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SARS-CoV-2 variants, spike mutations and immune escape
Open accessAbstract
Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.
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“D614G is again associated with the increase in transmissibility, infectivity, and viral load, making the Lambda variant even more lethal [55].”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [55]
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“Each pathogen poses a unique set of challenges, including high lethality, rapid mutations, immune evasion, new strains and variants252–258.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [252]
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“Mutations in the spike protein and RBD have been shown to affect antibody neutralisation and thus reduce vaccine-induced immunity [22].”
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“The Lambda variant spike protein is found to be 3.3 times more resistant to neutralization by the convalescent sera than the parent D614G spike protein and 4.9 times to that of the Alpha variant ones.”
From Waves and variants of SARS-CoV-2: understanding the causes and effect of the COVID-19 catastrophe (2022) · cites this paper as [55]
Experimental — accuracy not yet measuredIn the citing paper
“However, reduced sensitivity of SARS-CoV-2 variants to antibody and serum neutralization has been widely observed (18–21).”
From Deep learning guided optimization of human antibody against SARS-CoV-2 variants with broad neutralization (2022) · cites this paper as [19]
In the citing paper
“both being immunodominant targets of neutralizing antibodies elicited by COVID-19 vaccines or by SARS-CoV-2 infection (5, 6).”
From Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human sera (2022) · cites this paper as [6]
In the citing paper
“However, sequencing data of SARS-CoV-2 from patients revealed persistent accumulation of new mutations over the last two years of the Covid19 pandemic, leading to the emergence of new viral strains that can be more transmissible or virulent5,6 or evade vaccines7–9.”
From The roles of APOBEC-mediated RNA editing in SARS-CoV-2 mutations, replication and fitness (2022) · cites this paper as [8]
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Widera, M., Wilhelm, A., Hoehl, S., Pallas, C., Kohmer, N., Wolf, T., Rabenau, H. F., Corman, V. M., Drosten, C., Vehreschild, M. J. G. T., et al. (2021) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiab355 · Cited by 88
“Amino acid substitutions hinders spike proteins to be bound by antibodies, resulting in reduced protection against SARS-CoV-2 infection [12].”
BackgroundEmerging evidence on Omicron (B.1.1.529) SARS‐CoV‐2 variant
Sharma, V., Rai, H., Gautam, D. N. S., Prajapati, P., & Sharma, R. (2022) · Journal of Medical Virology · doi:10.1002/jmv.27626 · Cited by 81
“Omicron has a number of novel mutations in or near the NTD, RBD, RBM, furin cleavage site, and S2 domains, which are thought to affect ACE2 binding and/or antibody binding based on previous research on spike protein‐ACE2 or antibody interactions.(46) As a result, the Omicron variant could be more infectious or vaccine…”
BackgroundA Global Picture: Therapeutic Perspectives for COVID-19
Chavda, V. P., Kapadia, C., Soni, S., Prajapati, R., Chauhan, S. C., Yallapu, M. M., & Apostolopoulos, V. (2022) · Immunotherapy · doi:10.2217/imt-2021-0168 · Cited by 88
“As of February 2022, over 5 million SARS-CoV-2 RNA genomes had been shared through the global initiative on sharing all influenza data [10,11].”
BackgroundBarin, B., Kasap, U., Selçuk, F., Volkan, E., & Uluçkan, Ö. (2022) · The Lancet Microbe · doi:10.1016/s2666-5247(21)00305-0 · Cited by 80
Clinical development and approval of COVID-19 vaccines
Kalinke, U., Barouch, D. H., Rizzi, R., Lagkadinou, E., Türeci, Ö., Pather, S., & Neels, P. (2022) · Expert Review of Vaccines · doi:10.1080/14760584.2022.2042257 · Cited by 86
“Challenges now relate to waning vaccine effectiveness [76] and the emerging SARS-CoV-2 variants [77], some of which are known to cause more serious clinical severity or an increase in infectivity (for a recent review, see Harvey et al. 2021 [78]).”
BackgroundNewman, J., Thakur, N., Peacock, T. P., Bialy, D., Elrefaey, A. M. E., Bogaardt, C., Horton, D. L., Ho, S., Kankeyan, T., Carr, C., et al. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01163-3 · Cited by 85
“Changes at position 417 affect class 1 antibody binding, while 484 modifications affect the epitope bound by class 2 antibodies, which dominate the polyclonal response to the RBD 35 .”
Shrestha, S., Yoshinaga, E., Chapagain, S. K., Mohan, G., Gasparatos, A., & Fukushi, K. (2021) · Water · doi:10.3390/w13202897 · Cited by 81
“Because of their higher transmission rate, higher disease severity, higher reinfection rate, reduction of therapy effectiveness, and reduction in the neutralization efficacy of sera from convalescent patients or vaccines [31,32], it is the utmost important issue for countries to be able to conduct the real-time survei…”
BackgroundEmerging SARS-CoV-2 Variants: Genetic Variability and Clinical Implications
Dubey, A., Choudhary, S., Kumar, P., & Tomar, S. (2021) · Current Microbiology · doi:10.1007/s00284-021-02724-1 · Cited by 79
“L452R mutation results in a higher free binding energy of SARS-CoV-2:ACE2 complex, leading to a stronger attachment between host cell receptor and virus [7].”
BackgroundThe puzzling mutational landscape of the SARS‐2‐variant Omicron
Fantini, J., Yahi, N., Colson, P., Chahinian, H., Scola, B. L., & Raoult, D. (2022) · Journal of Medical Virology · doi:10.1002/jmv.27577 · Cited by 80
Omicron variant: Current insights and future directions
Rana, R., Kant, R., Huirem, R. S., Bohra, D., & Ganguly, N. K. (2022) · Microbiological Research · doi:10.1016/j.micres.2022.127204 · Cited by 83
Towards evolutionary predictions: Current promises and challenges
Wortel, M. T., Agashe, D., Bailey, S. F., Bank, C., Bisschop, K., Blankers, T., Cairns, J., Colizzi, E. S., Cusseddu, D., Desai, M. M., et al. (2022) · Evolutionary Applications · doi:10.1111/eva.13513 · Cited by 80
Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda
Acevedo, M. L., Alonso-Palomares, L., Bustamante, A., Gaggero, A., Paredes, F., Cortés, C. P., Valiente-Echeverría, F., & Soto-Rifo, R. (2021) · doi:10.1101/2021.06.28.21259673 · Cited by 99
Pinato, D. J., Ferrante, D., Hanbury, G., Bower, M., Salazar, R., Mirallas, O., Sureda, A. M., Plaja, A., Cucurull, M., Mesı́a, R., et al. (2022) · The Lancet Oncology · doi:10.1016/s1470-2045(22)00273-x · Cited by 81
Klompas, M., Milton, D. K., Rhee, C., Baker, M. A., & Leekha, S. (2021) · Annals of Internal Medicine · doi:10.7326/m21-2780 · Cited by 86
“Increased contagiousness may be due to higher viral loads or greater emissions from source patients leading to greater viral exposure; alternatively, enhanced binding to target cells, immune naivety, and/or immune escape may lower the threshold dose likely to cause infection (55, 57).”
BackgroundStructural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain
Smith, K. N., Clark, S. A., Shankar, S., Pan, J., Clark, L. E., Yang, P., Coscia, A., McKay, L. G. A., Varnum, H., Brusic, V., et al. (2022) · Science · doi:10.1126/science.abl6251 · Cited by 77
“A s severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to replicate in humans under selective pressure from natural and vaccine-induced immunity, variants of concern (VOCs) with increased transmissibility or virulence continue to emerge (1).”
BackgroundSARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies
Reincke, S. M., Yuan, M., Kornau, H., Corman, V. M., van Hoof, S., Sánchez-Sendín, E., Ramberger, M., Yu, W., Hua, Y., Tien, H. J., et al. (2022) · Science · doi:10.1126/science.abm5835 · Cited by 75
Schäfer, A., Martinez, D. R., Won, J. J., Meganck, R. M., Moreira, F. R., Brown, A. J., Gully, K. L., Zweigart, M. R., Conrad, W. S., May, S. R., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abm3410 · Cited by 100
Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein
Calvaresi, V., Wrobel, A. G., Toporowska, J., Hammerschmid, D., Doores, K. J., Bradshaw, R. T., Parsons, R. B., Benton, D. J., Roustan, C., Reading, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36745-0 · Cited by 81
Rotondo, J. C., Martini, F., Maritati, M., Mazziotta, C., Mauro, G. D., Lanzillotti, C., Barp, N., Gallerani, A., Tognon, M. G., & Contini, C. (2021) · Viruses · doi:10.3390/v13091687 · Cited by 81
Melo-González, F., Soto, J. A., González, L. A., Fernández, J. O., Duarte, L. F., Schultz, B. M., Gálvez, N. M. S., Pacheco, G. A., Ríos, M., Vázquez, Y., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.747830 · Cited by 75
An early warning system for emerging SARS-CoV-2 variants
Subissi, L., von Gottberg, A., Thukral, L., Worp, N., Munnink, B. B. O., Rathore, S., Abu-Raddad, L. J., Aguilera, X., Alm, E., Archer, B. N., et al. (2022) · Nature Medicine · doi:10.1038/s41591-022-01836-w · Cited by 79
Self-citationMicrobiome Analysis for Wastewater Surveillance during COVID-19
Brumfield, K. D., Leddy, M. B., Usmani, M., Cotruvo, J. A., Tien, C.-T., Dorsey, S., Graubics, K., Fanelli, B. C., Zhou, I., Registe, N., et al. (2022) · mBio · doi:10.1128/mbio.00591-22 · Cited by 83
“Although most mutations may be deleterious or neutral, a few have the potential to affect viral function, potentially altering infectivity and/or disease severity (76).”
BackgroundHe, P., Liu, B., Gao, X., Yan, Q., Pei, R., Sun, J., Chen, Q., Hou, R., Li, Z., Zhang, Y., et al. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01235-4 · Cited by 76
Ramzi, Z. S. (2021) · The American Journal of Emergency Medicine · doi:10.1016/j.ajem.2021.10.059 · Cited by 77
Digital PCR Applications in the SARS-CoV-2/COVID-19 Era: a Roadmap for Future Outbreaks
Nyaruaba, R., Mwaliko, C., Dobnik, D., Neužil, P., Amoth, P., Mwau, M., Yu, J., Yang, H., & Wei, H. (2022) · Clinical Microbiology Reviews · doi:10.1128/cmr.00168-21 · Cited by 77
SARS-CoV-2 Omicron sublineages exhibit distinct antibody escape patterns
Gruell, H., Vanshylla, K., Korenkov, M., Tober‐Lau, P., Zehner, M., Münn, F., Janicki, H., Augustin, M., Schommers, P., Sander, L. E., et al. (2022) · Cell Host & Microbe · doi:10.1016/j.chom.2022.07.002 · Cited by 77
A variant-proof SARS-CoV-2 vaccine targeting HR1 domain in S2 subunit of spike protein
Pang, W., Lu, Y., Zhao, Y., Shen, F., Fan, C., Wang, Q., He, W.-Q., He, X.-Y., Li, Z., Chen, T., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00746-3 · Cited by 76
COVID-19 and Selenium Deficiency: a Systematic Review
Fakhrolmobasheri, M., Mazaheri‐Tehrani, S., Kieliszek, M., Zeinalian, M., Abbasi, M., Karimi, F., & Mozafari, A. M. (2021) · Biological Trace Element Research · doi:10.1007/s12011-021-02997-4 · Cited by 76
“The researchers divided patients into 2 groups (severe = 35, non-severe = 45) based on the diagnostic and treatment guidelines for SARS-CoV-2 issued by the Chinese National Health Committee [28].”
BackgroundInfluentialDoes vitamin D supplementation reduce COVID-19 severity?: a systematic review
Shah, K. H., Varna, V. P., Sharma, U., & Mavalankar, D. V. (2022) · QJM · doi:10.1093/qjmed/hcac040 · Cited by 76
“Many countries reported a sharp spike in the cases, almost doubling in just over a day.(1) With vaccine inequity and hesitancy, experts are already predicting that there might be emergence of new variants.”
Machado, B. A. S., Hodel, K. V. S., Fonseca, L. M. D. S., Pires, V. C., Mascarenhas, L. A. B., Andrade, L. P. C. D. S., Moret, M. A., & Badaró, R. J. D. S. (2022) · Vaccines · doi:10.3390/vaccines10040591 · Cited by 79
“Modifications found in the structure of the S protein of SARS-CoV-2 have been attributed to the greater ability of the virus to escape the action of neutralizing antibodies [43,45].”
BackgroundA broad and potent neutralization epitope in SARS-related coronaviruses
Yuan, M., Zhu, X., He, W., Zhou, P.-P., Kaku, C. I., Capozzola, T., Zhu, C. Y., Yu, X., Liu, H., Yu, W., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2205784119 · Cited by 77
Nanopore sequencing technology and its applications
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Stærke, N. B., Reekie, J., Nielsen, H., Benfield, T., Wiese, L., Knudsen, L. S., Iversen, M. B., Iversen, K. K., Fogh, K., Bodilsen, J., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32254-8 · Cited by 74
Mutational and phylogenetic analyses of the two lineages of the Omicron variant
Majumdar, S., & Sarkar, R. (2021) · Journal of Medical Virology · doi:10.1002/jmv.27558 · Cited by 71
Role of genomics in combating COVID-19 pandemic
Saravanan, K. A., Panigrahi, M., Kumar, H., Rajawat, D., Nayak, S. S., Bhushan, B., & Dutt, T. (2022) · Gene · doi:10.1016/j.gene.2022.146387 · Cited by 81
Gittelman, R. M., Lavezzo, E., Snyder, T. M., Zahid, H. J., Carty, C. L., Elyanow, R., Dalai, S. C., Kirsch, I. R., Baldo, L., Manuto, L., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.151849 · Cited by 78
“Given the continued emergence of new viral variants capable of at least partial evasion of vaccine-induced immunity (23), there is a strong need for correlates of protection against severe disease.”
BackgroundGregory, D. A., Trujillo, M., Rushford, C., Flury, A. G., Kannoly, S., San, K. M., Lyfoung, D. T., Wiseman, R. W., Bromert, K. H., Zhou, M.-Y., et al. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010636 · Cited by 72
Origin and evolution of SARS-CoV-2
Pagani, I., Ghezzi, S., Alberti, S., Poli, G., & Vicenzi, E. (2023) · The European Physical Journal Plus · doi:10.1140/epjp/s13360-023-03719-6 · Cited by 85
High Asymptomatic Carriage With the Omicron Variant in South Africa
Garrett, N., Tapley, A., Andriesen, J. G., Seocharan, I., Fisher, L. H., Bunts, L., Espy, N., Wallis, C. L., Randhawa, A. K., Miner, M. D., et al. (2022) · Clinical Infectious Diseases · doi:10.1093/cid/ciac237 · Cited by 193
“VoC that exhibit levels of resistance to the immunodominant epitopes associated with immune protection may be a factor in these differences [17].”
Lee, I., Sun, C., Wu, P., Lan, Y.-H., Wang, I.-H., Liu, W., Yuan, J. P., Chang, Y.-W., Tseng, S.-C., Tsung, S.-I., et al. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00830-1 · Cited by 66
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Theoharides, T. C., & Kempuraj, D. (2023) · Cells · doi:10.3390/cells12050688 · Cited by 82
SARS-CoV-2 spike S2-specific neutralizing antibodies
Li, C., & Chang, S. (2023) · Emerging Microbes & Infections · doi:10.1080/22221751.2023.2220582 · Cited by 73
COVID-19 Mechanisms in the Human Body—What We Know So Far
Kumar, A., Narayan, R. K., Prasoon, P., Kumari, C., Kaur, G., Kumar, S., Kulandhasamy, M., Sesham, K., Pareek, V., Faiq, M. A., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.693938 · Cited by 76
Metadata
- Authors
- Harvey, W. T., Carabelli, A. M., Jackson, B., Gupta, R. K., Thomson, E. C., Harrison, E. M., Ludden, C., Reeve, R., Rambaut, A., COVID-19 Genomics UK (COG-UK) Consortium, Peacock, S. J., & Robertson, D. L.
- Affiliations
- MRC University of Glasgow Centre for Virus Research (GB)
- University of Cambridge (GB)
- University of Edinburgh (GB)
- Wellcome Sanger Institute (GB)
- University of Glasgow (GB)
- Corresponding author
- Robertson, David L.
- ORCID
- Venue
- Nature Reviews Microbiology
- Published
- 2021-06-01
- Volume
- 19
- Issue
- 7
- Pages
- 409-424
- ISSN
- 1740-1526 (ISSN-L)
- 1740-1534
- PMC
- PMC8167834
- OpenAlex
- W3165479483
- Cited by
- 3,528
- References
- 103
- Citations by year
- 2026: 220 · 2025: 310 · 2024: 475 · 2023: 801 · 2022: 1283 · 2021: 420
- FWCI
- 87.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Reviews Microbiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Northumbria Research Link (Northumbria University) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Wellcome Trust (Z/17/Z, 206298/Z/17/Z, 220977/Z/20/Z, 220977/Z/20/Z, 206298/Z/17/Z, 206298)
- UK Research and Innovation (MR/W005611/1/, MC_PC_19027)
- National Institute for Health and Care Research
- Academy of Medical Sciences (AMS-CSF4-Torok)
- University of Glasgow
- Directorate for Biological Sciences
- Medical Research Council (MC_UU_12014, MC UU 12014/12, MC_PC_19026, MR/W005611/1, MR/S00291X/1, COVID-19, MR/R024758/1)
- Biotechnology and Biological Sciences Research Council (BB/R012679/1)
- H2020 European Research Council (725422)
- 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
- SARS-CoV-2, spike protein mutations, variants of concern, immune evasion, antigenicity, neutralizing antibodies, vaccine effectiveness, vaccine update, viral evolution, mutation frequency, COVID-19 pandemic
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, Amino Acids, Epitopes, Antigenic Variation, Humans, Mutation, Protein Conformation, Immune Evasion, Spike Glycoprotein, Coronavirus
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