Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths.
Bastard P., Gervais A., Le Voyer T., Rosain J., Philippot Q., Manry J., Michailidis E., Hoffmann H-H., Eto S., Garcia-Prat M., Bizien L., Parra-Martínez A., Yang R., Haljasmägi L., Migaud M., Särekannu K., Maslovskaja J., de Prost N., Tandjaoui-Lambiotte Y., Luyt C-E., Amador-Borrero B., Gaudet A., Poissy J., Morel P., Richard P., Cognasse F., Troya J., Trouillet-Assant S., Belot A., Saker K., Garçon P., Rivière JG., Lagier J-C., Gentile S., Rosen LB., Shaw E., Morio T., Tanaka J., Dalmau D., Tharaux P-L., Sene D., Stepanian A., Megarbane B., Triantafyllia V., Fekkar A., Heath JR., Franco JL., Anaya J-M., Solé-Violán J., Imberti L., Biondi A., Bonfanti P., Castagnoli R., Delmonte OM., Zhang Y., Snow AL., Holland SM., Biggs C., Moncada-Vélez M., Arias AA., Lorenzo L., Boucherit S., Coulibaly B., Anglicheau D., Planas AM., Haerynck F., Duvlis S., Nussbaum RL., Ozcelik T., Keles S., Bousfiha AA., El Bakkouri J., Ramirez-Santana C., Paul S., Pan-Hammarström Q., Hammarström L., Dupont A., Kurolap A., Metz CN., Aiuti A., Casari G., Lampasona V., Ciceri F., Barreiros LA., Dominguez-Garrido E., Vidigal M., Zatz M., van de Beek D., Sahanic S., Tancevski I., Stepanovskyy Y., Boyarchuk O., Nukui Y., Tsumura M., Vidaur L., Tangye SG., Burrel S., Duffy D., Quintana-Murci L., Klocperk A., Kann NY., Shcherbina A., Lau Y-L., Leung D., Coulongeat M., Marlet J., Koning R., Reyes LF., Chauvineau-Grenier A., Venet F., Monneret G., Nussenzweig MC., Arrestier R., Boudhabhay I., Baris-Feldman H., Hagin D., Wauters J., Meyts I., Dyer AH., Kennelly SP., Bourke NM., Halwani R., Sharif-Askari NS., Dorgham K., Sallette J., Sedkaoui SM., AlKhater S., Rigo-Bonnin R., Morandeira F., Roussel L., Vinh DC., Ostrowski SR., Condino-Neto A., Prando C., Bonradenko A., Spaan AN., Gilardin L., Fellay J., Lyonnet S., Bilguvar K., Lifton RP., Mane S., HGID Lab None., COVID Clinicians None., COVID-STORM Clinicians None., NIAID Immune Response to COVID Group None., NH-COVAIR Study Group None., Danish CHGE None., Danish Blood Donor Study None., St. James's Hospital None., SARS CoV2 Interest group None., French COVID Cohort Study Group None., Imagine COVID-Group None., Milieu Intérieur Consortium None., CoV-Contact Cohort None., Amsterdam UMC Covid-19 None., Biobank Investigators None., COVID Human Genetic Effort None., CONSTANCES cohort None., 3C-Dijon Study None., Cerba Health-Care None., Etablissement du Sang study group None., Anderson MS., Boisson B., Béziat V., Zhang S-Y., Vandreakos E., Hermine O., Pujol A., Peterson P., Mogensen TH., Rowen L., Mond J., Debette S., de Lamballerie X., Duval X., Mentré F., Zins M., Soler-Palacin P., Colobran R., Gorochov G., Solanich X., Susen S., Martinez-Picado J., Raoult D., Vasse M., Gregersen PK., Piemonti L., Rodríguez-Gallego C., Notarangelo LD., Su HC., Kisand K., Okada S., Puel A., Jouanguy E., Rice CM., Tiberghien P., Zhang Q., Cobat A., Abel L., Casanova J-L.
Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/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 (100 pg/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 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.