Development of Safe and Highly Protective Live-Attenuated SARS-CoV-2 Vaccine Candidates by Genome Recoding

Abstract

Safe and effective vaccines are urgently needed to stop the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We constructed a series of live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome, and assessed 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 did not cause clinical symptoms, but were highly immunogenic and induced strong protective immunity. Attenuated viruses replicated efficiently in the upper but not in the lower airways, causing only mild pulmonary histopathology. After challenge, hamsters developed no signs of disease and rapidly cleared 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.

Funding: This research was supported by the Deutsche Forschungsgemeinschaft (DFG), grant OS143/16-1 and COVID-19 grants from Freie Universität Berlin and Berlin University Alliance awarded to NO, the DFG grant SFB-TR84/Z01b awarded to ADG and JT and the SwissNational Science Foundation, grants 31CA30_196644, 31CA30_196062, and 310030_173085 awarded to VT.

Conflict of Interest: The authors declare no competing interests.

Ethical Approval: In vitro and animal work was done under biosafety conditions in the BSL-3 facility at the Institut für Virologie, Freie Universität Berlin, Germany. All animal experiments wereapproved by the Landesamt für Gesundheit und Soziales in Berlin, Germany (permit number0086/20) and done in compliance with relevant national and international guidelines for care and humane use of animals.

Keywords: coronavirus, SARS-CoV-2, COVID-19, live attenuated vaccine, genome recoding, codon pair deoptimization, synthetic attenuated virus engineering, Syrian hamster