PT  - JOURNAL ARTICLE
AU  - William N. Voss
AU  - Yixuan J. Hou
AU  - Nicole V. Johnson
AU  - Jin Eyun Kim
AU  - George Delidakis
AU  - Andrew P. Horton
AU  - Foteini Bartzoka
AU  - Chelsea J. Paresi
AU  - Yuri Tanno
AU  - Shawn A. Abbasi
AU  - Whitney Pickens
AU  - Katia George
AU  - Daniel R. Boutz
AU  - Dalton M. Towers
AU  - Jonathan R. McDaniel
AU  - Daniel Billick
AU  - Jule Goike
AU  - Lori Rowe
AU  - Dhwani Batra
AU  - Jan Pohl
AU  - Justin Lee
AU  - Shivaprakash Gangappa
AU  - Suryaprakash Sambhara
AU  - Michelle Gadush
AU  - Nianshuang Wang
AU  - Maria D. Person
AU  - Brent L. Iverson
AU  - Jimmy D. Gollihar
AU  - John Dye
AU  - Andrew Herbert
AU  - Ralph S. Baric
AU  - Jason S. McLellan
AU  - George Georgiou
AU  - Jason J. Lavinder
AU  - Gregory C. Ippolito
TI  - Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes in COVID-19 convalescent plasma
AID  - 10.1101/2020.12.20.423708
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.20.423708
4099  - http://biorxiv.org/content/early/2020/12/21/2020.12.20.423708.short
4100  - http://biorxiv.org/content/early/2020/12/21/2020.12.20.423708.full
AB  - 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 Å2). 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.Competing Interest StatementThe authors have declared no competing interest.