SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Authors: 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, Susanna Dunachie, Paul Klenerman, 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, Laura Thomson, 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, Sharon Campbell, 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. Pinckert, Myra Hosmillo, Rhys Izuagbe, Yasmin Chaudhry, Felicity Ryan, Hannah Lowe, Samuel Moses, Luke Bedford, James S. Cargill, Warwick Hughes, Jonathan P. Moore, Susanne Stonehouse, Divya Shah, Jack C. D. Lee, Julianne R. Brown, Kathryn Harris, Laura Atkinson, Nathaniel Storey, Moira Spyer, Flavia Flaviani, Adela Alcolea-Medina, Jasveen Sehmi, John Ramble, Natasha Ohemeng-Kumi, Perminder Smith, Beatrice Bertolusso, Claire Thomas, Gabrielle Vernet, Jessica Lynch, Nathan Moore, Nicholas Cortes, Rebecca Williams, Stephen P. Kidd, Lisa J. Levett, Monika Pusok, Paul R. Grant, Stuart A. Kirk, Wendy Chatterton, Li Xu-McCrae, Darren Smith, Gregory R. Young, Matthew Bashton, Katie Kitchman, Kavitha Gajee, Kirstine Eastick, Patrick Lillie, Phillipa Burns, William V. Everson, Alison D. Cox, Alison Holmes, Frances Bolt, James Price, Marcus Pond, Paul Randell, Pinglawathee Madona, Siddharth Mookerjee, Erik Volz, Lily Geidelberg, Manon Ragonnet‐Cronin, Olivia Boyd, Rob Johnson, Cassie F. Pope, Adam A. Witney, Irene M. Monahan, Kenneth G. Laing, Katherine Smollett, Alan McNally, Claire McMurray, 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, David J. Pascall, Afrida Mukaddas, Alice Broos, Ana da Silva Filipe, Daniel Mair, David L. Robertson, Derek Wright, Emma C. Thomson, Igor Starinskij, Ioulia Tsatsani, James G. Shepherd, Jenna Nichols, Joseph Hughes, Kyriaki Nomikou, L. Tong, Richard Orton, Vattipally B. Sreenu, William T. Harvey, Roy Sanderson, Sarah H. O’Brien, Steven Rushton, Jon Perkins, Rachel Blacow, Rory Gunson, Abbie Gallagher, Elizabeth Wastnedge, Kate Templeton, M. McHugh, Rebecca Dewar, Seb Cotton, Lindsay Coupland, Rachael Stanley, Samir Dervisevic, Lewis G. Spurgin, Louise Smith, Clive Graham, Debra Padgett, Edward Barton, Garren Scott, Aidan Cross, Mariyam Mirfenderesky, Emma Swindells, Jane Greenaway, Rebecca Denton-Smith, Robyn Turnbull, Giles Idle, Kevin Cole, Amy Hollis, Andrew Nelson, Clare M. McCann, John Henderson, Matthew Crown, Wen C. Yew, William T. Stanley, Nichola Duckworth, Phillip Clarke, Sarah Walsh, Tim J. Sloan, Kelly Bicknell, Robert Impey, Sarah Wyllie, Scott Elliott, Sharon Glaysher, Declan Bradley, Nicholas F. Killough, Tim Wyatt, Andrew Bosworth, Barry Vipond, Clare Pearson, Elias Allara, Esther Robinson, Hannah M. Pymont, Husam Osman, Peter Muir, Richard Hopes, Stephanie Hutchings, Martin D. Curran, Surendra Parmar, Alicia Thornton, Angie Lackenby, Chloe Bishop, David Bibby, David Lee, Eileen Gallagher, Gavin Dabrera, Ian Harrison, Jonathan Hubb, Katherine A. Twohig, Meera Chand, Nicholas Ellaby, Nikos Manesis, Richard Myers, Steven G. Platt, Tamyo Mbisa, Vicki Chalker, Gonzalo Yebra, Matthew T. G. Holden, Sharif Shaaban, 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. Murray, Maimuna Kimuli, Donald Dobie, Paula Ashfield, Angus Best, Benita Percival, Emma Moles-Garcia, Fiona Ashford, Jeremy Mirza, Liam Crawford, Megan Mayhew, Nicola Cumley, Oliver Megram, Dan Frampton, Judith Heaney, Matthew Byott, Catherine Houlihan, Charlotte A. Williams, Eleni Nastouli, Helen L. Lowe, John A. Hartley, Judith Breuer, Laurentiu Maftei, Leah Ensell, Marius Cotic, Matteo Mondani, Megan Driscoll, Nadua Bayzid, Rachel Williams, Sunando Roy, Adhyana I. K. Mahanama, Buddhini Samaraweera, Eleri Wilson-Davies, Emanuela Pelosi, Helen Umpleby, Helen Wheeler, Jacqui Prieto, Kordo Saeed, Matthew Harvey, Sarah Jeremiah, Siona Silviera, Stephen Aplin, Thea Sass, Ben Macklin, Dorian Crudgington, Liz A. Sheridan, Benjamin J. Cogger, Cassandra S. Malone, Florence Munemo, Hannah Huckson, Jonathan Lewis, Lisa J. Easton, Manasa Mutingwende, Michelle J. Erkiert, Mohammed O. Hassan-Ibrahim, Nicola J. Chaloner, Olga Podplomyk, Paul Randell, Roberto Nicodemi, Sarah Lowdon, Thomas Somassa, Alex Richter, Andrew D. Beggs, Andrew R. Hesketh, Colin P. Smith, Giselda Bucca, Chris Ruis, Claire Cormie, Ellen E. Higginson, Jamie Young, Joana Angélica Andrade Dias, Leanne M. Kermack, Mailis Maes, Ravindra K. Gupta, Sally Forrest, Sophia T. Girgis, Rose K. Davidson, Áine O’Toole, Andrew Rambaut, Ben Jackson, Carlos E. Balcazar, Daniel Maloney, Emily Scher, J. T. McCrone, Kathleen A. Williamson, Michael D. Gallagher, Nathan Medd, Rachel Colquhoun, Thomas D. Stanton, Thomas Williams, Verity Hill, Aaron R. Jeffries, Ben Temperton, Christine Sambles, David J. Studholme, Joanna Warwick-Dugdale, Leigh Jackson, Michelle L. Michelsen, Robin Manley, Stephen L. Michell, Alistair C. Darby, Anita O. Lucaci, Charlotte Nelson, Claudia Wierzbicki, Edith E. Vamos, Hermione J. Webster, Kathryn Jackson, Lucille Rainbow, Margaret Hughes, Mark Whitehead, Matthew Gemmell, Miren Iturriza-Gomara, Richard Eccles, Richard I. Gregory, Sam Haldenby, Steve Paterson, Adrienn Angyal, Alexander J. Keeley, Benjamin H. Foulkes, Benjamin B. Lindsey, Dennis Wang, Hailey Hornsby, Luke R. Green, Manoj Pohare, Marta Gallis, Matthew D. Parker, Max Whiteley, Darren Smith, Paige Wolverson, Peijun Zhang, Samantha E. Hansford, Sharon N. Hsu, Stavroula F. Louka, Thushan I. de Silva, Timothy M. Freeman, Matilde Mori, Emily J. Park, Jack D. Hill, Jayasree Dey, Jonathan K. Ball, Joseph Chappell, C. Patrick McClure, Timothy Byaruhanga, Arezou Fanaie, Geraldine Yaze, Rachel A. Hilson, Amy Trebes, Angie Green, David Buck, George MacIntyre-Cockett, John A. Todd, Andrew R. Bassett, Andrew Whitwham, Cordelia F. Langford, Diana Rajan, Dominic Kwiatkowski, Ewan M. Harrison, Iraad F. Bronner, Jaime M. Tovar-Corona, Jennifier Liddle, Jillian Durham, Katherine L. Bellis, Kevin Lewis, Louise Aigrain, Nicholas Redshaw, Robert M. Davies, Robin J. Moll, Shane McCarthy, Stefanie V. Lensing, Steven Leonard, Ben W. Farr, Carol Scott, Charlotte Beaver, Cristina V. Ariani, Danni Weldon, David K. Jackson, Emma Betteridge, Gerry Tonkin‐Hill, Ian Johnston, Inigo Martincorena, James Bonfield, Jeffrey C. Barrett, John Sillitoe, Jon-Paul Keatley, Karen Oliver, Keith James, Lesley Shirley, Liam Prestwood, Luke Foulser, Marina Gourtovaia, Matthew J. Dorman, Michael A. Quail, Michael H. Spencer Chapman, Naomi R. Park, Rich Livett, Roberto Amato, Sally Kay, Scott Goodwin, Scott A. J. Thurston, Shavanthi Rajatileka, Sónia Gonçalves, Stephanie W. Lo, Theo Sanderson, Alasdair Maclean, Emily J. Goldstein, Lynne Ferguson, Rachael Tomb, Jana Catalan, Neil Jones, John Haughney, David L. Robertson, Massimo Palmarini, Surajit Ray, Emma C. Thomson - Nature Microbiology 2022 cited by 724

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.