![]() ![]() 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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