Such major changes in the antigenicity and replicative biology of the virus likely underlie the global spread and decreased virulence of Omicron. Experiments using chimeric spike proteins revealed that impaired cell–cell fusion was determined by changes within the receptor-binding domain (RBD) of the spike protein, while endosomal entry was associated with changes in the S2 domain. Instead, Omicron variants entered cells preferentially via a TMPRSS2-independent endosomal entry pathway, thereby altering the cell tropism of the virus. Attempting to understand the underlying cause(s) of immune escape, we studied the virological properties of Omicron in vitro and unexpectedly found that the variant did not induce cell–cell fusion, a phenomenon observed in preceding variants that results from activation of the spike protein at the cell membrane by the cell surface protease TMPRSS2. These data were mirrored by a substantial reduction in real-world vaccine effectiveness, which was partially restored by booster vaccination. Vaccine effectiveness was estimated in the Evaluation of Variants Affecting Deployed COVID-19 Vaccine (EVADE) study that links vaccine response with genetic variants in Scotland.Īs suggested by the ‘early warning’ signal from sequencing data that predicted substantial immune escape 1, we found markedly reduced neutralization of Omicron BA.1 and BA.2 variants by sera from recipients of two or three doses of vaccine, while T cell responses were relatively preserved. Neutralizing antibodies and spike-specific T cells were quantified in samples from recipients of deployed vaccines in the COVID-19 Deployed Vaccine Cohort Study (DOVE). We further investigated the biological properties of the virus in vitro, in order to understand the mechanisms of reduced disease severity. In this study, we explored the immune evasion characteristics of the Omicron variant through assays of immune function and through estimates of real-world vaccine effectiveness. As predicted, Omicron rapidly outpaced the preceding Delta variant, although, fortuitously, early signals suggested that it was associated with less severe disease. The emergence of the virus in the United Kingdom was monitored by the UK public health agencies and members of the COVID-19 Genomics UK (COG-UK) Consortium by high-throughput sequencing. Such apprehension stemmed from the predicted structure of the spike protein, indicating that the virus had changed substantially, thus presenting a potential risk of vaccine escape (Fig. When scientists in South Africa first identified the Omicron variant of SARS-CoV-2, there was real concern for the potential of a new global wave of infection.
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