Development of safe and highly protective live-attenuated SARS-CoV-2 vaccine candidates by genome recoding

Safe and effective vaccines are urgently needed to stop the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We construct a series of live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome and assess their safety and efficacy in Syrian hamsters. Animals were vaccinated with a single dose of the respective recoded virus and challenged 21 days later. Two of the tested viruses do not cause clinical symptoms but are highly immunogenic and induce strong protective immunity. Attenuated viruses replicate efficiently in the upper but not in the lower airways, causing only mild pulmonary histopathology. After challenge, hamsters develop no signs of disease and rapidly clear challenge virus: at no time could infectious virus be recovered from the lungs of infected animals. The ease with which attenuated virus candidates can be produced and administered favors their further development as vaccines to combat the ongoing pandemic. [Display omitted] •Live attenuated vaccine candidates are made by recoding the SARS-CoV-2 genome•The lead vaccine candidate sCPD9 is virtually apathogenic in two hamster species•Vaccination with sCPD9 elicits strong neutralizing antibody responses•A single intranasal droplet vaccination induces sterilizing immunity in hamsters Trimpert et al. construct safe and efficacious live attenuated SARS-CoV-2 vaccine candidates by recoding the SARS-CoV-2 genome. The lead vaccine candidate, sCPD9, is apathogenic in Syrian and Roborovski dwarf hamsters. A single intranasal droplet vaccination with sCPD9 induces strong neutralizing antibody responses and protects hamsters from disease caused by SARS-CoV-2.