The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism

Brian J. Willett, Joe Grove, Oscar A MacLean, Craig Wilkie, Nicola Logan, Giuditta De Lorenzo, Wilhelm Furnon, Sam Scott, Maria Manali, Agnieszka Szemiel, Shirin Ashraf, Elen Vink, William Harvey, Chris Davis, Richard Orton, Joseph Hughes, Poppy Holland, Vanessa Silva, David Pascall, Kathryn Puxty, Ana da Silva Filipe, Gonzalo Yebra, Sharif Shaaban, Matthew T. G. Holden, Rute Maria Pinto, Rory Gunson, Kate Templeton, Pablo Murcia, Arvind H. Patel, The COVID-19 DeplOyed VaccinE (DOVE) Cohort Study investigators, The COVID-19 Genomics UK (COG-UK) Consortium, The G2P-UK National Virology Consortium, The Evaluation of Variants Affecting Deployed COVID-19 Vaccines (EVADE) investigators, John Haughney, David L. Robertson, Massimo Palmarini, Surajit Ray & Emma C. Thomson (2022) medRxiv doi: PDF

Vaccination-based exposure to spike protein derived from early SARS-CoV-2 sequences is the key public health strategy against COVID-19. Successive waves of SARS-CoV-2 infections have been characterised by the evolution of highly mutated variants that are more transmissible and that partially evade the adaptive immune response. Omicron is the fifth of these “Variants of Concern” (VOC) and is characterised by a step change in transmission capability, suggesting significant antigenic and biological change. It is characterised by 45 amino acid substitutions, including 30 changes in the spike protein relative to one of the earliest sequences, Wuhan-Hu-1, of which 15 occur in the receptor- binding domain, an area strongly associated with humoral immune evasion. In this study, we demonstrate both markedly decreased neutralisation in serology assays and real-world vaccine effectiveness in recipients of two doses of vaccine, with efficacy partially recovered by a third mRNA booster dose. We also show that immunity from natural infection (without vaccination) is more protective than two doses of vaccine but inferior to three doses. Finally, we demonstrate fundamental changes in the Omicron entry process in vitro, towards TMPRSS2-independent fusion, representing a major shift in the replication properties of SARS-CoV-2. Overall, these findings underlie rapid global transmission and may alter the clinical severity of disease associated with the Omicron variant.