This reduced cleavage is also associated with poorer cell-cell fusion and syncytia formation, and these characteristics raise the possibility of altered pathogenesis.

However, contrary to predictions based on mutational profiling of the S1/2 cleavage region, Omicron spike is relatively poorly cleaved, and shows impaired entry and replication in lung cells expressing TMPRSS2, a serine protease enriched in lung alveolar type 1 and 2 cells. Here we show that as expected from mutational profiling, Omicron has significantly reduced sensitivity to neutralising monoclonal antibodies in clinical use and vaccine elicited antibodies in sera. Omicron has three mutations in the furin cleavage site region (P681H, H655Y and N679K) and was initially predicted to be highly infectious 5, fit and able to induce cell-cell fusion 6. Delta spike was previously shown to confer more efficient cell-cell fusion kinetics compared to Wuhan-1 3, and syncytia formation has previously been associated with pathogenesis 4. In contrast to immune evasion, data on replication and cell entry efficiency are limited. Omicron appears to be competing with the Delta variant in the UK, and this may be due to an advantage in vaccinated / previously exposed populations and/or increased replication (UKHSA technical report 32, Dec 17th). It has been associated with very rapid increases in case numbers and recent data demonstrate significant evasion of neutralising antibody responses 1, 2. The SARS-CoV-2 Omicron variant was first detected in South Africa and has now spread internationally 1. Overall, Omicron appears to have gained significant immune evasion properties whilst modulating viruscell interactions that alter tropism with implications for in vivo disease progression and transmission. These in vitro data indicate that suboptimal Omicron S1/S2 cleavage reduces efficient infection of lower airway cells expressing TMPRSS2, but not TMPRSS2 negative cells such as those found in the upper airway. Cell-cell fusion mediated by spike glycoprotein is known require S1/S2 cleavage, but is also dependent on presence of TMPRSS2 fusogenicity of the Omicron BA.1 spike was severely impaired despite TMPRSS2 expression, leading to marked reduction in syncytium formation compared to Delta spike. This phenotype was reflected in cells where TMPRSS2 expression could be manipulated, with Omicron showing no change in entry in the presence of TMPRSS2. Indeed we showed that in lung cells expressing TMPRSS2, live Omicron virus demonstrated significantly lower replication in comparison to Delta. This defect for Omicron, but not Delta spike PV, correlated with higher cellular expression of TMPRSS2 transcripts, as determined by single cell RNA seq. Omicron spike pseudotyped virus (PV) entry into lower airway organoids and Calu-3 lung cells was impaired.

Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is substantially lower than for Delta. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1.

mRNA vaccination as a third vaccine dose rescues and broadens neutralisation in the short term. Here we show that compared to the Delta variant, Omicron BA.1 confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains.

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