Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma

Voss, William N.; Hou, Yixuan J.; Johnson, Nicole V.; Kim, Jin Eyun; Delidakis, George; Horton, Andrew P.; Bartzoka, Foteini; Paresi, Chelsea J.; Tanno, Yuri; 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; Baric, Ralph S.; McLellan, Jason S.; Georgiou, George; Lavinder, Jason J.; Ippolito, Gregory C.

Although humoral immunity is essential for control of SARS-CoV-2, the molecular composition, binding epitopes and effector functions of the immunoglobulin G (IgG) antibodies that circulate in blood plasma following infection are unknown. Proteomic deconvolution of the circulating IgG repertoire (Ig-Seq1) to the spike ectodomain (S-ECD2) in four convalescent study subjects revealed that the plasma response is oligoclonal and directed predominantly (>80%) to S-ECD epitopes that lie outside the receptor binding domain (RBD). When comparing antibodies directed to either the RBD, the N-terminal domain (NTD) or the S2 subunit (S2) in one subject, just four IgG lineages (1 anti-S2, 2 anti-NTD and 1 anti-RBD) accounted for 93.5% of the repertoire. Although the anti-RBD and one of the anti-NTD antibodies were equally potently neutralizing in vitro, we nonetheless found that the anti-NTD antibody was sufficient for protection to lethal viral challenge, either alone or in combination as a cocktail where it dominated the effect of the other plasma antibodies. We identified in vivo protective plasma anti-NTD antibodies in 3/4 subjects analyzed and discovered a shared class of antibodies targeting the NTD that utilize unmutated or near-germline IGHV1-24, the most electronegative IGHV gene in the human genome. Structural analysis revealed that binding to NTD is dominated by interactions with the heavy chain, accounting for 89% of the entire interfacial area, with germline residues uniquely encoded by IGHV1-24 contributing 20% (149 Ã…2). Together with recent reports of germline IGHV1-24 antibodies isolated by B-cell cloning3,4 our data reveal a class of shared IgG antibodies that are readily observed in convalescent plasma and underscore the role of NTD-directed antibodies in protection against SARS-CoV-2 infection.