Nasally-delivered interferon-? in mice protects against upper and lower respiratory tract infection of SARS-CoV-2 variants including Omicron

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has had devastating impacts on our global society. Although vaccines and monoclonal antibody countermeasures have reduced the morbidity and mortality associated with SARS-CoV-2 infection, variants with constellations of mutations in the spike gene threaten their efficacy. Therefore, antiviral interventions that are resistant to further virus evolution may be needed. Here, we show IFN-? protects against SARS-CoV-2 B.1.351 (Beta) and B.1.1529 (Omicron) variants in three strains of conventional and human ACE2 transgenic mice. Prophylaxis or therapy with nasally-delivered IFN-?2 limited infection of historical or variant (B.1.351 and B.1.1.529) SARS-CoV-2 strains in both the upper and lower respiratory tracts without causing excessive inflammation. In the lung, IFN-? was produced preferentially in epithelial cells and acted on radio-resistant cells to protect against of SARS-CoV-2 infection. Thus, inhaled IFN-? may have promise as a treatment for evolving SARS-CoV-2 variants that develop resistance to antibody-based countermeasures. Overall design: RNA sequencing of lung homogenates of naive female K18-hACE2 mice (control) or mice treated with 2 µg of murine IFN-?2 by intranasal routfor 1 (D+1) or 3 (D+3) days.