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, 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
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.