A neutralizing epitope on the SD1 domain of SARS-CoV-2 Spike targeted following infection and vaccination.

SARS-CoV-2 Spike is the target for neutralizing antibodies elicited following both infection and vaccination. Whilst 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 broad neutralizing antibodies that bind an epitope on the Spike subdomain 1 (SD1), and that have arisen from infection or vaccination. Using cryogenic 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 thus-far uncharacterized conformation of the viral glycoprotein vulnerable to neutralization.