A significant number of COVID‐19 patients were shown to have neutralizing antibodies (NAB) against IFN; however, NAB specificity, fluctuation over time, associations with biochemical and hematological parameters, and IFN gene expression are not well characterized.

Binding antibodies (BAB) to IFN‐α/‐β were screened in COVID‐19 patients’ serum. All BAB positive sera, and a subset of respiratory samples, were tested for NAB against IFN‐α/‐β/‐ω, using an antiviral bioassay. Transcript levels of IFN‐α/‐β/‐ω and IFN‐stimulated genes (ISGs) were quantified.

Anti‐IFN‐I BAB were found in 61 out of 360 (17%) of patients. Among BAB positive sera, 21.3% had a high NAB titer against IFN‐α. A total of 69.2% of anti‐IFN‐α NAB sera displayed cross‐reactivity to IFN‐ω. Anti‐IFN‐I NAB persisted in all patients. NAB to IFN‐α were also detected in 3 out of 17 (17.6%) of respiratory samples. Anti‐IFN‐I NAB were higher in males (p = 0.0017), patients admitted to the ICU (p < 0.0001), and patients with a fatal outcome (p < 0.0001). NAB were associated with higher levels of CRP, LDH, d‐Dimer, and higher counts of hematological parameters. ISG‐mRNAs were reduced in patients with persistently NAB titer.

NAB are detected in a significant proportion of severe COVID‐19. NAB positive patients presented a defective IFN response and increased levels of laboratory biomarkers of disease severity.