Ferrets not infected by SARS-CoV-2 in a high-exposure domestic setting

Ferrets () are mustelids of special relevance to laboratory studies of respiratory viruses and have been shown to be susceptible to SARS-CoV-2 infection and onward transmission. Here, we report the results of a natural experiment where 29 ferrets in one home had prolonged, direct contact and constant environmental exposure to two humans with symptomatic COVID-19. We observed no evidence of SARS-CoV-2 transmission from humans to ferrets based on RT-PCR and ELISA. To better understand this discrepancy in experimental and natural infection in ferrets, we compared SARS-CoV-2 sequences from natural and experimental mustelid infections and identified two surface glycoprotein (Spike) mutations associated with mustelids. While we found evidence that ACE2 provides a weak host barrier, one mutation only seen in ferrets is located in the novel S1/S2 cleavage site and is computationally predicted to decrease furin activity. These data support that host factors interacting with the novel S1/S2 cleavage site may be a barrier in ferret SARS-CoV-2 susceptibility and that domestic ferrets are at low risk of natural infection from currently circulating SARS-CoV-2. This may be overcome in laboratory settings using concentrated viral inoculum, but the effects of ferret host-adaptations require additional investigation.