RESEARCH ARTICLE | MEDICAL SCIENCES OPEN ACCESS The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies Significance neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y There is growing evidence that old in the general population. With a sample of 1,261 unvaccinated deceased patients preexisting autoantibodies and 34,159 individuals of the general population sampled before the pandemic, we esti- neutralizing type I interferons (IFNs) mated both IFR and relative risk of death (RRD) across age groups for individuals are strong determinants of life- carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD threatening COVID-19 pneumonia. It associated with any combination of autoantibodies was higher in subjects under 70 y is important to estimate their old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: quantitative impact on COVID-19 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, mortality upon SARS-CoV-2 infection, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to by age and sex, as both the 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging prevalence of these autoantibodies from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to and the risk of COVID-19 death 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies increase with age and are higher in against type I IFNs increase IFRs, and are associated with high RRDs, especially when men. Using an unvaccinated sample neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas of 1,261 deceased patients and RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predic- 34,159 individuals from the general tor of COVID-19 death. population, we found that autoantibodies against type I IFNs COVID-19 j type I IFNs j autoantibodies j relative risk j infection fatality rate strongly increased the SARS-CoV-2 infection fatality rate at all ages, in There have already been more than 250 million severe acute respiratory syndrome both men and women. coronavirus 2 (SARS-CoV-2) infections and at least 5 million deaths from COVID-19 Autoantibodies against type I IFNs worldwide. Interindividual clinical variability in the course of infection with SARS- are strong and common predictors CoV-2 is immense, ranging from silent infection in about 40% of cases to acute respi- of life-threatening COVID-19. Testing ratory distress syndrome in ∼3% of cases (1–5). Death occurs in ∼1% of cases (6). Age is the strongest epidemiological predictor of COVID-19 death, with the risk of death for these autoantibodies should be doubling every 5 y of age from childhood onward (6, 7). Men are also at greater risk of considered in the general death than women (5, 8). Based on previously identified inborn errors of type I inter- population. feron (IFN) immunity (9), the COVID Human Genetic Effort (10) has shown that type I IFN immunity is essential for protective immunity to respiratory infection with Copyright © 2022 the Author(s). Published by PNAS. SARS-CoV-2 (11–14). We have reported that inborn errors of Toll-like receptor 3 This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). (TLR3)-dependent type I IFN immunity can underlie life-threatening COVID-19 1 To whom correspondence may be addressed. Email: pneumonia in a small subset of patients (14). Biochemically deleterious mutations of jeremy.manry@inserm.fr, casanova@rockefeller.edu, or aurelie.cobat@inserm.fr. eight genes were found in 23 patients with critical COVID-19 (3.5% of 659 patients), 2 P. Bastard, A. Gervais, T.L.V., J.R., and Q.P. contributed including 18 patients under 60 y old. Remarkably, four unrelated patients, aged 25 y equally to this work. to 50 y, had autosomal recessive (AR) deficiencies of IFNAR1 or IRF7, including three 3 E.M., H.-H.H., S.E., M.G.-P., L. Bizien, A.P.-M., R.Y., L. homozygotes (two for IFNAR1 and one for IRF7) and one compound heterozygote Haljasma €gi, M.M., K. Sa €rekannu, and J. Maslovskaja contributed equally to this work. (for IRF7). Three other patients with AR IFNAR1 or TBK1 deficiency were indepen- 4 Present address: Hypoxia and Lung INSERM U1272, dently reported (15–17). The penetrance of those defects is unknown, but it is proba- Pneumologie & Infectiologie INSERM UMR 1137, Infection Antimicrobials Modelling Evolution, Centre bly higher for AR than for autosomal dominant disorders. We then reported that Hospitalier Saint-Denis, 93200 Saint-Denis, France. X-linked recessive TLR7 deficiency accounted for 1.8% of cases of life-threatening 5 Present address: National Academy of Medicine of COVID-19 in men under 60 y old (13, 18). The penetrance of this disorder is appar- Colombia, 110231 Bogota, Colombia. 6 ently high but incomplete, especially in children. Deficiencies of IFNAR1 and IRF7 Lists of members of consortia are available in SI Appendix. 7 blunt type I IFN immunity across cell types, whereas defects of the TLR3 and TLR7 E.A., O.H., A. Pujol, P.P., T.H.M., L. Rowen, J. Mond, S. Debette, X.d.L., C.B., L. Bouadma, M. Zins, P.S.-P., R. pathway preferentially affect respiratory epithelial cells and plasmacytoid dendritic cells, Colobran, G.G., X.S., S. Susen, J.M.-P., D.R., M. Vasse, P.K.G., L.P., and C.R.-G. contributed equally to this work. respectively (13, 19). 8 Present address: Gain Therapeutics, 6900 Lugano, We have also reported the presence of autoantibodies (auto-Abs) neutralizing high Switzerland. concentrations (10 ng/mL, with plasma diluted 1/10) of IFN-α2 and/or IFN-ω in 9 L.D.N., H.C.S., K.K., S.O., A. Puel, E.J., C.M.R., P.T., Q.Z. about 10% of patients with critical COVID-19 pneumonia but not in individuals with contributed equally to this work. asymptomatic or mild infection (12). This finding has already been replicated in 14 10 J.-L.C., L.A., and A.C. contributed equally to this work. This article contains supporting information online at other cohorts (20–35). We then detected auto-Abs neutralizing lower, more physiolo- http://www.pnas.org/lookup/suppl/doi:10.1073/pnas. gical concentrations (100 pg/mL, with plasma diluted 1/10) of IFN-α2 and/or IFN-ω 2200413119/-/DCSupplemental. in 13.6% of patients with life-threatening COVID-19, and 18% of deceased patients Published May 16, 2022. PNAS 2022 Vol. 119 No. 21 e2200413119 https://doi.org/10.1073/pnas.2200413119 1 of 10 Table 1. Lines of evidence suggesting that auto-Abs against type I IFNs are strong determinants of the risk of life- threatening COVID-19 Evidence Examples References Auto-Abs against type I IFNs are present In patients for whom a sample collected before the COVID-19 (36) before SARS-CoV-2 infection pandemic was available, the auto-Abs were found to preexist infection. These auto-Abs are found in the uninfected general population, (11) and their prevalence increases after the age of 65 y. Auto-Abs are associated with COVID-19 Patients with inborn errors underlying these auto-Abs from (36) severity infancy onward (e.g., APS-1) have a very high risk of developing critical COVID-19 pneumonia. The population of patients with critical disease includes a higher (11) proportion of individuals producing these auto-Abs than the population of patients with silent or mild infection (ORs depending on the nature, number, and concentrations of type I IFN neutralized). The results concerning the proportions of critical cases with (20, 23–35) auto-Abs against type I IFNs have already been replicated in >15 different cities (Americas, Europe, Asia). Auto-Abs against type I IFNs neutralize These auto-Abs neutralize the antiviral activity of type I IFNs (12) host antiviral activity against SARS-CoV-2 in vitro. These auto-Abs are found in vivo in the blood of SARS-CoV-2- (37) infected patients, where they neutralize type I IFN. These auto-Abs are found in vivo in the respiratory tract of (38–40) patients, where they neutralize type I IFN. A key virulence factor of SARS-CoV-2 in vitro is its capacity to (41) impair type I IFN immunity. Animals with type I IFN deficiency develop critical disease, (42) including animals treated with mAbs that neutralize type I IFNs. Auto-Abs against cytokines are clinical Patients with auto-Abs against type I IFNs are phenocopies (14) phenocopies of the corresponding of IFNAR1/, IFNAR2/, and IRF7/ patients with critical inborn errors COVID-19 pneumonia. Patients with auto-Abs against IL-6, IL-17, GM-CSF, and type II (43–51) IFN are phenocopies of the corresponding inborn errors and underlie staphylococcal disease, mucocutaneous candidiasis, nocardiosis, and mycobacterial diseases, respectively. (11). The proportion of male patients was greater in patients Results with auto-Abs than in patients without auto-Abs (11, 12). In addition, 1.3% of patients with critical COVID-19 had auto-Abs Patients and Controls. We estimated the RRD of individuals neutralizing IFN-β (10 ng/mL, with plasma diluted 1/10), most carrying auto-Abs neutralizing type I IFNs relative to noncar- without auto-Abs neutralizing IFN-α2 or IFN-ω. The prevalence riers by Firth’s logistic regression, using large samples of 1,261 of auto-Abs neutralizing IFN-α2 and/or IFN-ω in the general patients who died from COVID-19 and 34,159 individuals population increased with age, from 0.18% for 10 ng/mL and from the general population from whom samples were collected 1% for 100 pg/mL in individuals between 18 y and 69 y old to before the pandemic. In this study design, in which controls 3.4% for 10 ng/mL and 6.3% for 100 pg/mL for individuals are sampled from the baseline population regardless of disease over 80 y old (11). The prevalence of auto-Abs against IFN-β status, the ORs obtained by logistic regression approximate the did not increase with age. The crude odds ratios (ORs) for critical relative risks (RRs) in the absence of the assumption of rare dis- COVID-19 as opposed to asymptomatic or mild infection in ease (54) (SI Appendix, Supplementary Materials and Methods). auto-Ab carriers relative to noncarriers ranged from 3 to 67, We confirmed that this statement remains valid in our study depending on the type I IFNs recognized and the concentrations design, using Firth’s logistic regression by a simulation study neutralized (11). At least 12 lines of evidence strongly suggest (SI Appendix, Supplementary Materials and Methods and Fig. that auto-Abs against type I IFNs are strong determinants of S1). For auto-Abs neutralizing low concentrations (100 pg/mL) COVID-19 death (Table 1). The specific impact of these auto- of IFN-α2 and/or IFN-ω, we used 1,121 patients who died Abs on COVID-19 mortality according to age and sex remains from COVID-19, and 10,778 individuals from the general unknown and is of major interest (52, 53), as both the prevalence population (Table 2). Assessments of auto-Abs neutralizing of these auto-Abs and the risk of death increase with age and are high concentrations (10 ng/mL) of IFN-α2 and/or IFN-ω were higher in men. Here, using data reported by Bastard et al. (11), available for 1,094 deceased patients, and 34,159 individuals we estimated the relative risk of COVID-19 death (RRD) for from the general population (Table 2). We also had assessments type I IFN auto-Ab carriers relative to noncarriers and the corre- of auto-Abs neutralizing 10 ng/mL of IFN-β for a subsample of sponding SARS-CoV-2 infection fatality rate (IFR), by sex and 636 deceased patients, and 9,126 individuals from the general age category. population (Table 2). RRDs were estimated by means of Firth’s 2 of 10 https://doi.org/10.1073/pnas.2200413119 pnas.org Table 2. Characteristics of the general population cohort and of the cohort of patients who died from COVID-19 Neutralization 100 pg/mL Neutralization 10 ng/mL General population Deceased patients General population Deceased patients Characteristics (n = 10,778) (n = 1,121) (n = 34,159) (n = 1,094) Male – no. (percent) 5,429 (50.4)* 821 (73.2) 17,859 (52.3) 805 (73.5) Mean age ± SD* – 62.3 ± 17.2 70.7 ± 13.0 52.7 ± 18.2 70.6 ± 13.1 years Age distribution – no. (percent) 20 y to 39 y 1,251 (11.6) 17 (1.5) 9,102 (26.6) 15 (1.4) 40 y to 49 y 1,459 (13.5) 43 (3.8) 5,403 (15.8) 47 (4.3) 50 y to 59 y 1,736 (16.1) 144 (12.8) 6,414 (18.9) 152 (13.9) 60 y to 69 y 2,475 (23.0) 307 (27.4) 6,881 (20.1) 289 (26.4) 70 y to 79 y 1,790 (16.6) 307 (27.4) 3,721 (10.9) 296 (27.1) ≥80 y 2,067 (19.2) 303 (27.0) 2,638 (7.7) 295 (27.0) Auto-Ab – no. of carriers (percent) IFN-α2 and IFN-ω 65 (0.6) 102 (9.1) 45 (0.1) 75 (6.8) IFN-α2 or IFN-ω 246 (2.3) 203 (18.1) 181 (0.5) 130 (11.9) IFN-α2 151 (1.4) 140 (12.5) 117 (0.3) 118 (10.8) IFN-ω 160 (1.5) 165 (14.7) 109 (0.3) 87 (8.0) IFN-β† NA NA 24 (0.3) 6 (0.9) NA, not available. *Age is given in years and corresponds to age at the time of recruitment for members of the general population cohort (controls) and age at death for COVID-19 patients. † IFN-β neutralization experiments were performed only for a concentration of 10 ng/mL, on 9,126 individuals (49.5% male, mean age 60.6 y) from the general population and 636 COVID-19 patients (71.1% male, mean age 72.9 y). bias-corrected logistic regression, considering death as a binary population attributable fraction (PAF), to assess the proportion outcome and adjusting for sex and age in six classes (20 y to of COVID-19 deaths attributable to auto-Abs (SI Appendix, 39 y, 40 y to 49 y, 50 y to 59 y, 60 y to 69 y, 70 y to 79 y, Supplemental Materials and Methods). Given the high RRD esti- and ≥80 y). For assessment of the effect of age and sex on mated for all combinations of auto-Abs neutralizing low con- RRD, we added interaction terms between auto-Abs and age, centrations of type I IFNs, the PAF was very close to the preva- and auto-Abs and sex terms to the logistic model (Materials lence of these auto-Abs in deceased patients (SI Appendix, and Methods and SI Appendix, Supplementary Materials Table S3). and Methods). RRD for Carriers of Auto-Abs Neutralizing High Concentra- RRD for Carriers of Auto-Abs Neutralizing Low Concentrations tions of Type I IFNs. We then estimated the RRD for the of Type I IFNs. We first estimated the RRD for individuals car- presence versus the absence of auto-Abs neutralizing high con- rying auto-Abs neutralizing low concentrations of IFN-α2 or centrations (10 ng/mL) of type I IFN. The effect of age on IFN-ω. As expected, increasing age and maleness were highly RRD was similar to that observed with auto-Abs neutralizing significantly associated with greater risk of COVID-19 death low concentrations of type I IFN, with the use of two age clas- (P values ≤ 1016; SI Appendix, Table S1). Different age classes ses providing the best fit (SI Appendix, Tables S2 and S4), were used to test the interaction with the presence of auto-Abs, and a decrease of RRD with age (Fig. 2B and SI Appendix, and the best fit was obtained with a two-age class model (20 y Table S5). The RRD for carriers of IFN-α2 or IFN-ω auto-Abs to 69 y and ≥70 y; SI Appendix, Table S2) with a significant decreased from 62.4 (38.4 to 101.3) before the age of 70 y to effect of the interaction term between auto-Abs and age (P 6.8 (5.1 to 9.2) after the age of 70 y, whereas carriers of auto- value = 4 × 106). The RRD associated with auto-Abs did not Abs against both IFN-α2 and IFN-ω had the highest RRD, vary significantly with sex (P value = 0.81). These interaction estimated at 156.5 (57.8 to 423.4) and 12.9 (8.4 to 19.9) for results are fully consistent with the distribution of RRD accord- subjects <70 y and ≥70 y old, respectively (Fig. 2B and SI ing to age (Fig. 1A) and sex (Fig. 1B), with a clear decrease in Appendix, Table S5). Individuals carrying auto-Abs neutralizing RRD after the age of 70 y, and no sex effect. Overall, the RRD high concentrations of IFN-α2 and/or IFN-ω had a signifi- for individuals carrying auto-Abs neutralizing IFN-α2 or IFN- cantly higher RRD than individuals carrying only auto-Abs ω decreased from 17.0 (95% CI: 11.7 to 24.7) before the age neutralizing low concentrations (SI Appendix, Supplemental of 70 y to 5.8 (4.5 to 7.4) for individuals ≥70 y old (Fig. 2A Materials and Methods). This finding, consistent with the higher and SI Appendix, Table S3). We then applied the same strategy proportion of auto-Abs neutralizing high concentrations in to other combinations of auto-Abs neutralizing low concentra- deceased patients than in the general population (SI Appendix, tions of IFN, and observed similar age effects on RRDs (SI Fig S2), suggests a more deleterious impact of auto-Abs neutraliz- Appendix, Table S1). The presence of auto-Abs neutralizing ing high concentrations of IFN-α2 and/or IFN-ω on COVID-19 both IFN-α2 and IFN-ω was associated with the highest RRD, outcomes. Finally, auto-Abs neutralizing high doses of IFN-β had estimated at 188.3 (45.8 to 774.4) for individuals under the the lowest RRD before 70 y (7.0 [2.2 to 22.4]), with no signifi- age of 70 y and 7.2 (5.0 to 10.3) for those over 70 y old (Fig. cant age-dependent association (P value = 0.37). The PAF for 2A and SI Appendix, Table S3). We also estimated the auto-Abs neutralizing high concentrations of type I IFNs was also PNAS 2022 Vol. 119 No. 21 e2200413119 https://doi.org/10.1073/pnas.2200413119 3 of 10 A B 40 100 100 35 Females Males 30 IFRAAB 50 50 25 IFR 20 20 20 15 10 IFRmales RRD IFR 10 10 5 0 5 5 <40 40-49 50-59 60-69 70-79 ≥80 Age (years) Sample size: COVID-19 deaths 17 43 144 307 307 303 General population 1,251 1,459 1,736 2,475 1,790 2,067 2 2 Fig. 3. SARS-CoV-2 IFRs by age. IFRs are provided for the general popula- tion for both sexes (gray) and for males only (blue), from the data of O’Dris- coll et al. (6); IFRAAB (green) are shown for individuals carrying auto-Abs 1 1 neutralizing low concentrations of IFN-α2 or IFN-ω. Auto-Abs against type I <40 40-49 50-59 60-69 70-79 ≥80 <70 ≥70 IFNs are associated with high RRDs and strongly increase the IFR, to a Age (years) Age (years) much greater extent than being male, and, by inference, than other com- mon classical risk factors providing ORs of death similar to that for being Fig. 1. RRDs for individuals with auto-Abs neutralizing low concentrations male (around two), such as certain comorbid conditions, or the most signif- of IFN-α2 or IFN-ω relative to individuals without such auto-Abs, by age and icant common genetic variant on chromosome 3 (5). sex. RRDs are displayed on a logarithmic scale (A) for six age classes and (B) for male and female subjects under and over the age of 70 y. Vertical bars represent the 95% CI. low concentrations of type I IFNs (IFRAAB). According to Bayes’ theorem, IFRAAB can be expressed as a function of the age- close to the prevalence of these auto-Abs in deceased patients (SI dependent prevalence of auto-Abs in deceased patients and in the Appendix, Table S5). general population together with the reported age-specific IFR IFR in Individuals Carrying Auto-Abs Neutralizing Low Con- (6) (SI Appendix). For all combinations of auto-Abs, the IFRAAB centrations of Type I IFNs. We then estimated the IFR in was much higher than the overall IFR. Fig. 3 illustrates this SARS-CoV-2–infected individuals carrying auto-Abs neutralizing much higher IFR for carriers of auto-Abs neutralizing low con- centrations of IFN-α2 or IFN-ω; it exceeded 1% and 10% for subjects over the ages of 40 y and 60 y, respectively. Considering A B other combinations of auto-Abs, the highest IFRAAB was observed 1000 1000 for carriers of auto-Abs neutralizing both IFN-α2 and IFN-ω, reaching 40.5% (27.8 to 61.2) in individuals over 80 y old (Fig. 500 500 4A and SI Appendix, Table S6). IFRAAB values were similar for all other combinations of auto-Abs. For example, the IFRAAB for 200 200 individuals carrying auto-Abs neutralizing either IFN-α2 or IFN- 100 100 ω ranged from 0.17% (0.12 to 0.31) in individuals under 40 y old to 26.7% (20.3 to 35.2) in individuals over 80 y old. An 50 50 exception was noted for the IFRAAB of carriers of anti-IFN-α2 RRD auto-Abs, which was 1.8 to 2.6 times higher than that for carriers 20 20 of auto-Abs neutralizing IFN-α2 or IFN-ω in subjects under 60 y old. The IFRAAB was also generally higher in male subjects 10 10 than in female subjects, particularly in individuals carrying auto- Abs neutralizing both IFN-α2 and IFN-ω (∼2.7 times higher) 5 5 (SI Appendix, Fig. S3). 2 2 IFR in Individuals Carrying Auto-Abs Neutralizing High Concentrations of Type I IFNs. The age-, sex-, and type I 1 1 <70 ≥70 <70 ≥70 IFN–dependent patterns of IFRAAB observed for carriers of Age (years) Age (years) auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-α2 and -ω IFN-α2 or -ω IFN-α2 IFN-ω IFN-β IFN-ω were similar to those previously obtained for carriers of auto-Abs neutralizing low concentrations of these molecules, Fig. 2. RRDs for individuals with auto-Abs neutralizing different combina- but with higher values. For example, IFRAAB ranged from tions of type I IFNs relative to individuals without such auto-Abs, by age. RRDs are displayed on a logarithmic scale for individuals under and over 3.1% (1.3 to 20.8) before 40 y of age to 68.7% (42.5 to 95.8) 70 y of age with (A) auto-Abs neutralizing low concentrations of IFN-α2 and in those over 80 y old for carriers of auto-Abs neutralizing high IFN-ω, IFN-α2 or IFN-ω, IFN-α2, and IFN-ω and (B) auto-Abs neutralizing concentrations of both IFN-α2 and IFN-ω (Fig. 4B and SI high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, IFN-ω, and IFN-β, relative to individuals without such combinations of auto-Abs. Appendix, Table S7). IFRAAB values were ∼5 times higher in Vertical bars represent the 95% CI. male than in female subjects, across all age groups and auto- 4 of 10 https://doi.org/10.1073/pnas.2200413119 pnas.org A 100 B 100 50 50 20 20 10 10 5 5 2 2 IFRAAB 1 1 0.5 0.5 0.2 0.2 0.1 0.1 0.05 0.05 0.02 0.02 0.01 0.01 <40 40-49 50-59 60-69 70-79 ≥80 <40 40-49 50-59 60-69 70-79 ≥80 Age (years) Age (years) IFN-α2 and -ω IFN-α2 or -ω IFN-α2 IFN-ω IFN-β Fig. 4. SARS-CoV-2 IFRs for carriers of various combinations of neutralizing auto-Abs, by age. IFRAAB values (percent) are displayed, on a logarithmic scale, by age, for individuals with (A) auto-Abs neutralizing low concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, and IFN-ω and (B) auto-Abs neutralizing high concentrations of IFN-α2 and IFN-ω, IFN-α2 or IFN-ω, IFN-α2, IFN-ω, and IFN-β. Vertical bars represent the 95% CI. Horizontal black lines represent the IFR provided by O’Driscoll et al. (6). Abs combinations (SI Appendix, Fig. S4). For carriers of auto- of age and >4% over 70 y of age), whereas the proportion of Abs neutralizing IFN-β (tested only at high concentration), deceased patients with these auto-Abs is stable across age cate- IFRAAB was lower (by a factor of 6 to 71) than for individuals gories (∼15 to 20%). The lower RRD observed in the elderly under the age of 80 y with auto-Abs neutralizing IFN-α2 may be partly explained epidemiologically, by the larger contri- and/or IFN-ω. It ranged from 0.04% (0.01 to 0.16) for indi- bution of other mortality risk factors, such as comorbid condi- viduals under the age of 40 y to 2.2% (0.2 to 9.3) for the tions, which become more frequent with increasing age. At the 70- to 79-y age group. In the oldest age class, IFRAAB was 31. cellular level, aging is associated with immunosenescence, 0% (2.4 to 88.1), similar to that for carriers of auto-Abs against which may contribute to a defective innate and adaptive IFN-α2 or IFN-ω, albeit with a large confidence interval. response to SARS-CoV-2 infection, thereby conferring a predis- position to severe COVID-19 (55). At the molecular level, Discussion global type I IFN immunity in the blood (plasmacytoid den- dritic cells) and respiratory tract (respiratory epithelial cells) has In this study, we took advantage of our previous data (11) to been shown to decline with age (56–59). These epidemiologi- estimate RRDs associated with auto-Abs across age groups. We cal, cellular, and molecular factors probably overlap. Thus, also confirmed, by a simulation study, that, in our design, ORs despite their increasing prevalence with age, auto-Abs against obtained by Firth’s logistic regression were reliable estimates of type I IFNs make a decreasing contribution to the risk of RR. In addition, we used IFR values previously reported for COVID-19 death with age, due to the progressive development the general population (6) to estimate IFRAAB under the plausi- of additional age-dependent risk factors, including other mech- ble hypothesis that the prevalence of auto-Abs in the general anisms of type I IFN deficiency. However, for the very same population is a reliable estimation of the prevalence of auto-Abs reasons, IFRAAB increases dramatically with age in patients with in infected individuals (SI Appendix, Supplemental Materials auto-Abs, reaching 68.7% for carriers of auto-Abs neutralizing and Methods). We report high RRDs for carriers of auto-Abs high concentrations of both IFN-α2 and IFN-ω. neutralizing type I IFNs, ranging from 2.6 for auto-Abs neu- RRD and IFRAAB varied considerably with the IFNs recog- tralizing IFN-β (high concentration) in subjects over 70 y old nized and the concentrations neutralized by auto-Abs. For com- to >150 for auto-Abs neutralizing both IFN-α2 and IFN-ω in binations involving auto-Abs against IFN-α2 and/or IFN-ω, the subjects under 70 y old. For all types of auto-Abs, RRDs were neutralization of low concentrations was associated with a lower 3 to 26 times higher in subjects under 70 y old than in older RRD and a lower IFRAAB than the neutralization of high con- individuals. This is consistent with the increasing prevalence of centrations, suggesting that residual type I IFN activity may be auto-Abs in the general population with age (∼1% under 70 y beneficial in at least some patients. Blood IFN-α concentrations PNAS 2022 Vol. 119 No. 21 e2200413119 https://doi.org/10.1073/pnas.2200413119 5 of 10 during acute asymptomatic or paucisymptomatic SARS-CoV-2 appears to have a much greater predictive value for death, and, infection typically range from 1 pg/mL to 100 pg/mL (11). In by inference, hospitalization and critical COVID-19, than sex, addition, the presence of auto-Abs neutralizing both IFN-α2 comorbidities, and common genetic variants (Fig. 3). and IFN-ω was associated with the highest RRD and IFRAAB values. Interestingly, IFN-α2 and IFN-ω are encoded by two Materials and Methods genes, IFNA2 and IFNW1, that have been shown to have evolved under strong selective constraints (60), consistent with Study Design. We enrolled 1,261 patients aged 20 y to 99 y old who died from COVID-19 pneumonia before SARS-CoV-2 vaccines became available, and their neutralization being harmful to the host. In addition, 34,159 controls from the adult general population from whom samples were patients with auto-Abs against IFN-α2 have been shown to neu- collected before the COVID-19 pandemic, as previously described (11). The tralize all 13 IFN-α subtypes (11, 12), rendering any potential experiments involving human subjects were performed in accordance with insti- IFN-α redundancy inoperative (11, 12). Accordingly, the tutional, local, and national ethical guidelines. Approval was obtained from the IFRAAB values for carriers of auto-Abs against IFN-α2 were French Ethics Committee “Comite de Protection des Personnes,” the French higher than those for carriers of auto-Abs against IFN-ω in sub- National Agency for Medicine and Health Product Safety, and the “Institut jects under 60 y of age. In older age groups, this difference National de la Sante et de la Recherche Medicale,” in France (protocol C10-13, tended to disappear, consistent with the lower impact of auto- ID-RCB number 2010-A00634-35), and the Rockefeller University Institutional Abs in the elderly, as discussed above. Finally, auto-Abs neutral- Review Board in New York (protocol JCA-0700). Participants were consented izing IFN-β were less common, and associated with lower RRD prior to sampling and collection of clinical data. Auto-Ab determinations were and IFRAAB values (by about one order of magnitude) than performed as described by Bastard et al. (11, 66), and were classified as neutral- auto-Abs against IFN-α2 and/or IFN-ω, in all age groups except izing high concentrations (10 ng/mL) of IFN-α2, IFN-ω, or IFN-β, or low concen- the over-80s. This less deleterious effect of auto-Abs neutralizing trations (100 pg/mL) of IFN-α2 or IFN-ω (SI Appendix, Supplemental Materials IFN-β is consistent with a mouse study showing that the block- and Methods). ade of IFN-β alone does not alter the early dissemination of lym- RRDs and IFRs for Carriers of Neutralizing Autoantibodies. We estimated phocytic choriomeningitis virus (61). Overall, auto-Abs against the RRD in individuals carrying auto-Abs neutralizing type I IFNs relative to non- type I IFNs are associated with very high RRD and IFR values, carriers, using large samples of patients who died from COVID-19 and of individ- and the magnitude of this effect appears to be much larger than uals from the general population. For each combination of auto-Abs, a Firth’s that of other known common risk factors apart from age, such bias-corrected logistic regression model, including auto-Ab status, sex, and age, as maleness (Fig. 4), comorbidities, or the most significant com- was fitted (SI Appendix, Table S1). For assessments of the effect of age and sex mon genetic variant on chromosome 3, all of which have been on the RRD due to auto-Abs, we added interaction terms between auto-Abs and associated with life-threatening COVID-19 with ORs of about sex, and auto-Abs and age (SI Appendix, Supplemental Materials and Methods). two (5). A similar Firth’s logistic regression model was used in the subsample of carriers Despite the lower prevalence of these auto-Abs in younger of auto-Abs, to assess the deleteriousness of auto-Abs neutralizing high con- than in older individuals, the much higher IFRAAB observed in centrations relative to those neutralizing low concentrations of type I IFNs individuals with these auto-Abs suggests that the testing of (SI Appendix, Supplemental Materials and Methods). From the RRD, we infected individuals in all age groups is warranted. Particular calculated the PAF to assess the proportion of COVID-19 deaths attributable to attention should be paid to patients, especially children, with auto-Abs. The PAF can be estimated as follows: P(auto-Abs/death) * (1  1/RRD) known autoimmune or genetic conditions associated with the (67), where P(auto-Abs/death) is the prevalence of auto-Abs in deceased production of auto-Abs against type I IFNs. Early treatments patients. could be provided (62), including monoclonal antibodies (63), Our goal was also to estimate the fatality rate upon infection with SARS-CoV-2 new antiviral drugs, and/or IFN-β in the absence of auto-Abs (IFR) in unvaccinated subjects carrying auto-Abs against type I IFNs across age against IFN-β (64, 65). Rescue treatment by plasma exchange groups and sexes. To this end, we used the fatality rate upon infection with is a therapeutic option in patients who already have pneumonia SARS-CoV-2 in the general unvaccinated population provided by O’Driscoll et al. (36). A screening of uninfected elderly people could be consid- (6). We estimated the IFR for carriers of neutralizing auto-Abs infected with SARS- CoV-2 (IFRAAB) following Bayes’ theorem, and using the age-dependent preva- ered, given that these auto-Abs are found in 4% of individuals lence of auto-Abs in deceased patients and in the general population together over 70 y old. Carriers of auto-Abs should be vaccinated against with the reported age-specific IFR (6) as detailed in SI Appendix, Supplemental SARS-CoV-2 as a priority, and should benefit from a booster, Materials and Methods. whatever their age, and, ideally, from a monitoring of their antibody response to the vaccine. They should not receive live- Data Availability. All the data are available in the manuscript or in the sup- attenuated vaccines, including the yellow fever vaccine (YFV- porting information. Plasma, cells, and genomic DNA are available from J.-L.C. 17D) and anti-SARS-CoV-2 vaccines based on the YFV-17D under a material transfer agreement (MTA) with The Rockefeller University or the backbone (66). In cases of SARS-CoV-2 infection, vaccinated 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 patients should be closely monitored. As SARS-CoV-2 vaccina- used are almost exclusively commercially available and nonproprietary. Materials tion coverage increases and mortality due to COVID-19 derived from human samples may be made available on request, subject to any decreases over time, it will be important to reevaluate the risk underlying restrictions concerning such samples. of fatal COVID-19 in vaccinated individuals with and without ACKNOWLEDGMENTS. We thank the patients and their families for placing auto-Abs. It is currently unclear whether these auto-Abs impair their trust in us. We thank the members of both branches of the Laboratory of antibody responses to vaccines, and whether a vaccine-triggered Human Genetics of Infectious Diseases. We thank Y. Nemirovskaya, M. Woollett, antibody response can overcome type I IFN deficiency in D. Liu, S. Boucherit, C. Rivalain, M. Chrabieh, and L. Lorenzo for administrative response to large or even medium-sized viral inocula. Finally, assistance. We also thank the staff of the Imagine facilities: C. Bureau, L. further investigations are required to determine the contribu- Colonna, S. Paillet, N. Ghouas, and M. Sy. We are also grateful to the legal team tion of these auto-Abs to other severe viral diseases, and to elu- and technology transfer staff of the Imagine Institute: M. Pilorges, R. Marlanges, cidate the mechanisms underlying their development, which E. Rubino, W. Loewen, D. Beudin, and N. Wuylens. We thank all the staff of the may be age dependent. In the meantime, auto-Abs against type Imagine Institute, Necker Hospital, and Necker sorting center for help. We thank I IFNs should be considered as a leading common predictor of S. Nagashima (Department of Epidemiology, Infectious Disease Control and Pre- life-threatening COVID-19, after age, as their detection vention, Graduate School of Biomedical and Health Sciences, Hiroshima 6 of 10 https://doi.org/10.1073/pnas.2200413119 pnas.org University, Hiroshima, Japan). The Laboratory of Human Genetics of Infectious Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller Research and Development (Grant JP20fk0108531). G.G. was supported by the University; the St. Giles Foundation; the NIH (Grants R01AI088364 and ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medi- R01AI163029); the National Center for Advancing Translational Sciences; NIH cine from Sorbonne University iCOVID programs. The 3C Study was conducted Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast under a partnership agreement between INSERM, Victor Segalen Bordeaux 2 Grant from Emergent Ventures; Mercatus Center at George Mason University; University, and Sanofi-Aventis. The Fondation pour la Recherche Medicale the Yale Center for Mendelian Genomics and the Genome Sequencing Program funded the preparation and initiation of the study. The 3C Study was also sup- Coordinating Center funded by the National Human Genome Research Institute ported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salaries, (Grants UM1HG006504 and U24HG008956); the Yale High Performance Com- Direction generale de la Sante, Mutuelle Generale de l’Education Nationale, puting Center (Grant S10OD018521); the Fisher Center for Alzheimer’s Research Institut de la Longevite, Conseils Regionaux of Aquitaine and Bourgogne, Fonda- Foundation; the Meyer Foundation; the JPB Foundation; the French National tion de France, and Ministry of Research–INSERM Program “Cohortes et collec- Research Agency (ANR) under the “Investments for the Future” program (Grant tions de donnees biologiques.” S. Debette was supported by the University ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Labo- of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National ratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Cancer Institute, NIH, under Contract 75N91019D00024, Task Order Medical Research (FRM) (Grant EQU201903007798); the French Agency for 75N91021F00001. J.W. is supported by a Research Foundation - Flanders Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the (FWO) Fundamental Clinical Mandate (Grant 1833317N). Sample processing at ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-CO11-0001), IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR- at Vall d’Hebron was also partly supported by research funding from Instituto de 0039) projects; the Square Foundation; Grandir–Fonds de solidarite pour l’En- Salud Carlos III Grant PI17/00660 cofinanced by the European Regional Devel- fance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; opment Fund (ERDF/FEDER). C.R.-G. and colleagues from the Canarian Health The French Ministry of Higher Education, Research, and Innovation (Grant System Sequencing Hub were supported by the Instituto de Salud Carlos III MESRI-COVID-19); Institut National de la Sante et de la Recherche Medicale (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science (INSERM), REACTing-INSERM; and the University Paris Cite. P. Bastard was sup- and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundacion ported by the FRM (Award EA20170638020). P. Bastard., J.R., and T.L.V. were DISA (Grants OA18/017 and OA20/024), and Cabildo Insular de Tenerife (Grants supported by the MD-PhD program of the Imagine Institute (with the support of CGIEU0000219140 and “Apuestas cientıficas del ITER para colaborar en la lucha Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab contra la COVID-19”). T.H.M. was supported by grants from the Novo Nordisk received funding from Centre for Biomedical Research on Rare Diseases Foundation (Grants NNF20OC0064890 and NNF21OC0067157). C.M.B. is sup- (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research ported by a Michael Smith Foundation for Health Research Health Professional- and innovation program under grant agreement 824110 (EASI Genomics). Work Investigator Award. P.Q.H. and L. Hammarstr€om were funded by the European in the Laboratory of Virology and Infectious Disease was supported by the NIH Union’s Horizon 2020 research and innovation program (Antibody Therapy (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Against Coronavirus consortium, Grant 101003650). Work at Y.-L.L.’s laboratory Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable in the University of Hong Kong (HKU) was supported by the Society for the Relief Foundation. The Infanta Leonor University Hospital supported the research of the of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Department of Internal Medicine and Allergology. The French COVID Cohort Croucher Foundation. J.L.F. was supported in part by the Evaluation-Orientation study group was sponsored by INSERM and supported by the REACTing consor- de la Cooperation Scientifique (ECOS) Nord - Cooperation Scientifique France- tium and by a grant from the French Ministry of Health (Grant PHRC 20-0424). Colombie (ECOS-Nord/Columbian Administrative department of Science, Tech- The Cov-Contact Cohort was supported by the REACTing consortium, the French nology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education Ministry of Health, and the European Commission (Grant RECOVER WP 6). This [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad work was also partly supported by the Intramural Research Program of the [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code National Institute of Allergy and Infectious Diseases and the National Institute of 111574455633]). A. Klocperk was, in part, supported by Grants NU20-05-00282 Dental and Craniofacial Research, NIH (Grants ZIA AI001270 to L.D.N. and and NV18-05-00162 issued by the Czech Health Research Council and Ministry 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR- la Recherche (Grant ANR-10-LABX-69-01). K.K.’s group was supported by the UniSR and Ministero della Salute (Grant COVID-2020-12371617). I.M. is a Estonian Research Council, through Grants PRG117 and PRG377. R.H. was sup- Senior Clinical Investigator at the Research Foundation–Flanders and is sup- ported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United ported by the CSL Behring Chair of Primary Immunodeficiencies (PID); by the Arab Emirates, and a COVID-19 research grant (Grant CoV19-0307) from the Uni- Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for versity of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Biotechnology-Grand Challenges - PID grant; by the FWO Grants G0C8517N, Program Grants awarded by the National Health and Medical Research Council G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has of Australia and a University of New South Wales COVID Rapid Response Initia- received funding under the European Union’s Horizon 2020 research and inno- tive Grant. L.I. reports funding from Regione Lombardia, Italy (project “Risposta vation program (Grant Agreement 948959). E.A. received funding from the Hel- immune in pazienti con COVID-19 e co-morbidita”). This research was partially lenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports received funding from the S~ao Paulo Research Foundation (Grant 2020/09702- funding from Biomedical Advanced Research and Development Authority 1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was sup- (Grant HHSO10201600031C). S.O. reports funding from Research Program on ported by a grant from the Meath Foundation. re Je my Manrya,b,1, Paul Bastard a,b,c,2, Adrian Gervaisa,b,2, Tom Le Voyera,b,2, Je remie Rosain a,b,2, Quentin Philippota,b,2, Eleftherios Michailidis d,3, d,3 e,3 Hans-Heinrich Hoffmann , Shohei Eto , Marina Garcia-Prat , Lucy Bizien f,3 a,b,3 , Alba Parra-Martınezf,3, Rui Yang c,3, Liis Haljasma lanie €gig,3, Me Migauda,b,3, Karita Sa €rekannug,3, Julia Maslovskajag,3, Nicolas de Prosth,i, Yacine Tandjaoui-Lambiottej,4, Charles-Edouard Luytk,l, Blanca Amador-Borrerom, Alexandre Gaudetn,o, Julien Poissyn,o, Pascal Morelp,q, Pascale Richardp, Fabrice Cognasser,s, Jesu  s Troya t, Sophie Trouillet-Assantu,v,w, Alexandre Belotu,v,x,y u,v z , Kahina Saker , Pierre Garçon , Jacques G. Rivie re , Jean-Christophe Lagier , Ste f aa phanie Gentilebb,cc, Lindsey B. Rosendd, Elana Shawdd, ee ff Tomohiro Morio , Junko Tanaka , David Dalmau gg,hh , Pierre-Louis Tharaux , Damien Senem, Alain Stepanianjj,kk, Bruno Me ii garbanell, Vasiliki Triantafylliamm, Arnaud Fekkara,nn, James R. Heathoo, Jose  Luis Francopp, Juan-Manuel Anayaqq,5, Jordi Sole -Viola nrr,ss,tt, Luisa Imbertiuu, Andrea Biondivv, Paolo Bonfanti ww, Riccardo Castagnolidd,xx, Ottavia M. Delmontedd, Yu Zhangdd,yy, Andrew L. Snow zz, Steven M. Hollanddd, Catherine M. Biggsaaa, Marcela Moncada-Velezc, Andre s Augusto Ariasc,bbb,ccc, Lazaro Lorenzoa,b, Soraya Boucherita,b, Dany Anglicheauddd,eee, Anna M. Planas fff,ggg, Filomeen Haerynck , Sotirija Duvlis , Tayfun Ozcelikkkk, Sevgi Keleslll, Ahmed A. Bousfihammm,nnn, Jalila El Bakkourimmm,nnn, Carolina Ramirez-Santanaooo, hhh iii,jjj phane Paul ppp, Qiang Pan-Hammarstro Ste € mqqq, Lennart Hammarstro € mqqq, Annabelle Dupontrrr, Alina Kurolapsss, Christine N. Metzttt, Alessandro PNAS 2022 Vol. 119 No. 21 e2200413119 https://doi.org/10.1073/pnas.2200413119 7 of 10 Aiutiuuu, Giorgio Casariuuu, Vito Lampasonavvv, Fabio Ciceriwww, Lucila A. Barreirosxxx, Elena Dominguez-Garridoyyy, Mateus Vidigalzzz, Mayana Zatzzzz, Diederik van de Beekaaaa, Sabina Sahanicbbbb, Ivan Tancevskibbbb, Yurii Stepanovskyycccc, Oksana Boyarchukdddd, Yoko Nukuieeee, Miyuki Tsumurae, Loreto Vidaurffff,gggg, Stuart G. Tangyehhhh,iiii, Sonia Burreljjjj, Darragh Duffy kkkk, Lluis Quintana-Murcillll,mmmm, Adam Klocperknnnn, Nelli Y. Kannoooo, Anna Shcherbinaoooo, Yu-Lung Laupppp, Daniel Leungpppp, Matthieu Coulongeatqqqq, Julien Marlet rrrr,ssss, Rutger Koningaaaa, Luis Felipe Reyestttt,uuuu, Angelique Chauvineau-Greniervvvv, Fabienne Venet wwww,xxxx,yyyy, Guillaume Monneretwwww,yyyy, Michel C. Nussenzweigzzzz,aaaaa, Romain Arrestierh,i, Idris Boudhabhayddd,eee, Hagit Baris-Feldmansss,bbbbb, David Haginbbbbb,ccccc, Joost Wautersddddd, Isabelle Meytseeeee,fffff, Adam H. Dyer ggggg,hhhhh, Sean P. Kennellyggggg,hhhhh, Nollaig M. Bourkehhhhh, Rabih Halwaniiiiii,jjjjj, Fatemeh Saheb Sharif-Askariiiiii, Karim Dorghamkkkkk, Je ro ^ me Sallettelllll, Souad Mehlal lllll Sedkaoui , Suzan AlKhater mmmmm,nnnnn , Rau l Rigo-Bonnin ooooo , Francisco Morandeira ppppp , Lucie Roussel qqqqq,rrrrr , Donald C. Vinhqqqqq,rrrrr, Christian Erikstrup sssss , Antonio Condino-Neto xxx ttttt cccc , Carolina Prando , Anastasiia Bondarenko , Andras N. Spaan  c,uuuuu , Laurent Gilardinvvvvv,wwwww, Jacques Fellay xxxxx,yyyyy,zzzzz, Stanislas Lyonnetaaaaaa, Kaya Bilguvar bbbbbb,cccccc,dddddd,eeeeee, Richard P. Liftonbbbbbb,cccccc,ffffff, Shrikant Manecccccc, HGID Lab6, COVID Clinicians6, COVID-STORM Clinicians6, NIAID Immune Response to COVID Group6, NH-COVAIR Study Group6, Danish CHGE6, Danish Blood Donor Study6, St. James's Hospital, SARS CoV2 Interest Group6, French COVID Cohort Study Group6, Imagine COVID-Group6, The Milieu Inte rieur Consortium6, CoV-Contact Cohort , Amsterdam UMC Covid-19 Biobank Investigators , COVID Human Genetic Effort , CP-COVID-19 Group , CONSTANCES cohort6, 3C- 6 6 6 6 Dijon Study6, Cerba Health-Care6, Etablissement Français du Sang Study group6, Mark S. Andersongggggg, Bertrand Boisson a,b,c, Vivien Be ziat a,b,c, Shen-Ying Zhang a,b,c , Evangelos Andreakos mm,7 , Olivier Hermine b,hhhhhh,7 , Aurora Pujoliiiiii,jjjjjj,kkkkkk,7 €rt Peterson , Trine H. Mogensen , Pa g,7 llllll,mmmmmm,7 , Lee Rowenoo,7, James Mondnnnnnn,7,8, Ste phanie Debetteoooooo,pppppp,7, Xavier de Lamballerieqqqqqq,7, Charles Burdetrrrrrr,ssssss,tttttt,7, Lila Bouadmassssss,uuuuuu,7, Marie Zinsvvvvvv,7, Pere Soler-Palacinf,7, Roger Colobranwwwwww,7, Guy Gorochov kkkkk,xxxxxx,7, Xavier Solanich yyyyyy,7, Sophie Susenrrr,7, Javier Martinez- Picado zzzzzz,aaaaaaa,bbbbbbb,ccccccc,ddddddd,7, Didier Raoultaa,7, Marc Vasseeeeeeee,7, Peter K. Gregersenttt,7, Lorenzo Piemontivvv,7, Carlos Rodrıguez- Gallegott,fffffff,7, Luigi D. Notarangelodd,9, Helen C. Sudd,ggggggg,9, Kai Kisandg,9, Satoshi Okadae,9, Anne Puel a,b,c,9, Emmanuelle Jouanguya,b,c,9, Charles M. Rice d,9, Pierre Tiberghienp,q,9, Qian Zhang a,b,c,9, Jean-Laurent Casanova a,b,c,aaaaa,1,10, Laurent Abela,b,c,10 and Aure lie Cobat a,b,c,1,10 Contributed by Jean-Laurent Casanova; received January 10, 2022; accepted March 17, 2022; reviewed by Mary Carrington, Antoine Flahault, and Amalio Telenti France; mmLaboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation of the Academy of Athens, Author affiliations: aLaboratory of Human Genetics of Infectious Diseases, Necker 11527 Athens, Greece; nnService de Parasitologie-Mycologie, Groupe Hospitalier Pitie  Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; Salpe ^ trie  re, Assistance Publique-Ho ^ pitaux de Paris, 75013 Paris, France; ooInstitute for b pp Imagine Institute, University of Paris, 75015 Paris, France; cSt. Giles Laboratory of Systems Biology, Seattle, WA 98109; Primary Immunodeficiencies Group, Department Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New of Microbiology and Parasitology, School of Medicine, University of Antioquia UdeA, York, NY 10065; dLaboratory of Virology and Infectious Disease, Rockefeller University, 050010 Medellın, Colombia; qqCenter for Autoimmune Disease Research, School of New York, NY 10065; eDepartment of Pediatrics, Graduate School of Biomedical and Medicine and Health Sciences, Universidad del Rosario, 110111 Bogota , Colombia; Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan; fPediatric Infectious rr Intensive Care Medicine, University Hospital of Gran Canaria Dr. Negrın, Canarian Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Vall ss Health System, 35010 Las Palmas de Gran Canaria, Spain; Centro de Investigacio n d’Hebron Research Institute, Universitat Auto  noma de Barcelona, 08035 Barcelona, Biome  dica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain; gInstitute of Biomedicine and Translational Medicine, University of Tartu, 50090 28029 Madrid, Spain; ttDepartment of Clinical Sciences, Universidad Fernando Pessoa h Tartu, Estonia; Service de Me  decine Intensive Re  animation, Ho ^ pitaux Universitaires Canarias, 35450 Las Palmas de Gran Canaria, Spain; uuCHemato-oncology Research Henri Mondor, Assistance Publique-Ho ^ pitaux de Paris, 94010 Cre teil, France; iGroupe Laboratory of Associazione italiana contro le leucemie-linfomi e mieloma, Diagnostic de Recherche Clinique Cardiovascular and Respiratory Manifestations of Acute Lung Departement, Azienda Socio Sanitaria Territoriale, Spedali Civili di Brescia, 25123 Injury and Sepsis (CARMAS), Faculte  de sante  de Cre teil, Universite  Paris Est Cre  teil, Brescia, Italy; vvPediatric Department and Centro Tettamanti-European Reference 94010 Cre teil Cedex, France; jHypoxia and Lung, INSERM U1272, Avicenne Hospital, Network PaedCan, EuroBloodNet, European Reference Network for Rare Hereditary Assistance Publique-Ho ^ pitaux de Paris, 93022 Bobigny, France; Sorbonne Universite k , Metabolic Disorders (MetabERN), University of Milano Bicocca, Fondazione Monza Ho ^ pital Pitie  Salpe ^triere, Me  decine Intensive Re animation, Assistance Publique- Brianza Bambino Mamma (MBBM), Ospedale San Gerardo, 20900 Monza, Italy; Ho ^ pitaux de Paris, 75013 Paris, France; lINSERM, UMRS 1166-iCAN, Institute of ww Department of Infectious Diseases, San Gerardo Hospital, University of Milano Cardiometabolism and Nutrition, 75013 Paris, France; mInternal Medicine Department, Bicocca, 20900 Monza, Italy; xxPediatric Clinic, Fondazione Istituto di Ricovero e Cura a Lariboisie  re Hospital, Assistance Publique-Ho ^ pitaux de Paris, University of Paris, 75010 carattere scientifico (IRCCS) Policlinico San Matteo, Department of Clinical, Surgical, Paris, France; nINSERM U1019–CNRS UMR9017, Center for Infection and Immunity of Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; yyNational Lille, Institut Pasteur de Lille, University of Lille, 59000 Lille, France; oCentre Hospitalier Institute of Allergy and Infectious Diseases (NIAID) Clinical Genomics Program, NIH, Universitaire, de Lille, Po ^ le de Re  animation, Ho ^ pital Roger Salengro Lille, 59000 Lille, Bethesda, MD 20892; zzDepartment of Pharmacology and Molecular Therapeutics, France; pEtablissement Français du Sang, 93218 La Plaine Saint-Denis, France; Uniformed Services University of the Health Sciences, Bethesda, MD 20814; q ^  Interactions Hote-Greffon-Tumeur et Ingenierie Cellulaire et Ge nique (RIGHT), INSERM, aaa Department of Pediatrics, British Columbia Children’s Hospital, University of British Etablissement Français du Sang, Universite  de Franche-Comte  , 25000 Besançon, Columbia, Vancouver, BC V6H 0B3, Canada; bbbPrimary Immunodeficiencies Group, France; Sante r  Inge nie  rie Biologie St-Etienne (SAINBIOSE), INSERM U1059, University of University of Antioquia UdeA, 050010 Medellin, Colombia; cccSchool of Microbiology, Lyon, Universite  Jean Monnet Saint-Etienne, 42000 Saint-Etienne,  France; University of Antioquia UdeA, 050010 Medellin, Colombia; dddDepartment of s Etablissement Français du Sang, Auvergne-Rho  ^ ne-Alpes, 42000 Saint-Etienne, France; Nephrology and Transplantation, Necker University Hospital, Assistance Publique- t Department of Internal Medicine, Infanta Leonor University Hospital, 28031 Madrid, Ho ^ pitaux de Paris, 75743 Paris, France; eeeInstitut Necker Enfants Malades, INSERM Spain; uHospices Civils de Lyon, 69002 Lyon, France; vInternational Center of Research U1151–CNRS UMR 8253, Universite  de Paris, 75015 Paris, France; fffInstitute for in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, Ecole Nationale Biomedical Research, Spanish National Research Council, 08036 Barcelona, Spain; Supe  rieure, Universite  Claude Bernard Lyon 1 (UCBL), 69365 Lyon, France; wJoint ggg Institut d’Investigacions Biome  diques August Pi i Sunyer, 08036 Barcelona, Spain; Research Unit, Hospices Civils de Lyon-BioMe  rieux, Hospices Civils de Lyon, Lyon Sud hhh Department of Paediatric Immunology and Pulmonology, Center for Primary Hospital, 69495 Pierre-Be  nite, France; xNational Referee Centre for Rheumatic, and Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, Ghent Autoimmune and Systemic Diseases in Children, 69000 Lyon, France; University Hospital, 9000 Ghent, Belgium; iiiFaculty of Medical Sciences, University y Immunopathology Federation Lyon Immunopathology Federation (LIFE), Hospices “Goce Delchev,” Stip  2000, Republic of North Macedonia; jjjInstitute of Public Health of Civils de Lyon, 69002 Lyon, France; zIntensive Care Unit, Grand Ho ^ pital de l’Est the Republic of North Macedonia, Skopje 1000, Republic of North Macedonia; Francilien Site de Marne-La-Valle  e, 77600 Jossigny, France; aaMicrobes, Evolution, kkk Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Phyloge  nie et Infection (MEPHI), Institut Hospitalo-Universitaire Me  diterrane e Infection, Turkey; lllMeram Faculty of Medicine, Necmettin Erbakan University, 42080 Konya, Institut de Recherche pour le De  veloppement, Assistance Publique Ho ^ pitaux de Turkey; mmmClinical Immunology Unit, Department of Pediatric Infectious Disease, Marseille, Aix-Marseille Universite , 13005 Marseille, France; bbService d’Evaluation Centre Hospitalier-Universitaire Ibn Roucshd, 20360 Casablanca, Morocco; Me  dicale, Ho ^ pitaux Universitaires de Marseille Assistance Publique Ho ^ pitaux de nnn Laboratoire d’Immunologie Clinique, Inflammation et Allergie (LICIA), Faculty of Marseille, 13005 Marseille, France; ccAix-Marseille University, School of Medicine, EA Medicine and Pharmacy, Hassan II University, 20250 Casablanca, Morocco; oooCenter  3279, Centre d'Etudes et de Recherche sur les Services de Sante et la Qualite   de vie for Autoimmune Disease Research, School of Medicine and Health Sciences, (CEReSS)–Health Service Research and Quality of Life Center, 13385 Marseille, France; Universidad del Rosario, 111211 Bogota , Colombia; pppDepartment of Immunology, dd Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, CIC1408, Groupe sur l’Immunite  des Muqueuses et des Agents Pathoge  nes (GIMAP) National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892; Centre International de Recherche en Infectiologie, INSERM U1111, University Hospital ee Department of Pediatrics and Developmental Biology, Graduate School of Medical   of Saint-Etienne, 42000 Saint-Etienne, France; qqq Department of Biosciences and and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; Nutrition, Karolinska Institutet, 171 77 Stockholm, Sweden; rrrUniversity of Lille, ff Department of Epidemiology, Infectious Disease Control and Prevention, Graduate INSERM, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011- School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, European Genomic Institute for Diabetes (EGID), F-59000 Lille, France; sssThe Genetics Japan; ggHospital Universitari Mu  tuaTerrassa, Universitat de Barcelona, 08193 Institute and Genomics Center, Tel Aviv Sourasky Medical Center, 6423906 Tel Aviv, Barcelona, Spain; hhFundacio  Doce  ncia i Recerca Mutua Terrassa, 08221 Terrassa, Israel; tttFeinstein Institutes for Medical Research, Northwell Health, Manhasset, NY ii Spain; Paris Cardiovascular Research Center (PARCC), INSERM, Universite  de Paris, 11030; uuuVita-Salute San Raffaele University, and Clinical Genomics, Istituto di 75015 Paris, France; jjService d’He matologie Biologique, Ho ^ pital Lariboisie re, Assistance Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, ^  Publique-Hopitaux de Paris, Universite de Paris, 75010 Paris, France; EA3518, Institut kk Italy; vvvDiabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico Universitaire d’He matologie-Ho ^ pital Saint Louis, Universite  de Paris, 75010 Paris, (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy; wwwHematology and Bone France; llRe animation Me  dicale et Toxicologique, Ho ^ pital Lariboisie  re Assistance Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Publique-Ho ^ pitaux de Paris, Universite  de Paris, INSERM, UMRS-1144, 75010 Paris, Ospedale San Raffaele University Vita-Salute San Raffaele, 20132 Milano, Italy; 8 of 10 https://doi.org/10.1073/pnas.2200413119 pnas.org xxx Department of Immunology, Institute of Biomedical Sciences, University of Sa ~o Genetics, Yale University School of Medicine, New Haven, CT 06520; ddddddDepartment Paulo, 05508-060 Sa ~o Paulo, Brazil; yyyFundacio  n Rioja Salud, Centro de Investigacio n of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510;  Biomedica de La Rioja, 26006 Logrono, Spain; ~ zzz ~ University of Sao Paulo, 05508-060 eeeeee Department of Medical Genetics, Acibadem University School of Medicine, 34750 Sa~o Paulo, Brazil; aaaaDepartment of Neurology, Amsterdam UMC, Amsterdam Istanbul, Turkey; ffffffLaboratory of Human Genetics and Genomics, Rockefeller Neuroscience, University of Amsterdam, , Amsterdam, 1105 AZ, The Netherlands; University, New York, NY 10065; ggggggDiabetes Center, University of California, San bbbb Department of Internal Medicine II, Medical University of Innsbruck, 6020 Francisco, CA 94143; hhhhhhDepartment of Hematology, Necker Hospital, Assistance Innsbruck, Austria; ccccShupyk National Healthcare University of Ukraine, 04112 Kyiv, Publique-Ho ^ pitaux de Paris, 75015 Paris, France; iiiiiiNeurometabolic Diseases Ukraine; ddddDepartment of Children’s Diseases and Pediatric Surgery, I. Horbachevsky Laboratory, The Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Ternopil National Medical University, 46022 Ternopil, Ukraine; eeeeDepartment of Spain; jjjjjjCentre for Biomedical Research on Rare Diseases (CIBERER) U759, Instituto de Infection Control and Prevention, Medical Hospital, Tokyo Medical and Dental Salud Carlos III, 28029 Madrid, Spain; kkkkkkCatalan Institution of Research and University, Tokyo 113-8655, Japan; ffffIntensive Care Medicine, Donostia University Advanced Studies (ICREA), 08010 Barcelona, Spain; llllllDepartment of Infectious Hospital, Biodonostia Institute of Donostia, 20014 San Sebastia n, Spain; ggggCentro de Diseases, Aarhus University Hospital, 8000 Aarhus, Denmark; mmmmmmDepartment of Investigacio  n Biome  dica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Biomedicine, Aarhus University, 8000 Aarhus, Denmark; nnnnnnADMA Biologics Inc., hhhh Salud Carlos III, 28029 Madrid, Spain; Garvan Institute of Medical Research, Sydney, Ramsey, NJ 07446; ooooooUniversity of Bordeaux, INSERM, Bordeaux Population Health NWS 2010, Australia; iiiiSt Vincent’s Clinical School, Faculty of Medicine and Health, Center, UMR1219, F-33000 Bordeaux, France; ppppppDepartment of Neurology, Institute University of New South Wales, Sydney, NWS 2010, Australia; jjjjSorbonne Universite , of Neurodegenerative Diseases, Bordeaux University Hospital, F-33000 Bordeaux, INSERM U1136, Institut Pierre Louis d'Epide  miologie et de Sante  Publique, Assistance diterrane  e Infection, Unite des Virus France; qqqqqqInstitut Hospitalo-Universitaire Me Publique-Ho ^ pitaux de Paris, Ho ^ pital Pitie  Salpe ^ trie  re, Service de Virologie, 75013 Paris,   veloppment Emergents, Aix-Marseille University, Institut pour la Recherche et le De France; kkkkTranslational Immunology Unit, Institut Pasteur, Universite  Paris Cite  , 75015 rrrrrr  miologie clinique du Centre (IRD) 190, INSERM 1207, 13005 Marseille, France; Epide Paris, France; llllHuman Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, d’Investigation Clinique (CIC-EP), INSERM CIC 1425, Ho ^ pital Bichat, 75018 Paris, France; 75015 Paris, France; mmmm Department of Human Genomics and Evolution, Colle  ge de ssssss  Universite de Paris, Infection Antimicrobials Modelling Evolution (IAME), UMR 1137, France, 75231 Paris, France; nnnnDepartment of Immunology, 2nd Faculty of Medicine, partement Epide  miologie, Biostatistiques et INSERM, 75870 Paris, France; ttttttDe Charles University and University Hospital in Motol, 150 06 Prague, Czech Republic; ^ pital Bichat, Assistance Publique-Ho ^ pitaux de Paris, 75018 Paris, oooo Recherche Clinique, Ho Department of Immunology, Dmitry Rogachev National Medical Research Center of uuuuuu  animation Me  dicale et des Maladies Infectieuses, Ho ^ pital France; Service de Re Pediatric Hematology, Oncology and Immunology, Moscow, Russia 117997; ^ pitaux de Paris, Nord Universite  de Paris, F-75018 Paris, pppp Bichat, Assistance Publique-Ho Department of Paediatrics and Adolescent Medicine, University of Hong Kong, vvvvvv France; Cohorte Constances Groupe Hospitalier Universitaire centre, Assistance Hong Kong 999077, China; qqqqDivision of Geriatric Medicine, Tours University Medical Publique-Ho ^ pitaux de Paris, Universite  de Paris, 94800 Villejuif, France; Center, 37044 Tours, France; rrrrINSERM U1259, Morphogene  se et Antige  nicite  du VIH wwwwww et des Virus des He  patites (MAVIVH), Universite  de Tours, 37044 Tours, France; Immunology Division, Genetics Department, Hospital Universitari Vall d’Hebron, ssss    Vall d’Hebron Research Institute, Universitat Auto  noma de Barcelona, 08035 Barcelona, Service de Bacteriologie, Virologie et Hygiene Hospitaliere, Centre Hospitalier Spain; xxxxxxDe partement d’Immunologie, Assistance Publique-Ho ^ pitaux de Paris, Universitaire de Tours, 37044 Tours, France; ttttDepartment of Microbiology, Ho^ pital Pitie-Salpetrie re, 75015 Paris, France; yyyyyyDepartment of Internal Medicine, Universidad de La Sabana, 250001 Chıa, Colombia; uuuuDepartment of Critical Care Medicine, Clınica Universidad de La Sabana, 250001 Chıa, Colombia; vvvvService de Hospital Universitari de Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), Biologie Me dicale, Centre Hospitalier Intercommunal Robert Ballanger, 93600 Aulnay- 08908 Barcelona, Spain; zzzzzzIrsiCaixa AIDS Research Institute, 08916 Badalona, Spain; aaaaaaa sous-Bois, France; wwwwLaboratoire d’Immunologie, Hospices Civils de Lyon, Ho ^ pital Institute for Health Science Research Germans Trias i Pujol (IGTP), 08916 Edouard Herriot, 69437 Lyon, France; xxxxCentre International de Recherche en Badalona, Spain; bbbbbbbDepartment of Infectious Diseases and Immunity, University of Infectiologie, INSERM U1111, CNRS, UMR5308, Ecole Normale Supe  rieure de Lyon, Vic-Central University of Catalonia, 08500 Vic, Spain; cccccccCatalan Institution of Universite  Claude Bernard Lyon 1, 69007 Lyon, France; yyyyEA 7426, Pathophysiology of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain; dddddddConsorcio Injury-Induced Immunosuppression, Universite  Claude Bernard Lyon 1, Hospices Civils Centro de Investigacio  n Biome dica en Red de Enfermedades Infecciosas (CIBERINFEC), de Lyon, BioMe  rieux, Ho ^ pital Edouard Herriot, 69437 Lyon, France; zzzzLaboratory of Instituto de Salud Carlos III, 28029 Madrid, Spain; eeeeeeeService de Biologie Clinique Molecular Immunology, Rockefeller University, New York, NY 10065; aaaaaHHMI, and UMR-S 1176, Ho ^ pital Foch, 92150 Suresnes, France; fffffffDepartment of Rockefeller University, New York, NY 10065; bbbbbSackler Faculty of Medicine, Tel Aviv Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, University, 6997801 Tel Aviv, Israel; cccccAllergy and Clinical Immunology Unit, 35010 Las Palmas de Gran Canaria, Spain; and gggggggDepartment of Pathology and Department of Medicine, Tel Aviv Sourasky Medical Center, 6423906 Tel Aviv, Israel; Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, ddddd Medical Intensive Care Unit, University Hospitals Leuven, 3000 Leuven, Belgium; Philadelphia, PA 19104 eeeee Laboratory of Inborn Errors of Immunity, Department of Microbiology, Author contributions: J. Manry, L.A., and A.C. designed research; J. Manry, P. Bastard, Immunology and Transplantation, Katholieke Universiteit Leuven, 3000 Leuven, A. Gervais, T.L.V., J.R., Q.P., E.M., H.-H.H., S.E., M.G.-P., L. Bizien, A.P.-M., R.Y., Belgium; fffffDepartment of Pediatrics, Jeffrey Modell Diagnostic and Research Network €gi, M.M., K. Sa €rekannu, J. Maslovskaja, C.-E.L., S.T.-A., A. Belot, K. Saker, L. Haljasma Center, University Hospitals Leuven, 3000 Leuven, Belgium; gggggDepartment of Age- L.B.R., E.S., A. Fekkar, O.M.D., Y.Z., S.M.H., M.M.-V., A.A.A., B.B., V.B., S.-Y.Z., L.D.N., Related Healthcare, Tallaght University Hospital, Dublin D24 NR0A, Ireland; hhhhh H.C.S., K.K., S.O., A. Puel, E.J., C.M.R., Q.Z., and A.C. performed research; P. Bastard, J.R., Department of Medical Gerontology, School of Medicine, Trinity College Dublin, N.d.P., Y.T.-L., B.A.-B., A. Gaudet, J.P., P.M., P.R., F. Cognasse, J. Troya, S.T.-A., A. Belot, K. Dublin D08 W9RT, Ireland; iiiiiSharjah Institute for Medical Research, College of Saker, P.G., J.G.R., J.-C.L., S.G., T.M., J. Tanaka, D. Dalmau, P.-L.T., D.S., A. Stepanian, Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates; jjjjjImmunology B.M., V.T., J.R.H., J.L.F., J.-M.A., J.S.-V., L.I., A. Biondi, P. Bonfanti, R. Castagnoli, A.L.S., Research Lab, College of Medicine, King Saud University, 11362 Riyadh, Saudi Arabia; kkkkk Sorbonne Universite , INSERM, Centre d’Immunologie et des Maladies Infectieuses, C.M.B., L.L., S. Boucherit, D.A., A.M.P., F.H., S. Duvlis, T.O., S.K., A.A.B., J.E.B., C.R.-S., S.P., Q.P.-H., L. Hammarstro € m, A.D., A. Kurolap, C.N.M., A.A., G.C., V.L., F. Ciceri, L.A.B., E.D.-G., 75013 Paris, France; lllllCerba HealthCare, 92130 Issy-les-Moulineaux, France; mmmmm Department of Pediatrics, King Fahad Hospital of the University, Al Khobar M. Vidigal, M. Zatz, D.v.d.B., S. Sahanic, I.T., Y.S., O.B., Y.N., M.T., L.V., S.G.T., S. Burrel, D. 34445, Saudi Arabia; nnnnnCollege of Medicine, Imam Abdulrahman Bin Faisal Duffy, L.Q.-M., A. Klocperk, N.Y.K., A. Shcherbina, Y.-L.L., D.L., M. Coulongeat, J. Marlet, University, Dammam 34212, Saudi Arabia; oooooDepartment of Clinical Laboratory, R.K., L.F.R., A.C.-G., F.V., G.M., M.C.N., R.A., I.B., H.B.-F., D.H., J.W., I.M., A.H.D., S.P.K., Hospital Universitari de Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), N.M.B., R.H., F.S.S.-A., K.D., J.S., S.M.S., S.A., R.R.-B., F.M., L. Roussel, D.C.V., C.E., A.C.-N., 08908 Barcelona, Spain; pppppDepartment of Immunology, Hospital Universitari de C.P., A. Bondarenko, A.N.S., L.G., J.F., S.L., K.B., R.P.L., S.M., M.S.A., E.A., O.H., A. Pujol, Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain; P.P., T.H.M., L. Rowen, J. Mond, S. Debette, X.d.L., C.B., L. Bouadma, M. Zins, P.S.-P., qqqqq Department of Medicine, Division of Infectious Diseases, McGill University Health R. Colobran, G.G., X.S., S. Susen, J.M.-P., D.R., M. Vasse, P.K.G., L.P., C.R.-G., L.D.N., Centre, Montre  al, QC H4A 3J1, Canada; rrrrrInfectious Disease Susceptibility Program, H.C.S., P.T., Q.Z., and J.-L.C. contributed new reagents/analytic tools; J. Manry, L.A., and Research Institute of the McGill University Health Centre, Montre al, QC H4A 3J1, A.C. analyzed data; and J. Manry, J.-L.C., L.A., and A.C. wrote the paper. Canada; sssssDepartment of Clinical Immunology, Aarhus University Hospital, 8000 Reviewers: M. Carrington, Frederick National Laboratory for Cancer Research; A. Aarhus, Denmark; ttttt Faculdades Pequeno Prıncipe, Instituto de Pesquisa Pele  Pequeno Flahault, Universite de Geneve Institut de Sante Globale; and A.T., Scripps Center for Prıncipe, 80250-200 Curitiba, Brazil; uuuuuDepartment of Medical Microbiology, Integrative Medicine. vvvvv University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Service de Me  decine Interne, Ho ^ pital Universitaire Jean-Verdier, Assistance Publique-Ho ^ pitaux de The authors declare a competing interest. J.-L.C. is an inventor on patent application Paris, 93140 Bondy, France; wwwwwINSERM U1138, Centre de Recherche des Cordeliers, PCT/US2021/042741, filed 22 July 2021, submitted by The Rockefeller University, which 75006 Paris, France; xxxxxSchool of Life Sciences, Ecole  Polytechnique Fe  de rale de covers diagnosis of, susceptibility to, and treatment of viral disease and viral vaccines, Lausanne, 1015 Lausanne, Switzerland; yyyyyPrecision Medicine Unit, Lausanne including COVID-19 and vaccine-associated diseases. M.C.N. is an inventor on patent University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; zzzzzSwiss application PCT/US2021/070472 submitted by The Rockefeller University that covers Institute of Bioinformatics, 1015 Lausanne, Switzerland; aaaaaaImagine Institute, neutralizing anti-SARS-CoV-2 antibodies and methods of the use thereof. M.C.N. 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