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Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement
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Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo–electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.
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“Several VOCs which have mutated, such as Beta1 and Omicron2, evade humoral responses elicited by vaccines based on ancestral S-protein sequences3.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [2]
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“Reinfections and vaccine breakthrough infections accounted for the majority of Omicron BA.1/2 infections, likely attributable to a minority of population remaining naïve prior to the Omicron BA.1/2 wave and to Omicron BA.1/2's immune-escape properties 16,21,22 .”
From Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa (2023) · cites this paper as [22]
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“However, the region comprising residues 366 to 375, which harbors the S371L/S373P/S375F substitutions, deviates markedly from the conformation observed for the Wuhan-Hu-1 RBD, irrespective of the presence of bound linoleic acid ( 4 , 42 , 43 ).”
Self-citationREFMAC 5 for the refinement of macromolecular crystal structures
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“The variant has 37 mutations on the receptor binding domain (RBD) ( 10 ).”
The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution
Moulana, A., Dupic, T., Phillips, A. M., Chang, J., Roffler, A. A., Greaney, A. J., Starr, T. N., Bloom, J. D., & Desai, M. M. (2023) · eLife · doi:10.7554/elife.83442 · Cited by 62
Šmíd, M., Berec, L., Přibylová, L., Májek, O., Pavlík, T., Jarkovský, J., Weiner, J., Barusová, T., & Trnka, J. (2022) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiac161 · Cited by 67
“This rapid 62 spread was at least in part brought about by a degree of immune evasion due to a 63 large number of mutations in the viral S-protein, which led to changes in epitopes 64 recognised by antibodies elicited by vaccination or previous infection [2].”
Structures of Omicron spike complexes and implications for neutralizing antibody development
Guo, H., Gao, Y., Li, T., Li, T., Lu, Y., Zheng, L., Liu, Y., Yang, T., Luo, F., Song, S., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110770 · Cited by 61
“As reported previously, S309 has shown enhanced SARS-CoV-2 neutralization when in combination with other antibodies (McCallum et al., 2022; Pinto et al., 2020).”
Choosing a cellular model to study SARS-CoV-2
de Souza, G. A. P., Bideau, M. L., Boschi, C., Wurtz, N., Colson, P., Aherfi, S., Devaux, C. A., & Scola, B. L. (2022) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2022.1003608 · Cited by 63
Fumagalli, V., Ravà, M., Marotta, D., Lucia, P. D., Bono, E. B., Giustini, L., Leo, F. D., Casalgrandi, M., Monteleone, E., Mouro, V., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01787-z · Cited by 61
“This vulnerability is further exacerbated by the emergence of viral variants that can evade these responses 9–11 .”
Grobbelaar, L. M., Kruger, A., Venter, C., Burger, E. M., Laubscher, G. J., Maponga, T. G., Kotze, M. J., Kwaan, H. C., Miller, J. B., Fulkerson, D. H., et al. (2022) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-0042-1756306 · Cited by 61
Recent insights into SARS‐CoV‐2 omicron variant
da Silva, S. J. R., Kohl, A., Pena, L., & Pardee, K. (2022) · Reviews in Medical Virology · doi:10.1002/rmv.2373 · Cited by 56
Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2
Fang, Z., Peng, L., Filler, R. B., Suzuki, K., McNamara, A., Lin, Q., Renauer, P. A., Yang, L., Menasché, B. L., Sanchez, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30878-4 · Cited by 55
SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity
Meng, B., Datir, R. P., Choi, J., Baker, S. G., Dougan, G., Hess, C., Kingston, N., Lehner, P. J., Lyons, P., Matheson, N. J., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111220 · Cited by 58
“The lack of allostery of the Omicron NTD may reside in the unique nature of its spike (Cerutti et al., 2022; Cui et al., 2022; Gobeil et al., 2022; Mannar et al., 2022; McCallum et al., 2022; Stalls et al., 2022; Ye et al., 2022; Zhang et al., 2022).”
Generation of SARS-CoV-2 escape mutations by monoclonal antibody therapy
Ragonnet‐Cronin, M., Nutalai, R., Huo, J., Dijokaite-Guraliuc, A., Das, R., Tuekprakhon, A., Supasa, P., Liu, C., Selvaraj, M., Groves, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37826-w · Cited by 61
Yadav, P. K., Kumar, A., Upadhyay, S., Kumar, A., Srivastava, A., Srivastava, M., & Srivastava, S. (2024) · Microchimica Acta · doi:10.1007/s00604-024-06442-w · Cited by 56
“Label-free, real-time, fast, and on-site detection of biomolecular binding interactions and a variety of biomarkers is made possible by SPR-based biosensing technology, which offers several advantages such as simple operation, fast reaction times, and exceptional selectivity [249].”
Lai, J., Coleman, K. K., Tai, S., German, J. R., Hong, F. H., Albert, B., Esparza, Y., Srikakulapu, A. K., Schanz, M., Maldonado, I. S., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciac846 · Cited by 60
A highly efficient needle-free-injection delivery system for mRNA-LNP vaccination against SARS-CoV-2
Mao, S., Li, S., Zhang, Y., Long, L., Peng, J., Cao, Y., Mao, J. Z., Qi, X., Qi, X., San, G., et al. (2022) · Nano Today · doi:10.1016/j.nantod.2022.101730 · Cited by 55
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Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro
Zeng, L., Liu, Y., Wrynla, X. H., Abbott, T. R., Han, M., Zhu, Y., Chemparathy, A., Lin, X., Chen, X., Wang, H., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-30546-7 · Cited by 53
“Some monoclonal antibodies have shown impaired binding to the spike protein of variants 51,54,60,61 .”
Du, W., Hurdiss, D. L., Drabek, D., Mykytyn, A. Z., Kaiser, F. K., González-Hernández, M., Muñoz‐Santos, D., Lamers, M. M., van Haperen, R., Li, W., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abp9312 · Cited by 56
Structural basis for the evolution and antibody evasion of SARS-CoV-2 BA.2.86 and JN.1 subvariants
Yang, H., Guo, H., Wang, A., Cao, L., Fan, Q., Jiang, J., Wang, M., Lin, L., Ge, X., Wang, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51973-8 · Cited by 50
“Previous studies on the S protein of SARS-CoV-2 primarily demonstrated either a complete “ up ” or “ down ” conformationinRBDs 15,16,41 .”
Structural conservation among variants of the SARS-CoV-2 spike postfusion bundle
Yang, K., Wang, C., White, K. I., Pfuetzner, R. A., Esquivies, L. R., & Brünger, A. T. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2119467119 · Cited by 55
Luo, S., Zhang, J., Kreutzberger, A. J. B., Eaton, A., Edwards, R. J., Jing, C., Dai, H., Sempowski, G. D., Cronin, K. D., Parks, R., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.add5446 · Cited by 53
Arunachalam, P. S., Feng, Y., Ashraf, U., Hu, M., Walls, A. C., Edara, V. V., Zarnitsyna, V. I., Aye, P. P., Golden, N., Miranda, M. C., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abq4130 · Cited by 53
Self-citationLi, L., Han, P., Huang, B., Xie, Y., Li, W., Zhang, D., Han, P., Xu, Z., Bai, B., Zhou, J., et al. (2022) · Cell Discovery · doi:10.1038/s41421-022-00431-0 · Cited by 49
“Y34 Y453 (2), R493 (22), S494 (15, 1), S496 (1)”
InfluentialImmune Escape Associated with RBD Omicron Mutations and SARS-CoV-2 Evolution Dynamics
Kudriavtsev, A. V., Vakhrusheva, A., Novoseletsky, V. N., Bozdaganyan, M. E., Шайтан, К. В., Kirpichnikov, M. P., & Sokolova, O. S. (2022) · Viruses · doi:10.3390/v14081603 · Cited by 52
“Only therapeutic antibodies of class 3 (S309) and 4 (A3, CR3022, S2A4, S304, S2X35, H014, COVA1-16, S2X259, and DH1047) targeting regions that do not directly interact with ACE2, but interfere with its binding, can potently neutralize Omicron with some efficiency [48,49,50].”
Forsyth, C. B., Zhang, L., Bhushan, A., Swanson, B. A., Zhang, L., Mamede, J. I., Voigt, R. M., Shaikh, M. W., Engen, P. A., & Keshavarzian, A. (2022) · Microorganisms · doi:10.3390/microorganisms10101996 · Cited by 52
Structural Plasticity and Immune Evasion of SARS-CoV-2 Spike Variants
Ghimire, D., Han, Y., & Lu, M. (2022) · Viruses · doi:10.3390/v14061255 · Cited by 44
“Reduced: wide range >1- to >100-fold to total loss (D614G) [63,85,87,101] Completely reduced: [63,101] Increased: <10-fold (D614G) [63,102–104].”
InfluentialThe Current Status and Future Promise of SPR Biosensors
Chiu, N. (2022) · Biosensors · doi:10.3390/bios12110933 · Cited by 50
Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa
Sun, K., Tempia, S., Kleynhans, J., von Gottberg, A., McMorrow, M. L., Wolter, N., Bhiman, J. N., Moyes, J., Carrim, M., Martinson, N. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-022-35652-0 · Cited by 45
Cao, L., Lou, J., Chan, S. Y., Zheng, H., Liu, C., Zhao, S., Li, Q., Mok, C. K. P., Chan, R. W. Y., Chong, K. C., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01877-1 · Cited by 49
Human coronavirus HKU1 recognition of the TMPRSS2 host receptor
McCallum, M., Park, Y., Stewart, C., Sprouse, K. R., Addetia, A., Brown, J. T., Tortorici, M. A., Gibson, C. A., Wong, E., Ieven, M. M., et al. (2024) · Cell · doi:10.1016/j.cell.2024.06.006 · Cited by 51
“These findings may explain the observed polymorphism of TMPRSS2-interacting residues among HKU1 isolates and are reminiscent of observations made for SARS-CoV-2 62,72,73 and 229E 71,74 .”
Self-citationMaeda, R., Fujita, J., Konishi, Y., Kazuma, Y., Yamazaki, H., Anzai, I., Watanabe, T., Yamaguchi, K., Kasai, K., Nagata, K., et al. (2022) · Communications Biology · doi:10.1038/s42003-022-03630-3 · Cited by 47
Immune evasion of neutralizing antibodies by SARS-CoV-2 Omicron
Wang, L., Møhlenberg, M., Wang, P., & Zhou, H. (2023) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2023.03.001 · Cited by 49
“Secondly, although several point mutations reduce the binding of RBD to angiotensin-converting enzyme 2 (ACE2), the presence of compensatory mutations can restore the higher affinity of RBD to ACE2 [49] (Fig.”
InfluentialMultiple independent acquisitions of ACE2 usage in MERS-related coronaviruses
Ma, C., Liu, C., Park, Y., Tang, J., Chen, J., Xiong, Q., Lee, J., Stewart, C., Asarnow, D. E., Brown, J. T., et al. (2025) · Cell · doi:10.1016/j.cell.2024.12.031 · Cited by 47
“58,59 However, a recent study reported that PnNL2180B (PN-β CoV) primarily exhibits intestinal tropism in its natural bat host, suggesting a potential fecal-oral route used by these viruses in bats.”
Self-citationNi, D., Turelli, P., Beckert, B., Nazarov, S., Uchikawa, E., Myasnikov, A. G., Pojer, F., Trono, D., Stahlberg, H., & Lau, K. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011206 · Cited by 47
“1 variant was first reported with increased resistance to antibodies and significantly stronger binding to hACE2.[60,68] We also observe that mACE2 also shows drastically increased binding (almost 10-fold) to the Omicron BA.”
Nguyen, H. L., Thai, N. Q., Nguyen, P. H., & Li, M. S. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.2c01048 · Cited by 46
Antibody Titers and Protection against Omicron (BA.1 and BA.2) SARS-CoV-2 Infection
Dimeglio, C., Migueres, M., Bouzid, N., Chapuy‐Regaud, S., Gernigon, C., Da-Silva, I., Porcheron, M., Martin‐Blondel, G., Hérin, F., & Izopet, J. (2022) · Vaccines · doi:10.3390/vaccines10091548 · Cited by 45
“1 and the ancestral SARS-CoV-2 strain used in current vaccines and immunoassays [24].”
Molecular insights into the adaptive evolution of SARS-CoV-2 spike protein
Yao, Z., Zhang, L., Duan, Y., Tang, X., & Lü, J. (2024) · Journal of Infection · doi:10.1016/j.jinf.2024.106121 · Cited by 49
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs
Iketani, S., & Ho, D. D. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.03.008 · Cited by 49
Molecular basis of convergent evolution of ACE2 receptor utilization among HKU5 coronaviruses
Park, Y., Liu, C., Lee, J., Brown, J. T., Ma, C., Liu, P., Gen, R., Xiong, Q., Zepeda, S. K., Stewart, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.12.032 · Cited by 47
Self-citationMechanism and evolution of human ACE2 binding by SARS-CoV-2 spike
Wrobel, A. G. (2023) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2023.102619 · Cited by 48
Chen, Z., Zhang, Y., Wang, M., Islam, M. S., Liao, P., Hu, Y., & Chen, X. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.73583 · Cited by 42
Kumar, S., Patel, A. B., Lai, L., Chennareddy, C., Valanparambil, R. M., Reddy, E. S., Gottimukkala, K. P., Davis-Gardner, M. E., Edara, V. V., Linderman, S. L., et al. (2022) · Science Advances · doi:10.1126/sciadv.add2032 · Cited by 41
“Structural studies have reported that SARS-CoV-2 bnAbs target only a few antigenic sites on the RBD, which are majorly recognized by class 3 and class 4 mAbs ( 12 , 13 , 18 , 19 ).”
Rapid escape of new SARS-CoV-2 Omicron variants from BA.2-directed antibody responses
Dijokaite-Guraliuc, A., Das, R., Zhou, D., Ginn, H. M., Liu, C., Duyvesteyn, H. M. E., Huo, J., Nutalai, R., Supasa, P., Selvaraj, M., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112271 · Cited by 46
“2–5, 13, 15, 21, 24, 34, 36) showed little or no ACE2-blocking function.”
Metadata
- Authors
- McCallum, M., Czudnochowski, N., Rosen, L. E., Zepeda, S. K., Bowen, J. E., Walls, A. C., Hauser, K., Joshi, A., Stewart, C., Dillen, J. R., Powell, A. E., Croll, T. I., Nix, J., Virgin, H. W., Corti, D., Snell, G., & Veesler, D.
- Affiliations
- University of Washington (US)
- VIR Biotechnology (United States) (US)
- Howard Hughes Medical Institute (US)
- University of Cambridge (GB)
- Lawrence Berkeley National Laboratory (US)
- Washington University in St. Louis (US)
- Vir Biotechnology (Switzerland) (CH)
- Corresponding author
- McCallum, Matthew
- Czudnochowski, Nadine
- Snell, Gyorgy
- Veesler, David
- ORCID
- Venue
- Science
- Published
- 2022-02-25
- Volume
- 375
- Issue
- 6583
- Pages
- 864-868
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC9427005
- OpenAlex
- W4220861013
- Cited by
- 535
- References
- 85
- Citations by year
- 2026: 25 · 2025: 56 · 2024: 85 · 2023: 122 · 2022: 246
- FWCI
- 62.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute (DE-AC02-05CH11231)
- U.S. Department of Energy (-AC02-05CH11231, Contract No. DE-AC02-05-CH11231, 05CH11231, No. DE-AC02-05-CH11231, DE AC02 05CH11231, DE-AC02-)
- Burroughs Wellcome Fund (DE-AC02-05CH11231)
- University of Washington
- Wellcome Trust (Z/17/Z, 209407/Z/17/Z)
- Fast Grants
- National Institutes of Health (S10 OD032290, DE-AC02–05CH11231, 1s10od023476-01, HHSN272201700059C)
- Office of Science (No. DE-AC02- 05-CH11231, DEAC02–05CH11231, AC02-05CH11231, DE-AC02, 05CH11231, Contract No. DE-AC02-05CH11231)
- National Institute of General Medical Sciences (DE-AC02-05CH11231, R01GM120553, T32GM008268, P30GM124169)
- National Institute of Allergy and Infectious Diseases (HHSN272201700059C, DP1AI158186)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- Omicron variant, spike protein, receptor binding domain, antibody escape, sotrovimab, ACE2 receptor, antigenic shift, spike protein mutations, antibody affinity
- MeSH terms
- Protein Domains, Broadly Neutralizing Antibodies, Receptors, Coronavirus, Angiotensin-Converting Enzyme 2, SARS-CoV-2, Antigenic Drift and Shift, Antibodies, Monoclonal, Antibodies, Viral, Humans, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Crystallography, X-Ray, Amino Acid Substitution, Cryoelectron Microscopy, Protein Interaction Domains and Motifs, Immune Evasion, Spike Glycoprotein, Coronavirus
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