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Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in Syrian hamsters

View ORCID ProfileRana Abdelnabi, View ORCID ProfileDirk Jochmans, Kim Donckers, Bettina Trüeb, Nadine Ebert, Birgit Weynand, Volker Thiel, Johan Neyts
doi: https://doi.org/10.1101/2022.09.28.509903
Rana Abdelnabi
1KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, B-3000 Leuven, Belgium
2The VirusBank, BioIncubator 4, Gaston Geenslaan, B-3000 Leuven, Belgium
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Dirk Jochmans
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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Kim Donckers
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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Bettina Trüeb
3Institute of Virology and Immunology, University of Bern, 3012, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Nadine Ebert
3Institute of Virology and Immunology, University of Bern, 3012, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Birgit Weynand
4KU 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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Volker Thiel
3Institute of Virology and Immunology, University of Bern, 3012, Bern, Switzerland; Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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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
2The VirusBank, BioIncubator 4, Gaston Geenslaan, B-3000 Leuven, Belgium
5Global Virus Network, GVN
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  • For correspondence: johan.neyts@kuleuven.be
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Abstract

The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic target for the treatment of COVID-19. Nirmatrelvir is the only the 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization; other 3Lpro inhibitors are in development. We recently repored on the in vitro selection of a SARS-CoV2 3CLpro (L50F-E166A-L167F; short 3CLprores) virus that is cross-resistant with nirmatrelvir and yet other 3CLpro inhibitors. Here, we demonstrate that the resistant virus replicates efficiently in the lungs of intranassaly infected hamsters and that it causes a lung pathology that is comparable to that caused by the WT virus. Moreover, 3CLprores infected hamsters transmit the virus efficiently to co-housed non-infected contact hamsters. Fortunately, resistance to Nirmatrelvir does not readily develop (in the clinical setting) since the drug has a relatively high barrier to resistance. Yet, as we demonstrate, in case resistant viruses emerge, they may easily spread and impact therapeutic options for others. Therefore, the use of SARS-CoV-2 3CLpro protease inhibitors in combinations with drugs that have a different mechanism of action, may be considered to avoid the development of drug-resistant viruses in the future.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
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 September 28, 2022.
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Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in Syrian hamsters
Rana Abdelnabi, Dirk Jochmans, Kim Donckers, Bettina Trüeb, Nadine Ebert, Birgit Weynand, Volker Thiel, Johan Neyts
bioRxiv 2022.09.28.509903; doi: https://doi.org/10.1101/2022.09.28.509903
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Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in Syrian hamsters
Rana Abdelnabi, Dirk Jochmans, Kim Donckers, Bettina Trüeb, Nadine Ebert, Birgit Weynand, Volker Thiel, Johan Neyts
bioRxiv 2022.09.28.509903; doi: https://doi.org/10.1101/2022.09.28.509903

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