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Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge

Kathryn A. Ryan, Kevin R. Bewley, Susan A. Fotheringham, Phillip Brown, Yper Hall, Anthony C. Marriott, Julia A. Tree, Lauren Allen, Marilyn J. Aram, Emily Brunt, Karen R. Buttigieg, Breeze E. Cavell, Daniel P. Carter, Rebecca Cobb, Naomi S. Coombes, Kerry J. Godwin, Karen E. Gooch, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Holly E. Humphries, Laura Hunter, Catherine M. K. Ho, Chelsea L. Kennard, Stephanie Leung, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven T. Pullan, Emma Rayner, Gillian S. Slack, Kimberley Steeds, Irene Taylor, Tom Tipton, Stephen Thomas, Nadina I. Wand, Robert J. Watson, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Julian A. Hiscox, Simon Funnell, Mike J. Dennis, Catherine J. Whittaker, Michael G. Catton, Julian Druce, Francisco J. Salguero, Miles W. Carroll
doi: https://doi.org/10.1101/2020.05.29.123810
Kathryn A. Ryan
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Kevin R. Bewley
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Susan A. Fotheringham
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Phillip Brown
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Yper Hall
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Anthony C. Marriott
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Julia A. Tree
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Lauren Allen
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Marilyn J. Aram
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Emily Brunt
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Karen R. Buttigieg
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Breeze E. Cavell
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Daniel P. Carter
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Rebecca Cobb
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Naomi S. Coombes
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Kerry J. Godwin
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Karen E. Gooch
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Jade Gouriet
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Rachel Halkerston
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Debbie J. Harris
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Holly E. Humphries
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Laura Hunter
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Catherine M. K. Ho
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Chelsea L. Kennard
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Stephanie Leung
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Didier Ngabo
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Karen L. Osman
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Jemma Paterson
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Elizabeth J. Penn
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Steven T. Pullan
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Emma Rayner
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Gillian S. Slack
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Kimberley Steeds
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Irene Taylor
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Tom Tipton
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Stephen Thomas
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Nadina I. Wand
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Robert J. Watson
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Nathan R. Wiblin
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Sue Charlton
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Bassam Hallis
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Julian A. Hiscox
2Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom, L69 2BE
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Simon Funnell
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Mike J. Dennis
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Catherine J. Whittaker
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Michael G. Catton
3Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, At the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
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Julian Druce
3Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, At the Peter Doherty Institute for Infection and Immunity, Victoria, 3000, Australia
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Francisco J. Salguero
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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Miles W. Carroll
1National Infection Service, Public Health England (PHE), Porton Down, Salisbury, Wiltshire, United Kingdom SP4 0JG
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  • For correspondence: miles.carroll@phe.gov.uk
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Abstract

In December 2019 an outbreak of coronavirus disease (COVID-19) emerged in Wuhan, China. The causative agent was subsequently identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread worldwide causing a pandemic. Currently there are no licensed vaccines or therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in development and repurposed drugs are being tested in the clinic. There is a vital need for authentic COVID-19 animal models to further our understanding of pathogenesis and viral spread in addition to pre-clinical evaluation of candidate interventions.

Here we report a dose titration study of SARS-CoV-2 to determine the most suitable infectious dose to use in the ferret model. We show that a high (5×106 pfu) and medium (5×104 pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral RNA shedding in both groups of six challenged animals, whilst a low dose (5×102 pfu) resulted in only one of six displaying signs of URT viral RNA replication. The URT shedding lasted up to 21 days in the high dose animals with intermittent positive signal from day 14. Sequential culls revealed distinct pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were observed although animals did present with a consistent post-viral fatigue lasting from day 9-14 in the medium and high dose groups. After virus shedding ceased, re-challenged ferrets were shown to be fully protected from acute lung pathology. The endpoints of URT viral RNA replication in addition to distinct lung pathology and post viral fatigue were observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 14-21 parallel observations reported in a minority of clinical cases.

  • Ferret
  • COVID
  • SARS-CoV-2
  • animal model
  • coronavirus

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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Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge
Kathryn A. Ryan, Kevin R. Bewley, Susan A. Fotheringham, Phillip Brown, Yper Hall, Anthony C. Marriott, Julia A. Tree, Lauren Allen, Marilyn J. Aram, Emily Brunt, Karen R. Buttigieg, Breeze E. Cavell, Daniel P. Carter, Rebecca Cobb, Naomi S. Coombes, Kerry J. Godwin, Karen E. Gooch, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Holly E. Humphries, Laura Hunter, Catherine M. K. Ho, Chelsea L. Kennard, Stephanie Leung, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven T. Pullan, Emma Rayner, Gillian S. Slack, Kimberley Steeds, Irene Taylor, Tom Tipton, Stephen Thomas, Nadina I. Wand, Robert J. Watson, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Julian A. Hiscox, Simon Funnell, Mike J. Dennis, Catherine J. Whittaker, Michael G. Catton, Julian Druce, Francisco J. Salguero, Miles W. Carroll
bioRxiv 2020.05.29.123810; doi: https://doi.org/10.1101/2020.05.29.123810
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Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge
Kathryn A. Ryan, Kevin R. Bewley, Susan A. Fotheringham, Phillip Brown, Yper Hall, Anthony C. Marriott, Julia A. Tree, Lauren Allen, Marilyn J. Aram, Emily Brunt, Karen R. Buttigieg, Breeze E. Cavell, Daniel P. Carter, Rebecca Cobb, Naomi S. Coombes, Kerry J. Godwin, Karen E. Gooch, Jade Gouriet, Rachel Halkerston, Debbie J. Harris, Holly E. Humphries, Laura Hunter, Catherine M. K. Ho, Chelsea L. Kennard, Stephanie Leung, Didier Ngabo, Karen L. Osman, Jemma Paterson, Elizabeth J. Penn, Steven T. Pullan, Emma Rayner, Gillian S. Slack, Kimberley Steeds, Irene Taylor, Tom Tipton, Stephen Thomas, Nadina I. Wand, Robert J. Watson, Nathan R. Wiblin, Sue Charlton, Bassam Hallis, Julian A. Hiscox, Simon Funnell, Mike J. Dennis, Catherine J. Whittaker, Michael G. Catton, Julian Druce, Francisco J. Salguero, Miles W. Carroll
bioRxiv 2020.05.29.123810; doi: https://doi.org/10.1101/2020.05.29.123810

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