Paul Bastard

Adrian Gervais

Tom Le Voyer

Jeremie Rosain

Quentin Philippot

Jérémy Manry

Eleftherios Michailidis

Hans-Heinrich Hoffmann

Shohei Eto

Marina Garcia-Prat

Jérémie Rosain

Lucy Bizien

Alba Parra-Martínez

Rui Yang

Liis Haljasmägi

Mélanie Migaud

Karita Särekannu

Julia Maslovskaja

Nicolas De Prost

Yacine Tandjaoui-Lambiotte

Charles-Edouard Luyt

Blanca Amador-Borrero

Alexandre Gaudet

Julien Poissy

Pascal Morel

Pascale Richard

Fabrice Cognasse

Jesus Troya

Sophie Trouillet-Assant

Alexandre Belot

Kahina Saker

Pierre Garçon

Jacques G Rivière

Jean-Christophe Lagier

Stéphanie Gentile

Lindsey B Rosen

Elana Shaw

Tomohiro Morio

Junko Tanaka

David Dalmau

Pierre-Louis Tharaux

Damien Sene

Alain Stepanian

Bruno Megarbane

Vasiliki Triantafyllia

Arnaud Fekkar

James R Heath

José Luis Franco

Juan-Manuel Anaya

Jordi Solé-Violán

Luisa Imberti

Andrea Biondi

Paolo Bonfanti

Riccardo Castagnoli

Ottavia M Delmonte

Yu Zhang

Andrew L Snow

Steven M Holland

Catherine M Biggs

Marcela Moncada-Vélez

Andrés Augusto Arias

Lazaro Lorenzo

Soraya Boucherit

Boubacar Coulibaly

Dany Anglicheau

Anna M Planas

Filomeen Haerynck

Sotirija Duvlis

Robert L Nussbaum

Tayfun Ozcelik

Sevgi Keles

Ahmed A Bousfiha

Jalila El Bakkouri

Carolina Ramirez-Santana

Stéphane Paul

Qiang Pan-Hammarström

Lennart Hammarström

Annabelle Dupont

Alina Kurolap

Christine N Metz

Alessandro Aiuti

Giorgio Casari

Vito Lampasona

Fabio Ciceri

Lucila A Barreiros

Elena Dominguez-Garrido

Mateus Vidigal

Mayana Zatz

Diederik Van De Beek

Sabina Sahanic

Ivan Tancevski

Yurii Stepanovskyy

Oksana Boyarchuk

Yoko Nukui

Miyuki Tsumura

Loreto Vidaur

Stuart G Tangye

Sonia Burrel

Darragh Duffy

Lluis Quintana-Murci

Adam Klocperk

Nelli Y Kann

Anna Shcherbina

Yu-Lung Lau

Daniel Leung

Matthieu Coulongeat

Julien Marlet

Rutger Koning

Luis Felipe Reyes

Angélique Chauvineau-Grenier

Fabienne Venet

Guillaume Monneret

Michel C Nussenzweig

Romain Arrestier

Idris Boudhabhay

Hagit Baris-Feldman

David Hagin

Joost Wauters

Isabelle Meyts

Adam H Dyer

Sean P Kennelly

Nollaig M Bourke

Rabih Halwani

Narjes Saheb

Karim Dorgham

Jérome Sallette

Souad Mehlal Sedkaoui

Suzan Alkhater

Raúl Rigo-Bonnin

Francisco Morandeira

Lucie Roussel

Donald C Vinh

Sisse Rye Ostrowski

Antonio Condino-Neto

Carolina Prando

Anastasiia Bondarenko

András N Spaan

3C-Dijon Study || ||

Healthcare Cerba

Etablissement du Sang study group || Mark S ||

Anderson

Bertrand Boisson

Vivien Béziat

Shen-Ying Zhang

Evangelos Andreakos

Olivier Hermine

Aurora Pujol

Pärt Peterson

Trine H Mogensen

Lee Rowen

James Mond

Stéphanie Debette

Xavier De Lamballerie

Xavier Duval

France Mentré

Marie Zins

Pere Soler-Palacin

Roger Colobran

Guy Gorochov

Xavier Solanich

Sophie Susen

Javier Martinez-Picado

Didier Raoult

Marc Vasse

Peter K Gregersen

Lorenzo Piemonti

Carlos Rodríguez-Gallego

Luigi D Notarangelo

Helen C Su

Kai Kisand

Satoshi Okada

Anne Puel

Emmanuelle Jouanguy

Charles M Rice

Pierre Tiberghien

Qian Zhang

Aurélie Cobat

Laurent Abel

Jean-Laurent 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

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

Since the start of the coronavirus disease 2019 (COVID-19) pandemic in December 2019, more than 200 million people have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in at least 4 million deaths and probably closer to 7 to 9 million deaths worldwide. Interindividual clinical variability in the course of acute infection is vast, extending from silent or mild infection in about 90% of individuals to pneumonia and respiratory failure, both requiring hospitalization, in less than 10 and 2% of cases, respectively. Age is the major epidemiological risk factor for hospitalization or death from pneumonia, the risk doubling with every 5 years of age (1,2). The frequencies of critical disease and death from COVID-19 are higher in men than in women [START_REF] Williamson | Factors associated with COVID-19-related death using OpenSAFELY[END_REF][START_REF] Brodin | Immune determinants of COVID-19 disease presentation and severity[END_REF](5). With the COVID Human Genetic Effort (6), we previously reported that inborn errors of Toll-like receptor 3 (TLR3)-and interferon (IFN) regulatory factor 7 (IRF7)-dependent type I IFN induction and amplification can underlie life-threatening COVID-19 pneumonia in a small subset of patients (7,[START_REF] Novelli | COVID-19 one year into the pandemic: From genetics and genomics to therapy, vaccination, and policy[END_REF]. Autosomal dominant disorders were found in 19 patients, but our cohort also included four previously healthy unrelated adults aged 25 to 50 years with autosomal recessive, complete IRF7 (N = 2) or IFN-/ receptor 1 (IFNAR1) (N = 2) deficiency. These findings indicated that type I IFN immunity is essential for protective immunity to respiratory infection with SARS-CoV-2 but unexpectedly redundant otherwise. We also reported that an autoimmune phenocopy of inborn errors of type I IFN-dependent immunity can underlie critical COVID-19 pneumonia (9). Autoantibodies (auto-Abs) neutralizing IFN-2 and/ or IFN- (10 ng/ml) were found in the blood of at least 10% of an international cohort of patients with life-threatening COVID-19 pneumonia but in none of the tested individuals with asymptomatic or paucisymptomatic infection (9). These auto-Abs were detected in serum or plasma diluted 1:10. The auto-Abs in the patients' undiluted [START_REF] Panem | Antibodies to alpha-interferon in a patient with systemic lupus erythematosus[END_REF] blood can therefore probably neutralize as much as IFN-2 and/or IFN- (100 ng/ml). The 17 subtypes of type I IFNs-including 13 IFN- subtypes, IFN-, IFN-, IFN-, and IFN--bind to the same heterodimeric receptor (IFNAR1 and IFNAR2) [START_REF] Lazear | Shared and distinct functions of type I and type III interferons[END_REF]. The 13 IFN- subtypes and IFN- are closely related phylogenetically, whereas IFN-, IFN-, and IFN- are more distant (9). The auto-Abs to IFN-2 and/or IFN- were mostly found in men (95%) and in the elderly (half the patients with antibodies being over the age of 65 years) (9). These findings were later replicated in independent cohorts from Amsterdam, Lyon, Madrid, New Haven, and San Francisco [START_REF] Koning | Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients[END_REF](12)[START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF][START_REF] Goncalves | Antibodies against type-I Interferon: Detection and association with severe clinical outcome in COVID-19 patients[END_REF][START_REF] Wang | Diverse functional autoantibodies in patients with COVID-19[END_REF][START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF].

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These auto-Abs against type I IFNs were found in about 0.3% of a general population sample of 1227 individuals collected before the pandemic and aged 20 to 69 years, suggesting that they predated SARS-CoV-2 infection and caused critical COVID-19 rather than being triggered by it (9). Moreover, production of these antibodies can be genetically driven and can begin during early childhood, as attested by their presence in almost all patients with autoimmune polyendocrine syndrome type-1 (APS-1) due to germline mutations of AIRE [START_REF] Levin | Anti-interferon auto-antibodies in autoimmune polyendocrinopathy syndrome type 1[END_REF][START_REF] Meager | Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1[END_REF](19). Patients with APS-1 are at very high risk of developing severe or critical COVID-19 pneumonia [START_REF] Bastard | Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1[END_REF][START_REF] Meisel | Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1[END_REF]. These auto-Abs are also found in patients with combined immunodeficiency and hypomorphic mutations of RAG1 or RAG2 [START_REF] Walter | Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency[END_REF]; in men with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome and mutations of FOXP3 [START_REF] Rosenberg | Neutralizing anti-cytokine autoantibodies against interferon- in immunodysregulation polyendocrinopathy enteropathy X-linked[END_REF]; and in women with incontinentia pigmenti and heterozygous null mutations of X-linked NEMO (9). They are also seen in patients treated with IFN- or IFN- (24, 25) and in patients with systemic lupus erythematosus [START_REF] Panem | Antibodies to alpha-interferon in a patient with systemic lupus erythematosus[END_REF]27), thymoma [START_REF] Shiono | Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma cells from myasthenia gravis patients suggests autoimmunization in the tumor[END_REF], or with myasthenia gravis [START_REF] Bello-Rivero | Characterization of the immunoreactivity of anti-interferon alpha antibodies in myasthenia gravis patients. Epitope mapping[END_REF][START_REF] Meager | Anti-cytokine autoantibodies in autoimmunity: Preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis[END_REF]. Last, they underlie a third of adverse reactions to the 17D live-attenuated vaccine against yellow fever virus (YFV), further suggesting that they were present in these patients, as in patients with critical COVID-19, before viral infection [START_REF] Bastard | Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine[END_REF]. For all patients tested, the auto-Abs neutralized the protective effect of IFN-2 (~400 pg/ml) against SARS-CoV-2 or YFV-17D in vitro, even when the plasma was diluted by >1:1000 (9). Because blood IFN- concentrations during acute asymptomatic or paucisymptomatic SARS-CoV-2 infection typically range from 1 to 100 pg/ml (32,[START_REF] Trouillet-Assant | Type I IFN immunoprofiling in COVID-19 patients[END_REF] and IFN- levels in the respiratory tract might be even lower yet protective, we hypothesized that auto-Abs neutralizing concentrations of type I IFNs below 10 ng/ml may underlie life-threatening COVID-19 pneumonia in more than 10% of cases. We also hypothesized that the prevalence of auto-Abs against type I IFNs in the general, uninfected population may increase with age and that these antibodies may be more common in men than in women.

RESULTS

High and intermediate levels of IgG auto-Abs against IFN-2 and/or IFN- in ~20% of patients with critical COVID-19

We recruited a cohort of 3595 patients hospitalized with critical COVID-19 pneumonia [hereafter referred to as "critical patients" and defined as pneumonia in patients with critical disease, including (i) pulmonary, with high-flow oxygen (>6 liters/min) or mechanical ventilation (continuous positive airway pressure, bilevel positive airway pressure, and intubation), (ii) cardiovascular shock, or (iii) any other organ failure requiring admission to an intensive care unit], including 566 patients of our previously described cohort of 987 patients with critical COVID-19 pneumonia for whom residual samples were available (9), 623 individuals with severe COVID-19 pneumonia (with less than 6 liters/min of oxygen supplementation, hereafter referred to as "severe patients"), and 1639 individuals with asymptomatic or paucisymptomatic (mild) upper respiratory tract SARS-CoV-2 infection {the "controls," infected with SARS-CoV-2 [as demonstrated by a positive polymerase chain reaction (PCR) and/ or serological test and/or displaying typical manifestations, such as anosmia/ageusia after exposure to a confirmed COVID-19 case] who remained asymptomatic or developed mild, self-healing, ambulatory disease with no evidence of pneumonia}, including 427 samples from the initial control cohort of 663 individuals (9). The patients originated from 38 different countries, across all continents. We did not include patients with moderate pneumonia who did not receive oxygen therapy (7,9). We searched for auto-Abs against IFN-2 and IFN- by establishing novel, sensitive, and robust assays for the detection of circulating immunoglobulin G (IgG) auto-Abs. We used Gyros Technology [START_REF] Honda | Simultaneous multiple immunoassays in a compact disc-shaped microfluidic device based on centrifugal force[END_REF], a high-throughput automated enzymelinked immunosorbent assay (ELISA)-like assay capable of detecting a large range of auto-Ab levels (fig. S1A). We 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-2 and/or anti-IFN- auto-Abs on ELISA, as reported in our previous studies (defined as an optical density > 0.5), had high levels of auto-Abs when assessed with Gyros (defined as levels >100) (fig. S1B). We then screened newly recruited critical or severe patients and controls from our COVID-19 cohort (Fig. 1A). We found high levels of anti-IFN-2 and/or anti-IFN- auto-Abs in 6.9% of critical patients, 3.4% of patients with severe COVID-19, and only 0.6% of the asymptomatic or paucisymptomatic controls (Fig. 1A). We also found that another 12.7% of patients with critical COVID-19 had intermediate levels of anti-IFN-2 and/or anti-IFN- auto-Abs in Gyros assays (defined as levels >30 and <100, based on the distribution observed in healthy controls), whereas this was the case for 8.6% of patients with severe COVID-19 and 11% of the individuals in our control cohort. Collectively, these findings replicate and extend our previous results and those of other groups (9,[START_REF] Koning | Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients[END_REF](12)[START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF][START_REF] Goncalves | Antibodies against type-I Interferon: Detection and association with severe clinical outcome in COVID-19 patients[END_REF][START_REF] Wang | Diverse functional autoantibodies in patients with COVID-19[END_REF][START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF] while suggesting that intermediate levels of auto-Abs against type I IFNs might be neutralizing and underlie critical disease.

Auto-Abs neutralizing IFN-2 and/or IFN- (10 ng/ml) in almost 10% of the critical patients

We investigated the ability of these auto-Abs to neutralize high concentrations of type I IFNs, as defined in our previous reports [IFN-2 or IFN- (10 ng/ml) in medium containing 1:10 plasma or serum, the equivalent of IFN-2 or IFN- (100 ng/ml) in undiluted plasma]. We tested not only the patients with high levels of auto-Abs, as in our previous study (9), but also all the available patients with critical COVID-19 (N = 3136), or severe COVID-19 (N = 623), and controls (N = 1076) from our expanded cohort. We designed a high-throughput luciferase assay in which we transfected human embryonic kidney (HEK) 293 T cells with (i) a plasmid containing five IFN-stimulated response element (ISRE) repeats and a firefly luciferase reporter and (ii) a plasmid encoding the Renilla luciferase. We stimulated these cells with an individual recombinant type I IFN (IFN-2 or IFN-) in the presence of plasma diluted 1:10 (plasma 1:10) from patients or controls. We then measured firefly luciferase induction, normalized against Renilla luciferase activity (Fig. 1B). We confirmed the robustness of this assay by comparing the results with our previous phosphorylated signal transducer and activator of transcription 1 (pSTAT1) flow cytometry data (9). Consistent results were obtained for all 50 patients tested with both techniques

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(fig. S1, C andD). We then tested all patients and controls. Most plasma samples with high auto-Ab levels (>100) against IFN-2 according to the Gyros assay were neutralizing (fig. S1E). We found that 9.8% (307 of 3136) of the critical patients tested and that 3.53% (22 of 623) of the severe patients had auto-Abs neutralizing IFN-2 and/or IFN- versus only 0.37% (four of 1076) controls (Fig. 1C, Table 1, and table S1). In the patients with neutralizing auto-Abs, these auto-Abs were able to neutralize both IFN-2 and IFN- in 175 of the 307 critical patients (57%), six of the severe patients (27%), and none of the controls; IFN-2 alone in 106 critical patients (34.5%), 11 severe patients (50%), and only one of the controls (25%); and IFN- alone in 26 of critical patients (8.5%), five severe patients (22%), and three controls (75%) (table S1). None of the patients with these auto-Abs had inborn errors of TLR3-or TLR7-dependent type I IFN immunity (7,35).

Auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) in at least 13.6% of critical patients and 6.8% of severe patients Because the amounts of circulating type I IFNs in infected individuals are 100 to 1000 times lower than the amounts tested previously (32,[START_REF] Trouillet-Assant | Type I IFN immunoprofiling in COVID-19 patients[END_REF], we investigated the neutralization of more physiological concentrations of type I IFNs by performing assays with type I IFN (100 pg/ml). We observed a robust response in our luciferase system in the presence of 1:10 dilutions of control plasma (fig. S1F). The plasma or serum was diluted 1:10, so the concentration neutralized corresponds to IFN (1 ng/ml) in circulating whole blood. With diluted plasma samples from a positive control, we gained at least two orders of magnitude of sensitivity in terms of neutralizing activity, providing proof of concept that these auto-Abs can neutralize lower, more physiological, amounts of type I IFNs (Fig. 1D and fig. S1G), lower than the concentrations previously tested by a factor of 100 (9). We then retested all available samples from our extended cohort. Overall, 13.6% of all critical patients tested (N = 489 of 3595), 6.5% (N = 34 of 522) of the severe patients, and 1% of the controls (N = 17 of 1639) had circulating auto-Abs that neutralized IFN-2 and/or IFN- (100 pg/ml) in plasma 1:10 (Fig.

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patients (6%), and 12 controls (70%) (table S1). Further dilution of a plasma sample from one patient neutralizing type I IFNs (100 pg/ml) led to a loss of neutralizing activity (Fig. 1D and fig. S1G). For four unrelated patients, all of whom suffered from critical COVID-19, including one who died, samples collected before COVID-19 were available and tested positive for neutralizing auto-Abs against type I IFNs. One neutralized IFN-2 and IFN- at a concentration of 10 ng/ml, two neutralized both cytokines at 100 pg/ml, and one neutralized IFN- only at 100 pg/ml (fig. S1H). The four patients tested therefore had auto-Abs neutralizing IFN-2 and/or IFN- (10 ng/ml or 100 pg/ml) before infection with SARS-CoV-2. These four patients and another two reported in our previous study (9) all, therefore, had auto-Abs neutralizing type I IFNs before infection with SARS-CoV-2. We then assessed the risk, adjusted for age and sex, of having critical or severe disease for individuals carrying auto-Abs against each individual IFN and the different possible combinations. We found that all auto-Abs, except those neutralizing only IFN- at a concentration of 10 ng/ml, were highly significant risk factors in comparisons of patients with critical or severe COVID-19 with controls (Table 1 and table S2). The strongest association was with auto-Abs against both IFN-2 and IFN- neutralizing concentrations at 10 ng/ml [odds ratio (OR) = 67, P = 8 × 10 -13 ] and 100 pg/ml (OR = 54, P < 10 -13 ), followed by those against IFN-2 ± IFN- neutralizing concentrations at 10 ng/ml (OR = 45, P < 10 -13 ) and 100 pg/ml (OR = 23, P < 10 -13 ) (Table 1). Because the serum/plasma samples were diluted 1:10 in these assays, these findings suggest that more than 13.6% of patients with life-threatening COVID-19 have circulating auto-Abs neutralizing IFN-2 and/or IFN- (1 ng/ml) in vivo, a greater proportion than the 10% of patients with auto-Abs neutralizing 100 ng/ml reported in previous studies (9,[START_REF] Koning | Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients[END_REF](12)[START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF][START_REF] Goncalves | Antibodies against type-I Interferon: Detection and association with severe clinical outcome in COVID-19 patients[END_REF][START_REF] Wang | Diverse functional autoantibodies in patients with COVID-19[END_REF][START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF].

Auto-Abs neutralize low concentrations of IFN-2 protective against SARS-CoV-2

We previously reported that plasma diluted 1:100 from patients with auto-Abs against type I IFNs neutralized the ability of IFN-2 (at a concentration of 20 pM, about 400 pg/ml) to block SARS-CoV-2 and YFV-17D replication in Huh-7.5 cells (9,[START_REF] Bastard | Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine[END_REF]. This neutralization was seen in all patients tested, even for a 1000-fold dilution, and, in most patients, it was more potent than the neutralizing effect of a commercially available neutralizing monoclonal Ab (mAb) against IFN-2. These auto-Abs against type I IFNs were, therefore, able to neutralize IFN-2 at concentrations well beyond physiological levels. We therefore hypothesized that patients with lower titers of auto-Abs against type I IFNs, which can neutralize 100 pg/ml but not 10 ng/ml in plasma diluted 1:10, would also neutralize the protective effect of IFN-2 against SARS-CoV-2. We therefore performed our SARS-CoV-2 assay with 5 pM (~100 pg/ml) or 20 pM (~400 pg/ml) IFN-2 on five samples from patients with life-threatening COVID-19 and two samples from uninfected elderly individuals with auto-Abs neutralizing IFN-2 (100 pg/ml but not 10 ng/ml). As controls, we tested a commercial mAb against IFN-2, a sample from a patient with auto-Abs neutralizing IFN-2 (10 ng/ml), samples from three patients with life-threatening COVID-19, and three healthy controls without detectable auto-Abs against type I IFNs. We found that the 1:100 dilutions of plasma from four of the five patients with critical COVID-19 and one of the two elderly individuals with auto-Abs neutralizing IFN-2 (100 pg/ml) were able to neutralize the protective effect of IFN-2 (~400 pg/ml) against SARS-CoV-2, whereas samples from all these individuals fully or partially neutralized IFN-2 (~100 pg/ml) (Fig. 2A). No such neutralizing effect was observed for any of the auto-Ab-negative controls. Overall, our findings indicate that auto-Abs against type I IFNs capable of neutralizing IFN (100 pg/ml) in 1% plasma can block the protective effect of IFN-2 (~100 or ~400 pg/ml) against SARS-CoV-2. These findings raise the possibility that even 100-fold lower levels of auto-Abs against type I IFNs, capable of neutralizing lower, physiological concentrations of IFN-2 (10 pg/ml) may be present in an even larger proportion of patients. The testing of this hypothesis will require the development of new, more sensitive methods to screen for neutralization.

Neutralization of type I IFNs in the absence of detectable auto-Abs against IFN-2 or IFN-

The neutralization assays performed on all patients and controls revealed that some patients with neutralizing activity against IFN-2 and/or IFN- (10 ng/ml), as shown in luciferase assays, did not have high or even intermediate levels of IgG auto-Abs in Gyros assays (fig. S1E). We also observed that some patients with neutralizing auto-Abs had low or undetectable levels of auto-Abs in Luminex assays (fig. S1I). For these individuals, we assessed the prevalence of IgA and IgM auto-Abs against type I IFNs and found that none of the patients tested (N = 12) had detectable titers of IgA or IgM auto-Abs (fig. S1J). We then tested the alternative hypothesis that these auto-Abs were directed against the IFNAR1 or IFNAR2 chain of type I IFN receptors, assessing the ability of plasma samples from these patients to neutralize IFN-. None of the samples from these patients neutralized IFN-, suggesting that the auto-Abs in these patients were not directed against IFNAR1 or IFNAR2 (fig. S1K).

An alternative plausible hypothesis is that the epitope recognized by the auto-Abs might be concealed by the binding of the cytokine to the plate (ELISA), biotinylation of the cytokine (Gyros), or covalent coupling of the cytokine to magnetic beads at lysine residues (Luminex) (19). This observation has important clinical implications, suggesting that a lack of detection of auto-Abs against type I IFNs does not rule out the possibility of such antibodies being present and having neutralization capacity.

Auto-Abs typically neutralize the 13 IFN- subtypes and/or IFN-

In six patients with auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml but not 10 ng/ml), we tested the reactivity of the antibodies against the 17 type I IFNs (the 13 IFN- forms, IFN-, IFN-, IFN-, and IFN-). Similar to patients with auto-Abs neutralizing type I IFNs (10 ng/ml) (9), those capable of neutralizing only 100 pg/ml had detectable auto-Abs against most of the 13 IFN- forms and/or IFN-, albeit at lower levels (Fig. 2B). Of the six patients with auto-Abs against IFN- and/or IFN- tested, only one also had auto-Abs against IFN-, and none had detectable auto-Abs against IFN- or IFN-. Overall, the patients with auto-Abs against IFN-2 and/or IFN- capable of neutralizing IFN (100 pg/ ml) displayed patterns of reactivity to the 17 type I IFNs similar to those reported in previously described patients with auto-Abs neutralizing 10 ng/ml (9). We then set up an assay for assessing neutralization of the 13 IFN- forms using our luciferase-based assay. We tested two patients with auto-Abs neutralizing IFN-2 and IFN-, two patients with auto-Abs neutralizing only IFN-2, and two patients with auto-Abs neutralizing only IFN-. We found that the patient with APS-1 and the two patients with auto-Abs neutralizing IFN-2 and IFN- (10 ng/ml) were able to neutralize all 13 IFN- subtypes, as were the two patients with neutralizing auto-Abs against IFN-2. Conversely, in the conditions tested, the two patients with auto-Abs neutralizing IFN- only, but not IFN-2, were not able to neutralize any of the 13 IFN- subtypes (Fig. 2C). In addition, to confirm that the IgG auto-Abs detected were the cause of the neutralization activity observed, we performed an IgG depletion experiment and found that the removal of the IgG fraction abolished the neutralizing activity, whereas the purified IgG fraction had full neutralizing activity (fig. S2A). Thus, patients with neutralizing auto-Abs against only IFN- do not seem to neutralize any of the 13 IFN- subtypes, whereas patients with auto-Abs neutralizing IFN-2 neutralize all these subtypes.

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Auto-Abs neutralizing IFN- in 1.3% of critical patients We previously reported that auto-Abs neutralizing IFN- were detected in only two of 101 critical patients with auto-Abs neutralizing IFN-2 and/or IFN- (10 ng/ml) (9). Given the potential therapeutic use of IFN- [START_REF] Bastard | Interferon- therapy in a patient with incontinentia pigmenti and autoantibodies against type I IFNs infected with SARS-CoV-2[END_REF]37) and the absence of IFN- neutralization data for patients with COVID-19, we tested a larger number of patients and controls, including patients without auto-Abs against IFN- or IFN-, for auto-Abs against IFN-, assessing the levels and neutralizing activity of auto-Abs against IFN- (10 ng/ml). We screened 1773 patients with critical COVID-19 pneumonia and found that 1.3% (N = 23) had neutralizing auto-Abs against IFN-; by contrast, such antibodies were present in none of the 187 severe patients tested and in only two of the 1044 controls tested (0.18%) (Fig. 2D, fig. S2B, and table S3). Only 6 of the 23 (21.7%) critical patients also had auto-Abs neutralizing IFN-2 and/or IFN- at 100 pg/ml, and none of the controls had such antibodies. Five of these six patients had auto-Abs neutralizing all three cytokines. All the other critical patients and controls had only neutralizing auto-Abs against IFN-.

The presence of neutralizing auto-Abs against IFN- was significantly associated with critical, but not severe, disease relative to the controls (Table 1 and tables S2 and S3). Gyros did not appear to be able to detect auto-Abs against IFN-, perhaps because of the biotinylation of the cytokine hiding the epitope recognized by the auto-Abs.

Because most (78.3%) of the patients with neutralizing auto-Abs against IFN- did not have neutralizing auto-Abs against IFN-2 or IFN-, this suggests that auto-Abs against IFN- alone may also underlie life-threatening COVID-19 (Table 1).

Neutralizing auto-Abs against type I IFNs in at least 20% of critical patients over 80 years of age

We further assessed the percentage of patients with critical COVID-19 positive for neutralizing auto-Abs per decade of life and by sex (Fig. 3, A to J; fig. S3,A to W; and tables S1 to S4). In our previous report, we found that patients with critical COVID-19 with auto-Abs neutralizing IFN-2 or IFN- at 10 ng/ml were older (more than half the patients with auto-Abs were over the age of 65 years) and more likely to be male (95% of the antibody carriers were men) (9). These results have been confirmed by other groups, albeit with a smaller proportion of men [START_REF] Koning | Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients[END_REF](12)[START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF][START_REF] Goncalves | Antibodies against type-I Interferon: Detection and association with severe clinical outcome in COVID-19 patients[END_REF][START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF]. In our expanded cohort of patients with critical COVID-19 pneumonia (N = 3595), the mean age was 61 years, and 73% of the patients were men (Fig. 3A and table S4). We confirmed that critical patients with auto S3, T to W) and sex (Firth's multivariable logistic regression, P = 0.44). Similar results were obtained for patients with critical COVID-19 with auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) but with even higher proportions (Fig. 3, G to J, and fig. S3, L to S) (table S1). The proportion of patients with auto-Abs ranged from 9.6% of patients below the age of 40 years to more than 21% of those over 80 (Fig. 3, G to J, and fig. S3, L to S). In men, the proportion of patients with critical COVID-19 carrying auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) increased up to 23% over 80 years of age. A very different pattern was seen for auto-Abs neutralizing IFN- (10 ng/ml), with a more stable proportion of auto-Abs carriers according to age (Firth's multivariable logistic regression, P = 0.68; fig. S3, J and K) (table S3). Overall, the prevalence of auto-Abs neutralizing IFN-2 and/or IFN- (10 ng/ml and/or 100 pg/ml) increased sharply with age in critical patients. A notable enrichment in patients with neutralizing auto-Abs against IFN-2 and/or IFN- was observed in the elderly, with more than 20% of patients and 23% of men, over the age of 80 years with critical COVID-19 having neutralizing auto-Abs against these type I IFNs.

Neutralizing auto-Abs against type I IFNs in at least 18% of deceased patients

The prevalence of auto-Abs against type I IFNs in patients dying from COVID-19 pneumonia is unknown. For the 3595 patients with critical COVID-19, we analyzed data for the 1124 who died. These patients were aged 20 days to 99 years (mean age: 71 years), 73% were male, and all had confirmed SARS-CoV-2 infection and critical COVID-19 pneumonia before death (Fig. 4A). In these patients, we analyzed the presence of neutralizing auto-Abs against type I IFNs at concentrations of 10 ng/ml and 100 pg/ml for IFN-2 and IFN-, respectively, and at 10 ng/ml for IFN- (Fig. 4, B to J, and fig. S4, A to K). We found that 13.3% of the deceased patients carried auto-Abs neutralizing IFN-2 and/or IFN- (10 ng/ml) (Fig. 4, B to F, and fig. S4, A to E). A total of 18.5% carried auto-Abs neutralizing 100 pg/ml of either or both cytokines (Fig. 4, G to J, and fig. S4, F to I). In addition, 0.9% had auto-Abs neutralizing IFN- (fig. S4, J andK). An analysis of the prevalence of neutralizing auto-Abs against type I IFNs in these patients who died of COVID-19 by decade of age revealed a moderate increase with age for auto-Abs neutralizing 10 ng/ml (Firth's multivariable logistic regression, P = 0.03) or 100 pg/ml (Firth's multivariable logistic regression, P = 0.01) (tables S1 and S2). For a type I IFN concentration (100 pg/ ml), the prevalence of auto-Abs neutralizing IFN-2 and/or IFN- was 20% below the age of 40 years, 14% for individuals between 40 and 49 years old, 12.5% for those between 50 and 60 years old, 16.3% for those between 60 and 69 years old, 17.9% for those between 70 and 79 years old, and greater than 23% for those over the age of 80 years. Overall, at least 18% of patients dying from COVID-19 pneumonia have auto-Abs capable of neutralizing type I IFNs (100 pg/ml) in plasma 1:10.

Auto-Abs capable of neutralizing IFN-2 and/or IFN- at 10 ng/ml in 0.53% and at 100 pg/ml in 2.3% of individuals from the general population

We previously tested a sample of 1227 individuals aged 20 to 65 years from the general population collected in 2015-2017. This sample had an equal sex distribution, and we identified four individuals with auto-Abs against type I IFNs among the 1227 tested (0.3%), suggesting that the auto-Abs predated COVID-19 (9). These findings were replicated at the University of California, San Francisco in a sample of 4041 individuals aged 4 to 90 years (0.32%) [START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF]. In the current study, we tested a much larger cohort of 34,159 individuals on the samples collected in 2019 and included only the individuals who had not been infected with SARS-CoV-2 in the sample. We used Gyros to screen this whole cohort for IgG auto-Abs against IFN-2 and IFN- (Fig. 5B and fig. S5A). We did not measure auto-Abs against IFN- by Gyros. We found that only 0.05 and 4.2% had anti-IFN-2 and/or anti-IFN- auto-Abs above the thresholds of 100 and 30, respectively (Fig. 5B and fig. S5A). We then assessed the ability of these antibodies to neutralize IFN-2 or IFN- (10 ng/ml) for all individuals with a high or intermediate level of IgG auto-Abs against IFN-2 or IFN-. We found 181 individuals with neutralizing auto-Abs, for whom 1:10 dilutions of plasma neutralized IFN-2

and/or IFN- (10 ng/ml), giving an overall prevalence of 0.53% (Fig. 5, C to F, and fig. S5, B to I) (table S5 and S6), consistent with our two previous reports (9,[START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF]. We may have slightly underestimated the number of positive individuals, because some may have had neutralizing auto-Abs at too low a titer for detection. Next, we assessed the prevalence of auto-Abs neutralizing IFN- (10 ng/ml) in 9583 individuals and found an overall prevalence of 0.26% (Fig. 5, G and H and table S5 andS6). Last, for a subset of 10,778 samples, we further assessed the ability of serum/plasma samples (diluted 1:10) to neutralize IFN-2 and/or IFN- (100 pg/ml) in the luciferase assay (Figs. 5, I and J, and 6, A to H). The prevalence of

A B D C F E H G

Fig. 6. Neutralizing auto-Abs against IFN-2 and/or IFN- at 100 pg/ml are more prevalent in the elderly, in the general population. (A to H) Proportion, binned every 5 years, of individuals from the general population and positive for neutralizing auto-Abs (in plasma 1:10) against (A) IFN-2 and/or IFN-, at 100 pg/ml, for both sexes. (B) IFN-2 and/or IFN-, at 100 pg/ml, for men or women. (C) IFN-2 and IFN-, at 100 pg/ml, for both sexes. (D) IFN-2 and IFN-, at 100 pg/ml, for or women. (E) IFN-2, at 100 pg/ml, for both sexes. (F) at 100 pg/ml, for men or women. (G) IFN-, at 100 pg/ml, for both sexes. (H) IFN-, at 100 pg/ml, for men or women. Downloaded from https://www.science.org September 29, 2021 auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) was 2.3% (table S1).

Sharp increase in the prevalence of auto-Abs against IFN-2 and/or IFN- after the age of 70 years in the general population

We then assessed the percentage of individuals from the general population positive for neutralizing auto-Abs per decade of life and by sex. We noted that the prevalence of auto-Abs neutralizing type I IFN (10 ng/ml) was more than 10 times higher in individuals over the age of 70 years than in those below this age (Firth's multivariable logistic regression, P < 10 -13 ) (Fig. 5, C to F; fig. S5,B to I; and tables S5 and S6). The prevalence of auto-Abs capable of neutralizing IFN-2 and/or IFN- (10 ng/ml) was 0.17% in individuals below 70 years of age, 0.9% in individuals between 70 and 75 years of age, 1.6% between the ages of 75 and 80 years, and more than 4% between the ages of 80 and 85 years. After 85 years, the prevalence of these antibodies decreased to about 2.6%. These findings were replicated independently in two cohorts of 703 and 376 elderly individuals from Estonia and Japan, tested with luciferase-based immunoprecipitation (IP) assay (LIPS) and ELISA assays, respectively (fig. S5, J andK). A strong increase in the prevalence of auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) was observed with age (Fig. 6, A to H, and fig. S6,A to D), with the prevalence almost doubling with every 5 years from 65 to 85 years of age. A total of 0.87% of individuals between the ages of 65 and 70 years, 1.73% of those between 70 and 75 years, and 7.1% of those between 75 and 80 years were positive for auto-Abs. There was an overall decrease in the prevalence of auto-Abs after 85 years of age, especially in men. By contrast, the prevalence of auto-Abs neutralizing IFN- did not vary significantly with age (Fig. 5, G and H, and table S4). We then assessed the risk, adjusted for age and sex, of having critical or severe disease, for individuals carrying auto-Abs against each individual IFN and the different possible combinations, relative to the general population. We also found that all auto-Abs were highly significant risk factors in comparisons of patients with critical or severe COVID-19 with the general population (Table 1 and table S2). The strongest association was again that for auto-Abs neutralizing both IFN-2 and IFN- at 10 ng/ml (OR = 30, P < 1 × 10 -13 ), followed by those neutralizing IFN-2 ± IFN- at 10 ng/ml (OR = 20, P < 10 -13 ) and IFN- ± IFN-2 at 10 ng/ml (OR = 15, P < 10 -13 ) (Table 1). Auto-Abs neutralizing both IFN-2 and IFN- at 100 pg/ml were also highly significant risk factors (OR [95% confidence interval (CI)] = 12 [9 to 16], P < 10 -13 ) (Table 1). Overall, these findings indicate that there is a sharp increase in the prevalence of auto-Abs neutralizing type I IFNs with age in elderly uninfected individuals, with at least 4% of those over the age of 70 years positive for auto-Abs against IFN-2 and/or IFN-, and that these auto-Abs predate COVID-19.

DISCUSSION

We report that at least 20% of patients over 80 years of age with life-threatening COVID-19 pneumonia carry circulating auto-Abs neutralizing IFN-2 and/or IFN- (100 pg/ml) and that such antibodies are present in more than 13.6% of patients of all ages with this condition. Some of these auto-Abs are not identified by immunoassays and are only detectable by a neutralization assay. In addition, at least 18% of deceased individuals in most age groups were found to have such auto-Abs. We also report that auto-Abs against IFN- are found in about 1.3 and 0.9% of critical and deceased patients, most of whom do not have auto-Abs against IFN-2 and/or IFN-. In all four patients tested for whom pre-COVID-19 samples were also available, the auto-Abs against IFN-2 and/or IFN- were clearly present before SARS-CoV-2 infection, as in patients with APS-1 (9,[START_REF] Bastard | Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1[END_REF] and in two other previously described patients (9). Auto-Abs capable of neutralizing high concentrations of type I IFNs have been found in patients without inborn errors of TLR3-or TLR7dependent type I IFN immunity (7,35), suggesting that both inborn errors and auto-Abs are independently causal of critical disease. It is also notable that inborn errors are more common in patients under the age of 60 years, whereas auto-Abs are more common in patients over the age of 70 years. We also report that the prevalence of auto-Abs neutralizing (10 ng/ml and 100 pg/ml) type I IFNs, except for IFN-, increases significantly with age in the general population, with 0.17% (1.1%) of individuals positive for these antibodies before the age of 70 years and more than 1.4% (4.4%) positive after the age of 70 years, with a prevalence of 4.2% (7.1%) between the ages of 80 and 85 years.

These auto-Abs provide an explanation for the major increase in the risk of critical COVID-19 in the elderly. This increase with age is consistent with studies of various auto-Abs since the 1960s [START_REF] Hooper | Autoimmunity in a rural community[END_REF][START_REF] Shu | Incidence and titers of antinuclear, antismooth muscle, and other autoantibodies in blood donors[END_REF][START_REF] Potocka-Płazak | Prevalence of autoantibodies in serum of healthy persons over 85 years of age[END_REF][START_REF] Parks | Reproductive and hormonal risk factors for antinuclear antibodies (ANA) in a representative sample of U.S. women[END_REF][START_REF] Myasoedova | Is the epidemiology of rheumatoid arthritis changing? Results from a population-based incidence study, 1985-2014[END_REF]. These auto-Abs appear to have remained clinically silent in these individuals until SARS-CoV-2 infection. Our results also suggest that the neutralization of only one type I IFN (IFN-2, IFN-, or IFN-) can underlie life-threatening COVID-19 (Table 1 and tables S1 to S3). Auto-Abs neutralizing IFN- (10 ng/ml) have a frequency only about one-tenth that of auto-Abs neutralizing the same concentrations of IFN-2 and/or IFN- (Table 1 and table S3). We have shown that auto-Abs neutralizing type I IFN (100 pg/ml) in plasma diluted 1:10, corresponding to the neutralization of IFN (1 ng/ml) in vivo, can account for at least 18% of deaths and more than 20% of critical cases in the elderly >80 years of age. It is tempting to speculate that an even greater proportion of life-threatening COVID-19 cases are due to auto-Abs neutralizing lower, physiological concentrations of type I IFNs. In vitro, concentrations of type I IFN as low as 100 pg/ml can impair SARS-CoV-2 replication in epithelial cells (Fig. 2A). Moreover, the levels of type I IFN detected in the blood of patients with acute and benign SARS-CoV-2 infections are in the range of 1 to 100 pg/ml (32,[START_REF] Trouillet-Assant | Type I IFN immunoprofiling in COVID-19 patients[END_REF].

Our findings have immediate clinical applications. First, it is quick and easy to test for auto-Abs against type I IFNs in patients infected with SARS-CoV-2. Screening for these antibodies is even possible in the general population before infection. The type I IFN-neutralizing activity of these antibodies is a better readout than their mere detection, which can be falsely negative. Tests should be performed for auto-Abs against at least three individual IFNs: IFN-2, IFN-, and IFN-. Particular attention should be paid to elderly individuals and patients with known autoimmune or genetic conditions associated with auto-Abs against type I IFNs (17-20, 22, 23, 26-29). Second, patients with auto-Abs against type I IFN should be vaccinated against COVID-19 as a priority. Third, live-attenuated vaccines, including YFV-17D and vaccines using the YFV-17D backbone against SARS-CoV-2, should not be given to patients with auto-Abs [START_REF] Bastard | Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine[END_REF][START_REF] Sanchez-Felipe | A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate[END_REF]. Fourth, these patients appeared to be healthy before SARS-CoV-2 infection, but they should also be carefully followed for other viral illnesses as exemplified by adverse reactions to YFV-17D [START_REF] Bastard | Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine[END_REF] against type I IFNs, the patients should be hospitalized for prompt management. Early treatment with mAbs [START_REF] Chen | BLAZE-1 Investigators, SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19[END_REF][START_REF] Weinreich | Trial Investigators, REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19[END_REF] can be administered in patients without symptoms of severe COVID-19 pneumonia, and IFN- can be administered in the absence of both pneumonia and auto-Abs against IFN- (36, 37). Rescue treatment by plasma exchange is another therapeutic option in patients who already have pneumonia [START_REF] De Prost | Plasma exchange to rescue patients with autoantibodies against type I interferons and life-threatening COVID-19 pneumonia[END_REF].

Sixth, blood products, especially plasma, should be screened for anti-IFN auto-Abs and any products containing such antibodies should be excluded from donation [START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF]. Plasma from donors convalescing from COVID-19 should be tested for such auto-Abs [START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF]. Seventh, given the documented innocuity and potential efficacy of a single injection, early therapy with IFN- may be considered for the contacts of contagious individuals or during the first week after infection, even in the absence of, or before the documentation of auto-Abs against type I IFNs in elderly patients who have a higher risk of critical pneumonia and auto-Abs against IFN-2 and IFN- but not IFN- [START_REF] Vinh | Harnessing type I IFN immunity against SARS-CoV-2 with early administration of IFN-[END_REF]. Another possibility would be the administration of mAbs that can neutralize SARS-CoV-2 [START_REF] Chen | BLAZE-1 Investigators, SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19[END_REF][START_REF] Weinreich | Trial Investigators, REGN-COV2, a neutralizing antibody cocktail, in outpatients with Covid-19[END_REF]. Last, it will be important to decipher the mechanism underlying the development of these auto-Abs, which may differ in patients over and under 65 years of age. Overall, our findings show that auto-Abs neutralizing concentrations of type I IFN lower than previously reported (9,[START_REF] Koning | Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients[END_REF](12)[START_REF] Vazquez | Neutralizing autoantibodies to type I interferons in COVID-19 convalescent donor plasma[END_REF][START_REF] Goncalves | Antibodies against type-I Interferon: Detection and association with severe clinical outcome in COVID-19 patients[END_REF][START_REF] Wang | Diverse functional autoantibodies in patients with COVID-19[END_REF][START_REF] Van Der Wijst | Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19[END_REF], but still higher than physiological concentrations, are common in the elderly population. Their prevalence increases with age in the uninfected general population, reaching more than 4% of individuals after the age of 70 years. They underlie about 20% of cases of critical COVID-19 pneumonia in patients over the age of 80 years and about 20% of total COVID-19 deaths. We previously reported that they can underlie severe adverse reactions to the live-attenuated vaccine against YFV [START_REF] Bastard | Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine[END_REF]. It is tempting to speculate that they may also underlie other severe viral diseases, especially in the elderly.

MATERIALS AND METHODS

Study design

We enrolled, from 38 countries across all continents, 3595 patients with proven critical COVID-19, 623 with severe COVID-19, 1639 asymptomatic or individuals with proven COVID-19, and 34,159 healthy controls in this study. We collected plasma or serum samples for all these individuals to test by immunoassay for the presence of IgG auto-Abs to type I IFNs. All individuals were recruited according to protocols approved by local Institutional Review Boards (IRBs).

COVID-19 classification

The severity of COVID-19 was assessed for each patient as follows (7,9): "Critical COVID-19 pneumonia" was defined as pneumonia developing in patients with critical disease, whether pulmonary, with high-flow oxygen, mechanical (continuous positive airway pressure, bilevel positive airway pressure, and intubation), septic shock, or with damage to any other organ requiring admission to the intensive care unit. "Severe COVID-19" was defined as pneumonia developing in patients requiring low-flow oxygen (<6 liters/min). The controls were individuals infected with SARS-CoV-2 (as demonstrated by a positive and/or serological test and/or typical symptoms, such as anosmia/ageusia after exposure to a confirmed COVID-19 who remained asymptomatic or developed mild, self-healing, ambulatory disease with no evidence of pneumonia.

Detection of anti-cytokine auto-Abs Gyros

Cytokines, recombinant human (rh)IFN-2 (Miltenyi Biotec, reference number 130-108-984) or rhIFN- (Merck, reference number SRP3061), were first biotinylated with EZ-Link Sulfo-NHS-LC-Biotin Scientific, catalog number A39257), according to the manufacturer's instructions, with a biotin-to-protein ratio of 1:12. The detection reagent contained a secondary antibody [Alexa Fluor 647 goat anti-human IgG (Thermo Fisher Scientific, reference A21445)] diluted in Rexxip F (Gyros Protein Technologies, reference number P0004825; 1:500 dilution of the 2 mg/ml stock to yield a final concentration of 4 g/ml). Buffer phosphate-buffered saline, Tween 20 (PBS-T) and Gyros Wash (Gyros Technologies, reference number P0020087) were prepared according to the manufacturer's instructions. Plasma or serum samples were then diluted 1:100 in 0.01% PBS-T and tested with the Bioaffy 1000 CD (Gyros Protein Technologies, reference number P0004253) and the Gyrolab xPand (Gyros Technologies, reference P0020520). cycles were performed in 20% ethanol.

Multiplex particle-based assay

Serum/plasma samples for auto-Abs against IFN-2 and IFN- in multiplex assay in which magnetic beads with differential fluorescence were covalently coupled to recombinant human proteins (2.5 g per reaction). Beads were combined and incubated with 1:100 diluted serum/plasma samples 30 min. Each sample was tested once. The beads were then washed and with phycoerythrin goat anti-human IgG g/ml) for an additional 30 min. They were washed again and used for a multiplex assay a Bio-Plex instrument. Enzyme-linked assays ELISA was performed previously described. 96-well ELISA plates Thermo Fisher Scientific) were coated by incubation overnight at 4°C with rhIFN-2 (2 g/ml; Miltenyi Biotec, reference number 130-108-984) and rhIFN- (Merck, reference number SRP3061). Plates were then washed (PBS, 0.005% 20), blocked by incubation with 5% nonfat milk powder in the buffer, washed, and incubated with 1:50 dilutions of from the patients or controls for 2 hours at room with specific mAbs as positive controls). Each sample was tested once.

were thoroughly washed. Horseradish peroxidase-conjugated Fc-specific IgG fractions from polyclonal goat antiserum against human IgG, IgM, or IgA (Nordic Immunological were added to a final concentration of 2 g/ml. Plates were incubated for 1 hour at temperature and Substrate was added, the density was measured. A similar protocol was used test for antibodies against 12 subtypes of IFN-, except that the plates were coated with cytokines from PBL Assay Science (catalog no. 11002-1), or IFN- (Miltenyi Biotech, reference number 130-107-888).

Functional evaluation of anti-cytokine auto-Abs

Luciferase reporter assays

The blocking activity of anti-IFN-2 and anti-IFN- auto-Abs was determined with a reporter luciferase activity. Briefly, HEK293T cells were transfected with a plasmid containing the firefly luciferase gene under the control of the human ISRE promoter in the pGL4.45 backbone and a plasmid constitutively expressing Renilla luciferase for normalization (pRL-SV40). Cells were transfected in the presence of the X-tremeGENE9 transfection reagent (Sigma-Aldrich, reference Downloaded from https://www.science.org on September 29, 2021 number 6365779001) for 24 hours. Cells in Dulbecco's modified Eagle medium (DMEM; Thermo Fisher Scientific) supplemented with 2% fetal calf serum and 10% healthy control or patient serum/plasma (after inactivation at 56°C for 20 min) were either left unstimulated or were stimulated with IFN-2 (Miltenyi Biotec, reference number 130-108-984) and IFN- (Merck, reference number SRP3061) at 10 ng/ml or 100 pg/ml or IFN- (Miltenyi Biotech, reference number 130-107-888) at 10 ng/ml for 16 hours at 37°C. Each sample was tested once for each cytokine and dose. Last, cells were lysed for 20 min at room temperature, and luciferase levels were measured with the Dual-Luciferase Reporter 1000 Assay System (Promega, reference number E1980) according to the manufacturer's protocol. Luminescence intensity was measured with a VICTOR-X Multilabel Plate (PerkinElmer Life Sciences, USA). Firefly luciferase values were normalized against Renilla luciferase activity values. These were then normalized against the median induction for nonneutralizing samples and expressed as a percentage. Samples were considered neutralizing if luciferase induction, normalized against Renilla luciferase activity, was below 15% of the median values for controls tested the same day. A similar protocol was used to test for auto-Abs against 12 subtypes of IFN-, except that we used cytokines from PBL Assay Science (catalog no. 11002-1) at 1 ng/ml for stimulation.

pSTAT1 induction in PBMC

The blocking activity of anti-IFN-2 and anti-IFN- auto-Abs was determined by assessing STAT1 phosphorylation in healthy control cells after stimulation with the appropriate cytokines in the presence of 10% healthy control or patient serum/plasma. Surface-stained healthy control peripheral blood mononuclear cells (PBMCs) (350,000 per reaction) were cultured in serum-free RPMI 1640 medium with 10% healthy control or patient serum/plasma and were either left unstimulated or were stimulated with IFN-2 or IFN- (10 ng/ml) for 15 min at 37°C. Each sample was tested once. Cells were fixed, permeabilized, and stained for intranuclear p STAT1 (Y701). Cells were acquired on a BD LSRFortessa cytometer with gating on CD14 + monocytes, and the data were analyzed with FlowJo software.

Luciferase-based immunoprecipitation assay

Levels of auto-Abs against IFN- subtypes were measured in LIPS, as previously described (9). IFNA1, IFNA2, IFNA8, and IFNA21 sequences were inserted into a modified pPK-CMV-F4 fusion vector (PromoCell GmbH, Germany), in which the firefly luciferase replaced the NanoLuc luciferase (Promega, USA). The resulting constructs were used to transfect HEK293 cells, and the IFNAluciferase fusion proteins were collected in the tissue culture supernatant. For auto-Ab screening, we combined 2 × 10 6 luminescence units (LU) of IFNA1, IFNA2, IFNA8, and IFNA21 in a single IP reaction mixture (pool 1) and IFNA4, IFNA5, IFNA6, and IFNA7 in another IP reaction mixture (pool 2). Serum samples were incubated with Protein G agarose beads (Exalpha Biologicals, USA) at room temperature for 1 hour in a 96-well microfilter plate (Merck Millipore, Germany), and we then added 2 × 10 6 LU of antigen and incubated for another hour. Each sample was tested once. The plate was washed with a vacuum system, and Nano-Glo Luciferase Assay Reagent (Promega, USA) was added. Luminescence intensity was measured with a VICTOR X Multilabel Plate Reader (PerkinElmer Life Sciences, USA). The results are expressed in arbitrary units as a fold-difference relative to the mean of the negative control samples.

IgG purification

We demonstrated that the IFN-2-or IFN--neutralizing activity observed was due to auto-Abs and not another plasma factor by depleting IgG from the plasma with a protein G buffer (Pierce Protein G IgG Binding Buffer, 21011) and column (NAb Protein G Spin Columns, 89953). All buffers were homemade: 0.1 M glycine (pH 2.7) and 1.5 M tris (pH 8). Total plasma was loaded onto the column. Each sample was tested once. Purified IgG were then concentrated [Pierce Protein Concentrators polyethersulfone (PES), 50K molecular weight cut-off (MWCO), 88504]. Without eluting the IgG, the flow-through fraction (IgG depleted) was then collected and compared to total plasma in the luciferase neutralization assay.

Statistical analysis

OR and P values for the effect of auto-Abs neutralizing each type I IFN on critical or severe COVID-19, using asymptomatic/mild patients or the general population as controls and adjusted on age in years and sex, were estimated by means of Firth's bias-corrected logistic regression [START_REF] Firth | Bias reduction of maximum likelihood estimates[END_REF][START_REF] Heinze | A solution to the problem of separation in logistic regression[END_REF] as implemented in the "logistf" R package (https://rdrr.io/cran/logistf/). Effect of age (quantitative in years or binary ± 65 years) and sex on the presence of neutralizing auto-Abs in each cohort (critical, severe, deceased, and general population) was tested by multivariable Firth's bias-corrected logistic regression. The SE of the prevalence of neutralizing auto-Abs to each type I IFN per age groups and sex was estimated using the Agresti-Coull approximation (50).

Schematic representation

Schematic representations (Fig. 1B) were created with BioRender.com.

SARS-CoV-2 experiment

SARS-CoV-2 strain USA-WA1/2020 was obtained from BEI Resources and amplified in Caco-2 cells at 37°C. Viral titers were measured on Huh-7.5 hepatoma cells in a standard plaque assay. Caco-2 (Homo sapiens, sex: male, colon epithelial) and Huh-7.5 cells (H. sapiens, sex: male, liver epithelial) were cultured in DMEM supplemented with 1% nonessential amino acids and 10% fetal bovine serum at 37°C under an atmosphere containing 5% CO 2 . Both cell lines have been tested negative for contamination with mycoplasma. SARS-CoV-2 experiments were performed as follows: Huh-7.5 cells were used to seed 96-well plates at a density of 7.5 × 10 3 cells per well. The following day, plasma samples or a commercial anti-IFN-2 antibody (catalog number 21100-1; R&D Systems) was diluted to 1% and incubated with 5 pM (~100 pg/ml) or 20 pM (~400 pg/ml) recombinant IFN-2 (catalog number 11101-2, R&D systems) for 1 hour at 37°C (dilutions: plasma samples = 1:100 and anti-IFN-2 antibody = 1:1000). Molar ratio was calculated according to the manufacturer's datasheet and with http://molbiol.ru/eng/scripts/01_04. html. After this incubation period, the cell culture medium was removed from the 96-well plates by aspiration and replaced with the plasma/anti-IFN-2 antibody and IFN-2 mixture. Each sample was tested once in triplicate. The plates were incubated overnight, and the plasma/anti-IFN-2 antibody plus IFN-2 mixture was removed by aspiration. The cells were washed once with PBS to remove potential anti-SARS-CoV-2-neutralizing antibodies, and fresh medium was then added. Cells were then infected with SARS-CoV-2 by directly adding the virus to the wells. Cells infected at a multiplicity of infection of 0.05 plaque-forming units per cell and incubated at 33°C for 48 hours. The cells were fixed with 7% formaldehyde, stained for SARS-CoV-2 with an anti-N antibody (catalog no. GTX135357, GeneTex), imaged, and analyzed as previously described (9).

SUPPLEMENTARY MATERIALS

www.science.org/doi/10.1126/sciimmunol.abl4340 Materials and Methods Figs. S1 to S6 Tables S1 to S6 View/request a protocol for this paper from Bio-protocol.

Fig. 1 .

 1 Fig. 1. Neutralizing auto-Abs against IFN-2 and/or IFN- in patients with life-threatening COVID-19. (A) Gyros (high-throughput automated ELISA) results for auto-Abs against IFN-2 and/or IFN- in patients with critical COVID-19 (N = 2240), severe COVID-19 (N = 500), or asymptomatic/mild SARS-CoV-2 infection (N = 663).(B) Schematic representation of the neutralization assay developed in HEK293T cells using a luciferase system. ISRE, interferon (IFN)-sensitive response elements. (C) Results for the neutralization of IFN-2 or IFN- (10 ng/ml) in the presence of plasma 1:10 from patients with critical COVID-19 (N = 3136), severe COVID-19 (N = 623), or controls with mild/asymptomatic infection (N = 1076). Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against Renilla luciferase activity) after stimulation with IFN-2 or IFN- (10 ng/ml) in the presence of plasma 1:10. RLA, relative luciferase activity. (D) RLA after stimulation with IFN-2 at a concentration of 10 ng/ml or 100 pg/ml, with various dilutions of plasma from a positive control (from 1:10 to 1:10 7 ) neutralizing 10 ng/ml of type I IFNs (AAB + pt, 10 ng/ml), a patient neutralizing type I IFNs (100 pg/ml) but not 10 ng/ml (AAB + pt, 100 pg/ml), and a healthy control (HC). AAB, auto-Ab. Pt, patient. (E) Neutralization IFN-2 or IFN- (100 pg/ml) in the presence of plasma 1:10 from patients with critical COVID-19 (N = 3595), severe COVID-19 (N = 522), or controls with asymptomatic/mild infection (N = 1639). (F) Plot showing luciferase induction after stimulation with IFN-2 (10 ng/ml or 100 pg/ml), in the presence of plasma from patients with critical COVID-19. Dotted lines indicate neutralizing levels, defined as induction levels below 15% of the mean value for controls tested the same day. Patients with auto-Abs neutralizing both IFN-2 (10 ng/ml and 100 pg/ml) are shown in the bottom left corner, whereas the patients in the bottom right corner had auto-Abs capable of neutralizing only IFN-2 (100 pg/ml). (G) Plot showing luciferase induction after stimulation with IFN- (10 ng/ml or 100 pg/ml) for patients with critical COVID-19.

Fig. 2 .Fig. 3 .

 23 Fig. 2. Enhanced SARS-CoV-2 replication, despite the presence of IFN-2, in the presence of plasma from patients with auto-Abs neutralizing IFN-2(100 pg/ml). (A) SARS-CoV-2 replication in Huh-7.5 cells untreated (in dark blue) or treated with IFN-2 (~100 or ~400 pg/ml) in the presence of 1:100 plasma from healthy controls without auto-Abs (N = 3, in blue), from patients with life-threatening COVID-19 but without auto-Abs against IFN-2 (N = 3, in black), a commercial anti-IFN-2 antibody (mAb; in red); from a patient with life-threatening COVID-19 and auto-Abs neutralizing IFN-2 (10 ng/ml) in plasma 1:100 (COVID-19 AAB + ; N = 1, in orange), from patients with life-threatening COVID-19 and auto-Abs neutralizing IFN-2 (100 pg/ml) in plasma 1:100 (N = 5, in gray); and from elderly individuals with auto-Abs neutralizing IFN-2 (100 pg/ml) in plasma 1:100 (N = 2, in purple). Each dot represents a technical replicate. All experiments were done in triplicate. (B) ELISA for auto-Abs against the 13 IFN- forms, IFN-, IFN-, IFN-, and IFN- in patients with life-threatening COVID-19 and auto-Abs neutralizing IFN-2 (100 pg/ml) (N = 6), patient with APS-1 with life-threatening COVID-19 and auto-Abs neutralizing IFN-2 and IFN- (10 ng/ml) (N = 1), and healthy controls (N = 2). (C) RLA after stimulation with the all individual IFN- at a concentration of 1 ng/ml, with 1:10 plasma from a healthy control (negative control), a patient with APS-1 (positive control), and patients with life-threatening COVID-19 and neutralizing IFN-2 and/or IFN- or a mAb anti-IFN-2. (D) Neutralization of IFN- (10 ng/ml) in the presence of plasma 1:10 from patients with critical COVID-19 (N = 1773), severe COVID-19 (N = 187), or asymptomatic/mild controls (N = 1044). Downloaded from https://www.science.org on[START_REF]L'Hospitalet de Llobregat[END_REF]

11 of 26 aged 20 Fig. 4 .Fig. 5 .

 11262045 Fig. 4. Higher prevalence of neutralizing auto-Abs against type I IFNs in patients who died of COVID-19. (A) Bar plot of the age and sex distribution of the patients who died of COVID-19 included in our cohort (N = 1124). (B) Graph showing the anti-IFN-2 auto-Ab levels, assessed by Gyros, in patients who died of COVID-19. Men or women are shown separately. The upper section of the y axis starts at 3%. (C to J) Proportion by decade of patients who died of COVID-19 and positive for neutralizing auto-Abs (in plasma 1:10) against (C) IFN-2 and/or IFN-, at 10 ng/ml, for both sexes. (D) IFN-2 and/or IFN-, at 10 ng/ml, for men or women. (E) IFN-2 and IFN-, at 10 ng/ml, for both sexes. (F) IFN-2 and IFN-, at 10 ng/ml, for men or women. (G) IFN-2 and/or IFN-, at 100 pg/ml, for both sexes. (H) IFN-2 and/or IFN-, at 100 pg/ml, for men or women. (I) IFN-2 and IFN-, at 100 pg/ml, for both sexes. (J) IFN-2 and IFN-, at 100 pg/ml, for men or women.

  Fifth, in cases of SARS-CoV-2 infection in unvaccinated individuals with auto-Abs Downloaded from https://www.science.org on September 29, 2021 Bastard et al., Sci. Immunol. 2021; 6 : eabl4340 19 August 2021 S C I E N C E I M M U N O L O G Y | R E S E A R C H A R T I C L E 15 of 26

  Downloaded from https://www.science.org on[START_REF]L'Hospitalet de Llobregat[END_REF]

Bastard et al., Sci. Immunol. 2021; 6 : eabl4340 19 August 2021

Table 1 . Risk of critical COVID-19 pneumonia for individuals carrying auto-Abs to specific sets of type I IFNs, when compared with that of asymptomatic/mild infection, adjusted on age and sex. OR

 1 and P values were estimated by means of Firth's bias-corrected logistic regression.

	1, E to G, Table 1,

Anti-type I IFN auto-Ab positive (amount of type I IFN neutralized, in plasma diluted 1:10) Proportion of critical patients with neutralizing auto-Abs OR [95% CI] P value

	Anti-IFN-2 and anti-IFN- auto-Abs (10 ng/ml)	5.6%	67 [4-1109]	7.8 × 10 -13
	Anti-IFN-2 and/or anti-IFN- auto-Abs (10 ng/ml)	9.8%	17 [7-45]	<10 -13
	Anti-IFN-2 auto-Abs (10 ng/ml)	9%	45 [9-225]	<10 -13
	Anti-IFN-2 auto-Abs only (10 ng/ml)	3.4%	21 [4-107]	1.8 × 10 -09
	Anti-IFN- auto-Abs (10 ng/ml)	6.4%	13 [4-38]	1.4 × 10 -12
	Anti-IFN- auto-Abs only (10 ng/ml)	0.8%	3 [0.9-10]	0.057
	Anti-IFN-2 and anti-IFN- auto-Abs (100 pg/ml)	7.1%	54 [11-275]	<10 -13
	Anti-IFN-2 and/or anti-IFN- auto-Abs (100 pg/ml)	13.6%	13 [8-21]	<10 -13
	Anti-IFN-2 auto-Abs (100 pg/ml)	10%	23 [10-55]	<10 -13
	Anti-IFN-2 auto-Abs only (100 pg/ml)	2.9%	10 [3-26]	2.8 × 10 -09
	Anti-IFN- auto-Abs (100 pg/ml)	10.7%	13 [7-23]	<10 -13
	Anti-IFN- auto-Abs only (100 pg/ml)	3.6%	6 [3-12]	3.9 × 10 -10
	Anti-IFN- auto-Abs (10 ng/ml)	1.3%	8 [2-36]	1.7 × 10 -3

Anti-IFN- auto-Abs only (10 ng/ml) 0.96% 5 [1-25] 0.043 Anti-IFN- auto-Abs (10 ng/ml) and anti-IFN-2 and/or anti-IFN- auto-Abs (100 pg/ml) 0.34% 16 [0.5-497] 0.018 Anti-IFN- (10 ng/ml) and anti-IFN-2 and anti-IFN- auto-Abs (100 pg/ml) 0.28% 16 [0.5-502] 0.019 Downloaded from https://www.science.org on September 29, 2021 Bastard et al., Sci. Immunol. 2021; 6 : eabl4340 19 August 2021

Downloaded from https://www.science.org on September 29, 2021 Bastard et al., Sci. Immunol. 2021; 6 : eabl4340 19 August 2021

Department of Intensive Care, Amsterdam UMC, Amsterdam, Netherlands.

Department ofInfectious Diseases, Amsterdam UMC, Amsterdam, Netherlands.

Experimental Immunology, Amsterdam UMC, Amsterdam, Netherlands.

Department of Neurology, Amsterdam UMC, Amsterdam Neuroscience, Amsterdam, Netherlands.

Department of Pulmonology, Downloaded from https://www.science.org on September 29, 2021 Bastard et al., Sci. Immunol. 2021;

: eabl4340 19 August 2021

Acknowledgments:

We thank the patients and their families for placing trust in us. We thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases. We thank Y. Nemirovskaya, M. Woollett, D. Liu, S. Boucherit, C. Rivalain, M. Chrabieh, and L. Lorenzo for administrative assistance. We also thank the staff of the Imagine facilities: C. Bureau, L. Colonna, S. Paillet, N. Ghouas, and M. Sy. We are also grateful to the legal team and technology transfer staff of the Imagine Institute: M. Pilorges, R. Marlanges, E. Rubino, W. Loewen, D. Beudin, and N. Wuylens. We thank all the staff of the Imagine Institute, Necker Hospital, and Necker sorting center for help. We thank S. Nagashima (Department of générale de la Santé, Mutuelle Générale de l'Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research-INSERM Programme "Cohortes et collections de données biologiques". S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under contract no. 75N91019D00024, task order no. 75N91021F00001. J.W. is supported by an FWO Fundamental Clinical Mandate (1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d'Hebron was also partly supported by research funding from Instituto de Salud Carlos III grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF). C.R.-G. and colleagues of the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334, Spanish Ministry for Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE), Fundación DISA (OA18/017 and OA20/024), and Cabildo Insular de Tenerife (CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19"). C.M.B. is supported by a MSFHR Health Professional-Investigator Award. P.Q.H. and L.H. were funded by the European Union's Horizon 2020 research and innovation program (ATAC, 101003650). Work at Y.-L.L.'s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Coopération Scientifique France-Colciencias (ECOS-Nord/ COLCIENCIAS/MEN/ICETEX (806-2018) and Colciencias contract 713-2016 (code 111574455633)]. A.K. was in part supported by grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation-Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies; by the KU Leuven C1 grant C16/18/007; by a VIB-GC PID grant; by the FWO frants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). M.Vi received funding from the São Paulo Research Foundation (FAPESP) (grant number 2020/09702-1) and JBS SA (grant number 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation. Author contributions: P.B., A.Ge., T.L.V., J.R., Q.P., E.M., H.-H.H., S.E., L.H., M.G.-P., L.B., A.P.-M., R.Y., M.M., P.P., K.Sa, J.Man., S.T.-A., A.B., K.S., E.S., L.B.R., M.M., A.A., B.C., A.F., S.M.H., O.M.D., Y.Z., B.B., V.B., S.-Y.Z., L.D.N., H.C.S., K.K., S.O., A.Pu., E.J., C.M.R., and Q.Z. performed or supervised experiments, generated and analyzed data, and contributed to the manuscript by providing figures and tables. J.Man., A.C., and L.A. performed computational analyses of data. P.B., N.d.P., Y.T.-L., C.-E.L., B.A.-B., A.G., J.P., P.M., P.R., F.C., J.T., J.R., L.L., J.-C.L., S.G., S.T.-A., A.B., K.S., P.G., D.D., P.-L.T., D.S., A.S., B.M., V.T., J.R.H., J.C.F., J.-M.A., A.C.-N., L.I., A.B., R.Ca., P.Bo., A.Bi., A.L.S., A.M.P., F.H., S.Du., R.L.N., T.M., A.A.B., T.O., S.K., C.R.G., S.P., Q.P.H., L.H., A.D., A.Ku., C.N.M., A.A., G.C., V.L., F.Ci., L.A.B., E.D.-G., L.V., D.v.d.B., S.G.T., S.Bo., D.Da., L.Q.-M., M.C.N., R.A., D.A., I.B., H.B.-F., J.W., I.M., D.H., N.S.S.-A., R.H., K.D., J.S., S.M.S., L.G., A.K., F.M., Y.N., J.S.-V., A.H.D., S.P.K., N.M.B., S.A.-K., Y.S., J.Tr., O.B., N.Y.K., Y.-L.L, D.L., M.C., J.Mo., R.K., L.F.R., C.B., M.S.A., R.R.-B., R.M., M.Vi., M.Za., A.C.-G., F.V., G.M., D.C.V., L.Ro., S.R.O., A.S., E.A., S.Sa., I.T., J.F., S.L., K.B., R.P.L., S.M., S.B., V.V., O.H., A.Pu., T.H.M., L.R., J.M., S.D., X.d.L., X.D., F.M., M.Z., P.S.-P., R.C., G.G., X.S., S.S., J.M.-P., D.R., M.V., P.K.G., L.P., C.R.-G., L.D.N., H.C.S., P.T., Q.Z., and J.-L.C. evaluated and recruited patients to COVID and/or control cohorts of patients, and/or cohorts of individuals from the general population. P.B. and J.-L.C. wrote the manuscript. J.-L.C. supervised the project. All the authors edited the manuscript. Competing interests: J.-L.C. is an inventor on patent application PCT/US2021/042741, filed 22 July 2021, submitted by The Rockefeller University, which covers diagnosis of, susceptibility to, and treatment of viral disease and viral vaccines, including COVID-19 and vaccine-associated diseases. M.C.N. is an inventor on patent application PCT/US2021/070472 submitted by The Rockefeller University that covers neutralizing anti-SARS-CoV-2 antibodies and methods of use thereof. M.C.N. reports being on the Scientific Advisory Board of Celldex and Frontier Biotechnologies. R.P.L. reports being a non-executive director of Roche. F. Mentré receives fees for consulting from IPSEN and Da Volterra, and her research group receives research grants from Roche, Sanofi, and Da Volterra. Data and materials availability: All the data are available in the manuscript or in the Supplementary Materials. Plasma, cells, and genomic DNA are available from J.-L.C. under a material transfer agreement (MTA) with The Rockefeller University or the Imagine Institute. Huh-7.5 cells are available on request from C.M.R. under an MTA with The Rockefeller University and Apath LLC. The materials and reagents used are almost exclusively commercially available and nonproprietary. Materials derived from human samples may be made available on request, subject to any underlying restrictions concerning such samples. For patients enrolled in the Italian cohort, patient specimens may be available from Monza, subject to approval by their local IRB, through an MTA. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. This license does not apply to figures/photos/artwork or other content included in the article that is Downloaded from https://www.science.org on September 29, 2021

Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan). Funding: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Awards (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union's Horizon 2020 research and innovation programme under grant agreement no. 824110 (EASI-Genomics), the Square Foundation, Grandir-Fonds de solidarité pour l'Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University of Paris. P.B. was supported by the FRM (EA20170638020). P.B., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt Schueller). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the NIAID and NIDCR, NIH (grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.

). This program is supported by the Agence Nationale de la Recherche (reference ANR-10-LABX-69-01). K.K.'s group was supported by the Estonian Research Council grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (AJF202019), Dubai, UAE, and a COVID-19 research grant (CoV19-0307) from the University of Sharjah, UAE. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a UNSW Sydney COVID Rapid Response Initiative Grant. L.I. reported funding from Regione Lombardia, Italy (project "Risposta immune in pazienti con COVID-19 e co-morbidità"). L.I. and G. L. Marseglia reported funding from Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidità). This research was partially supported by the Instituto de Salud Carlos III (COV20/0968). J.R.H. reported funding from Biomedical Advanced Research and Development Authority HHSO10201600031C. S.O. reports funding Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development, AMED (grant number JP20fk0108531). G.G. was supported by ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The Three-City (3C) Study was conducted under a partnership agreement among the INSERM, the Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d'Assurance Maladie des Travailleurs Salariés, Direction Members of the COVID Clinicians: Jorge Abad 1 , Giulia Accordino 2 , Cristian Achille 3 , Sergio Aguilera-Albesa 4 , Aina Aguiló-Cucurull 5 , Alessandro AIUTI 6 , Esra Akyüz Özkan 7 , Ilad Alavi Darazam 8 , Jonathan Antonio Roblero Albisures 9 , Juan C. Aldave 10 , Miquel Alfonso Ramos 11 , Taj Ali Khan 12 , Anna Aliberti 13 , Seyed Alireza Nadji 14 , Gulsum Alkan 15 , Suzan A. AlKhater 16 , Jerome Allardet-Servent 17 , Luis M. Allende 18 , Rebeca ALONSO-ARIAS 19 , Mohammed S. Alshahrani 20 , Laia Alsina 21 , Marie-Alexandra Alyanakian 22 , Blanca Amador Borrero 23 , Zahir Amoura 24 , Arnau Antolí 25 , Romain Arrestier 26 , Mélodie Aubart 27 , Teresa Auguet 28 , Iryna Avramenko 29 , Gökhan Aytekin 30 , Axelle Azot 31 , Seiamak Bahram 32 , Fanny Bajolle 33 , Fausto Baldanti 34 , Aurélie Baldolli 35 , Maite Ballester 36 , Hagit Baris Feldman 37 , Benoit Barrou 38 , Federica BARZAGHI 6 , Sabrina Basso 39 , Gulsum Iclal BAYHAN 40 , Alexandre Belot 41 , Liliana BEZRODNIK 42 , Agurtzane Bilbao 43 , Geraldine Blanchard-Rohner 44 , Ignacio Blanco 45 , Adeline Blandinières 46 , Daniel Blázquez-Gamero 47 , Alexandre Bleibtreu 48 , Marketa Bloomfield 49 , Mireia Bolivar-Prados 50 , Anastasiia Bondarenko 51 , Alessandro Borghesi 3 , Raphael Borie 52 , Elisabeth Botdhlo-Nevers 53 , Ahmed A. Bousfiha 54 , Aurore Bousquet 55 , David Boutolleau 56 , Claire Bouvattier 57 , Oksana Boyarchuk 58 , Juliette Bravais 59 , M. Luisa Briones 60 , Marie-Eve Brunner 61 , Raffaele Bruno 62 , Maria Rita P. Bueno 63 , Huda Bukhari 64 , Jacinta Bustamante 33 , Juan José Cáceres Agra 65 , Ruggero Capra 66 , Raphael Carapito 67 , Maria Carrabba 68 , Giorgio CASARI 6 , Carlos Casasnovas 69 , Marion Caseris 70 , Irene Cassaniti 34 , Martin Castelle 71 , Francesco Castelli 72 , Martín Castillo de Vera 73 , Mateus V. Castro 63 , Emilie Catherinot 74 , Jale Bengi Celik 75 , Alessandro Ceschi 76 , Martin Chalumeau 77 , Bruno Charbit 78 , Matthew P. Cheng 79 , Père Clavé 50 , Bonaventura Clotet 80 , Anna Codina 81 , Yves Cohen 82 , Roger Colobran 83 , Cloé Comarmond 84 , Alain Combes 85 , Patrizia Comoli 39 , Angelo G. Corsico 2 , Taner Coşkuner 86 , Aleksandar Cvetkovski 87 , Cyril Cyrus 88 , David Dalmau 89 , François Danion 90 , David Ross Darley 91 , Vincent Das 92 , Nicolas Dauby 93 , Stéphane Dauger 94 , Paul De Munter 95 , Loic de Pontual 96 , Amin Dehban 97 , Geoffroy Delplancq 98 , Alexandre Demoule 99 , Isabelle Desguerre 100 , Antonio Di Sabatino 101 , Jean-Luc Diehl 102 , Stephanie Dobbelaere 103 , Elena Domínguez-Garrido 104 , Clément Dubost 105 , Olov EKWALL 106 , Şefika Elmas Bozdemir 107 , Marwa H. Elnagdy 108 , Melike Emiroglu 15 , Akifumi Endo 109 , Emine Hafize Erdeniz 110 , Selma Erol Aytekin 111 , Maria Pilar ETXART LASA 112 , Romain Euvrard 113 , Giovanna Fabio 68 , Laurence Faivre 114 , Antonin Falck 115 , Muriel Fartoukh 116 , Morgane Faure 117 , Miguel Fernandez Arquero 118 , Ricard Ferrer 119 , Jose Ferreres 120 , Carlos Flores 121 , Bruno Francois 122 , Victoria Fumadó 123 , Kitty S. C. Fung 124 , Francesca Fusco 125 , Alenka Gagro 126 , Blanca Garcia Solis 127 , Pascale Gaussem 128 , Zeynep GAYRETLI 129 , Juana Gil-Herrera 130 , Laurent Gilardin 131 , Audrey Giraud Gatineau 132 , Mònica Girona-Alarcón 133 , Karen Alejandra Cifuentes Godínez 134 , Jean-Christophe Goffard 135 , Nacho Gonzales 136 , Luis I. Gonzalez-Granado 137 , Rafaela González-Montelongo 138 , Antoine Guerder 139 , Belgin Gülhan 140 , Victor Daniel Gumucio 141 , Leif Gunnar Hanitsch 142 , Jan Gunst 143 , Marta Gut 144 , Jérôme Hadjadj 145 , Filomeen Haerynck 146 , Rabih Halwani 147 , Lennart Hammarström 148 , Selda HANCERLI 149 , Tetyana Hariyan 150 , Nevin Hatipoglu 151 , Deniz Heppekcan 152 , Elisa Hernandez-Brito 153 , Po-ki Ho 154 , María Soledad Holanda-Peña 155 , Juan P. Horcajada 156 , Sami Hraiech 157 , Linda Humbert 158 , Ivan F. N. Hung 159 , Alejandro D. Iglesias 160 , Antonio Íñigo-Campos 138 , Matthieu Jamme 161 , María Jesús Arranz 89 , Marie-Thérèse Jimeno 162 , Iolanda Jordan 133 , Saliha Kanık-Yüksek 163 , Yalcin Burak Kara 164 , Aydın Karahan 165 , Adem Karbuz 166 , Kadriye Kart Yasar 167 , Ozgur Kasapcopur 168 , Kenichi Kashimada 169 , Sevgi Keles 111 , Yasemin Kendir Demirkol 170 , Yasutoshi Kido 171 , Can Kizil 172 , Ahmet Osman Kılıç 173 , Adam Klocperk 174 , Antonia Koutsoukou 175 , Zbigniew J. Król 176 , Hatem Ksouri 177 , Paul Kuentz 178 , Arthur M. C. Kwan 179 , Yat Wah M. Kwan 180 , Janette S. Y. Kwok 181 , Jean-Christophe Lagier 182 , David S. Y. Lam 183 , Vicky Lampropoulou 310 , Fanny Lanternier 185 , Yu-Lung Lau 186 , Fleur Le Bourgeois 94 , Yee-Sin Leo 187 , Rafael Leon Lopez 188 , Daniel Leung 186 , Michael Levin 189 , Michael Levy 94 , Romain Lévy 33 , Zhi Li 78 , Daniele Lilleri 34 , Edson Jose Adrian Bolanos Lima 190 , Agnes Linglart 191 , Eduardo López-Collazo 192 , José M. Lorenzo-Salazar 138 , Céline Louapre 193 , Catherine Lubetzki 193 , Kwok-Cheung Lung 194 , Charles-Edouard Luyt 195 , David C. Lye 196 , Cinthia Magnone 197 , Davood Mansouri 198 , Enrico Marchioni 199 , Carola Marioli 2 , Majid Marjani 200 , Laura Marques 201 , Jesus Marquez Pereira 202 , Andrea Martín-Nalda 203 , David Martínez Pueyo 204 , Javier Martinez-Picado 205 , Iciar Marzana 206 , Carmen Mata-Martínez 207 , Alexis Mathian 24 , Larissa RB Matos 63 , Gail V. Matthews 208 , Julien Mayaux 209 , Raquel McLaughlin-Garcia 210 , Philippe Meersseman 211 , Jean-Louis Mège 212 , Armand Mekontso-Dessap 213 , Isabelle Melki 115 , Federica Meloni 2 , Jean-François Meritet 214 , Paolo Merlani 215 , Özge Metin Akcan 216 , Isabelle Meyts 217 , Mehdi Mezidi 218 , Isabelle Migeotte 219 , Maude Millereux 220 , Matthieu Million 221 , Tristan Mirault 222 , Clotilde Mircher 223 , Mehdi Mirsaeidi 224 , Yoko Mizoguchi 225 , Bhavi P. Modi 226 , Francesco Mojoli 13 , Elsa Moncomble 227 , Abián Montesdeoca Melián 228 , Antonio Morales Martinez 229 , Francisco Morandeira 230 , Pierre-Emmanuel Morange 231 , Clémence Mordacq 158 , Guillaume Morelle 232 , Stéphane J. Mouly 233 , Adrián Muñoz-Barrera 138 , Cyril Nafati 234 , Shintaro Nagashima 235 , Yu Nakagama 171 , Bénédicte Neven 236 , João Farela Neves 237 , Lisa F. P. Ng 238 , Yuk-Yung Ng 239 , Hubert Nielly 105 , Yeray Novoa Medina 210 , Esmeralda Nuñez Cuadros 240 , J. Gonzalo Ocejo-Vinyals 241 , Keisuke Okamoto 109 , Mehdi Oualha 33 , Amani Ouedrani 22 , Tayfun Özçelik 242 , Aslinur Ozkaya-Parlakay 140 , Michele Pagani 13 , Qiang Pan-Hammarström 148 , Maria Papadaki 310 , Christophe Parizot 209 , Philippe Parola 244 , Tiffany Pascreau 245 , Stéphane Paul 246 , Estela Paz-Artal 247 , Sigifredo Pedraza 248 , Nancy Carolina González Pellecer 134 , Silvia Pellegrini 249 , Rebeca Pérez de Diego 127 , Xosé Luis Pérez-Fernández 141 , Aurélien Philippe 250 , Quentin Philippot 116 , Adrien Picod 251 , Marc Pineton de Chambrun 85 , Antonio Piralla 34 , Laura Planas-Serra 252 , Dominique Ploin 253 , Julien Poissy 254 , Géraldine Poncelet 70 , Garyphallia Poulakou 175 , Marie S. Pouletty 255 , Persia Pourshahnazari 256 , Jia Li Qiu-Chen 257 , Paul Quentric 209 , Thomas Rambaud 258 , Didier Raoult 212 , Violette Raoult 259 , Anne-Sophie Rebillat 223 , Claire Redin 260 , Léa Resmini 261 , Pilar Ricart 262 , Jean-Christophe Richard 263 , Raúl Rigo-Bonnin 264 , Nadia rivet 46 , Jacques G. Rivière 265 , Gemma Rocamora-Blanch 25 , Mathieu P. Rodero 266 , Carlos Rodrigo 267 , Luis Antonio Rodriguez 190 , Carlos Rodriguez-Gallego 268 , Agustí Rodriguez-Palmero 269 , Carolina Soledad Romero 270 , Anya Rothenbuhler 271 , Damien Roux 272 , Nikoletta Rovina 175 , Flore Rozenberg 273 , Yvon Ruch 90 , Montse Ruiz 274 , Maria Yolanda Ruiz del Prado 275 , Juan Carlos Ruiz-Rodriguez 119 , Joan Sabater-Riera 141 , Kai Saks 276 , Maria Salagianni 184 , Oliver Sanchez 277 , Adrián Sánchez-Montalvá 278 , Silvia Sánchez-Ramón 279 , Laire Schidlowski 280 , Agatha Schluter 252 , Julien Schmidt 281 , Matthieu Schmidt 282 , Catharina Schuetz 283 , Cyril E. Schweitzer 284 , Francesco Scolari 285 , Anna Sediva 286 , Luis Seijo 287 , Analia Gisela Seminario 42 , Damien Sene 23 , Piseth Seng 221 , Sevtap Senoglu 167 , Mikko Seppänen 288 , Alex Serra Llovich 289 , Mohammad Shahrooei 97 , Anna Shcherbina 290 , Virginie Siguret 291 , Eleni Siouti 310 , David M. Smadja 293 , Nikaia Smith 78 , Ali Sobh 294 , Xavier Solanich 25 , Jordi Solé-Violán 295 , Catherine Soler 296 , Pere Soler-Palacín 297 , Betül Sözeri 86 , Giulia Maria Stella 2 , Yuriy Stepanovskiy 298 , Annabelle Stoclin 299 , Fabio Taccone 219 , Yacine Tandjaoui-Lambiotte 300 , Jean-Luc Taupin 301 , Simon J. Tavernier 302 , Loreto Vidaur 112 , Benjamin Terrier 303 , Guillaume Thiery 304 , Christian Thorball 260 , Karolina Thorn 305 , Caroline Thumerelle 158 , Imran Tipu 306 , Martin Tolstrup 307 , Gabriele Tomasoni 308 , Julie Toubiana 77 , Josep Trenado Alvarez 309 , Sophie Trouillet-Assant 311 , Jesús Troya 312 , Owen T. Y. Tsang 313 , Liina Tserel 314 , Eugene Y. K. Tso 315 , Alessandra Tucci 316 , Şadiye Kübra Tüter Öz 15 , Matilde Valeria Ursini 125 , Takanori Utsumi 225 , Yurdagul Uzunhan 317 , Pierre Vabres 318 , Juan Valencia-Ramos 319 , Ana Maria Van Den Rym 127 , Isabelle Vandernoot 320 , Valentina Velez-Santamaria 321 , Silvia Patricia Zuniga Veliz 134 , Mateus C. Vidigal 322 , Sébastien Viel 253 , Cédric Vilain 323 , Marie E. Vilaire-Meunier 223 , Judit Villar-García 324 , Audrey Vincent 57 , Guillaume Vogt 325 , Guillaume Voiriot 326 , Alla Volokha 327 , Fanny Vuotto 158 , Els Wauters 328 , Joost Wauters 329 , Alan K. L. Wu 330 , Tak-Chiu Wu 331 , Aysun Yahşi 332 , Osman Yesilbas 333 , Mehmet Yildiz 168 , Barnaby E. Young 187 , Ufuk Yükselmiş 334 , Mayana Zatz 63 , Marco Zecca 39 , Valentina Zuccaro 62 , Jens Van Praet 335 , Bart N. Lambrecht 336 , Eva Van Braeckel 336 , Cédric Bosteels 336 , Levi Hoste 337 , Eric Hoste 338 , Fré Bauters 336 , Jozefien De Clercq 336 , Cathérine Heijmans 339 , Hans Slabbynck 340 , Leslie Naesens 341 , Benoit Florkin 342 , Cécile Boulanger 343 , Dimitri Vanderlinden 344 Pauline Caraux Paz 14 , Minerva Cervantes-Gonzalez 6 , Anissa Chair 6 , Catherine Chirouze 15 , Alexandra Coelho 16 , Hugues Cordel 17 , Camille Couffignal 6 , Sandrine Couffin-Cadiergues 18 , Eric d'Ortenzio 7 , Etienne De Montmollin 6 , Alexa Debard 19 , Marie-Pierre Debray 6 , Dominique Deplanque 20 , Diane Descamps 6 , Mathilde Desvallée 21 , Alpha Diallo 7 , Jean-Luc Diehl 22 , Alphonsine Diouf 16 , Céline Dorival 12 , François Dubos 23 , Xavier Duval 6 , Philippine Eloy 6 , Downloaded from https://www.science.org on September 29, 2021 Bastard et al., Sci. Immunol. 2021; 6 : eabl4340 19 August 2021

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Vincent Enouf 9 , Olivier Epaulard 24 , Hélène Esperou 18 , Marina Esposito-Farase 6 , Manuel Etienne 25 , Denis Garot 26 , Nathalie Gault 6 , Alexandre Gaymard 13 , Jade Ghosn 6 , Tristan Gigante 27 , Morgane Gilg 27 , François Goehringer 28 , Jérémie Guedj 29 , Alexandre Hoctin 16 , Isabelle Hoffmann 6 , Ikram Houas 18 , Jean-Sébastien Hulot 22 , Salma Jaafoura 18 , Ouifiya Kafif 6 , Florentia Kaguelidou 30 , Sabrina Kali 6 , Younes Kerroumi 31 , Antoine Khalil 6 , Coralie Khan 21 , Antoine Kimmoun 32 , Fabrice Laine 33 , Cédric Laouénan 6 , Samira Laribi 6 , Minh Le 6 , Cyril Le Bris 34 , Sylvie Le Gac 6 , Quentin Le Hingrat 6 , Soizic Le Mestre 7 , Hervé Le Nagard 35 , Adrien Lemaignen 26 , Véronique Lemee 25 , François-Xavier Lescure 6 , Sophie Letrou 6 , Yves Levy 6 , Bruno Lina 13 , Guillaume Lingas 35 , Jean Christophe Lucet 6 , Moïse Machado 37 , Denis Malvy 38 , Marina Mambert 16 , Aldric Manuel 39 , France Mentré 6 , Amina Meziane 12 , Hugo Mouquet 9 , Jimmy Mullaert 6 , Nadège Neant 35 , Duc Nguyen 38 , Marion Noret 40 , Aurélie Papadopoulos 18 , Christelle Paul 7 , Nathan Peiffer-Smadja 6 , Vincent Peigne 41 , Ventzislava Petrov-Sanchez 7 , Gilles Peytavin 6 , Huong Pham 6 , Olivier Picone 8 , Valentine Piquard 6 , Julien Poissy 23 , Oriane Puéchal 42 , Manuel Rosa-Calatrava 13 , Bénédicte Rossignol 27 , Patrick Rossignol 28 , Carine Roy 6 , Marion Schneider 6 , Richa Su 6 , Coralie Tardivon 6 , Marie-Capucine Tellier 6 , François Téoulé 12 , Olivier Terrier 13 , Jean-François Timsit 6 , Christelle Tual 43 , Sarah Tubiana 6 , Sylvie Van Der Werf 9 , Noémie Vanel 44 , Aurélie Veislinger 43 , Benoit Visseaux 6 , Aurélie Wiedemann 45 , Yazdan Yazdanpanah 6

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Members of the HGID Lab:

Benedetta Bigio 1 , Soraya Boucherit 2,3 , Aliénor de la Chapelle 2 , Jie Chen 1 , Maya Chrabieh 2,3 , Boubacar Coulibaly 2,3 , Dana Liu 1 , Yelena Nemirowskaya 1 , Inés Marín Cruz 2 , Marie Materna 2,3 , Sophie Pelet 2 , Yoann Seeleuthner 2,3 , Chloé Thibault 2,3 , Zhiyong Liu 1 1 St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 2 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.