Cell Rep

. 2022 Aug 11;111276.
doi: 10.1016/j.celrep.2022.111276. Online ahead of print.
A neutralizing epitope on the SD1 domain of SARS-CoV-2 spike targeted following infection and vaccination

Jeffrey Seow 1 , Hataf Khan 1 , Annachiara Rosa 2 , Valeria Calvaresi 3 , Carl Graham 1 , Suzanne Pickering 1 , Valerie E Pye 2 , Nora B Cronin 4 , Isabella Huettner 1 , Michael H Malim 1 , Argyris Politis 5 , Peter Cherepanov 6 , Katie J Doores 7



Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is the target for neutralizing antibodies elicited following both infection and vaccination. While extensive research has shown that the receptor binding domain (RBD) and, to a lesser extent, the N-terminal domain (NTD) are the predominant targets for neutralizing antibodies, identification of neutralizing epitopes beyond these regions is important for informing vaccine development and understanding antibody-mediated immune escape. Here, we identify a class of broadly neutralizing antibodies that bind an epitope on the spike subdomain 1 (SD1) and that have arisen from infection or vaccination. Using cryo-electron microscopy (cryo-EM) and hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), we show that SD1-specific antibody P008_60 binds an epitope that is not accessible within the canonical prefusion states of the SARS-CoV-2 spike, suggesting a transient conformation of the viral glycoprotein that is vulnerable to neutralization.

Keywords: CP: Immunology; CP: Microbiology; SARS-CoV-2; antibody; cryogenic electron microscopy; hydrogen-deuterium exchange; neutralizing epitope; omicron; spike subdomain 1.