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

Ryan, K. A.; Bewley, K. R.; Fotheringham, S. A.; Brown, P.; Hall, Y.; Marriott, A. C.; Tree, J. A.; Allen, L.; Aram, M. J.; Brunt, E.; Buttigieg, K. R.; Cavell, B. E.; Carter, D. P.; Cobb, R.; Coombes, N. S.; Godwin, K. J.; Gooch, K. E.; Gouriet, J.; Halkerston, R.; Harris, D. J.; Humphries, H. E.; Hunter, L.; Ho, C. M. K.; Kennard, C. L.; Leung, S.; Ngabo, D.; Osman, K. L.; Paterson, J.; Penn, E. J.; Pullan, S. T.; Rayner, E.; Slack, G. S.; Steeds, K.; Taylor, I.; Tipton, T.; Thomas, S.; Wand, N. I.; Watson, R. J.; Wiblin, N. R.; Charlton, S.; Hallis, B.; Hiscox, J. A.; Funnell, S.; Dennis, M

doi:10.1101/2020.05.29.123810

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bioRxiv · 10.1101/2020.05.29.123810

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

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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 (5x106 pfu) and medium (5x104 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 (5x102 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.

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Ryan, K. A., Bewley, K. R., Fotheringham, S. A., Brown, P., Hall, Y., Marriott, A. C., Tree, J. A., Allen, L., Aram, M. J., Brunt, E., Buttigieg, K. R., Cavell, B. E., Carter, D. P., Cobb, R., Coombes, N. S., Godwin, K. J., Gooch, K. E., Gouriet, J., Halkerston, R., Harris, D. J., Humphries, H. E., Hunter, L., Ho, C. M. K., Kennard, C. L., Leung, S., Ngabo, D., Osman, K. L., Paterson, J., Penn, E. J., Pullan, S. T., Rayner, E., Slack, G. S., Steeds, K., Taylor, I., Tipton, T., Thomas, S., Wand, N. I., Watson, R. J., Wiblin, N. R., Charlton, S., Hallis, B., Hiscox, J. A., Funnell, S., Dennis, M. 2020-06-01. Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge. https://doi.org/10.1101/2020.05.29.123810

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