Immunological and pathological outcomes of SARS-CoV-2 challenge following formalin-inactivated vaccine in ferrets and rhesus macaques

Bewley, Kevin R.; Gooch, Karen; Thomas, Kelly M.; Longet, Stephanie; Wiblin, Nathan; Hunter, Laura; Chan, Kin; Brown, Phillip; Russell, Rebecca A.; Ho, Catherine; Slack, Gillian; Humphries, Holly E.; Alden, Leonie; Allen, Lauren; Aram, Marilyn; Baker, Natalie; Brunt, Emily; Cobb, Rebecca; Fotheringham, Susan; Harris, Debbie; Kennard, Chelsea; Leung, Stephanie; Ryan, Kathryn; Tolley, Howard; Wand, Nadina; White, Andrew; Sibley, Laura; Sarfas, Charlotte; Pearson, Geoff; Rayner, Emma; Xue, Xiaochao; Lambe, Teresa; Charlton, Sue; Gilbert, Sarah; Sattentau, Quentin J.; Gleeson, Fergus; Hall, Yper; Funnell, Simon; Sharpe, Sally; Salguero, Francisco J.; Gorringe, Andrew; Carroll, Miles

There is an urgent requirement for safe and effective vaccines to prevent COVID-19. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferrets and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen 7 days after infection in ferrets. This increased lung pathology was observed at day 7 but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.