Omicron may be less efficient at replicating in the lungs than previous SARS-CoV-2 variants

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A new study by researchers from Cambridge Institute of Therapeutic Immunology and Infectious Disease lead by Professor Dr Ravi Gupta has found that the Omicron may be less efficient at replicating in the lungs than previous SARS-CoV-2 variants.

The findings have yet to be published and are in a preprint format on the Cambridge site. 

https://www.citiid.cam.ac.uk/wp-content/uploads/2021/12/FIGURES-OMICRON-PAPER.pdf

The Omicron variant was first detected in South Africa and has now spread internationally1. It has been associated with very rapid increases in case numbers and recent data demonstrate significant evasion of neutralising antibody responses1. 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. Data on replication are limited however.

Delta spike was previously shown to confer more efficient cell-cell fusion kinetics compared to Wuhan-12, and syncytia formation has previously been associated with pathogenesis3.

Moreover, changes in the PBCS have been associated with pathogenicity. Omicron has three mutations in the furin cleavage site region (P681H, H655Y and N679K) and has therefore been predicted to be highly infectious and fit.

Here we show that contrary to predictions based on mutational profiling of the PBCS region, Omicron spike is relatively poorly cleaved, and impaired in mediating cell-cell fusion and syncytia formation.

This reduced cleavage is also associated with poorer entry into target lung organoids or cell lines expressing endogenous levels of receptors. We also show that as expected from mutational profiling, omicron has significantly reduced sensitivity to neutralising antibodies and that AZ vaccine sera display lower titres as compared to mRNA vaccine sera.

Soon after a third dose with mRNA however, robust titres against Omicron can be achieved, thus supporting third dose ‘boosting’ strategies.

Discussion

Here we have shown that the Omicron spike confers very significant evasion of vaccine elicited neutralising antibodies that is more dramatic for ChAdOx-1 versus BNT162b2 vaccine sera. These data are supported by vaccine effectiveness measurements in the UK (UKHSA report Dec 2021). Third dose mRNA vaccination rescued neutralisation in the short term, though waning is expected to occur over time.

Importantly, we show that despite three mutations predicted to favour spike S1/S2 cleavage, observed cleavage efficiency is similar to wild type Wuhan-1 D614G and lower than Delta. As expected from suboptimal cleavage, we show poor fusogenic potential of the Omicron spike when expressed in cells.

This phenomenon could translate to impaired cell-cell spread, and indeed investigators have observed smaller plaque sizes (personal communication).

Omicron spike was also associated with poorer entry into target lung organoids or Calu-3 lung cell lines expressing endogenous levels of receptors.

These observations highlight that Omicron has gained immune evasion properties whilst compromising syncitia formation and cell entry in lung cells, with possible implications for pathogenicity. Critically, ChAdOx-1 is widely used in low income settings where third doses with mRNA not widely available, and Omicron may contribute to severe disease in such settings.

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