Amsterdam UMC, Amsterdam, Netherlands. ⁶Department of Anæsiology, Amsterdam UMC, Amsterdam, Netherlands. ⁷Amsterdam UMC Biobank Core Facility, Amsterdam UMC, Amsterdam, Netherlands. ⁸Department of Radiology, Amsterdam UMC, Amsterdam, Netherlands. ⁹Department of Medical Microbiology, Amsterdam UMC, Amsterdam, Netherlands. ¹⁰Department of Internal Medicine, Amsterdam UMC, Amsterdam, Netherlands. ¹¹Neurochemical Laboratory, Amsterdam UMC, Amsterdam, Netherlands. ¹²Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, Netherlands. ¹³Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, Netherlands.

**Members of the COVID Human Genetic Effort:** Laurent Abel¹, Alessandro Aiuti², Saleh Al-Muhsen³, Fahd Al-Mulla⁴, Mark S. Anderson⁵, Evangelos Andreichos⁶, Andrés A. Arias⁷, Hagit Baris Feldman⁸, Alexandre Belot⁹, Catherine M. Biggs¹⁰, Dusan Bogunovic¹¹, Alexandre Bolze¹², Anastasiia Bondarenko¹³, Ahmed A. Bousfiha¹⁴, Petter Brodin¹⁵, Yenan Bryceson¹⁶, Carlos D. Bustamante¹⁷, Manish J. Butte¹⁸, Giorgio Casari¹⁹ Samya Chakravorty²⁰, John Christodoulou²¹, Antonio Condingo-Neto²², Stefan N. Constantinescu²³, Megan A. Cooper²⁴, Clifton L. Dalgard²⁵, Murkesh Desai²⁶, Beth A. Døtter²⁷, Jamila El Baghdadi²⁸, Sara Espinosa-Padilla²⁹, Jacques Fellay³⁰, Carlos Flores³¹, José Luis Franco⁷, Antoine Froidure³², Peter K. Gregersen³³, Filomena Haerynck³⁴, David Hagin³⁵, Rabih Halwani³⁶, Lennart Hammarström³⁷, James R. Heath³⁸, Sarah E. Henrickson³⁹, Elena W. Y. Hsieh⁴⁰, Eysthen S. Husebye⁴¹, Kohsue Imai⁴², Yuval Itan⁴³, Erich D. Jarvis⁴⁴, Timokratis Karamitros⁴⁵, Kai Kisan⁴⁶, Cheng-Lung Ku⁴⁷, Yu-Lung Lau⁴⁸, Yun Ling⁴⁹, Carrie L. Lucas⁵⁰, Tom Maniatis⁵¹, Davood Mansouri⁵², László Maródi⁵³, Isabelle Meyts⁵⁴, Joshua D. Milner⁵⁵, Kristina Mironska⁵⁶, Trine H. Mogensen⁵⁷, Tomohiro Morio⁵⁸, Lisa F. P. Ng⁵⁹, Luigi D. Notaranfo⁶⁰, Antonio Novelli⁶¹, Giuseppe Novelli⁶², Cliona O'Farrelly⁶³, Satoshi Okada⁶⁴, Tayfun Ozcelik⁶⁵, Qiang Pan-Hammarström³⁷, Rebecca Perez de Diego⁶⁶, Anna M. Planas⁶⁷, Carolina Prando⁶⁸, Aurora Pujol⁶⁹, Luis Quintana-Murci⁷⁰, Laurent Renia⁵⁹, Igor Resnick⁷¹, Carlos Rodríguez-Gallego⁷², Vanessa Novo-Shimizu⁷³, Anna Sediva⁷⁴, Mikko R.J. Seppänen⁷⁵, Mohammed Shahrooee⁷⁶, Anna Shcherbina⁷⁷, Ondrej Slaby⁷⁸, Andrew L. Snow⁷⁹, Pere Soler-Palacín⁸⁰, András N. Spaan⁸¹, Ivan Tavceski⁸², Stuart G. Tangye⁸³, Ahmad Abou Tayoun⁸⁴, Sathishkumar Ramaswamy⁸⁴, Stuart E. Turvey⁸⁵, K. M. Furkan Uddin⁸⁶, Mohammed J. Uddin⁸⁷, Diederik van de Beek⁸⁸, Donald C. Vinh⁸⁹, Horst von Bernuth⁹⁰, Mayana Zatz⁹¹, Pawel Zawadzki⁹², Helen C. Su⁶⁰, Jean-Laurent Casanova⁹³

¹INSERM U1163, University of Paris, Imagine Institute, Paris, France. ²San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale San Raffaele, and Vita Salute San Raffaele University, Milan, Italy. ³Immunology Research City, Vita Salute San Raffaele, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia. ⁴Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Dasman, Kuwait. ⁵Diabetes Center, University of California San Francisco, San Francisco, CA, USA. ⁶Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. ⁷Group of Primary Immunodeficiencies, University of Antioquia UdeA, Medellin, Colombia. ⁸The Genetics Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. ⁹Pediatric Nephrology, Rheumatology, Dermatology, HFME, Hospices Civils de Lyon, National Referee Centre RAISE, and INSERM U1111, Université de Lyon, Lyon, France. ¹⁰Department of Pediatrics, British Columbia Children's Hospital, The University of British Columbia, Vancouver, BC, Canada ¹¹Icahn School of Medicine at Mount Sinai, New York, NY, USA. ¹²Helix, San Mateo, CA, USA. ¹³Shupky National Medical Academy for Postgraduate Education, Kiev, Ukraine. ¹⁴Clinical Immunology Unit, Department of Pediatric Infectious Disease, CHU Ibn Rushd and LICIA, Laboratoire d'Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco. ¹⁵SciLifeLab, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden ¹⁶Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. ¹⁷Stanford University, Stanford, CA, USA. ¹⁸Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and the Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA. ¹⁹Clinical Genomics, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy ²⁰Department of Pediatrics and Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA. ²¹Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Australia ²²Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. ²³de Duve Institute and Ludwig Cancer Research, Brussels, Belgium ²⁴Washington University School of Medicine, St. Louis, MO, USA. ²⁵Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. ²⁶Bai Jerbai Wadia Hospital for Children, Mumbai, India. ²⁷School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA. ²⁸Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco. ²⁹Instituto Nacional de Pediatria (National Institute of Pediatrics), Mexico City, Mexico. ³⁰School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ³¹Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain; Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain; Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, San Cristóbal de La Laguna, Spain;

CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. ³²Pulmonology Department, Cliniques Universitaires Saint-Luc; Institut de Recherche Experimontale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium. ³³Feinstein Institute for Medical Research, Northwell Health USA, Manhasset, NY, USA. ³⁴Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Laboratory, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium. ³⁵The Genetics Institute Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. ³⁶Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates. ³⁷Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. ³⁸Institute for Systems Biology, Seattle, WA, USA. ³⁹Department of Pediatrics, Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ⁴⁰Departments of Pediatrics, Immunology and Microbiology, University of Colorado, School of Medicine, Aurora, Colorado, USA. ⁴¹Department of Clinical Science and K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway. ⁴²Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University (TMDU) ⁴³Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ⁴⁴Laboratory of Neurogenetics of Language and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. ⁴⁵Bioinformatics and Applied Genomics Unit, Hellenic Pasteur Institute, Athens, Greece ⁴⁶Molecular Pathology, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu Estonia. ⁴⁷Chang Gung University, Taoyuan County, Taiwan. ⁴⁸Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, China. ⁴⁹Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. ⁵⁰Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. ⁵¹Columbia University Zuckerman Institute, New York, NY, USA. ⁵²Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. ⁵³Primary Immunodeficiency Clinical Unit and Laboratory, Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary. ⁵⁴Department of Pediatrics, University Hospitals Leuven, Department of Microbiology, Immunology and Transplantation, and Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium. ⁵⁵Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. ⁵⁶University Clinic for Children's Diseases, Department of Pediatric Immunology, Medical Faculty, University “St.Cyril and Methodij” Skopje, North Macedonia. ⁵⁷Department of Biomedicine, Aarhus University, Aarhus, Denmark ⁵⁸Tokyo Medical & Dental University Hospital, Tokyo, Japan. ⁵⁹A*STAR Infectious Disease Labs, Agency for Science, Technology and Research, Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore. ⁶⁰National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ⁶¹Laboratory of Medical Genetics, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. ⁶²Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy. ⁶³Comparative Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. ⁶⁴Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. ⁶⁵Department of Molecular Biology and Genetics, Bilkent University, Bilkent, Ankara, Turkey. ⁶⁶Laboratory of Immunogenetics of Human Diseases, Innate Immunity Group, IdiPAZ Institute for Health Research, La Paz Hospital, Madrid, Spain. ⁶⁷IIBB-CSIC, IDIBAPS, Barcelona, Spain. ⁶⁸Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil. ⁶⁹Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), IScIII, Barcelona, Spain. ⁷⁰Human Evolutionary Genetics Unit, CNRS U2000, Institut Pasteur, Paris, France; Human Genomics and Evolution, Collège de France, Paris, France. ⁷¹Department of Medical Genetics, Medical University, Varna and Department Hematology and BMT, University Hospital St. Marina, Bulgaria. ⁷²Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain; Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain ⁷³Department of Paediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Paediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK. ⁷⁴Department of Immunology, Second Faculty of Medicine Charles University, V Uvalu, University Hospital in Motol, Prague, Czech Republic. ⁷⁵Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland ⁷⁶Saeed Pathobiology and Genetics Lab, Tehran, Iran; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium. ⁷⁷Department of Immunology, Dmitry Rogachev National
Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.⁷⁸Central European Institute of Technology & Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.⁷⁹Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.⁸⁰Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.⁸¹St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands⁸²Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria.

⁸³Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia. ⁸⁴Al Jalila Children's Hospital, Dubai, UAE ⁸⁵BC Children's Hospital, The University of British Columbia, Vancouver, Canada

⁸⁶Centre for Precision Therapeutics, Genetic and Genomic Medicine Centre, NeuroGen Children Healthcare, Dhaka, Bangladesh; Holy Family Red Crescent Medical College, Dhaka, Bangladesh. ⁸⁷College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE; Cellular Intelligence (Ci) Lab, GenomeArc Inc., Toronto, ON, Canada

⁸⁸Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ⁸⁹Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada; Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada. ⁹⁰Department of Pediatric Pneumology, Immunology and Intensive Care, Charité Universitätsmedizin, Berlin University Hospital Center, Berlin, Germany; Labor Berlin GmbH, Department of Immunology, Berlin, Germany; Berlin Institutes of Health (BIH), Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.

⁹¹Biosciences Institute, University of São Paulo, São Paulo, Brazil. ⁹²Molecular Biophysics Division, Faculty of Physics, A. Mickiewicz University, Poznań, Poland. ⁹³The Rockefeller University & Howard Hughes Medical Institute, New York, NY, USA; Necker Hospital for Sick Children & INSERM, Paris, France.

**Members of the CONSTANCES cohort:** Rachel Nadif¹, Marcel Goldberg², Anna Ozguler², Joseph Henny², Sylvie Lemonnier², Mireille Coeuret-Pellicer³, Stéphane Le Got², Marie Zins²

¹Université de Paris-Saclay, UVSQ, Université Paris-Sud, Inserm, Equipe d'Epidémiologie Respiratoire Intégrative, Inserm CESP, Villejuif, France. ²Université de Paris, Université Paris-Saclay, UVSQ, Inserm UMS11, Villejuif, France. ³Inserm U011 Constances cohort, Villejuif, France.

**Members of the 3C-Dijon Study:** Christophe Tzourio¹, Stéphanie Debette², Carole Dufouil¹, Aïcha Soumaré¹, Morgane Lachaize², Nathalie Fievet³, Amandine Flaig³

¹University of Bordeaux; Bordeaux Population Health Center, INSERM U1219, Bordeaux, France. ²University of Bordeaux; Bordeaux Population Health Center, INSERM U1219; Bordeaux University Hospital, Department of Neurology, Institute of Neurodegenerative Diseases, Bordeaux, France. ³Laboratoire d'Analyses Génomiques - Centre de Ressources Biologiques; Institut Pasteur de Lille, Lille, France.

**Member of the Cerba HealthCare:** Fernando Martin¹

¹Cerba HealthCare, Issy-les-Moulineaux, France.

**Members of the Etablissement du Sang study group:** Brigitte Bonneau徒¹, Fabrice Cognasse⁵,⁶, Dorothée Cannet², Pierre Gallian³, Michel Jeanne⁴, Pascal Morel¹, Magali Perroquin⁴, Pascale Richard¹, Pierre Tiberghien¹, Hind Hamzeh-Cognasse⁵,⁶

¹Etablissement Français du sang, La Plaine St-Denis, France. ²Etablissement Français du sang, Dijon, France. ³Etablissement Français du sang, Marseille, France. ⁴Etablissement Français du sang, Bordeaux, France. ⁵Etablissement Français du sang, Saint-Étienne, France. ⁶ SAINBIOSE, INSERM, U1059, University of Lyon, Université Jean-Monnet Saint-Étienne.

Submitted 13 July 2021

Accepted 16 August 2021

Published First Release 19 August 2021

Final Published 14 September 2021

10.1126/sciimmunol.abl4340

**Citation:** P. Bastard, A. Gervais, T. Le Voyer, J. Rosain, Q. Philippot, J. Manry, E. Michailidis, H.-H. Hoffmann, S. Eto, M. Garcia-Prat, L. Bizien, A. Parra-Martinez, R. Yang, L. Haljasmägi, M. Migaud, K. Särekannu, J. Maslovskaja, N. de Prost, Y. Tandjaoui-Lambiotte, C.-E. Luyt, B. Amador-Borrero, A. Gaudet, J. Poissy, P. Morel, P. Richard, F. Cognasse, J. Troya, S. Trouillet-Assant, A. Belot, K. Saker, P. Garçon, J. G. Rivière, J.-C. Lagier, S. Gentile, L. B. Rosen, E. Shaw, T. Morio, J. Tanaka, D. Dalmau, P.-L. Tharaux, D. Sene, A. Stepanian, B. Megarbane, V. Triantafyllia, A. Fekkar, J. R. Heath, J. L. Franco, J.-M. Anaya, J. Solé-Violán, L. Imberti, A. Biondi, P. Bonfanti, R. Castagnoli, O. M. Delmonte, Y. Zhang, A. L. Snow, S. M. Holland, C. M. Biggs, M. Moncada-Vélez, A. A. Arias, L. Lorenzo, S. Boucherit, B. Coulibaly, D. Anglicheau, A. M. Planas, F. Haerynck, S. Duvlis, R. L. Nussbaum, T. Ozcelik, S. Keles, A. A. Bousfiha, J. El Bakkouri, C. Ramirez-Santana, S. Paul, Q. Pan-Hammarström, L. Hammarström, A. Dupont, A. Kurolap, C. N. Metz, A. Aiuti, G. Casari, V. Lampasona, F. Ciceri, L. A. Barreiros, E. Dominguez-Garrido, M. Vidigal, M. Zatz, D. van de Beek, S. Sahanic, I. Tancevski, Y. Stepanovskyy, O. Boyarchuk, Y. Nukui, M. Tsumura, L. Vidaur, S. G. Tangye, S. Burrel, D. Duffy, L. Quintana-Murci, A. Klocperk, N. Y. Kann, A. Shcherbina, Y.-L. Lau, D. Leung, M. Coulongeat, J. Marlet, R. Koning, L. F. Reyes, A. Chauvineau-Grenier, F. Venet, G. Monneret, M. C. Nussenzweig, R. Arrestier, I. Boudhabhay, H. Baris-Feldman, D. Hagin, J. Wauters, I. Meyts, A. H. Dyer, S. P. Kennelly, N. M. Bourke, R. Halwani, N. S. Sharif-Askari, K. Dorgham, J. Sallette, S. Mehlal Sedkaoui, S. Al-Khater, R. Rigo-Bonnin, F. Morandeira, L. Roussel, D. C. Vinh, S. R. Ostrowski, A. Condino-Neto, C. Prando, A. Bondarenko, A. N. Spaan, L. Gilardin, J. Fellay, S. Lyonnet, K. Bilguvar, R. P. Lifton, S. Mane, HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James's Hospital SARS CoV2 Interest group, French COVID Cohort Study Group, Imagine COVID-Group, The Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank Investigators, COVID Human Genetic Effort, CONSTANCES cohort, 3C-Dijon Study, Cerba HealthCare, Etablissement du Sang study group, M. S. Anderson, B. Boisson, V. Béziat, S.-Y. Zhang, E. Andreakos, O. Hermine, A. Pujol, P. Peterson, T. H. Mogensen, L. Rowen, J. Mond, S. Debette, X. de Lamballerie, X. Duval, F. Mentré, M. Zins, P. Soler-Palacín, R. Colobran, G. Gorochov, X. Solanich, S. Susen, J. Martinez-Picado, D. Raoult, M. Vasse, P. K. Gregersen, L. Piemonti, C. Rodríguez-Gallego, L. D. Notarangelo, H. C. Su, K. Kisand, S. Okada, A. Puel, E. Jouanguy, C. M. Rice, P. Tiberghien, Q. Zhang, A. Cobat, L. Abel, J.-L. Casanova, Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. *Sci. Immunol.* 6, eabl4340 (2021).
Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Paul BastardAdrian GervaisTom Le VoyerJérémie RosainQuentin PhilippotJérémy ManryEleftherios MichailidisHans-Heinrich HoffmannShohei EtoMarina Garcia-PratLucy BizienAlba Parra-MartínezRui YangLiis HaljasmägiMélanie MigaudKarita SerekannuJulia MaslovskajaNicolas de ProstYacine Tandjaoui-LambiotteCharles-Edouard LuytBlanca Amador-BorreroAlexandre GaudetJulien PoissyPascal MorelPascale RichardFabrice CognasseJesus TroyaSophie Trouillet-AssantAlexandre BelotKahina SakerPierre GarçonJacques G. RivièreJean-Christophe LagierStéphanie GentileLindsey B. RosenElana ShawTomohiro MorioJunko TanakaDavid DalmauPierre-Louis TharauxDamien SeneAlain StepanianBruno MegarbaneVasiliki TriantafylliaArnaud FekkarJames R. HeathJosé Luis FrancoJuan-Manuel AnayaJordi Solé-ViolánLuisa ImbertiAndrea BiondiPaolo BonfantiRiccardo CastagnoliOttavia M. DelmonteYu ZhangAndrew L. SnowSteven M. HollandCatherine M. BiggsMarcela Moncada-VélezAndrés Augusto AriasLazaro LorenzoSoraya BoucheritBoubacar CoulibalyDany AnglicheauAnna M. PlanasFilomeen HaerynckSotirija DuvlisRobert L. NussbaumTayfun OzcelikSevgi KelesAhmed A. BousfihaJalila El BakkouriCarolina Ramirez-SantanaStéphane PaulQiang Pan-HammarströmLennart HammarströmAnnabelle DupontAlina KurolapChristine N. MetzAlessandro AiutiGiorgio CasariVito LampasonaFabio CiceriLucila A. BarreirosElena Dominguez-GarridoMateus VidigalMayana ZatzDiederik van de BeekSabina SahanicIvan TancevskiYurii StepanovskyiOksana BoyarchukYoko NukuiMiyuki TsumuraLoreto VidaurStuart G. TangyeSonia BurrelDarragh DuffyLluis Quintana-MurciAdam KlocperkNelli Y. KannAnna ShcherbinaYu-Lung LauDaniel LeungMatthieu CoulongeatJulien MarletRutger KoningLuis Felipe ReyesAngélique Chauvineau-GrenierFabienne VenetGuillaume MonneretMichel C. NussenzweigRomain ArrestierIdris BoudhabhayHagit Baris-FeldmanDavid HaginJoost WautersIsabelle MeytsAdam H. DyerSean P. KennellyNollaig M. BourkeRabih HalwaniNarjes Saheb Sharif-AskariKarim DorghamJérôme SalletteSouad Mehlal SedkaouiSuzan AlKhaterRaúl Rigo-BonninFrancisco MorandeiraLucie RousselDonald C. VinhSisse Rye OstrowskiAntonio Condino-NetoCarolina PrandoAnastasiia BondarenkoAndrás N. SpaanLaurent GilardinJacques FellayStanislas LyonnetKaya BilguvarRichard P. LiftonShrikant ManeMark S. AndersonBertrand BoissonVivien BéziatShen-Ying ZhangEvangelos AndreakosOlivier HermineAurora PujolPärt PetersonTrine H. MogensenLee RowenJames MondStéphanie DebetteXavier de LamballerieXavier DuvalFrance MentréMarie ZinsPere Soler-PalacinRoger ColobranGuy GorochovXavier SolanichSophie SusenJavier Martinez-PicadoDidier RaoultMarc VassePeter K. GregersenLorenzo PiemontiCarlos Rodríguez-GallegoLuigi D. NotarangeloHelen C. SuKai KisandSatoshi OkadaAnne PuelEmmanuelle JouanguyCharles M. RicePierre TiberghienQian ZhangAurélie CobatLaurent AbelJean-Laurent Casanova

Sci. Immunol., 6 (62), eab14340. • DOI: 10.1126/sciimmunol.ab14340

COVID-19 vulnerability via autoantibodies

Type I interferons are potent antiviral cytokines induced promptly after human respiratory exposure to SARS-CoV-2 virus. Either genetic or acquired defects in type I interferon signaling can increase host vulnerability to developing severe COVID-19 (coronavirus disease 2019) disease. Bastard et al. used sensitive immunoassays and neutralization testing to detect presence of autoantibodies to #, #, or # type I interferons in plasma samples from a large cohort of patients with COVID-19 and prepandemic controls. The incidence of neutralizing autoantibodies to type I interferon increased with age in the control cohort, increasing sharply after the age of 70. These findings indicate that autoantibodies targeting type I IFNs represent a not uncommon type of acquired immunodeficiency that contributes to about 20% of all COVID-19 fatalities.

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