Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes

Voss, William N.; Hou, Yixuan J.; Johnson, Nicole V.; Delidakis, George; Kim, Jin Eyun; Javanmardi, Kamyab; Horton, Andrew P.; Bartzoka, Foteini; Paresi, Chelsea J.; Tanno, Yuri; Chou, Chia-Wei; Abbasi, Shawn A.; Pickens, Whitney; George, Katia; Boutz, Daniel R.; Towers, Dalton M.; McDaniel, Jonathan R.; Billick, Daniel; Goike, Jule; Rowe, Lori; Batra, Dhwani; Pohl, Jan; Lee, Justin; Gangappa, Shivaprakash; Sambhara, Suryaprakash; Gadush, Michelle; Wang, Nianshuang; Person, Maria D.; Iverson, Brent L.; Gollihar, Jimmy D.; Dye, John; Herbert, Andrew; Finkelstein, Ilya J.; Baric, Ralph S.; McLellan, Jason S.; Georgiou, George; Lavinder, Jason J.; Ippolito, Gregory C.

The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following SARS-CoV-2 infection are unknown. Proteomic deconvolution of the IgG repertoire to the spike glycoprotein in convalescent subjects revealed that the response is directed predominantly (>80%) against epitopes residing outside the receptor-binding domain (RBD). In one subject, just four IgG lineages accounted for 93.5% of the response, including an N-terminal domain (NTD)-directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multi-donor class of “public” antibodies revealed an NTD epitope that is recurrently mutated among emerging SARS-CoV-2 variants of concern. These data show that “public” NTD-directed and other non-RBD plasma antibodies are prevalent and have implications for SARS-CoV-2 protection and antibody escape.