The Role of Anti-Interferon-α Autoantibodies in Severe COVID-19: Implications for Vaccination Prioritization

Abstract

Background/Objectives: Neutralizing autoantibodies against type I interferons, particularly interferon-alpha (IFN-α), have been implicated in severe COVID-19 outcomes. This study investigated the prevalence and functional significance of anti-IFN-α autoantibodies (AAbs) in hospitalized unvaccinated COVID-19 patients and their association with COVID-19 disease severity. Methods: We retrospectively analyzed serum samples from 122 hospitalized COVID-19 patients (asymptomatic/mild: n = 69, moderate: n = 35, severe/critical: n = 18) and 32 healthy uninfected controls. Anti-IFN-α AAbs were quantified using a commercial enzyme-linked immunosorbent assay (ELISA) kit, with functional neutralization assessed via competitive ELISA and STAT1 phosphorylation inhibition. Statistical comparisons were performed using one-way ANOVA for parametric data and the Kruskal-Wallis test for non-parametric variables. Results: Anti-IFN-α AAbs were detected in 24.6% of COVID-19 patients, with all clinical subgroups showing significantly higher titers compared to healthy controls (p < 0.05). Although no significant differences in anti-IFN-α AAb levels were found between mild, moderate, and severe cases, patients with severe or critical COVID-19 had markedly higher mean titers (10,511.3 ng/mL) compared to non-severe (mild + moderate) cases (375.2 ng/mL, p < 0.001). Strongly neutralizing anti-IFN-α AAbs, with high titers (>20,000 ng/mL) and the ability to inhibit STAT1 phosphorylation, were identified in three severe COVID-19 cases. Anti-IFN-α AAb levels correlated positively with CRP (r = 0.80, p < 0.0001), LDH (r = 0.80, p = 0.001), and neutrophil count (r = 0.52, p = 0.003), and negatively with lymphocyte count (r = -0.59, p = 0.0006). Conclusions: Elevated and functionally neutralizing anti-IFN-α AAbs were associated with severe COVID-19. These findings support their role as a risk factor for poor outcomes and emphasize the importance of early COVID-19 vaccination. Screening may help identify high-risk individuals, particularly those unvaccinated or with immune vulnerabilities.

Keywords: COVID-19 vaccination; IFN-α; SARS-CoV-2; autoantibody; type I interferon.

Figure 1

Proportion of anti-IFN-α AAbs in hospitalized Singaporean COVID-19 patients.

Figure 2

Scatterplot comparing anti-IFN-α autoantibody (AAb) titers across four groups: normal controls and mild, moderate, and severe COVID-19 cases.

Figure 3

Lmpact of anti-IFN-α autoantibodies on COVID-19 severity. (A) In a normal immune response, SARS-CoV-2 infection activates respiratory epithelial cells to produce type I interferons (e.g., IFN-α) which bind to IFNAR, triggering the JAK-STAT signaling cascade and upregulation of ISGs that promote viral clearance. (B) In contrast, anti-IFN-α autoantibodies block this pathway, impairing ISG activation and resulting in viral persistence and excessive inflammation. (C) Among 122 hospitalized COVID-19 patients, anti-IFN-α autoantibodies were detected in 24.6%, with 4% harboring neutralizing activity. Strongly neutralizing antibodies were exclusively observed in patients with severe/critical COVID-19 infection. Abbreviations: IFNAR, Type I IFN receptor; ISC, IFN-stimulated gene; JAK, Janus kinase; STAT, signal transducer and activator of transcription.