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SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway
Brian J. Willett, Joe Grove, Oscar A. MacLean, Craig Wilkie, Giuditta De Lorenzo, Wilhelm Furnon, Diego Cantoni, Sam Scott, Nicola Logan, Shirin Ashraf, Maria Manali, Agnieszka M. Szemiel, Vanessa M. Cowton, Elen Vink, William T. Harvey, Christopher Davis, Patawee Asamaphan, Katherine Smollett, L. Tong, Richard Orton, Joseph Hughes, Poppy Holland, Vanessa Silva, David J. Pascall, Kathryn Puxty, Ana da Silva Filipe, Gonzalo Yebra, Sharif Shaaban, Matthew T. G. Holden, Rute Maria Pinto, Rory Gunson, Kate Templeton, Pablo R. Murcia, Arvind H. Patel, Paul Klenerman, Susanna Dunachie, Eleanor Barnes, Anthony Brown, Sandra Adele, Barbara Kronsteiner, Sam M. Murray, Priyanka Abraham, Alexandra Deeks, M. Azim Ansari, Thushan I. de Silva, Lance Turtle, Shona C. Moore, James Austin, Alex Richter, C.J. Duncan, Rebecca Payne, Amy Ash, Cherian Koshy, Beatrix Kele, Teresa Cutiño‐Moguel, Derek Fairley, James P. McKenna, Tanya Curran, Helen Adams, Christophe Fraser, David Bonsall, Helen Fryer, Katrina Lythgoe, Tanya Golubchik, Abigail Murray, Dawn Singleton, Shaun M. Beckwith, Anna Mantzouratou, Magdalena Barrow, Sarah L. Buchan, Nicola Reynolds, Ben Warne, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, John P.T. Mo, Robert Beer, Safiah Afifi, Sian Morgan, Andrew Mack, Angela Marchbank, Anna Price, Arthur Morriss, Catherine Bresner, Christine Kitchen, Ian Merrick, Joel Southgate, Martyn F. Guest, Owen Jones, Robert J. Munn, Thomas R. Connor, Thomas Whalley, Trudy Workman, William Fuller, Amita Patel, Bindi Patel, Gaia Nebbia, Jonathan Edgeworth, Luke B. Snell, Rahul Batra, Themoula Charalampous, Angela H. Beckett, Ekaterina Shelest, Samuel C. Robson, Anthony P. Underwood, Ben Taylor, Corin Yeats, David M. Aanensen, Khalil Abudahab, Mirko Menegazzo, Amelia Joseph, Gemma Clark, Hannah C. Howson‐Wells, Louise Berry, Manjinder Khakh, Michelle M. Lister, Tim Boswell, Vicki M. Fleming, Christopher W. Holmes, Claire McMurray, Jessica R. Shaw, Julian W. Tang, Karlie Fallon, Mina Odedra, Nicholas J. Willford, Paul Bird, Thomas Helmer, Lesley-Anne Williams, Nicola Sheriff, Veena Raviprakash, Victoria Blakey, Christopher Moore, Fei Sang, Johnny Debebe, Matthew Carlile, Matthew Loose, Nadine Holmes, Victoria Wright, M. Estee Torok, William L. Hamilton, Alessandro M. Carabelli, Andrew Jermy, Beth Blane, Carol Churcher, Catherine Ludden, Dinesh Aggarwal, Elaine Westwick, Ellena Brooks, Georgina M. McManus, Katerina Galai, Kenneth G. C. Smith, Kim S. Smith, MacGregor Cox, Mireille Fragakis, Patrick H. Maxwell, Sarah Judges, Sharon J. Peacock, Theresa Feltwell, Anita Kenyon, Sahar Eldirdiri, Thomas Davis, Joshua F. Taylor, Ngee Keong Tan, Alex E. Zarebski, Bernardo Gutiérrez, Jayna Raghwani, Louis du Plessis, Moritz U. G. Kraemer, Oliver G. Pybus, Sarah François, Stephen W. Attwood, Tetyana I. Vasylyeva, Aminu S. Jahun, Ian Goodfellow, Iliana Georgana, Malte L. 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Pope, Adam A. Witney, Irene M. Monahan, Kenneth G. Laing, Alan McNally, Joanne Stockton, Joshua Quick, Nicholas J. Loman, Radoslaw Poplawski, Samuel M. Nicholls, Will Rowe, Anibolina Castigador, Emily MacNaughton, Kate El Bouzidi, Malur Sudhanva, Temi Lampejo, Rocio T. Martinez Nunez, Cassie Breen, Graciela Sluga, Karen T. Withell, Nicholas W. Machin, Ryan P. George, Shazaad S. Y. Ahmad, David T. Pritchard, Debbie Binns, Nick Wong, Victoria James, Cheryl Williams, Chris J. Illingworth, Christopher Jackson, Daniela De Angelis, Afrida Mukaddas, Alice Broos, Daniel Mair, David L. Robertson, Derek Wright, Emma C. Thomson, Igor Starinskij, Ioulia Tsatsani, James G. Shepherd, Jenna Nichols, Kyriaki Nomikou, Vattipally B. Sreenu, Roy Sanderson, Sarah H. O’Brien, Steven Rushton, Jon Perkins, Rachel Blacow, Abbie Gallagher, Elizabeth Wastnedge, M. McHugh, Rebecca Dewar, Seb Cotton, Lindsay Coupland, Rachael Stanley, Samir Dervisevic, Lewis G. 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Platt, Tamyo Mbisa, Vicki Chalker, Stefan Rooke, Alec Birchley, Alexander Adams, Alisha Davies, Amy Gaskin, Bree Gatica-Wilcox, Caoimhe McKerr, Catherine Moore, Catryn Williams, Chris Williams, David Heyburn, Elen De Lacy, Ember Hilvers, Fatima Downing, Georgia Pugh, Hannah Jones, Hibo Asad, Jason Coombes, Jessica Hey, Jessica Powell, Joanne Watkins, Johnathan M. Evans, Laia Fina, Laura Gifford, Lauren Gilbert, Lee Graham, Malorie Perry, Mari Morgan, Matthew Bull, Nicole Pacchiarini, Noel Craine, Sally Corden, Sara Kumziene-Summerhayes, Sara Rey, Sarah Taylor, Simon Cottrell, Sophie Jones, Sue Edwards, Tara Annett, Alexander J. Trotter, Alison E. Mather, Alp Aydin, Andrew J. Page, David Baker, Ebenezer Foster-Nyarko, Gemma L. Kay, Justin O’Grady, Leonardo de Oliveira Martins, Lizzie Meadows, Nabil-Fareed Alikhan, Sophie J. Prosolek, Steven Rudder, Thanh Le-Viet, Anna Casey, Liz Ratcliffe, Aditi Singh, Arun Mariappan, Chris Baxter, Clara Radulescu, David Simpson, Deborah Lavin, Fiona Rogan, Julia Miskelly, Marc Fuchs, Miao Tang, Silvia Carvalho, Stephen Bridgett, Timofey Skvortsov, Zoltán Molnár, Newara Ramadan, Bridget Knight, Christopher R. Jones, Cressida Auckland, Helen Morcrette, Jennifer Poyner, Dianne Irish-Tavares, Eric Witele, Jennifer Hart, Tabitha Mahungu, Tanzina Haque, Yann Bourgeois, Christopher Fearn, Kate F. Cook, Katie F. Loveson, Salman Goudarzi, Cariad Evans, David G. Partridge, KATE JOHNSON, Mehmet Yavus, Mohammad Raza, Craig Mower, Paul Baker, Sarah Essex, Stephen Bonner, Leanne J. Murray, Louisa K. Watson, Steven Liggett, Andrew I. Lawton, Ronan A Lyons, Brendan Payne, Gary Eltringham, Jennifer Collins, Sheila Waugh, Shirelle Burton-Fanning, Yusri Taha, Christopher Jeanes, Andrea N. Gomes, Darren R. 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Bibliographic record
VenueNature Microbiology · 2022
Typearticle
Languageen
FieldMedicine
TopicSARS-CoV-2 and COVID-19 Research
Canadian institutionsnot available
FundersInstitute of Infection and ImmunityEngineering and Physical Sciences Research CouncilSheffield Teaching Hospitals NHS Foundation TrustNIHR Oxford Biomedical Research CentreSt George's University Hospitals NHS Foundation TrustOxford University Hospitals NHS Foundation TrustBarts Health NHS TrustGreat Ormond Street Hospital for ChildrenLiverpool University Hospitals NHS Foundation TrustNewcastle upon Tyne Hospitals NHS Foundation TrustCambridge University HospitalsCardiff UniversityUniversity of GlasgowUniversity of NottinghamNational Institute for Health Research Health Protection Research UnitUniversity of OxfordBiotechnology and Biological Sciences Research CouncilWellcome TrustNottingham University Hospitals NHS TrustUniversity College LondonImperial College Healthcare NHS TrustDirectorate for Biological SciencesImperial College LondonBournemouth UniversityUniversity of CambridgeAcademy of Medical SciencesNational Institute for Health and Care ResearchMedical Research CouncilDepartment of Health and Social CareUniversity Hospitals Birmingham NHS Foundation TrustBetsi Cadwaladr University Health BoardGreat Ormond Street Institute of Child HealthNewcastle UniversityAlan Turing InstituteKing's College LondonUniversity Hospitals of Leicester NHS TrustKing's College Hospital NHS Foundation TrustUK Research and InnovationUniversity of PortsmouthNorthumbria University
KeywordsEndosomeBiologyAntigenicityVirologyIn vitroNeutralizationLipid bilayer fusionViral entryImmune systemReceptorCell biologyGeneticsAntibodyVirus
Abstract
Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
metaresearch head score (Codex)0.000
metaresearch head score (Gemma)0.000
Version: metacan-v3-hybrid-931329e0061cValidation status: machine_predicted_unvalidated
Candidate categoriesnone
Consensus categoriesnone
DomainCandidate signal: none · Consensus signal: none
Study designCandidate signal: Bench or experimental · Consensus signal: Bench or experimental
GenreCandidate signal: Empirical · Consensus signal: Empirical
Teacher disagreement score0.001
Threshold uncertainty score0.004
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
Opus teacher head0.017
GPT teacher head0.295
Teacher spread0.278 · how far apart the two teachers sit on this one work
Validation status
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
The models applied no category: nothing in the taxonomy fit this work.
Study designBench or experimental
Domainnot available
GenreEmpirical
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".
Quick stats
Citations724
Published2022
Admission routes1
Has abstractyes