Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

Ryan, Kathryn A.; Bewley, Kevin R.; Fotheringham, Susan A.; Slack, Gillian S.; Brown, Phillip; Hall, Yper; Wand, Nadina I.; Marriott, Anthony C.; Cavell, Breeze E.; Tree, Julia A.; Allen, Lauren; Aram, Marilyn J.; Bean, Thomas J.; Brunt, Emily; Buttigieg, Karen R.; Carter, Daniel P.; Cobb, Rebecca; Coombes, Naomi S.; Findlay-Wilson, Steve J.; Godwin, Kerry J.; Gooch, Karen E.; Gouriet, Jade; Halkerston, Rachel; Harris, Debbie J.; Hender, Thomas H.; Humphries, Holly E.; Hunter, Laura; Ho, Catherine M. K.; Kennard, Chelsea L.; Leung, Stephanie; Longet, Stephanie; Ngabo, Didier; Osman, Karen L.; Paterson, Jemma; Penn, Elizabeth J.; Pullan, Steven T.; Rayner, Emma; Skinner, Oliver; Steeds, Kimberley; Taylor, Irene; Tipton, Tom; Thomas, Stephen; Turner, Carrie; Watson, Robert J.; Wiblin, Nathan R.; Charlton, Sue; Hallis, Bassam; Hiscox, Julian A.; Funnell, Simon; Dennis, Mike J.; Whittaker, Catherine J.; Catton, Michael G.; Druce, Julian; Salguero, Francisco J.; Carroll, Miles W.

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 10(6) pfu) and medium (5 × 10(4) pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 10(2) pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.