SARS-CoV-2 Omicron spike mediated immune escape, infectivity and cell-cell fusion

Abstract

The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. 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. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation in the short term. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. Despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is substantially lower than for Delta. Omicron spike pseudotyped virus (PV) entry into lower airway organoids and Calu-3 lung cells was impaired. This defect for Omicron, but not Delta spike PV, correlated with higher cellular expression of TMPRSS2 transcripts, as determined by single cell RNA seq. Indeed we showed that in lung cells expressing TMPRSS2, live Omicron virus demonstrated significantly lower replication in comparison to Delta. This phenotype was reflected in cells where TMPRSS2 expression could be manipulated, with Omicron showing no change in entry in the presence of TMPRSS2. 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. 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. 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.