The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism
Professor 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 T 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, Prof Rory N Gunson, Dr Kate E Templeton, Pablo R Murcia, Arvind H Patel, John Haughney, Prof David L Robertson, Massimo Palmarini, Surajit Ray, Professor Emma C Thomson
doi:10.1101/2022.01.03.21268111
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 receptorbinding 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.
Supplementary Information
Epidemiological description of the emergence of the Omicron variant in the UK On the 27 th November 2021, the UK Health Security Agency detected 2 cases of Omicron in England, the following day 6 Scottish cases were detected by community (Pillar 2) sequencing. Over the next 10 days (to 8 th December 2021) a further 95 genome sequences were obtained. Due to the rapid spread of Omicron and low genetic diversity, the genome sequences are highly related with mean genetic divergence of 1 single nucleotide polymorphisms (SNPs) and maximum 7 SNPs. The phylogenetic relationship to Omicron sequences from other countries is consistent with multiple introductions associated with travel to South Africa followed by community transmissions within Scotland. Amongst the Scottish samples diverged from the tree backbone, there were a number identified that are genetically divergent, i.e., greater than 2 single nucleotide polymorphisms from the nearest Scottish sample (Figure 1D ). Moreover, comparison to the wider international collection of Omicron samples revealed that they were more closely related to genomes from other countries than other Scottish samples. These samples therefore likely represent independent introductions to Scotland, but without more detailed epidemiological data, the number of introductions is unknown. Where there are indistinguishable samples in the phylogeny from Scotland and elsewhere in world, importation cannot be ruled out as a source..
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