syrian hamsters to establish a model to evaluate antiviral activity of small molecules in both an infection and a transmission setting. Upon intranasal infection, the animals developed high titers of SARS-CoV-2 in the lungs and pathology similar to that observed in mild COVID-19 patients. Treatment of SARS-CoV-2-infected hamsters with favipiravir or hydroxychloroquine (with and without azithromycin) resulted in respectively a mild or no reduction in viral RNA and infectious virus. Micro-CT scan analysis of the lungs showed no improvement compared to non-treated animals, which was confirmed by histopathology. In addition, both compounds did not prevent virus transmission through direct contact and thus failed as prophylactic treatments. By modelling the PK profile of hydroxychloroquine based on the trough plasma concentrations, we show that the total lung exposure to the drug was not the limiting factor. In conclusion, we here characterized a hamster infection and transmission model to be a robust model for studying in vivo efficacy of antiviral compounds. The information acquired using hydroxychloroquine and favipiravir in this model is of critical value to those designing (current and) future clinical trials. At this point, the data here presented on hydroxychloroquine either alone or combined with azithromycin (together with previously reported in vivo data in macaques and ferrets) provide no scientific basis for further use of the drug 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. It is made available under a CC-BY-NC-ND 4.0 International license.
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Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine
Suzanne JF Kaptein, Sofie Jacobs, Lana Langendries, Laura Seldeslachts, Sebastiaan ter Horst, Laurens Liesenborghs, Bart Hens, Valentijn Vergote, Elisabeth Heylen, Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants, Tina Van Buyten, Hendrik Jan Thibaut, Kai Dallmeier, Robbert Boudewijns, Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher Cawthorne, Birgit Weynand, Pieter Annaert, Isabel Spriet, Greetje Vande Velde, Johan Neyts, Joana Rocha-Pereira, Leen Delang
bioRxiv 2020.06.19.159053; doi: https://doi.org/10.1101/2020.06.19.159053
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Antiviral treatment of SARS-CoV-2-infected hamsters reveals a weak effect of favipiravir and a complete lack of effect for hydroxychloroquine
Suzanne JF Kaptein, Sofie Jacobs, Lana Langendries, Laura Seldeslachts, Sebastiaan ter Horst, Laurens Liesenborghs, Bart Hens, Valentijn Vergote, Elisabeth Heylen, Elke Maas, Carolien De Keyzer, Lindsey Bervoets, Jasper Rymenants, Tina Van Buyten, Hendrik Jan Thibaut, Kai Dallmeier, Robbert Boudewijns, Jens Wouters, Patrick Augustijns, Nick Verougstraete, Christopher Cawthorne, Birgit Weynand, Pieter Annaert, Isabel Spriet, Greetje Vande Velde, Johan Neyts, Joana Rocha-Pereira, Leen Delang
bioRxiv 2020.06.19.159053; doi: https://doi.org/10.1101/2020.06.19.159053

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