# The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Jérémy Manry, Paul Bastard, Adrian Gervais, Tom Le Voyer, Jérémie Rosain, Quentin Philippot, Eleftherios Michailidis, Hans-Heinrich Hoffmann, Shohei Eto, Marina Garcia-Prat, et al.

► To cite this version:

Jérémy Manry, Paul Bastard, Adrian Gervais, Tom Le Voyer, Jérémie Rosain, et al. The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Proceedings of the National Academy of Sciences of the United States of America, 2022, 119 (21), pp.349-363. 10.1073/pnas.2200413119. hal-03856619v2

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# 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 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 old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging 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 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

COVID-19 | type I IFNs | autoantibodies | relative risk | infection fatality rate

There have already been more than 250 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and at least 5 million deaths from COVID-19 worldwide. Interindividual clinical variability in the course of infection with SARS-CoV-2 is immense, ranging from silent infection in about 40% of cases to acute respiratory 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 doubling every 5 y of age from childhood onward (6, 7). Men are also at greater risk of death than women (5, 8). Based on previously identified inborn errors of type I interferon (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 SARS-CoV-2 (11–14). We have reported that inborn errors of Toll-like receptor 3 (TLR3)-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in a small subset of patients (14). Biochemically deleterious mutations of eight genes were found in 23 patients with critical COVID-19 (3.5% of 659 patients), including 18 patients under 60 y old. Remarkably, four unrelated patients, aged 25 y to 50 y, had autosomal recessive (AR) deficiencies of IFNAR1 or IRF7, including three homozygotes (two for *IFNAR1* and one for *IRF7*) and one compound heterozygote (for *IRF7*). Three other patients with AR IFNAR1 or TBK1 deficiency were independently reported (15–17). The penetrance of those defects is unknown, but it is probably higher for AR than for autosomal dominant disorders. We then reported that X-linked recessive TLR7 deficiency accounted for 1.8% of cases of life-threatening COVID-19 in men under 60 y old (13, 18). The penetrance of this disorder is apparently high but incomplete, especially in children. Deficiencies of IFNAR1 and IRF7 blunt type I IFN immunity across cell types, whereas defects of the TLR3 and TLR7 pathway preferentially affect respiratory epithelial cells and plasmacytoid dendritic cells, respectively (13, 19).

We have also reported the presence of autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, with plasma diluted 1/10) of IFN-α2 and/or IFN-ω in about 10% of patients with critical COVID-19 pneumonia but not in individuals with asymptomatic or mild infection (12). This finding has already been replicated in 14 other cohorts (20–35). We then detected auto-Abs neutralizing lower, more physiological concentrations (100 pg/mL, with plasma diluted 1/10) of IFN-α2 and/or IFN-ω in 13.6% of patients with life-threatening COVID-19, and 18% of deceased patients

## Significance

There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women.

Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

<footnote n="1">¹To whom correspondence may be addressed. Email: jeremy.manyry@inserm.fr, casanova@rockefeller.edu, or aurelie.cobat@inserm.fr.</footnote>

<footnote n="2">²P. Bastard, A. Gervais, T.L.V., J.R., and Q.P. contributed equally to this work.</footnote>

<footnote n="3">³E.M., H.-H.H., S.E., M.G.-P., L. Bizien, A.P.-M., R.Y., L. Haljasmägi, M.M., K. Särekannu, and J. Maslovskaja contributed equally to this work.</footnote>

<footnote n="4">⁴Present address: Hypoxia and Lung INSERM U1272, Pneumologie & Infectiologie INSERM UMR 1137, Infection Antimicrobials Modelling Evolution, Centre Hospitalier Saint-Denis, 93200 Saint-Denis, France.</footnote>

<footnote n="5">⁵Present address: National Academy of Medicine of Colombia, 110231 Bogota, Colombia.</footnote>

<footnote n="6">⁶Lists of members of consortia are available in SI Appendix.</footnote>

<footnote n="7">⁷E.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. 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.</footnote>

<footnote n="8">⁸Present address: Gain Therapeutics, 6900 Lugano, Switzerland.</footnote>

<footnote n="9">⁹L.D.N., H.C.S., K.K., S.O., A. Puel, E.J., C.M.R., P.T., Q.Z. contributed equally to this work.</footnote>

<footnote n="10">¹⁰J.-L.C., L.A., and A.C. contributed equally to this work.
This article contains supporting information online at http://www.pnas.org/lookup/suppl/doi:10.1073/pnas. 2200413119--/DCSupplemental.</footnote>
<table><caption>Table 1. Lines of evidence suggesting that auto-Abs against type I IFNs are strong determinants of the risk of life-threatening COVID-19</caption><thead><tr><th>Evidence</th><th>Examples</th><th>References</th></tr></thead><tbody><tr><td>Auto-Abs against type I IFNs are present before SARS-CoV-2 infection</td><td>In patients for whom a sample collected before the COVID-19 pandemic was available, the auto-Abs were found to preexist infection.<br>These auto-Abs are found in the uninfected general population, and their prevalence increases after the age of 65 y.</td><td>(36)</td></tr><tr><td>Auto-Abs are associated with COVID-19 severity</td><td>Patients with inborn errors underlying these auto-Abs from infancy onward (e.g., APS-1) have a very high risk of developing critical COVID-19 pneumonia.<br>The population of patients with critical disease includes a higher 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).<br>The results concerning the proportions of critical cases with auto-Abs against type I IFNs have already been replicated in >15 different cities (Americas, Europe, Asia).</td><td>(11)<br>(36)<br>(11)<br>(20, 23–35)</td></tr><tr><td>Auto-Abs against type I IFNs neutralize host antiviral activity</td><td>These auto-Abs neutralize the antiviral activity of type I IFNs against SARS-CoV-2 in vitro.<br>These auto-Abs are found in vivo in the blood of SARS-CoV-2-infected patients, where they neutralize type I IFN.<br>These auto-Abs are found in vivo in the respiratory tract of patients, where they neutralize type I IFN.<br>A key virulence factor of SARS-CoV-2 in vitro is its capacity to impair type I IFN immunity.<br>Animals with type I IFN deficiency develop critical disease, including animals treated with mAbs that neutralize type I IFNs.</td><td>(12)<br>(37)<br>(38–40)<br>(41)<br>(42)</td></tr><tr><td>Auto-Abs against cytokines are clinical phenocopies of the corresponding inborn errors</td><td>Patients with auto-Abs against type I IFNs are phenocopies of IFNAR1<sup>-/-</sup>, IFNAR2<sup>-/-</sup>, and IRF7<sup>-/-</sup> patients with critical COVID-19 pneumonia.<br>Patients with auto-Abs against IL-6, IL-17, GM-CSF, and type II IFN are phenocopies of the corresponding inborn errors and underlie staphylococcal disease, mucocutaneous candidiasis, nocardiosis, and mycobacterial diseases, respectively.</td><td>(14)<br>(43–51)</td></tr></tbody></table>

(11). The proportion of male patients was greater in patients with auto-Abs than in patients without auto-Abs (11, 12). In addition, 1.3% of patients with critical COVID-19 had auto-Abs neutralizing IFN-β (10 ng/mL, with plasma diluted 1/10), most without auto-Abs neutralizing IFN-α2 or IFN-ω. The prevalence of auto-Abs neutralizing IFN-α2 and/or IFN-ω in the general population increased with age, from 0.18% for 10 ng/mL and 1% for 100 pg/mL in individuals between 18 y and 69 y old to 3.4% for 10 ng/mL and 6.3% for 100 pg/mL for individuals over 80 y old (11). The prevalence of auto-Abs against IFN-β did not increase with age. The crude odds ratios (ORs) for critical COVID-19 as opposed to asymptomatic or mild infection in auto-Ab carriers relative to noncarriers ranged from 3 to 67, depending on the type I IFNs recognized and the concentrations neutralized (11). At least 12 lines of evidence strongly suggest that auto-Abs against type I IFNs are strong determinants of COVID-19 death (Table 1). The specific impact of these auto-Abs on COVID-19 mortality according to age and sex remains unknown and is of major interest (52, 53), as both the prevalence of these auto-Abs and the risk of death increase with age and are higher in men. Here, using data reported by Bastard et al. (11), we estimated the relative risk of COVID-19 death (RRD) for type I IFN auto-Ab carriers relative to noncarriers and the corresponding SARS-CoV-2 infection fatality rate (IFR), by sex and age category.

## Results

**Patients and Controls.** We estimated the RRD of individuals carrying auto-Abs neutralizing type I IFNs relative to noncarriers by Firth's logistic regression, using large samples of 1,261 patients who died from COVID-19 and 34,159 individuals from the general population from whom samples were collected before the pandemic. In this study design, in which controls are sampled from the baseline population regardless of disease status, the ORs obtained by logistic regression approximate the relative risks (RRs) in the absence of the assumption of rare disease (54) (*SI Appendix, Supplementary Materials and Methods*). We confirmed that this statement remains valid in our study design, using Firth's logistic regression by a simulation study (*SI Appendix, Supplementary Materials and Methods* and Fig. S1). For auto-Abs neutralizing low concentrations (100 pg/mL) of IFN-α2 and/or IFN-ω, we used 1,121 patients who died from COVID-19, and 10,778 individuals from the general population (Table 2). Assessments of auto-Abs neutralizing high concentrations (10 ng/mL) of IFN-α2 and/or IFN-ω were available for 1,094 deceased patients, and 34,159 individuals from the general population (Table 2). We also had assessments of auto-Abs neutralizing 10 ng/mL of IFN-β for a subsample of 636 deceased patients, and 9,126 individuals from the general population (Table 2). RRDs were estimated by means of Firth's
<table><caption>Table 2. Characteristics of the general population cohort and of the cohort of patients who died from COVID-19</caption><thead><tr><th rowspan="2">Characteristics</th><th colspan="2">Neutralization 100 pg/mL</th><th colspan="2">Neutralization 10 ng/mL</th></tr><tr><th>General population<br>(n = 10,778)</th><th>Deceased patients<br>(n = 1,121)</th><th>General population<br>(n = 34,159)</th><th>Deceased patients<br>(n = 1,094)</th></tr></thead><tbody><tr><td>Male – no. (percent)</td><td>5,429 (50.4)*</td><td>821 (73.2)</td><td>17,859 (52.3)</td><td>805 (73.5)</td></tr><tr><td>Mean age ± SD* –<br>years</td><td>62.3 ± 17.2</td><td>70.7 ± 13.0</td><td>52.7 ± 18.2</td><td>70.6 ± 13.1</td></tr><tr><td>Age distribution –<br>no. (percent)</td><td></td><td></td><td></td><td></td></tr><tr><td>20 y to 39 y</td><td>1,251 (11.6)</td><td>17 (1.5)</td><td>9,102 (26.6)</td><td>15 (1.4)</td></tr><tr><td>40 y to 49 y</td><td>1,459 (13.5)</td><td>43 (3.8)</td><td>5,403 (15.8)</td><td>47 (4.3)</td></tr><tr><td>50 y to 59 y</td><td>1,736 (16.1)</td><td>144 (12.8)</td><td>6,414 (18.9)</td><td>152 (13.9)</td></tr><tr><td>60 y to 69 y</td><td>2,475 (23.0)</td><td>307 (27.4)</td><td>6,881 (20.1)</td><td>289 (26.4)</td></tr><tr><td>70 y to 79 y</td><td>1,790 (16.6)</td><td>307 (27.4)</td><td>3,721 (10.9)</td><td>296 (27.1)</td></tr><tr><td>≥80 y</td><td>2,067 (19.2)</td><td>303 (27.0)</td><td>2,638 (7.7)</td><td>295 (27.0)</td></tr><tr><td>Auto-Ab – no. of<br>carriers (percent)</td><td></td><td></td><td></td><td></td></tr><tr><td>IFN-α2 and IFN-ω</td><td>65 (0.6)</td><td>102 (9.1)</td><td>45 (0.1)</td><td>75 (6.8)</td></tr><tr><td>IFN-α2 or IFN-ω</td><td>246 (2.3)</td><td>203 (18.1)</td><td>181 (0.5)</td><td>130 (11.9)</td></tr><tr><td>IFN-α2</td><td>151 (1.4)</td><td>140 (12.5)</td><td>117 (0.3)</td><td>118 (10.8)</td></tr><tr><td>IFN-ω</td><td>160 (1.5)</td><td>165 (14.7)</td><td>109 (0.3)</td><td>87 (8.0)</td></tr><tr><td>IFN-β†</td><td>NA</td><td>NA</td><td>24 (0.3)</td><td>6 (0.9)</td></tr></tbody></table>

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 outcome and adjusting for sex and age in six classes (20 y to 39 y, 40 y to 49 y, 50 y to 59 y, 60 y to 69 y, 70 y to 79 y, and ≥80 y). For assessment of the effect of age and sex on RRD, we added interaction terms between auto-Abs and age, and auto-Abs and sex terms to the logistic model (*Materials and Methods* and *SI Appendix, Supplementary Materials and Methods*).

**RRD for Carriers of Auto-Abs Neutralizing Low Concentrations of Type I IFNs.** We first estimated the RRD for individuals carrying auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω. As expected, increasing age and maleness were highly significantly associated with greater risk of COVID-19 death (P values ≤ 10⁻¹⁶; *SI Appendix, Table S1*). Different age classes were used to test the interaction with the presence of auto-Abs, and the best fit was obtained with a two-age class model (20 y to 69 y and ≥70 y; *SI Appendix, Table S2*) with a significant effect of the interaction term between auto-Abs and age (P value = 4 × 10⁻⁶). The RRD associated with auto-Abs did not vary significantly with sex (P value = 0.81). These interaction results are fully consistent with the distribution of RRD according to age (Fig. 1A) and sex (Fig. 1B), with a clear decrease in RRD after the age of 70 y, and no sex effect. Overall, the RRD for individuals carrying auto-Abs neutralizing IFN-α2 or IFN-ω decreased from 17.0 (95% CI: 11.7 to 24.7) before the age of 70 y to 5.8 (4.5 to 7.4) for individuals ≥70 y old (Fig. 2A and *SI Appendix, Table S3*). We then applied the same strategy to other combinations of auto-Abs neutralizing low concentrations of IFN, and observed similar age effects on RRDs (*SI Appendix, Table S1*). The presence of auto-Abs neutralizing both IFN-α2 and IFN-ω was associated with the highest RRD, estimated at 188.3 (45.8 to 774.4) for individuals under the age of 70 y and 7.2 (5.0 to 10.3) for those over 70 y old (Fig. 2A and *SI Appendix, Table S3*). We also estimated the

population attributable fraction (PAF), to assess the proportion of COVID-19 deaths attributable to auto-Abs (*SI Appendix, Supplemental Materials and Methods*). Given the high RRD estimated for all combinations of auto-Abs neutralizing low concentrations of type I IFNs, the PAF was very close to the prevalence of these auto-Abs in deceased patients (*SI Appendix, Table S3*).

**RRD for Carriers of Auto-Abs Neutralizing High Concentrations of Type I IFNs.** We then estimated the RRD for the presence versus the absence of auto-Abs neutralizing high concentrations (10 ng/mL) of type I IFN. The effect of age on RRD was similar to that observed with auto-Abs neutralizing low concentrations of type I IFN, with the use of two age classes providing the best fit (*SI Appendix, Tables S2 and S4*), and a decrease of RRD with age (Fig. 2B and *SI Appendix, Table S5*). The RRD for carriers of IFN-α2 or IFN-ω auto-Abs decreased from 62.4 (38.4 to 101.3) before the age of 70 y to 6.8 (5.1 to 9.2) after the age of 70 y, whereas carriers of auto-Abs against both IFN-α2 and IFN-ω had the highest RRD, estimated at 156.5 (57.8 to 423.4) and 12.9 (8.4 to 19.9) for subjects <70 y and ≥70 y old, respectively (Fig. 2B and *SI Appendix, Table S5*). Individuals carrying auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-ω had a significantly higher RRD than individuals carrying only auto-Abs neutralizing low concentrations (*SI Appendix, Supplemental Materials and Methods*). This finding, consistent with the higher proportion of auto-Abs neutralizing high concentrations in deceased patients than in the general population (*SI Appendix, Fig S2*), suggests a more deleterious impact of auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-ω on COVID-19 outcomes. Finally, auto-Abs neutralizing high doses of IFN-β had the lowest RRD before 70 y (7.0 [2.2 to 22.4]), with no significant age-dependent association (P value = 0.37). The PAF for auto-Abs neutralizing high concentrations of type I IFNs was also
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** RRDs for individuals with auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω relative to individuals without such auto-Abs, by age and 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.</figcaption></figure>

close to the prevalence of these auto-Abs in deceased patients (SI Appendix, Table S5).

**IFR in Individuals Carrying Auto-Abs Neutralizing Low Concentrations of Type I IFNs.** We then estimated the IFR in SARS-CoV-2-infected individuals carrying auto-Abs neutralizing

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** RRDs for individuals with auto-Abs neutralizing different combinations 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 70 y of age 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, relative to individuals without such combinations of auto-Abs. Vertical bars represent the 95% CI.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Fig. 3.** SARS-CoV-2 IFRs by age. IFRs are provided for the general population for both sexes (gray) and for males only (blue), from the data of O'Driscoll et al. (6); IFR<sub>AAB</sub> (green) are shown for individuals carrying auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω. Auto-Abs against type I IFNs are associated with high RRDs and strongly increase the IFR, to a much greater extent than being male, and, by inference, than other common classical risk factors providing ORs of death similar to that for being male (around two), such as certain comorbid conditions, or the most significant common genetic variant on chromosome 3 (5).</figcaption></figure>

low concentrations of type I IFNs (IFR<sub>AAB</sub>). According to Bayes' theorem, IFR<sub>AAB</sub> can be expressed as a function of the age-dependent prevalence of auto-Abs in deceased patients and in the general population together with the reported age-specific IFR (6) (SI Appendix). For all combinations of auto-Abs, the IFR<sub>AAB</sub> was much higher than the overall IFR. Fig. 3 illustrates this much higher IFR for carriers of auto-Abs neutralizing low concentrations of IFN-α2 or IFN-ω; it exceeded 1% and 10% for subjects over the ages of 40 y and 60 y, respectively. Considering other combinations of auto-Abs, the highest IFR<sub>AAB</sub> was observed 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. 4A and SI Appendix, Table S6). IFR<sub>AAB</sub> values were similar for all other combinations of auto-Abs. For example, the IFR<sub>AAB</sub> for individuals carrying auto-Abs neutralizing either IFN-α2 or IFN-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 exception was noted for the IFR<sub>AAB</sub> of carriers of anti-IFN-α2 auto-Abs, which was 1.8 to 2.6 times higher than that for carriers of auto-Abs neutralizing IFN-α2 or IFN-ω in subjects under 60 y old. The IFR<sub>AAB</sub> was also generally higher in male subjects than in female subjects, particularly in individuals carrying auto-Abs neutralizing both IFN-α2 and IFN-ω (~2.7 times higher) (SI Appendix, Fig. S3).

**IFR in Individuals Carrying Auto-Abs Neutralizing High Concentrations of Type I IFNs.** The age-, sex-, and type I IFN-dependent patterns of IFR<sub>AAB</sub> observed for carriers of auto-Abs neutralizing high concentrations of IFN-α2 and/or IFN-ω were similar to those previously obtained for carriers of auto-Abs neutralizing low concentrations of these molecules, but with higher values. For example, IFR<sub>AAB</sub> ranged from 3.1% (1.3 to 20.8) before 40 y of age to 68.7% (42.5 to 95.8) in those over 80 y old for carriers of auto-Abs neutralizing high concentrations of both IFN-α2 and IFN-ω (Fig. 4B and SI Appendix, Table S7). IFR<sub>AAB</sub> values were ~5 times higher in male than in female subjects, across all age groups and auto-
<figure><img src="image_6.png" /><figcaption>**Fig. 4.** SARS-CoV-2 IFRs for carriers of various combinations of neutralizing auto-Abs, by age. IFR<sub>AAB</sub> 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).</figcaption></figure>

Abs combinations (*SI Appendix*, Fig. S4). For carriers of auto-Abs neutralizing IFN-β (tested only at high concentration), IFR<sub>AAB</sub> was lower (by a factor of 6 to 71) than for individuals under the age of 80 y with auto-Abs neutralizing IFN-α2 and/or IFN-ω. It ranged from 0.04% (0.01 to 0.16) for individuals under the age of 40 y to 2.2% (0.2 to 9.3) for the 70- to 79-y age group. In the oldest age class, IFR<sub>AAB</sub> was 31.0% (2.4 to 88.1), similar to that for carriers of auto-Abs against IFN-α2 or IFN-ω, albeit with a large confidence interval.

Discussion

In this study, we took advantage of our previous data (11) to
estimate RRDs associated with auto-Abs across age groups. We
also confirmed, by a simulation study, that, in our design, ORs
obtained by Firth's logistic regression were reliable estimates of
RR. In addition, we used IFR values previously reported for
the general population (6) to estimate IFR<sub>AAB</sub> under the plausi-
ble hypothesis that the prevalence of auto-Abs in the general
population is a reliable estimation of the prevalence of auto-Abs
in infected individuals (SI Appendix, Supplemental Materials
and Methods). We report high RRDs for carriers of auto-Abs
neutralizing type I IFNs, ranging from 2.6 for auto-Abs neu-
ralizing IFN-β (high concentration) in subjects over 70 y old
to >150 for auto-Abs neutralizing both IFN-α2 and IFN-ω in
subjects under 70 y old. For all types of auto-Abs, RRDs were
3 to 26 times higher in subjects under 70 y old than in older
individuals. This is consistent with the increasing prevalence of
auto-Abs in the general population with age (~1% under 70 y

of age and >4% over 70 y of age), whereas the proportion of
deceased patients with these auto-Abs is stable across age cate-
gories (~15 to 20%). The lower RRD observed in the elderly
may be partly explained epidemiologically, by the larger contri-
bution of other mortality risk factors, such as comorbid condi-
tions, which become more frequent with increasing age. At the
cellular level, aging is associated with immunosenescence,
which may contribute to a defective innate and adaptive
response to SARS-CoV-2 infection, thereby conferring a predis-
position to severe COVID-19 (55). At the molecular level,
global type I IFN immunity in the blood (plasmacytoid den-
dritic cells) and respiratory tract (respiratory epithelial cells) has
been shown to decline with age (56–59). These epidemiologi-
cal, cellular, and molecular factors probably overlap. Thus,
despite their increasing prevalence with age, auto-Abs against
type I IFNs make a decreasing contribution to the risk of
COVID-19 death with age, due to the progressive development
of additional age-dependent risk factors, including other mech-
anisms of type I IFN deficiency. However, for the very same
reasons, IFR<sub>AAB</sub> increases dramatically with age in patients with
auto-Abs, reaching 68.7% for carriers of auto-Abs neutralizing
high concentrations of both IFN-α2 and IFN-ω.

RRD and IFR<sub>AAB</sub> varied considerably with the IFNs recog-
nized and the concentrations neutralized by auto-Abs. For com-
binations involving auto-Abs against IFN-α2 and/or IFN-ω, the
neutralization of low concentrations was associated with a lower
RRD and a lower IFR<sub>AAB</sub> than the neutralization of high con-
centrations, suggesting that residual type I IFN activity may be
beneficial in at least some patients. Blood IFN-α concentrations
during acute asymptomatic or paucisymptomatic SARS-CoV-2 infection typically range from 1 pg/mL to 100 pg/mL (11). In addition, the presence of auto-Abs neutralizing both IFN-α2 and IFN-ω was associated with the highest RRD and IFR<sub>AAB</sub> values. Interestingly, IFN-α2 and IFN-ω are encoded by two genes, *IFNA2* and *IFNW1*, that have been shown to have evolved under strong selective constraints (60), consistent with their neutralization being harmful to the host. In addition, patients with auto-Abs against IFN-α2 have been shown to neutralize all 13 IFN-α subtypes (11, 12), rendering any potential IFN-α redundancy inoperative (11, 12). Accordingly, the IFR<sub>AAB</sub> values for carriers of auto-Abs against IFN-α2 were higher than those for carriers of auto-Abs against IFN-ω in subjects under 60 y of age. In older age groups, this difference tended to disappear, consistent with the lower impact of auto-Abs in the elderly, as discussed above. Finally, auto-Abs neutralizing IFN-β were less common, and associated with lower RRD and IFR<sub>AAB</sub> values (by about one order of magnitude) than auto-Abs against IFN-α2 and/or IFN-ω, in all age groups except the over-80s. This less deleterious effect of auto-Abs neutralizing IFN-β is consistent with a mouse study showing that the blockade of IFN-β alone does not alter the early dissemination of lymphocytic choriomeningitis virus (61). Overall, auto-Abs against type I IFNs are associated with very high RRD and IFR values, and the magnitude of this effect appears to be much larger than that of other known common risk factors apart from age, such as maleness (Fig. 4), comorbidities, or the most significant common genetic variant on chromosome 3, all of which have been associated with life-threatening COVID-19 with ORs of about two (5).

Despite the lower prevalence of these auto-Abs in younger
than in older individuals, the much higher IFR<sub>AAB</sub> observed in
individuals with these auto-Abs suggests that the testing of
infected individuals in all age groups is warranted. Particular
attention should be paid to patients, especially children, with
known autoimmune or genetic conditions associated with the
production of auto-Abs against type I IFNs. Early treatments
could be provided (62), including monoclonal antibodies (63),
new antiviral drugs, and/or IFN-β in the absence of auto-Abs
against IFN-β (64, 65). Rescue treatment by plasma exchange
is a therapeutic option in patients who already have pneumonia
(36). A screening of uninfected elderly people could be consid-
ered, given that these auto-Abs are found in 4% of individuals
over 70 y old. Carriers of auto-Abs should be vaccinated against
SARS-CoV-2 as a priority, and should benefit from a booster,
whatever their age, and, ideally, from a monitoring of their
antibody response to the vaccine. They should not receive live-
attenuated vaccines, including the yellow fever vaccine (YFV-
17D) and anti-SARS-CoV-2 vaccines based on the YFV-17D
backbone (66). In cases of SARS-CoV-2 infection, vaccinated
patients should be closely monitored. As SARS-CoV-2 vaccina-
tion coverage increases and mortality due to COVID-19
decreases over time, it will be important to reevaluate the risk
of fatal COVID-19 in vaccinated individuals with and without
auto-Abs. It is currently unclear whether these auto-Abs impair
antibody responses to vaccines, and whether a vaccine-triggered
antibody response can overcome type I IFN deficiency in
response to large or even medium-sized viral inocula. Finally,
further investigations are required to determine the contribu-
tion of these auto-Abs to other severe viral diseases, and to elu-
cidate the mechanisms underlying their development, which
may be age dependent. In the meantime, auto-Abs against type
I IFNs should be considered as a leading common predictor of
life-threatening COVID-19, after age, as their detection

appears to have a much greater predictive value for death, and,
by inference, hospitalization and critical COVID-19, than sex,
comorbidities, and common genetic variants (Fig. 3).

**Materials and Methods**

**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 34,159 controls from the adult general population from whom samples were collected before the COVID-19 pandemic, as previously described (11). The experiments involving human subjects were performed in accordance with institutional, local, and national ethical guidelines. Approval was obtained from the French Ethics Committee "Comité de Protection des Personnes," the French National Agency for Medicine and Health Product Safety, and the "Institut National de la Santé et de la Recherche Médicale," in France (protocol C10-13, ID-RCB number 2010-A00634-35), and the Rockefeller University Institutional Review Board in New York (protocol JCA-0700). Participants were consented prior to sampling and collection of clinical data. Auto-Ab determinations were performed as described by Bastard et al. (11, 66), and were classified as neutralizing high concentrations (10 ng/mL) of IFN-α2, IFN-ω, or IFN-β, or low concentrations (100 pg/mL) of IFN-α2 or IFN-ω (SI Appendix, Supplemental Materials and Methods).

**RRDs and IFRs for Carriers of Neutralizing Autoantibodies.** We estimated the RRD in individuals carrying auto-Abs neutralizing type I IFNs relative to non-carriers, using large samples of patients who died from COVID-19 and of individuals from the general population. For each combination of auto-Abs, a Firth's bias-corrected logistic regression model, including auto-Abs status, sex, and age, was fitted (SI Appendix, Table S1). For assessments of the effect of age and sex on the RRD due to auto-Abs, we added interaction terms between auto-Abs and sex, and auto-Abs and age (SI Appendix, Supplemental Materials and Methods). A similar Firth's logistic regression model was used in the subsample of carriers of auto-Abs, to assess the deleteriousness of auto-Abs neutralizing high concentrations relative to those neutralizing low concentrations of type I IFNs (SI Appendix, Supplemental Materials and Methods). From the RRD, we calculated the PAF to assess the proportion of COVID-19 deaths attributable to auto-Abs. The PAF can be estimated as follows: P(auto-Abs/death) * (1 - 1/RRD) (67), where P(auto-Abs/death) is the prevalence of auto-Abs in deceased patients.

Our goal was also to estimate the fatality rate upon infection with SARS-CoV-2 (IFR) in unvaccinated subjects carrying auto-Abs against type I IFNs across age groups and sexes. To this end, we used the fatality rate upon infection with SARS-CoV-2 in the general unvaccinated population provided by O'Driscoll et al. (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 prevalence of auto-Abs in deceased patients and in the general population together with the reported age-specific IFR (6) as detailed in SI Appendix, Supplemental Materials and Methods.

**Data Availability.** All the data are available in the manuscript or in the supporting information. 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.

**ACKNOWLEDGMENTS.** We thank the patients and their families for placing their 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 Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima
University, Hiroshima, Japan). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute; The Rockefeller University; the St. Giles Foundation; the NIH (Grants R01AI088364 and R01AI163029); the National Center for Advancing Translational Sciences; NIH Clinical and Translational Science Awards program (Grant UL1 TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at George Mason University; the Yale Center for Mendelian Genomics and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (Grants UM1HG006504 and U24HG008956); the Yale High Performance Computing Center (Grant S100D018521); 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 (Grant ANR-10-IAHU-01); the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (Grant EQU201903007798); the French Agency for Research on AIDS and Viral hepatitis (ANRS) Nord-Sud (Grant ANRS-COV05); the ANR GENVIR (Grant ANR-20-CE93-003), AABIFNCOV (Grant ANR-20-C011-0001), CNSVIRGEN (Grant ANR-19-CE15-0009-01), and GenMIS-C (Grant ANR-21-COVR-0039) projects; the Square Foundation; Grandir-Fonds de solidarité pour l'Enfance; the Fondation du Souffle; the SCOR Corporate Foundation for Science; The French Ministry of Higher Education, Research, and Innovation (Grant MESRI-COVID-19); Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University Paris Cité. P. Bastard was supported by the FRM (Award EA20170638020). P. Bastard, J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt Schueller). Work at the Neurometabolic Disease lab received funding from Centre for Biomedical Research on Rare Diseases (CIBERER) (Grant ACCI20-767) and the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI Genomics). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (Grants P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The Infanta Leonor University Hospital supported the research of the Department of Internal Medicine and Allergology. 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 (Grant PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (Grant RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and the National Institute of Dental and Craniofacial Research, 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 (Grant ANR-10-LABX-69-01). K.K.'s group was supported by the Estonian Research Council, through Grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (Grant AJF202019), Dubai, United Arab Emirates, and a COVID-19 research grant (Grant Cov19-0307) from the University of Sharjah, United Arab Emirates. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a University of New South Wales COVID Rapid Response Initiative Grant. L.I. reports funding from Regione Lombardia, Italy (project "Risposta immune in pazienti con COVID-19 e co-morbilità"). This research was partially supported by the Instituto de Salud Carlos III (Grant COV20/0968). J.R.H. reports funding from Biomedical Advanced Research and Development Authority (Grant HHSO10201600031C). S.O. reports funding from Research Program on

Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development (Grant JP20fk0108531). G.G. was supported by the ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The 3C Study was conducted under a partnership agreement between INSERM, 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 générale de la Santé, Mutuelle Générale de l'Éducation Nationale, Institut de la Longévité, Conseils Régionaux de Aquitaine et Bourgogne, Fondation de France, and Ministry of Research-INSERM Program " 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 75N91019D00024, Task Order 75N91021F00001. J.W. is supported by a Research Foundation - Flanders (FWO) Fundamental Clinical Mandate (Grant 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/FEDER). C.R.-G. and colleagues from the Canaryan Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (Grants COV20_01333 and COV20_01334), the Spanish Ministry for Science and Innovation (RTC-2017-6471-1; AEI/FEDER, European Union), Fundación DISA (Grants OA18/017 and OA20/024), and Cabildol Insular de Tenerife (Grants CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19"). T.H.M. was supported by grants from the Novo Nordisk Foundation (Grants NNF200C0064890 and NNF210C0067157). C.M.B. is supported by a Michael Smith Foundation for Health Research Health Professional Investigator Award. P.Q.H. and L. Hammarström were funded by the European Union's Horizon 2020 research and innovation program (Antibody Therapy Against Coronavirus consortium, Grant 101003650). Work at Y.-LL.'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 Evaluation-Orientation de la Coopération Scientifique (ECOS) Nord - Coopération Scientifique FranÇo-Colombie (ECOS-Nord/Columbian Administrative department of Science, Technology and Innovation [COLCIENCIAS]/Colombian Ministry of National Education [MEN]/Colombian Institute of Educational Credit and Technical Studies Abroad [ICETEX, Grant 806-2018] and Colciencias Contract 713-2016 [Code 111574455633]). A. Klocperk 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 (Grant 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 (PID); by the Katholieke Universiteit Leuven C1 Grant C16/18/007; by a Flanders Institute for Biotechnology-Grand Challenges - PID grant; by the FWO Grants GOC8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union's Horizon 2020 research and innovation program (Grant Agreement 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (Grant INTERFLU 1574). M. Vidigal received funding from the São Paulo Research Foundation (Grant 2020/09702-1) and JBS SA (Grant 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation.

Jérémy Manny<sup>a,b,1</sup>, Paul Bastard<sup>a,b,c,2</sup>, Adrian Gervais<sup>a,b,2</sup>, Tom Le Voyer<sup>a,b,2</sup>, Jérémie Rosain<sup>a,b,2</sup>, Quentin Philippot<sup>a,b,2</sup>, Eleftherios Michailidis<sup>D,3</sup>, Hans-Heinrich Hoffmann<sup>d,3</sup>, Shohei Eto<sup>e,3</sup>, Marina Garcia-Prat<sup>f,3</sup>, Lucy Bizien<sup>a,b,3</sup>, Alba Parra-Martínez<sup>f,3</sup>, Rui Yang<sup>c,3</sup>, Liis Haljasmägi<sup>g,3</sup>, Mélanie Migaud<sup>a,b,3</sup>, Karita Särrekannu<sup>g,3</sup>, Julia Maslovskaja<sup>g,3</sup>, Nicolas de Prosth<sup>h,1</sup>, Yacine Tandjaoui-Lambiotte<sup>i,4</sup>, Charles-Edouard Luyt<sup>k,1</sup>, Blanca Amador-Borrero<sup>m</sup>, Alexandre Gaudet<sup>n,0</sup>, Julien Poissy<sup>n,0</sup>, Pascal Morel<sup>p,q</sup>, Pascale Richard<sup>p</sup>, Fabrice Cognasse<sup>r,s</sup>, Jesús Troya<sup>t</sup>, Sophie Trouillet-Assant<sup>u,v,w</sup>, Alexandre Belot<sup>u,v,x,y</sup>, Kahina Saker<sup>u,v</sup>, Pierre Garçon<sup>z</sup>, Jacques G. Rivière<sup>f</sup>, Jean-Christophe Lagier<sup>aa</sup>, Stéphanie Gentile<sup>bb,cc</sup>, Lindsey B. Rosen<sup>dd</sup>, Elana Shaw<sup>dd</sup>, Tomohiro Morio<sup>ee</sup>, Junko Tanaka<sup>ff</sup>, David Dalmau<sup>gg,hh</sup>, Pierre-Louis Tharaux<sup>g,ii</sup>, Damien Sene<sup>m</sup>, Alain Stepanian<sup>ll,kk</sup>, Bruno Mégarbane<sup>ll</sup>, Vasiliki Triantafyllia<sup>mm</sup>, Arnaud Fekkar<sup>aa,nn</sup>, James R. Heath<sup>oo</sup>, José Luis Franco<sup>pp</sup>, Juan-Manuel Anaya<sup>qq,5</sup>, Jordi Solé-Violán<sup>rr,ss,tt</sup>, Luisa Imberti<sup>uu</sup>, Andrea Biondi<sup>vv</sup>, Paolo Bonfanti<sup>ww</sup>, Riccardo Castagnoli<sup>dd,xx</sup>, Ottavia M. Delmonte<sup>dd</sup>, Yu Zhang<sup>dd,yy</sup>, Andrew L. Snow<sup>zz</sup>, Steven M. Holland<sup>dd</sup>, Catherine M. Biggs<sup>aaa</sup>, Marcela Moncada-Vélez<sup>z</sup>, Andrés Augusto Arias<sup>c,bbb,ccc</sup>, Lazaro Lorenzo<sup>ab</sup>, Soraya Boucherit<sup>a,b</sup>, Dany Anglicheau<sup>ddd,eee</sup>, Anna M. Planas<sup>ff,ggg</sup>, Filomenen Haerynck<sup>hhh</sup>, Sotirija Duvlis<sup>ij,jj</sup>, Tayfun Ozcelik<sup>kk</sup>, Sevgi Keles<sup>ll</sup>, Ahmed A. Bousfiha<sup>mmm,nn</sup>, Jalila El Bakkouri<sup>mmm,nn</sup>, Carolina Ramirez-Santana<sup>oo</sup>, Stéphane Paul<sup>ppp</sup>, Qiang Pan-Hammarström<sup>qqq</sup>, Lennart Hammarström<sup>qqq</sup>, Annabelle Dupont<sup>rrr</sup>, Alina Kurolap<sup>sss</sup>, Christine N. Metz<sup>ttt</sup>, Alessandro
Aiuti uuuu, Giorgio Casari uuu, Vito Lampasona wY, Fabio Ciceri wY, Lucila A. Barreiros xxx, Elena Dominguez-Garrido yY, Mateus Vidigal zzz, Mayana Zatz zzz, Diederik van de Beek aaa, Sabina Sahanic bbbb, Ivan Tancevski bbbb, Yurii Stepanovskyy cccc, Oksana Boyarchuk dddd, Yoko Nukui eee, Miyuki Tsumura e, Loreto Vidaur ffff, gggg, Stuart G. Tangey hhhh, iii, Sonia Burrell iii, Darragh Duffy i, kkk, Lluis Quintana-Murci iii, mmm, Adam Kloperk nnn, Nelli Y. Kann oooo, Anna Shcherbina ooooo, Yu-Lung Lau pppp, Daniel Leung pppp, Matthieu Coulongeat qqqq, Julien Marlet i, rrr, sss, Rutger Koning aaa, Luis Felipe Reyes tttt, uuu, Angélique Chauvineau-Grenier wY, Fabienne Venet i, pwww.xxxx.yyy, Guillaume Monneret wwww.yyy, Michel C. Nussenzweig zzzz, aaaa, Romain Arrestier h, i, Idris Boudhabhay ddd, eee, Hagit Baris-Feldman sss, bbbbb, David Hagin bbbbb, ccccc, Joost Wauters dddd, Isabelle Meyts eeeeee, fffff, Adam H. Dyer i, gggg, hhhh, Sean P. Kennelly gggg, hhhh, Nollraig M. Bourke hhhh, Rabih Halwani iiii, iii, Fatemeh Saheb Sharif-Askari iii, Karim Dorgham kkkk, Jérôme Sallette iii, Souad Mehlal Sedkaoui iii, Susan AlKhater mmmmm, nnnnn, Raúl Rigo-Bonnin ooooo, Francisco Morandeira ppppp, Lucie Roussel qqqqq, rrrrr, Donald C. Vinh qqqq, rrrrr, Christian Erikstrup sssss, Antonio Condino-Neto i, xxx, Carolina Prando ttttt, Anastasiia Bondarenko cccc, András N. Spaan c, uuuu, Laurent Gilardin wwwwww, Jacques Felly i, xxxxxx, yyy, zzzz, Stanislas Lyonette aaaaa, Kaya Bilguvar bbbbb, ccccc, dddddd, eee, Richard P. Lifton bbbbb, ccccc, fffff, Shrikant Mane ccccc, HGID Lab 6, COVID Clinicians 6, COVID-STORM Clinicians 6, NIAID Immune Response to COVID Group 6, NH-COVAIR Study Group 6, Danish CHGE 6, Danish Blood Donor Study 6, St. James's Hospital, SARS CoV2 Interest Group 6, French COVID Cohort Study Group 6, Imagine COVID-Group 6, The Milieu Intérieur Consortium 6, CoV-Contact Cohort 6, Amsterdam UMC Covid-19 Biobank Investigators 6, COVID Human Genetic Effort 6, CP-COVID-19 Group 6, CONSTANCES cohort 6, 3C-Dijon Study 6, Cerba Health-Care 6, Etablissement Français du Sang Study group 6, Mark S. Anderson gggggg, Bertrand Boisson i, a,b,c, Vivien Béziat i, a,b,c, Shen-Ying Zhang a,b,c, Evangelos Andreakos mm, 7, Olivier Hermine b, hhhhhh, 7, Aurora Pujol iiii, iii, kkkkk, 7, Pärt Peterson 8, 7, Trine H. Mogensen iii, mmmmm, 7, Lee Rowen o, 7, James Mond nnnnn, 7,8, Stéphanie Debette ooooo, pppppp, 7, Xavier de Lamballerie qqqqq, 7, Charles Burdet rrrrr, sssss, ttttt, 7, Lila Bouadma sssss, uuuuu, 7, Marie Zins wwww, 7, Pere Soler-Palinac f, 7, Roger Colobran wwwwww, 7, Guy Gorochov i, kkkk, xxxxx, 7, Xavier Solanich i, yyy, 7, Sophie Susen rrr, Javier Martinez-Picado i, zzzzz, aaaaa, bbbbbbbb, ccccccc, dddddd, 7, Didier Raoult 3a, 7, Marc Vasse eeeeee, 7, Peter K. Gregersen ttt, 7, Lorenzo Piemonti w, 7, Carlos Rodríguez-Gallegoltt, ffffff, 7, Luigi D. Notarangelo dd, 9, Helen C. Su ddd, gggggg, 9, Kai Kisand 8, 9, Satoshi Okada e, 9, Anne Puel i, a,b,c, 9, Emmanuelle Jouanguy a,b,c, 9, Charles M. Rice d, 9, Pierre Tiberghien p, q, 9, Qian Zhang i, a,b,c, 9, Jean-Laurent Casanova i, a,b,c, aaaaa, 1, 10, Laurent Abel a,b,c, 10 and Aurélie Cobat i, 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

Author affiliations: aLaboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, 75015 Paris, France; bImagine Institute, University of Paris, 75015 Paris, France; cSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065; dLaboratory of Virology and Infectious Disease, Rockefeller University, New York, NY 10065; eDepartment of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan; fPediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitaire Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; gInstitute of Biomedicine and Translational Medicine, University of Tartu, 50090 Tartu, Estonia; hService de Médecine Intensive Réanimation, Hopitaux Universitaires Henri Mondor, Assistance Publique-Hôpitaux de Paris, 94010 Créteil, France; iGroupe de Recherche Clinique Cardiovascular and Respiratory Manifestations of Acute Lung Injury and Sepsis (CARMAS), Faculté de santé de Créteil, Université Paris Est Créteil, 94010 Créteil Cedex, France; jHypoxia and Lung, INSERM U1272, Avicenne Hospital, Assistance Publique-Hôpitaux de Paris, 93022 Bobigny, France; kSorbonne Université, Hôpital Pitié Salpetrière, Médecine Intensive Réanimation, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France; lINSERM, UMRs 1166-ICAN, Institute of Cardiometabolism and Nutrition, 75013 Paris, France; mInternal Medicine Department, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris, 75010 Paris, France; nINSERM U1019-CNRS UMR9017, Center for Infection and Immunity of Lille, Institut Pasteur de Lille, University of Lille, 59000 Lille, France; oCentre Hospitalier Universitaire, de Lille, Polé de Réanimation, Hôpital Roger Salengro Lille, 59000 Lille, France; pEtablissement Français du Sang, 93218 La Plaine Saint-Denis, France; qInteractions Hôte-Greffon-Tumeur et Ingénierie Cellulaire et Génique (RIGHT), INSERM, Etablissement Français du Sang, Université de Franche-Comté, 25000 Besançon, France; rSanté Ingénierie Biologie St-Etienne (SAINBIOSE), INSERM U1059, University of Lyon, Université Jean Monnet Saint-Etienne, 42000 Saint-Etienne, France; eEstablishment Français du Sang, Auvergne-Rhône-Alpes, 42000 Saint-Etienne, France; fDepartment of Internal Medicine, Infanta Leonor University Hospital, 28031 Madrid, Spain; gHospices Civils de Lyon, 69002 Lyon, France; hInternational Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, Ecole Nationale Supérieure, Université Claude Bernard Lyon 1 (UCBL), 69365 Lyon, France; iJoint Research Unit, Hospices Civils de Lyon-BioMérieux, Hospices Civils de Lyon, Lyon Sud Hospital, 69495 Pierre-Benite, France; jNational Referee Center for Rheumatic, and Autoimmune and Systemic Diseases in Children, 69000 Lyon, France; kImmunopharmacology Federation Lyon Immunopathology Federation (LIFE), Hospices Civils de Lyon, 69002 Lyon, France; lIntensive Care Unit, Grand Hôpital de l'Est Francophone site de Marne-La-Vallée, 77600 Jossigny, France; mMicrobes, Evolution, Phylogénie et Infection (MEPHI), Institut Hospitalo-Universitaire Méditerranée Infection, Institut de Recherche pour le Développement, Assistance Publique Hôpitaux de Marseille, Aix-Marseille Université, 13005 Marseille, France; nService d'Evaluation Médicale, Hopitaux Universitaires de Marseille Assistance Publique Hôpitaux de Marseille, 13005 Marseille, France; oAix-Marseille University, School of Medicine, EA 3279, Centre d'Etudes et de Recherche sur les Services de Santé et la Qualité de vie (CERESs)-Health Service Research and Quality of Life Center, 13385 Marseille, France; pLaboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD 20892; qDepartment of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; rDepartment of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan; sHospital Universitari Mütua Terrassa, Universitat de Barcelona, 08193 Barcelona, Spain; tFundació Docència i Recerca Mutua Terrassa, 08221 Terrassa, Spain; uParis Cardiovascular Research Center (PARCC), INSERM, Université de Paris, 75015 Paris, France; vService d'Hématologie Biologique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université de Paris, 75010 Paris, France; wKEA3518, Institut Universitaire d'Hématologie-Hôpital Saint Louis, Université de Paris, 75010 Paris, France; xRéanimation Médicale et Toxicologique, Hôpital Lariboisière Assistance Publique-Hôpitaux de Paris, Université de Paris, INSERM, UMRs-1144, 75010 Paris,

France; mmLaboratory of Immunobiology, Center for Clinical, Experimental Surgery, and Translational Research, Biomedical Research Foundation on the Academy of Athens, 11527 Athens, Greece; nnService de Parasitologie-Mycologie, Groupe Hospitalier Pitié Salpetrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris, France; oooInstitute for Systems Biology, Seattle, WA 98109; ppPrimary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia Ude, 050010 Medellin, Colombia; qqCenter for Autoimmune Disease Research, School of Medicine and Health Sciences, Universidad del Rosario, 11011 Bogotá, Colombia; rrIntensive Care Medicine, University Hospital of Gran Canaria Dr. Negrin, Caribbean Health System, 35010 Las Palmas de Gran Canaria, Spain; ssCentro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; ttDepartment of Clinical Sciences, Universidad Fernando Pessoa Canarias, 35450 Las Palmas de Gran Canaria, Spain; uuChemato-oncology Research Laboratory of Associação italiana contro le leucemie-linfomi e mieloma, Diagnostic Department, Aziana Socio Sanitaria Territoriale, Spedali Civili di Brescia, 25123 Brescia, Italy; wePediatric Department and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), University of Milano Bicocca, Fondazione Monza Brianza Bambino Mamma (MBBM), Ospedale San Gerardo, 20900 Monza, Italy; wwDepartment of Infectious Diseases, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy; xxPediatric Clinic, Fondazione Istituto di Ricovero e Cura a carattere scientifico (IRCCS) Policlinico San Matteo, Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy; yyNational Institute of Allergy and Infectious Diseases (NIAID) Clinical Genomics Program, NIH, Bethesda, MD 20892; zdDepartment of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814; aaaDepartment of Pediatrics, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC V6H 0B3, Canada; bbbPrimary Immunodeficiencies Group, University of Antioquia Ude, 050010 Medellin, Colombia; cccSchool of Microbiology, University of Antioquia Ude, 050010 Medellin, Colombia; dddDepartment of Nephrology and Transplantation, Necker University Hospital, Assistance Publique-Hôpitaux de Paris, 75743 Paris, France; eeeInstitut Necker Enfants Malades, INSERM U1151-CNRS UMR 8253, Université de Paris, 75015 Paris, France; fffInstitute for Biomedical Research, Spanish National Research Council, 08036 Barcelona, Spain; gggInstitut d'Investigacions Biomediques August Pi i Sunyer, 08036 Barcelona, Spain; hhhDepartment of Paediatric Immunology and Pulmonology, Center for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Center, Ghent University Hospital, 9000 Ghent, Belgium; iiiFaculty of Medical Sciences, University "Goe Delchev," Stip 2000, Republic of North Macedonia; ivInstitute of Public Health of the Republic of North Macedonia, Skopje 1000, Republic of North Macedonia; kkkDepartment of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey; lllMeram Faculty of Medicine, Necmettin Erbakan University, 42080 Konya, Turkey; mmmClinical Immunology Unit, Department of Pediatric Infectious Disease, Centre Hospitalier-Universitaire Ibn Rouschd, 20360 Casablanca, Morocco; nnnLaboratoire d'Immunologie Clinique, Inflammation et Allergie (LICIA), Faculty of Medicine and Pharmacy, Hassan Il University, 20250 Casablanca, Morocco; oooCenter for Autoimmune Disease Research, School of Medicine and Health Sciences, Universidad del Rosario, 111211 Bogotá, Colombia; pppDepartment of Immunology, CIC1408, Groupe sur l'Imunité des Muqueuses et des Agents Pathogènes (GIMAP) Centre International de Recherche en Infectiologie, INSERM U1111, University Hospital of Saint-Etienne, 42000 Saint-Etienne, France; qqqDepartment of Biosciences and Nutrition, Karolinska Institutet, 171 77 Stockholm, Sweden; rrrUniversity of Lille, INSERM, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes (EGID), F-59000 Lille, France; sssThe Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, 6423906 Tel Aviv, Israel; tttFeinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030; uuuVita-Salute San Raffaele University, and Clinical Genomics, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, 20132 Milan, Italy; wwDiabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, 20132 Milan, Italy; wwwHematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele University Vita-Salute San Raffaele, 20132 Milano, Italy;
xxxDepartment of Immunology, Institute of Biomedical Sciences, University of São Paulo, 05508-060 São Paulo, Brazil; yyyFundación Rionda Salud, Centro de Investigación Biomédica de La Rioja, 26006 Logroño, Spain; zzzUniversity of São Paulo, 05508-060 São Paulo, Brazil; sssDepartment of Neurology, Amsterdam UMC, Amsterdam Neuroscience, University of Amsterdam, 1105 AZ, The Netherlands; bbbDepartment of Internal Medicine II, Amsterdam, University of Innsbruck, 6020 Innsbruck, Austria; cccShupky National Healthcare University of Ukraine, 04112 Kyiv, Ukraine; dddDepartment of Children's Diseases and Pediatric Surgery, I. Horbachskev Ternopil National Medical University, 46022 Ternopil, Ukraine; eeeDepartment of Infection Control and Prevention, Medical Hospital, Tokyo Medical and Dental University, Tokyo 113-8655, Japan; fffIntensive Care Medicine, Donostia University Hospital, Biodonostia Institute of Donostia, 20014 San Sebastian, Spain; gggCentro de Investigación Biomédica en Red (CIBER) de Enfermedades Respiratorias, Instituto de Salud Carlos III, 28029 Madrid, Spain; hhhhGarvan Institute of Medical Research, Sydney, NSW 2010, Australia; iiiSt Vincent's Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2010, Australia; iiiiiSorbonne University, INSERM U1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Assistance Publique-Hôpitaux de Paris, Hôpital Pitie Salpetrière, Service de Virologie, 75013 Paris, France; kkkTranslational Immunology Unit, Institut Pasteur, Université Paris Cité, 75015 Paris, France; lllHuman Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, France; mmmmDepartment of Human Genomics and Evolution, College de Médecine, 75231 Paris, France; nnnnDepartment of Immunology, 2nd Faculty of Medicine, Charles University and University Hospital in Motol, 150 06 Prague, Czech Republic; oooDepartment of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology and Immunology, Moscow, Russia 117997; pppppDepartment of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong 9999077, China; qqqqDivision of Geriatric Medicine, Tours University Medical Center, 37044 Tours, France; rrrrINSERM U1259, Morphogenèse et Antigènité du VIH et des Virus des Hépatites (MAVIVH), Université de Tours, 37044 Tours, France; sssssService de Bactériologie, Virologie et Hygiene Hospitalière, Centre Hospitalier Universitaire de Tours, 37044 Tours, France; ttttDepartment of Microbiology, Université de La Sabana, 250001 Chia, Colombia; uuuuDepartment of Critical Care Medicine, Clínica Universidad de La Sabana, 250001 Chia, Colombia; vvvvService de Biologie Médicale, Centre Hospitalier Intercommunal Robert Ballanger, 93600 Aulnay-sous-Bois, France; wwwLaboratoire d'Immunologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69437 Lyon, France; xxxCentre International de Recherche en Infectiologie, INSERM U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, 69007 Lyon, France; yyyEA 7426, Pathophysiology of Injury-Induced Immunosuppression, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, BioMérieux, Hôpital Edouard Herriot, 69437 Lyon, France; zzzzLaboratory of Molecular Immunology, Rockefeller University, New York, NY 10065; aaaaaHHMI, Rockefeller University, New York, NY 10065; bbbbSackler Faculty of Medicine, Tel Aviv University, 6997801 Tel Aviv, Israel; ccccAllelic and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center, 6423906 Tel Aviv, Israel; ddddddMedical Intensive Care Unit, University Hospitals Leuven, 3000 Leuven, Belgium; eeeeeeLaboratory of Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; iiiiiDepartment of Pediatrics, Jeffrey Model Diagnostic and Research Network Center, University Hospitals Leuven, 3000 Leuven, Belgium; gggggDepartment of Age-Related Healthcare, Tallaght University Hospital, Dublin D24 NROA, Ireland; hhhhhhDepartment of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin D08 W9RT, Ireland; iii Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, 27272 Sharjah, United Arab Emirates; iiiiiImmunology Research Lab, College of Medicine, King Saud University, 11362 Riyadh, Saudi Arabia; kkkkkSorbonne Université, INSERM, Centre d'Immunologie et des Maladies Infectieuses, 75013 Paris, France; llllCerba HealthCare, 92130 Issy-les-Moulineaux, France; mmmmmDepartment of Pediatrics, King Fahad Hospital of the University, Al Khobar 34445, Saudi Arabia; nnnnnCollege of Medicine, Imam Abdulrahman Bin Faisal University, Damمام 34212, Saudi Arabia; oooxxxDepartment of Clinical Laboratory, Hospital Universitari de Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), 08098 Barcelona, Spain; pppppDepartment of Immunology, Hospital Universitari de Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), 08098 Barcelona, Spain; qqqqqDepartment of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montreal, QC H4A 3J1, Canada; sssssDepartment of Clinical Immunology, Aarhus University Hospital, 8000 Aarhus, Denmark; tttttFacultades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, 80250-200 Curitiba, Brazil; uuuuDepartment of Clinical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; vvvvvService de Médecine Interne, Hôpital Universitaire Jean-Vernier, Assistance Publique-Hôpitaux de Paris, 93140 Bondy, France; wwwwwwINSERM U1138, Centre de Recherche des Cordeliers, 75006 Paris, France; wwwwwwSchool of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; yyyyyPrecision Medicine Unit, Lausanne University Hospital and University of Lausanne, 1011 Lausanne, Switzerland; zzzzzSwiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; aaaaaaImagine Institute, University de Paris, INSERM, UMR 1163, 75015 Paris, France; bbbbbby Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT 06511; ccccccDepartment of

1. B. Hu, H. Guo, P. Zhou, Z. L. Shi, Characteristics of SARS-CoV-2 and COVID-19. *Nat. Rev. Microbiol.* **19**, 141-154 (2021).

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Genetics, Yale University School of Medicine, New Haven, CT 06520; ddddddDepartment of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510; eeeeeeDepartment of Medical Genetics, Acibadem University School of Medicine, 34750 Istanbul, Turkey; ffffLaboratory of Human Genetics and Genomics, Rockefeller University, New York, NY 10065; gggggDiabetes Center, University of California, San Francisco, CA 94143; hhhhDepartment of Hematology, Necker Hospital, Assistance Publique-Hôpitaux de Paris, 75015 Paris, France; iiiiiNeurometabolic Diseases Laboratory, The Bellvitge Biomedical Research Institute (IDIBELL), 08098 Barcelona, Spain; iiiiiCentre for Biomedical Research on Rare Diseases (CIBER) U759, Instituto de Salud Carlos III, 28029 Madrid, Spain; kkkkkCatalan Institution of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain; iiiiiDepartment of Infectious Diseases, Aarhus University Hospital, 8000 Aarhus, Denmark; mmmmmmDepartment of Biomedicine, Aarhus University, 8000 Aarhus, Denmark; nnnnnnADMA Biologics Inc., Ramsey, NJ 07446; oooooUniversity of Bordeaux, INSERM, Bordeaux Population Health Center, UMR1219, F-33000 Bordeaux, France; pppppppDepartment of Neurology, Institute of Neurodegenerative Diseases, Bordeaux University Hospital, F-33000 Bordeaux, France; qqqqqqqInstitut Hospitalo-Universitaire Méditerranée Infection, Unité des Virus Emergents, Aix-Marseille University, Institut pour la Recherche et le Développement (IRD) 190, INSERM 1207, 13005 Marseille, France; rrrrrEpidémiologie clinique du Centre d'Investigation Clinique (CIC-EP), INSERM CIC 1425, Hôpital Bichat, 75018 Paris, France; sssssssUniversité de Paris, Infection Antimicrobials Modelling Evolution (IAME), UMR 1137, INSERM, 75870 Paris, France; iiiiiiDépartement Épidémiologie, Biostatistiques et Recherche Clinique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 75018 Paris, France; uuuuuuService de Rénovation Médicale et des Maladies Infectieuses, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Nord Université de Paris, F-75018 Paris, France; wwwCohorte Constances Groupe Hospitalier Universitaire centre, Assistance Publique-Hôpitaux de Paris, Université de Paris, 94800 Villejuif, Paris; wwwwwwImmunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain; xxxxxxxDépartement d'Immunologie, Assistance Publique-Hôpitaux de Paris, Hôpital Pitie-Salpetrière, 75015 Paris, France; yyyyyDepartment of Internal Medicine, Hospital Universitaire de Bellvitge, The Bellvitge Biomedical Research Institute (IDIBELL), 08098 Barcelona, Spain; zzzzzzzIrsCaixa AIDS Research Institute, 08916 Badalona, Spain; aaaaaaaaInstitute for Health Science Research Germans Trias i Pujol (IGTP), 08916 Badalona, Spain; bbbbbbbbDepartment of Infectious Diseases and Immunity, University of Vic-Central University of Catalonia, 08050 Vic, Spain; ccccccccCatalan Institution of Research and Advanced Studies (ICREA), 08010 Barcelona, Spain; ddddddConsorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINCIF), Instituto de Salud Carlos III, 28029 Madrid, Spain; eeeeeeService de Biologie Clinique and INSERM-S 1176, Hôpital Foch, 92150 Suresnes, France; iiiiiiDepartment of Immunology, University Hospital of Gran Canaria Dr. Negrin, Canarian Health System, 35010 Las Palmas de Gran Canaria, Spain; and gggggggDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Author contributions: J. Manry, L.A., and A.C. designed research: J. Manry, P. Bastard, L. Gervais, T.L.V., J.R., K. Sare, E.M., H-H.H., S.E., M.G.-P., L. Bizien, A.P.-M., R.Y., L. Halvasmiagi, M.M., K. Sarekannu, J. Maslovskaja, C.-E.L., S.T.-A., A. Belot, K. Saker, 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., 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., 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. Saker, P.G., J.G.R., J.-C.L., S.G., T.M., J. Tanaka, D. Dalmäu, P.-L.T., D.S., A. Stepanian, 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., C.M.B., L.L., S. Boucherit, D.A., A.M.P., F.H., S. Duvisl, T.O., S.K., A.A.B., J.E.B., C.R.-S., S.P., Q.P.-H., L. Hammarström, A.D., A. Kurolap, C.N.M., A.A., G.G., V.L., F. Ciceri, L.A.B., E.D.-G., M. Vidalig, 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. Duffy, L.Q.-M., A. Klopperk, N.Y.K., A. Schherbina, Y.-L.L., D.L., M. Coulongeat, J. Marlet, 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., 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., 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, P.P., T.H.M., L. Rowen, J. Mond, S. Debette, X.dL., C.B., L. Bouadma, M. Zins, P.S.-P., 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., H.C.S., P.T., Q.Z., and J.-L.C. contributed new reagents/analytic tools; J. Manry, L.A., and A.C. analyzed data; and J. Manry, J.-L.C., L.A., and A.C. wrote the paper.

Reviewers: M. Carrington, Frederick National Laboratory for Cancer Research; A. Flahault, Université de Genève Institut de la Sante Globale; and A.T., Scripps Center for Integrative Medicine.

The authors declare a competing interest. 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 the 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.

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