Comprehensive structural analysis reveals broad-spectrum neutralizing antibodies against SARS-CoV-2 Omicron variants

Abstract

The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread around the world. Mutant strains of SARS-CoV-2 are constantly emerging. At present, Omicron variants have become mainstream. In this work, we carried out a systematic and comprehensive analysis of the reported spike protein antibodies, counting the epitopes and genotypes of these antibodies. We further comprehensively analyzed the impact of Omicron mutations on antibody epitopes and classified these antibodies according to their binding patterns. We found that the epitopes of the H-RBD class antibodies were significantly less affected by Omicron mutations than other classes. Binding and virus neutralization experiments showed that such antibodies could effectively inhibit the immune escape of Omicron. Cryo-EM results showed that this class of antibodies utilized a conserved mechanism to neutralize SARS-CoV-2. Our results greatly help us deeply understand the impact of Omicron mutations. Meanwhile, it also provides guidance and insights for developing Omicron antibodies and vaccines.

Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern

“…While the V H domain had six SHMs, only two of eighteen total residues comprising the heavy chain paratope involved SHMs, whereas all V L domain paratope residues were germline encoded, suggesting that similar to other nAbs isolated following infection ( 23 ), C1596 has minimal somatic mutations involved at the contacting interface. Finally, we compared the binding pose of C1596 to C1791 ( IGHV3-23*01/IGKV1-17*01 ), an antibody described by our group ( 20 ), and S2L20 ( IGHV3-30/IGKV1-33 ) ( 39 ), a previously-described cross-reactive, but weakly neutralizing (IC 50 > 1 ug ml -1 ) antibody ( 80 ) (Supplemental Figure 5C-E). While the NTD footprint was similar across all antibodies and each interacted with the SD1 domain, available structures showed that only C1596 engaged the RBD within the same protomer (Supplemental Figure 5E).…”

Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain

“… 23 Despite the hydrophobic cavity domain in the NTD is considered as a promising target for developing neutralizing antibodies against Omicron, it is reported to be susceptible to immune escape, particularly against BA.2. 24 Additionally, no one targeting NTD is licensed for clinical trials yet ( https://clinicaltrials.gov/ ). Nevertheless, it is essential to comprehensively map the epitope landscape of the NTD and explore the conserved neutralization epitopes within it as promising candidates for developing cross-reactive antibodies against continuously evolving variants.…”