Potent neutralization of SARS-CoV-2 variants of concern by an antibody with an uncommon genetic signature and structural mode of spike recognition

Kramer, Kevin J.; Johnson, Nicole V.; Shiakolas, Andrea R.; Suryadevara, Naveenchandra; Periasamy, Sivakumar; Raju, Nagarajan; Williams, Jazmean K.; Wrapp, Daniel; Zost, Seth J.; Walker, Lauren M.; Wall, Steven C.; Holt, Clinton M.; Hsieh, Ching-Lin; Sutton, Rachel E.; Paulo, Ariana; Davidson, Edgar; Doranz, Benjamin J.; Crowe, James E.; Bukreyev, Alexander; Carnahan, Robert H.; McLellan, Jason S.; Georgiev, Ivelin S.

The emergence of SARS-CoV-2 lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable challenge to the clinical treatment of COVID-19. Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the LIBRA-seq technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryo-EM structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs.