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

Abstract

The molecular composition and binding epitopes of the immunoglobulin G (IgG) antibodies that circulate in blood plasma after severe acute respiratory syndrome coronavirus 2 (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 amino (N)-terminal domain (NTD)–directed antibody that was protective against lethal viral challenge. Genetic, structural, and functional characterization of a multidonor 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.

Reduced sensitivity of infectious SARS-CoV-2 variant B.1.617.2 to monoclonal antibodies and sera from convalescent and vaccinated individuals

“…Neutralizing antibodies also target non-RBD Spike epitopes, particularly in the NTD 26 . The role of the NTD during viral entry is not fully understood.…”

“…It has been proposed to recognize sugar moieties upon initial binding and might be involved in pre-fusion to post-fusion transition of the Spike 27 . Some mAbs targeting the NTD may exhibit high neutralization potency without preventing Spike binding to ACE2 26,27 . These non-RBD antibodies are highly prevalent and may represent more than 80% of the anti-Spike IgG response, even if 90% of the neutralizing activity targets the RBD 17,27 .…”

“…These non-RBD antibodies are highly prevalent and may represent more than 80% of the anti-Spike IgG response, even if 90% of the neutralizing activity targets the RBD 17,27 . VOC contain changes in the NTD that have been associated with antibody escape 10,26,28 . These NTD modifications include the 69-70 and 144-145 deletions in B.1.1.7, the 241-243 deletion and R246I in B.1.351, W152C in B.1.429, and L18F substitution in a small proportion of B.1.351 and P.1 10,26,28 .…”

High-affinity, neutralizing antibodies to SARS-CoV-2 can be made in the absence of T follicular helper cells

“…Somatic hypermutation has also been shown to occur at extrafollicular sites during both infection and chronic autoimmunity (78-80), and LN-Th1 cells could therefore help select B cells that acquire affinity-increasing BCR mutations. Alternatively, multiple studies have identified potent, neutralizing antibodies with minimal somatic hypermutation from COVID-19 patients, suggesting that the naïve repertoire in humans already harbors protective antibodies that do not require additional affinity maturation (81)(82)(83)(84)(85)(86)(87)(88)(89). Mice may also possess near-germline antibodies with high affinity to SARS-CoV-2, and therefore the role of LN-Th1 cells in this case would be to select and expand the B cells expressing these sequences.…”

A combination of RBD and NTD neutralizing antibodies limits the generation of SARS-CoV-2 spike neutralization-escape mutants

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is Although the most potent SARS-CoV-2 nAbs target the RBD (12,13,(15)(16)(17)(18)(19)(20), recent antibody profiling efforts and the emergence of multiple VOC with mutations in the NTD that affect the efficacy of nAbs suggesting that NTD-directed antibodies are important for effective control of virus infection (22)(23)(24)41). Therefore, we tested if COVID-19 convalescent sera-mediated neutralization of rVSV-SARS2 is altered by .…”