Monoclonal antibodies generated from COVID-19-recovered individuals shed light on the molecular basis of SARS-CoV-2 Omicron variant immune evasion

In a recent study posted to the bioRxiv* preprint server, researchers reported three human monoclonal antibodies (mAbs) generated from coronavirus disease 2019 (COVID-19)-recovered individuals during the initial wave of the pandemic in India.

Study: Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response. Image Credit: vipman/Shutterstock
Study: Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response. Image Credit: vipman/Shutterstock

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Background

The continual emergence of immune evasive and more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants has threatened anti-SARS-CoV-2 mAb and vaccine efficacy. A detailed understanding of the molecular characteristics of SARS-CoV-2-neutralizing epitopes developed by viral variants could guide the development of anti-SARS-CoV-2 agents.

The authors of the present study previously identified 92 receptor-binding domain (RBD)-binding mAbs isolated from five COVID-19-recovered individuals with ancestral SARS-CoV-2 WA.1 strain infections and a potent pan-Omicron subvariant neutralizing and broad-spectrum class 3 Ab (002-S21F2) in India.

About the study

In the present study, researchers further characterized three (002-13, 002-02, and 034-32) of the 92 previously isolated mAbs that showed potent WA.1 neutralization but differing SARS-CoV-2 variant neutralization.

Structural analysis of the three mAbs complexed with the trimeric spike (S) protein was performed, and the immunogenetic makeup, function, and structure of the mAbs were compared to that of 002-S21F2. Immunogenetic analysis of Ab genes, negative staining-electron microscopy (NS-EM), and cryo-EM were also performed. The epitope surface of the mAbs was evaluated to assess the impact of variant mutations on Ab functionality and their contribution to variant immune evasiveness.

The mAbs were genetically analyzed, and biolayer interferometry (BLI), enzyme-linked immunosorbent assay (ELISA)-based, and mesoscale electrochemiluminescence binding assays were performed to assess viral-mAb binding. Further, focus-reduction neutralization mNeonGreen (FRNT-mNG) assays were performed to assess variant neutralization and link the variant paratope mutational landscape to the Ab function. Epitope mapping analysis was performed to determine molecular determinants of epitope recognition, and molecular dynamic (MD) simulations were performed to evaluate the impact of RBD mutations on mAb binding.

Results

All three mAbs showed potent neutralization of SARS-CoV-2 Alpha and Delta variants but poor Beta variant neutralization and no Omicron BA.1 neutralization. The mAbs showed robust and bivalent SARS-CoV-2 spike (S) protein binding, and the 002-02 mAb and 034-32 mAb targeted class-1 RBD epitopes, whereas mAb 002-13 targeted class-4 RBD epitopes.

The mAbs were coded by the immunoglobulin heavy variable 3-30-3 (IGHV3-30) and IGHV3-53/66 genes, and their heavy chain-V (variable) genes were coded by shared public Ab responses as reported in the coronavirus Ab database (CoV-AbDab) of 6520 anti-RBD mAbs that have been isolated from individuals with SARS-CoV-2 infections and COVID-19 vaccinees. Of interest, the IGHV3-30 and IGHJ4 genes of 002-13 were the most commonly observed VJ pair utilized by anti-RBD mAbs.

002-13-resembling shared mAbs contained a CxGGxC conserved motif in the complementarity determining region H3 (CDRH3) comprising 22 residues coded by the IGHD2-8 (immunoglobulin heavy diversity 2-8) gene. The shared clonotype Ab response of IGHV3-53 (034-32) and IGHV3-66 (002-02) showed the characteristic motifs of SGGS and NY in their CDRH2 and CDRH1 sites, respectively. 002-13 RBD binding was dominated (76%) by heavy chains, and the total buried surface area was 887 Å2.

Interactions involving the S371- C379 residues in the RBD region and the heavy chain CDR3 loop were largely responsible for epitope recognition. Even though 002-13 was bound on the outer side of the receptor-binding motif (RBM) surface, the mAb could sterically block angiotensin-converting enzyme 2 (ACE2) binding due to the light chains’ orientation. 002-13 binding remained unaltered towards Alpha, Beta, and Delta variants, but the mAb could not neutralize Omicron.

Likewise, 034-32 and 002-02 showed comparable binding affinities and neutralization titers for Alpha, Delta, and WA.1, but much lower binding to Beta and could not neutralize Omicron. Regarding the 034-32 and 002-02, the majority of the RBD contacts were dominated (70%) by the heavy chain, and the total buried surface between mAb and RBD was 1058 Å2. Key mutations responsible for Beta immune evasion were E484A and K417N for 034-32 and 002-02.

Omicron contained six mutations (S477N, K417N, G496S, Q498R, N501Y, and Q493R) in 002-02/034-32 epitopes and three mutations (S373P, S375F, and S371L) in 002-13 binding epitopes, collectively responsible for Omicron immune evasiveness. Omicron mutations favoring the S “up” conformation could promote ACE2 interactions.

Conclusions

Overall, the study findings cataloged the epitope class-specific Ab susceptibility towards existing SARS-CoV-2 variants and could inform their actions on newly emerging variants. The findings indicated that immunological pressures exerted by the shared Ab response to SARS-CoV-2 could probably cause SARS-CoV-2 evolution with mutations in class-4 Ab epitope residues.

Specific mutational combinations impacted binding and neutralizing Ab titers against SARS-CoV-2 variants. The mutations should be tracked to develop efficient therapeutic strategies against novel emerging viruses. In addition, the study findings could aid the estimation of structural characteristics of emerging immune-evasive SARS-CoV-2 variants.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

Journal references:

Article Revisions

  • May 16 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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