Abstract
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals aged between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% > 80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals < 70 years, 2.3% between 70 and 80 years, and 6.3% > 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.
Highlights
Since the start of the COVID-19 pandemic in December2019, more than 200 million people have been infected with SARS-CoV-2, resulting in at least 4 million deaths, and probably closer to 7 to 9 million deaths worldwide
We immunology.sciencemag.org (Page numbers not final at time of first release) 4 confirmed that the Gyros technique was as sensitive as the techniques previously used (ELISA and Luminex), and that all tested patients with high levels of anti-IFN-α2 and/or antiIFN-ω auto-Abs on enzyme-linked immunosorbent assay (ELISA), as reported in our previous studies had high levels of autoAbs when assessed with Gyros (Fig. S1B)
We found that another 12.7% of patients with critical COVID-19 had intermediate levels of anti-IFN-α2 and/or IFN-ω auto-Abs in Gyros assays, whereas this was the case for 8.6% of patients with severe COVID-19 and 11% of the individuals in our control cohort
Summary
Since the start of the COVID-19 pandemic in December2019, more than 200 million people have been infected with SARS-CoV-2, resulting in at least 4 million deaths, and probably closer to 7 to 9 million deaths worldwide. Autosomal dominant disorders were found in 19 patients, but our cohort included four previously healthy unrelated adults aged 25 to 50 years with autosomal recessive, complete IRF7 (N=2) or IFNAR1 (N=2) deficiency. These findings indicated that type I IFN immunity is essential for protective immunity to respiratory infection with SARS-CoV2 but surprisingly redundant otherwise. Autoantibodies (auto-Abs) neutralizing 10 ng/mL IFN-α2 and/or -ω were found in the blood of at least 10% of an international cohort of patients with lifethreatening COVID-19 pneumonia, but in none of the tested individuals with asymptomatic or paucisymptomatic infection [9]. These findings were later replicated in independent cohorts from Amsterdam, Lyon, Madrid, New Haven, and San Francisco [11,12,13,14,15,16]
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