Avidity of autoantibodies against type I interferons as a factor associated with neurological complications in severe COVID-19.

Background: Autoantibodies against type I interferons (IFNs), particularly IFN-α2 and IFN-ω, are a recognized risk factor for severe COVID-19. Their functional characterization has largely focused on their neutralizing capacity. However, antibody binding avidity represents a distinct biophysical parameter that may be physiopathologically relevant. Whether avidity contributes to clinical outcomes in patient cohorts has not been evaluated. Methods: We characterized the avidity of IgG autoantibodies against IFN-α2 and IFN-ω by urea-dissociation ELISA in 95 patients with severe COVID-19 and confirmed anti-type I IFN autoantibodies. Avidity was classified as high (avidity index > 0.6) or low (avidity index ≤ 0.6). Clinical outcomes were compared between avidity groups, and patients were additionally stratified by combined avidity and neutralization profiles. Concordance between antibody subtypes was assessed by Cohen's kappa. Results: Among 95 patients, 75 were positive for anti-IFN-α2 autoantibodies (51 high, 24 low avidity) and 49 for anti-IFN-ω autoantibodies (31 high, 18 low avidity). Low anti-IFN-α2 avidity was significantly associated with neurological complications (6/24 [25%] vs. 3/51 [6%]; OR 0.21 [0.05-0.84]; p = 0.026). For anti-IFN-ω, a non-significant trend in the same direction was observed (3/18 [17%] vs. 2/31 [6%]; p = 0.342). Avidity and neutralizing capacity were related but not interchangeable, with a low positive predictive value of avidity for neutralization (47% for anti-IFN-α2, 16% for anti-IFN-ω). Stratification by the combined avidity/neutralization phenotype identified the low-avidity + non-neutralizing combination of anti-IFN-α2 autoantibodies as the subgroup with the highest neurological complication rate (6/18 [33%]). Concordance between anti-IFN-α2 and anti-IFN-ω avidity was modest (Cohen's κ = 0.24; 62% concordant). Conclusion: Antibody avidity is a functional characteristic of anti-type I IFN autoantibodies associated with neurological complications in severe COVID-19. In our cohort, avidity and neutralizing capacity are related but not equivalent, as a substantial proportion of high-avidity antibodies lack neutralizing activity, and the modest concordance between subtypes further suggests that these two autoantibody responses are partially independent. The combined assessment of avidity and neutralization identifies patients at higher neurological risk than either parameter alone, supporting avidity as an additional informative parameter in the functional characterization of anti-type I IFN autoantibodies.