Neutralisation of SARS-CoV-2 by destruction of the prefusion Spike

Huo, Jiandong; Zhao, Yuguang; Ren, Jingshan; Zhou, Daming; Duyvesteyn, Helen ME.; Ginn, Helen M.; Carrique, Loic; Malinauskas, Tomas; Ruza, Reinis R.; Shah, Pranav NM.; Tan, Tiong Kit; Rijal, Pramila; Coombes, Naomi; Bewley, Kevin R.; Tree, Julia A.; Radecke, Julika; Paterson, Neil G.; Supasa, Piyasa; Mongkolsapaya, Juthathip; Screaton, Gavin R.; Carroll, Miles; Townsend, Alain; Fry, Elizabeth E.; Owens, Raymond J.; Stuart, David I.

Summary There are as yet no licenced therapeutics for the COVID-19 pandemic. The causal coronavirus (SARS-CoV-2) binds host cells via a trimeric Spike whose receptor binding domain (RBD) recognises angiotensin-converting enzyme 2 (ACE2), initiating conformational changes that drive membrane fusion. We find that the monoclonal antibody CR3022 binds the RBD tightly, neutralising SARS-CoV-2 and report the crystal structure at 2.4 Ã… of the Fab/RBD complex. Some crystals are suitable for screening for entry-blocking inhibitors. The highly conserved, structure-stabilising, CR3022 epitope is inaccessible in the prefusion Spike, suggesting that CR3022 binding facilitates conversion to the fusion-incompetent post-fusion state. Cryo-EM analysis confirms that incubation of Spike with CR3022 Fab leads to destruction of the prefusion trimer. Presentation of this cryptic epitope in an RBD-based vaccine might advantageously focus immune responses. Binders at this epitope may be useful therapeutically, possibly in synergy with an antibody blocking receptor attachment.