SARS-CoV-2 Omicron variant virus isolates are highly sensitive to interferon treatment

The SARS-CoV-2 Omicron variant (B.1.1.529) causes less severe disease than previous SARS-CoV-2 variants, although immune protection provided by vaccinations and previous infections is reduced against Omicron compared to previous variants. In agreement, evidence is emerging that Omicron is inherently less pathogenic than previous SARS-CoV-2 variants. Omicron variant viruses cause less severe disease in animal studies and appear to display a lower capacity than other variants to replicate in the lower respiratory tract. Additionally, initial clinical data indicated that the Omicron variant causes less severe disease than previous SARS-CoV-2 variants in unvaccinated individuals.

We have most recently shown that Omicron variant viruses are less effective at antagonizing the host cell interferon response than Delta variant viruses, which provides a mechanistic explanation for the reduced clinical severity of Omicron disease in individuals without pre-existing adaptive immunity. Omicron virus replication was attenuated relative to Delta virus in interferon-competent Caco-2 and Calu-3 cells, but not in interferon-deficient Vero cells, and Omicron viruses caused enhanced interferon promoter activity compared to Delta viruses. Additionally, depletion of the pattern recognition receptor MDA5, which plays a critical role in SARS-CoV-2 detection and interferon response initiation4, resulted in increased Omicron virus replication in interferon-competent cells.

The exact molecular reasons for the alleviated interferon response antagonism by Omicron viruses remain to be elucidated. Notably, the Omicron and Delta virus isolates that we investigated (see Supplementary Information) display sequence variants in the viral interferon antagonists nsp3, nsp12, nsp13, nsp14, the membrane (M) protein, the nucleocapsid protein, and ORF3a5 (Supplementary Table S1), which may be of relevance.