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journal article·2026-07-13Open access

Somatic Evolution of a Germline Antibody Expands its Breadth to Neutralize Early SARS‐CoV‐2 Omicron Variants

Huibin Lv, Ziqi Feng, Qi Wen Teo, Chunke Chen, Akshita B. Gopal, Danbi Choi, Timothy J. C. Tan, Yun Sang Tang, Lewis Siu, Armita Nourmohammad, Roberto Bruzzone, Ian A. Wilson, Meng Yuan, Nicholas C. Wu, Chris K. P. Mok

Advanced Science
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Abstract

ABSTRACT Rapid antigenic drift of the SARS‐CoV‐2 receptor‐binding domain (RBD) underlies immune escape and continues to challenge the durability of antibody‐mediated protection. Among the major classes of RBD‐directed antibodies, germline‐encoded IGHV3‐53 responses are highly potent against early SARS‐CoV‐2 variants but are generally compromised by Omicron‐associated mutations. Here, we identify an intrinsically cross‐reactive IGHV3‐53 germline antibody that recognizes multiple pre‐Omicron variants, including SARS‐CoV‐2 wild‐type, Alpha, and Delta. Notably, we demonstrate that targeted somatic evolution can further expand this breadth to overcome the immune escape of different Omicron variants. Guided by integrated structural and sequence analyses, we introduce four somatic mutations (G26E, T28I, S53P, and Y58F) into the germline antibody, resulting in markedly enhanced binding and neutralization of Omicron BA.1, and BA.4/5. High‐resolution crystal structures reveal that these mutations re‐establish interactions disrupted by substitutions in the Omicron RBD and improve binding at a remodeled epitope interface. Collectively, our findings define the structural basis by which specific mutations enhance cross‐variant recognition of SARS‐CoV‐2. This work highlights the underappreciated breadth encoded within the naïve B‐cell repertoire and provides a conceptual framework for engineering and eliciting antibody responses resilient to future antigenic drift.
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Research context

OpenAlex topics: SARS-CoV-2 and COVID-19 Research · vaccines and immunoinformatics approaches · Monoclonal and Polyclonal Antibodies Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Carl R. Woese Institute for Genomic Biology University of Illinois at Urbana‐Champaign Urbana Illinois USA

Department of Biochemistry University of Illinois at Urbana‐Champaign Urbana Illinois USA

HKU‐Pasteur Research Pole School of Public Health Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong SAR China

Department of Integrative Structural and Computational Biology The Scripps Research Institute La Jolla California USA

The Jockey Club School of Public Health and Primary Care The Chinese University of Hong Kong Hong Kong SAR China

Li Ka Shing Institute of Health Sciences Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China

Center For Biophysics and Quantitative Biology University of Illinois at Urbana‐Champaign Urbana Illinois USA

Paul G. Allen School of Computer Science and Engineering University of Washington Seattle Washington USA

Department of Physics University of Washington Seattle Washington USA

Department of Applied Mathematics University of Washington Seattle Washington USA

Fred Hutchinson Cancer Center Seattle Washington USA

Yale Center for Systems and Engineering Immunology Yale University New Haven Connecticut USA

Istituto Pasteur Italia Rome Italy

Centre For Immunology & Infection Hong Kong SAR China

Skaggs Institute for Chemical Biology The Scripps Research Institute La Jolla California USA

Carle Illinois College of Medicine University of Illinois at Urbana‐Champaign Urbana Illinois USA

S. H. Ho Research Centre for Infectious Diseases The Chinese University of Hong Kong Hong Kong China

School of Biomedical Sciences The Chinese University of Hong Kong Hong Kong SAR China

Funding

Health and Medical Research Fund · Searle Scholars Program

References (60)

Show source-provided references
1. 10.1038/s41591‐021‐01678‐y10.1038/s41591‐021‐01678‐y ↗
2. 10.7554/eLife.6131210.7554/eLife.61312 ↗
3. 10.1016/j.cell.2021.01.03710.1016/j.cell.2021.01.037 ↗
4. 10.1038/s41586‐021‐04389‐z10.1038/s41586‐021‐04389‐z ↗
5. 10.1038/s41586‐022‐04594‐410.1038/s41586‐022‐04594‐4 ↗
6. 10.1016/j.coviro.2015.04.00210.1016/j.coviro.2015.04.002 ↗
7. 10.1016/j.immuni.2021.05.00110.1016/j.immuni.2021.05.001 ↗
8. 10.1016/j.immuni.2021.07.00810.1016/j.immuni.2021.07.008 ↗
9. 10.1126/sciimmunol.abg691610.1126/sciimmunol.abg6916 ↗
10. 10.1016/j.cell.2021.01.05010.1016/j.cell.2021.01.050 ↗
11. 10.1038/s41586‐021‐03207‐w10.1038/s41586‐021‐03207‐w ↗
12. 10.1038/s41586‐021‐04060‐710.1038/s41586‐021‐04060‐7 ↗
13. 10.1038/s41586‐021‐03696‐910.1038/s41586‐021‐03696‐9 ↗
14. 10.1016/j.celrep.2025.11596410.1016/j.celrep.2025.115964 ↗
15. 10.1016/j.cell.2021.12.03310.1016/j.cell.2021.12.033 ↗
16. 10.1016/j.cell.2021.12.04610.1016/j.cell.2021.12.046 ↗
17. 10.1038/s41591‐022‐01704‐710.1038/s41591‐022‐01704‐7 ↗
18. 10.1111/imr.1343110.1111/imr.13431 ↗
19. 10.1038/s41577‐022‐00784‐310.1038/s41577‐022‐00784‐3 ↗
20. 10.1016/j.str.2023.06.00510.1016/j.str.2023.06.005 ↗
21. 10.1016/j.celrep.2021.10917310.1016/j.celrep.2021.109173 ↗
22. 10.1056/NEJMoa210845310.1056/NEJMoa2108453 ↗
23. 10.1038/s41587‐020‐0631‐z10.1038/s41587‐020‐0631‐z ↗
24. 10.1038/s41586‐021‐04385‐310.1038/s41586‐021‐04385‐3 ↗
25. 10.1038/s41586‐021‐04388‐010.1038/s41586‐021‐04388‐0 ↗
26. 10.1016/j.ebiom.2024.10543910.1016/j.ebiom.2024.105439 ↗
27. 10.1126/science.abd232110.1126/science.abd2321 ↗
28. 10.1038/s41467‐021‐24514‐w10.1038/s41467‐021‐24514‐w ↗
29. 10.1126/sciimmunol.abo342510.1126/sciimmunol.abo3425 ↗
30. 10.1126/science.abh113910.1126/science.abh1139 ↗
31. 10.1016/j.xcrm.2024.10157710.1016/j.xcrm.2024.101577 ↗
32. 10.1371/journal.ppat.101185610.1371/journal.ppat.1011856 ↗
33. 10.1093/bioinformatics/btaa73910.1093/bioinformatics/btaa739 ↗
34. 10.1038/s41467‐021‐24123‐710.1038/s41467‐021‐24123‐7 ↗
35. 10.1016/j.cell.2021.03.02710.1016/j.cell.2021.03.027 ↗
36. 10.1016/j.cell.2021.04.03210.1016/j.cell.2021.04.032 ↗
37. 10.1126/scitranslmed.abf190610.1126/scitranslmed.abf1906 ↗
38. 10.1016/j.cell.2020.08.04610.1016/j.cell.2020.08.046 ↗
39. 10.1016/j.immuni.2020.06.00110.1016/j.immuni.2020.06.001 ↗
40. 10.1126/science.abc752010.1126/science.abc7520 ↗
41. 10.1080/22221751.2021.192559410.1080/22221751.2021.1925594 ↗
42. 10.1126/science.abc590210.1126/science.abc5902 ↗
43. 10.1038/s41586‐020‐2380‐z10.1038/s41586‐020‐2380‐z ↗
44. 10.1038/s41586‐020‐2456‐910.1038/s41586‐020‐2456‐9 ↗
45. 10.1128/mbio.03580‐2110.1128/mbio.03580‐21 ↗
46. 10.1080/22221751.2022.206307410.1080/22221751.2022.2063074 ↗
47. 10.1016/j.celrep.2023.11244310.1016/j.celrep.2023.112443 ↗
48. 10.1038/s41564‐025‐02030‐710.1038/s41564‐025‐02030‐7 ↗
49. 10.1016/j.celrep.2025.11680010.1016/j.celrep.2025.116800 ↗
50. 10.1007/978‐1‐4939‐8958‐4_510.1007/978‐1‐4939‐8958‐4_5 ↗
51. 10.1073/pnas.210398411810.1073/pnas.2103984118 ↗
52. 10.1016/j.celrep.2023.11341010.1016/j.celrep.2023.113410 ↗
53. 10.1126/science.120483910.1126/science.1204839 ↗
54. 10.1016/s0076‐6879(97)76066‐x10.1016/s0076‐6879(97)76066‐x ↗
55. 10.1107/S002188980702120610.1107/S0021889807021206 ↗
56. 10.1016/j.celrep.2025.11594810.1016/j.celrep.2025.115948 ↗
57. 10.1038/s41586‐020‐2180‐510.1038/s41586‐020‐2180‐5 ↗
58. 10.1107/S090744491000749310.1107/S0907444910007493 ↗
59. 10.1107/S090744490905292510.1107/S0907444909052925 ↗
60. 10.1126/scitranslmed.abj541310.1126/scitranslmed.abj5413 ↗