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# Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Paul Bastard, Sara Vazquez, Jamin Liu, Matthew T Laurie, Chung Yu Wang, Adrian Gervais, Tom Le Voyer, Lucy Bizien, Colin Zamecnik, Quentin Philippot, et al.

► To cite this version:

Paul Bastard, Sara Vazquez, Jamin Liu, Matthew T Laurie, Chung Yu Wang, et al. Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs. Science Immunology, 2022, 8 (90), 10.1126/sciimmunol.abp8966. hal-03948899

HAL Id: hal-03948899

https://hal.sorbonne-universite.fr/hal-03948899

Submitted on 20 Jan 2023

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Cite as: P. Bastard et al., Sci. Immunol. 10.1126/sciimmunol.abp8966 (2022).

CORONAVIRUS

# Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Paul Bastard<sup>1,2,3,4*</sup>, Sara Vazquez<sup>5,6,7*</sup>, Jamin Liu<sup>8,9*</sup>, Matthew T. Laurie<sup>8*</sup>, Chung Yu Wang<sup>10*</sup>, Adrian Gervais<sup>1,2*</sup>, Tom Le Voyer<sup>1,2*</sup>, Lucy Bizien<sup>1,2#</sup>, Colin Zamecnik<sup>11#</sup>, Quentin Philippot<sup>1,2#</sup>, Jérémie Rosain<sup>1,2#</sup>, Emilie Catherinot<sup>12</sup>, Andrew Willmore<sup>10</sup>, Anthea M. Mitchell<sup>10</sup>, Rebecca Bair<sup>11</sup>, Pierre Garçon<sup>13</sup>, Heather Kenney<sup>14</sup>, Arnaud Fekkar<sup>1,2,15</sup>, Maria Salagianni<sup>16</sup>, Garyphallia Poulakou<sup>17</sup>, Eleni Siouti<sup>16</sup>, Sabina Sahanic<sup>18</sup>, Ivan Tancevski<sup>18</sup>, Günter Weiss<sup>18</sup>, Laurenz Nagl<sup>19</sup>, Jérémy Manry<sup>1,2</sup>, Sotirija Duvlis<sup>20,21</sup>, Daniel Arroyo-Sánchez<sup>22</sup>, Estela Paz Artal<sup>22</sup>, Luis Rubio<sup>8</sup>, Cristiano Perani<sup>23</sup>, Michela Bezzi<sup>24</sup>, Alessandra Sottini<sup>25</sup>, Virginia Quaresima<sup>25</sup>, Lucie Roussel<sup>26,27</sup>, Donald C. Vinh<sup>26,27</sup>, Luis Felipe Reyes<sup>28,29</sup>, Margaux Garzaro<sup>30</sup>, Nevin Hatipoglu<sup>31</sup>, David Boutboul<sup>32</sup>, Yacine Tandjaoui-Lambiotte<sup>33,34,35</sup>, Alessandro Borghesi<sup>36</sup>, Anna Aliberti<sup>37</sup>, Irene Cassaniti<sup>38</sup>, Fabienne Venet<sup>39,40,41</sup>, Guillaume Monneret<sup>39,40</sup>, Rabih Halwani<sup>42,43</sup>, Narjes Saheb Sharif-Askari<sup>42</sup>, Jeffrey Danielson<sup>14</sup>, Sonia Burrel<sup>44</sup>, Caroline Morbieu<sup>45</sup>, Yurii Stepanovskyy<sup>46</sup>, Anastasia Bondarenko<sup>46</sup>, Alla Volokha<sup>46</sup>, Oksana Boyarchuk<sup>47</sup>, Alenka Gagro<sup>48</sup>, Mathilde Neuville<sup>49</sup>, Bénédicte Neven<sup>50</sup>, Sevgi Keles<sup>51</sup>, Romain Hernu<sup>52</sup>, Antonin Bal<sup>53</sup>, Antonio Novelli<sup>54</sup>, Giuseppe Novelli<sup>55</sup>, Kahina Saker<sup>56</sup>, Oana Ailioaie<sup>57</sup>, Arnau Antolí<sup>58</sup>, Eric Jeziorski<sup>59</sup>, Gemma Rocamora-Blanch<sup>58</sup>, Carla Teixeira<sup>60</sup>, Clarisse Delaunay<sup>61</sup>, Marine Lhuillier<sup>62</sup>, Paul Le Turnier<sup>61</sup>, Yu Zhang<sup>14,63</sup>, Matthieu Mahevas<sup>64,65,66</sup>, Qiang Pan-Hammarström<sup>67</sup>, Hassan Abolhassani<sup>67</sup>, Thierry Bompoil<sup>68</sup>, Karim Dorgham<sup>69</sup>, COVID HGE consortium†, French COVID study group†, COMET consortium†, Guy Gorochov<sup>69,70</sup>, Cédric Laouenan<sup>33,71,72</sup>, Carlos Rodríguez-Gallego<sup>73,74</sup>, Lisa F. P. Ng<sup>75</sup>, Laurent Renia<sup>75,76,77</sup>, Aurora Pujol<sup>78</sup>, Alexandre Belot<sup>56,79</sup>, François Raffi<sup>61</sup>, Luis M. Allende<sup>22</sup>, Javier Martinez-Picado<sup>80,81,82,83</sup>, Tayfun Ozcelik<sup>84</sup>, Sevgi Keles<sup>51</sup>, Luisa Imberti<sup>25</sup>, Luigi D. Notarangelo<sup>14</sup>, Jesus Troya<sup>85</sup>, Xavier Solanich<sup>58</sup>, Shen-Ying Zhang<sup>1,2,3</sup>, Anne Puel<sup>1,2,3</sup>, Michael R Wilson<sup>11</sup>, Sophie Trouillet-Assant<sup>86</sup>, Laurent Abel<sup>1,2,3</sup>, Emmanuelle Jouanguy<sup>1,2,3</sup>, Chun Jimmie Ye<sup>10,87,88,89,90#</sup>, Aurélie Cobat<sup>1,2,3#</sup>, Leslie M. Thompson<sup>91#</sup>, Evangelos Andreakos<sup>16#</sup>, Qian Zhang<sup>1,2,3#</sup>, Mark S. Anderson<sup>7,92#@</sup>, Jean-Laurent Casanova<sup>1,2,3,4,93#@</sup> and Joseph L. DeRisi<sup>8,10#@</sup>

*These authors contributed equally to this work.

§These authors contributed equally to this work.

¶These authors contributed equally to this work.

†These authors contributed equally to this work.

‡All collaborators and their affiliations appear at the end of this paper.

@corresponding authors: Mark.Anderson@ucsf.edu; jean-laurent.casanova@rockefeller.edu; jderisi@gmail.com

1. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France. 2. University of Paris Cité, Imagine Institute, Paris, France. 3. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. 4. Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France. 5. Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94143, USA. 6. Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA. 7. Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. 8. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. 9. University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, San Francisco, California, United States. 10. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. 11. Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 12. Pneumology Department, Foch Hospital, Suresne, France. 13. Intensive Care Unit, Grand Hôpital de l'Est Francilien Site de Marne-la-Vallée, Jossigny, France. 14. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA. 15. Service de Parasitologie-Mycologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 16. Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. 17. 3rd Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, "Sotiria" General Hospital of Chest Diseases, Athens, Greece. 18. Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria. 19. Department of Internal Medicine V, Medical University of Innsbruck, Innsbruck, Austria. 20. Faculty of Medical Sciences, University "Goce Delchev", Stip, Republic of North Macedonia. 21. Institute of public health of Republic of North Macedonia. 22. Department of Immunology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12) and Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, CIBERINFEC, Madrid, Spain.

23. Emergency Room, ASST Spedali Civili di Brescia, Brescia, Italy. 24. Covid Unit, ASST Spedali Civili, Brescia, Italy. 25. CREA Laboratory, Diagnostic Department, ASST Spedali Civili di Brescia, Brescia, Italy. 26. Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.

27. Infectious Disease Susceptibility Program, Research Institute-McGill University Health Centre, Montréal, Québec, Canada. 28. Department of Microbiology, Universidad de La Sabana, Chía, Colombia. 29. Department of Critical Care Medicine, Clínica Universidad de La Sabana, Chía, Colombia. 30. Department of Infectious Diseases, Necker Hospital for Sick Children, AP-HP, Paris, France. 31. Pediatric Infectious Diseases Unit, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey. 32. Department of Immunology, Saint-Louis Hospital, AP-HP, Paris, France. 33. INSERM UMR 1137 IAME, Paris, France. 34. INSERM UMR 1272 Hypoxie & Poumon, Bobigny, France. 35. Pneumology and infectiology department, CH Saint Denis, Saint-Denis, France. 36. Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 37. Anesthesia and Intensive Care, Rianimazione I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 38. Molecular Virology
Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. 39. Laboratoire d'Immunologie, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France. 40. EA 7426, Pathophysiology of Injury-Induced Immunosuppression, Université Claude Bernard Lyon 1, Hospices Civils de Lyon, Hôpital Edouard Herriot-BioMérieux, Lyon, France. 41. CIRI, INSERM U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Lyon, France. 42. Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates. 43. Immunology Research Laboratory, College of Medicine, King Saud University. 44. Sorbonne Université, INSERM U1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié Salpétrière, Service de Virologie, Paris, France. 45. Internal medicine department, Louis Mourier Hospital, AP-HP, Paris, France. 46. Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine. 47. Department of Children's Diseases and Pediatric Surgery, I.Horbachevsky Ternopil National Medical University, Ternopil, Ukraine. 48. Department of Pediatrics, Children's Hospital Zagreb, University of Zagreb School of Medicine, Zagreb, Josip Juraj Strossmayer University of Osijek, Medical Faculty Osijek, Osijek, Croatia. 49. Intensive care unit, Foch Hospital, Suresne, France. 50. Department of Pediatrics Hematology Immunology and Rheumatology, Necker Hospital for Sick Children, AP-HP, Paris, France. 51. Meram Medical Faculty, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey. 52. Service des Urgences, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France. 53. Laboratoire de virologie, Institut agent infectieux, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France. 54. Laboratory of Medical Genetics, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. 55. Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy. 56. Joint Research Unit, Hospices Civils de Lyon-bio Mérieux, Hospices Civils de Lyon, Lyon Sud Hospital, Pierre-Bénite, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France. 57. Service de Génétique, Hôpital Raymond Poincaré, AP-HP, Garches, France. 58. Department of Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain. 59. General pediatric department, PCCEI, CeréMAIA, Univ Montpellier, CHU Montpellier, Montpellier, France. 60. Unidade de Infecologia e Imunodeficiências, Centro Materno-infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal. 61. Department of Infectious Diseases, CHU Nantes, and INSERM UIC 1413, CHU Nantes, France. 62. Geriatric department, CHU Nantes, Hopital Bellier, Nantes, France. 63. NIAID Clinical Genomics Program, National Institutes of Health, Bethesda, USA 64. Necker Enfants Malades Institute (INEM), INSERM U1511/CNRS UMR 8253, University of Paris Cité, Paris, France. 65. Departement of Internal Medicine, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris-Est Créteil University (UPEC), Créteil, France. 66. INSERM U955, team 2. Mondor Biomedical Research Institute (IMRB), Paris-Est Créteil University (UPEC), Créteil, France. 67. Department of Biosciences and Nutrition, Carolinska Institutet, SE14183, Huddinge, Sweden. 68. Biologie/Pathologie, CHU-Nantes - Hôtel Dieu, Institut de Biologie, Nantes, France 69. Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses, (CIMI- Paris), Paris, France. 70. Département d'Immunologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpétrière, Paris, France. 71. Université de Paris, IAME UMR-S 1137, INSERM, Paris, France. 72. AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France. 73. Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Canary Islands, Spain. 74. Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain. 75. A*STAR Infectious Disease Labs, Agency for Science, Technology and Research, Singapore. 76. Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore. 77. School of Biological Sciences, Nanyang Technology University, Singapore. 78. Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. 79. CNRS UMR 5308, ENS, UCBL, Lyon, France; National Referee Centre for Rheumatic, and Autoimmune and Systemic Diseases in Children (RAISE), Lyon, France; Lyon; Immunopathology Federation LIFE, Hospices Civils de Lyon, Lyon, France. 80. IrsiCaixa AIDS Research Institute and Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain. 81. Infectious Diseases and Immunity, Center for Health and Social Care Research (CESS), Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain. 82. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain. 83. CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain. 84. Department of Molecular Biology and Genetics, Bilkent University, Bilkent - Ankara, Turkey. 85. Department of Internal Medicine, Infanta Leonor University Hospital, Madrid, Spain. 86. Hospices Civils de Lyon, Lyon, France; International Center of Research in Infectiology, Lyon University, INSERM U1111, CNRS UMR 5308, ENS, UCBL, Lyon, France. 87. ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA. 88. Departments of Epidemiology and Biostatistics and Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA. 89. Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA. 90. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. 91. Departments of Psychiatry and Human Behavior and Neurobiology and Behavior, University of California, Irvine, CA, USA. 92. Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. 93. Howard Hughes Medical Institute, New York, NY, USA.

Life-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

## INTRODUCTION

Since the start of the coronavirus disease 19 (COVID-19) pandemic (I), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), at least 6 million people have died from

COVID-19 (2). Although the majority of infected individuals recover, it remains important to identify factors that put patients at greater risk for severe disease. Age is the major epidemiological risk factor of death from pneumonia, the risk
doubling every five years of age from childhood onward (3-5). Patients with inborn errors (IE) of immunity affecting the production of, or response to type I IFNs, or both, are prone to critical COVID-19 pneumonia (6-8). These findings established the crucial role of type I IFNs in fending off SARS-CoV-2 (9). Moreover, auto-Abs neutralizing high concentrations (10 ng/mL in plasma diluted 1/10) of IFN-α2 and/or IFN-ω were found in at least 10% of individuals with critical COVID-19 (10), an observation replicated in various regions of the world (11-21). Patients with autoimmune polyendocrine syndrome type I (APS-1) harbor these neutralizing auto-Abs from early childhood and are at high risk of life-threatening COVID-19 (20, 21). Moreover, at least 13.6% of unvaccinated patients with critical COVID-19 had auto-Abs neutralizing lower, more physiological concentrations (100 pg/mL in plasma diluted 1/10) of IFN-α2 and/or IFN-ω, while auto-Abs neutralizing IFN-β were found in another 1% of patients (22). In more than 34,000 uninfected individuals aged 18 to 100 years, the prevalence of auto-Abs neutralizing 10 ng/mL (or 100 pg/mL) of IFN-α2 or IFN-ω increased significantly with age, with 0.17% (1.1%) of individuals positive for these auto-Abs under 70 years old, and more than 1.4% (4.4%) positive over 70 years old, consistent with the higher risk of life-threatening COVID-19 in the elderly population (22). These auto-Abs thus precede infection and are strong determinants of critical disease, only second to age among common risk factors (23). The odds ratios (ORs) of critical disease are the highest in individuals with auto-Abs neutralizing 10 ng/mL of both IFN-α2 and IFN-ω (OR = 67; p-value = 7.8x10⁻¹³) (22, 23).

RNA vaccines are highly effective at protecting against severe COVID-19 pneumonia (24, 25). Despite their efficacy, 'breakthrough' cases, i.e., individuals diagnosed with SARS-CoV-2 infection despite being vaccinated with 2 doses, have been reported worldwide (26, 27). Most breakthrough cases are asymptomatic or mild (26), but in rare cases they are severe, critical, or even fatal (28, 29). It is thought that these severe or critical cases can result from a pathologically deficient (including inherited and acquired deficiencies of adaptive immunity) or a physiologically waning antibody response to the vaccine (especially in aging individuals). Incomplete protection from viral genotypes with vaccine-resilient mutations (such as Delta or Omicron), can also result in insufficient viral neutralization in vivo, in individuals otherwise at risk of hypoxemic pneumonia (for example, due to their age, sex, co-morbidity, rare or common genetic variant, or auto-Abs to type I IFNs) (30). In other words, breakthrough critical cases are thought to be due to a poor antibody response to the vaccine in at-risk individuals (31). Yet, the human genetic and immunological determinants of critical 'breakthrough' cases remain unclear, especially in patients with normal antibody response to the vaccine. Moreover, the biological and

clinical efficacy of RNA vaccines in patients with known genetic or immunological determinants of critical COVID-19 pneumonia, i.e., in patients with IE of, or auto-Abs to type I IFNs, is not clear. With the COVID Human Genetic Effort (CHGE, www.covidhge.com), we recruited and tested patients with breakthrough COVID-19 and hypoxemic pneumonia. We tested the double hypothesis that some of these breakthrough cases of severe or critical COVID-19 pneumonia may have a normal antibody response to the vaccine and may also harbor auto-Abs to type I IFNs.

## RESULTS

### Fourty-two of 48 patients have normal antibody response to the vaccine

Forty-eight patients who suffered from hypoxemic COVID-19 pneumonia (severe or critical), despite having received 2 doses of mRNA vaccine, at least 2 weeks and up to 16 weeks (mean: 8 weeks) before infection were recruited from 6 countries (France, Greece, North Macedonia, Turkey, Ukraine, and United States of America). All COVID Human Genetic Effort (CHGE) patients whose samples were available were recruited; they had not been previously infected with SARS-CoV-2, as attested by the clinical information collected and/or a negative serology at the time of vaccination or performed at the onset of disease. These patients were aged 20 to 86 years (mean 53 years old) and included 34 men and 14 women. Five of them had a known deficiency of B cell immunity (immunosuppressive therapy in 3 individuals, and HIV infection in 1, and lymphoma with CAR-T cell treatment in one). We tested the 48 patients for their antibody response to SARS-CoV-2 mRNA vaccines. We found one of the 43 patients did not have a known B cell deficiency, but had an insufficient antibody response to the vaccine (defined as within 3 standard deviations from the mean of unvaccinated controls) (Arrow, Fig. 1A, S1A). The other patients had levels of antibody response to the vaccine similar to those of vaccinated controls (t-test, Supplementary Table 1). Of note, 3 of the 5 patients with a known B cell deficiency had a normal antibody response (above 3 standard deviations) (Fig. 1A). Overall, 42 patients had both no B cell deficiency and a normal antibody response to the vaccine, thus were further investigated.

### Auto-Abs against type I IFNs in 10 of 42 patients with normal Ab response to the vaccine

We next tested all the samples from the 42 patients without known B cell deficiency and with a normal Ab response to the mRNA vaccine for IgG auto-Ab to type I IFN levels using a radioligand binding assay (RLBA). Seven of 42 patients tested had elevated titers of anti-IFN-α2 auto-Abs in RLBA (Fig. 1B). We then tested all these samples for their neutralization activity against IFN-α2, IFN-, and IFN-β at 10 ng/mL, 100 pg/mL, and 10 ng/mL respectively. We identified ten (24%) patients with IgG auto-Abs neutralizing IFN-α2 and/or
IFN-ω, as did the APS-1 positive controls, while the healthy controls did not (Fig. 1C, D). Patients with neutralizing auto-Abs have lower luciferase induction (below threshold in dotted lines). All these patients had normal anti-SARS-CoV-2 Spike antibody response to the vaccine (Fig. S1D, E). In contrast, auto-Abs to type I IFN were not found in any of the 6 patients previously excluded because of a known B cell immunodeficiency (n=5) or an insufficient antibody response to the vaccine (n=1) (Fig. S1B, C). Of note, 8 of these 10 individuals (80%) had circulating auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only (20%), and none neutralized IFN-β (Fig. 1C-D and Table 2). In addition, plasma from 7 patients (diluted 1/10) neutralized a high concentration (10 ng/mL) of type I IFNs (70%), while 3 neutralized only the lower, more physiological, dose (100 pg/mL) of type I IFNs (including the 2 neutralizing IFN-ω only) (30%) (Fig. 1C, D and Table 2). Overall, auto-Abs neutralizing IFN-α2 and/or IFN-ω were found at the onset of disease in 10 of 42 patients (24%) with breakthrough COVID-19 who suffered from hypoxemic pneumonia, despite having a normal antibody response to an mRNA vaccine.

**Demographic, clinical, and virological features of the 10 patients with auto-Abs to type I IFNs**

The patients with hypoxemic breakthrough COVID-19 pneumonia and auto-Abs neutralizing type I IFNs included three women and seven men. They were aged 43 to 86 years old (mean: 75 years old) (Table 1). All were of European ancestry, except one Cambodian, and they originated from France (n=3), Greece (n=5), and the USA (n=2). None of these individuals reported having previously suffered from other severe viral infections. All 10 patients were hospitalized during COVID-19 for oxygen supplementation, including 5 hospitalized in an intensive care unit (ICU) who received mechanical ventilation, and one who received nasal oxygen high flow therapy but was recused of ICU because of age (P8). All of them survived. All presented with bilateral COVID-19 pneumonia and had a positive SARS-CoV-2 RT-PCR in the respiratory tract. The SARS-CoV-2 variants involved were unknown but most likely to be Delta variant, given the epidemiology at the location and time of sampling (i.e., before October 2021 for all samples tested). They had been vaccinated 2 to 16 weeks prior to the diagnosis of COVID-19. Of note, one individual (P2) had at least two auto-immune conditions (myasthenia gravis and Hashimoto's thyroiditis), while another (P10) had APS-1. Myasthenia gravis and APS-1 are associated with auto-Abs to type I IFNs, which had however not been measured prior to COVID-19 in these two individuals. Finally, one individual (P1) belonged to a large family, whose members had all been fully vaccinated, and many were infected at the same time as he did (32). He was nevertheless the only one to suffer from critical disease, and also the only one to harbor neutralizing auto-Abs to type I

IFNs. None of the 10 patients died of COVID-19, while more than 20% of unvaccinated individuals who died of COVID-19 harbored neutralizing auto-Abs (22) and 5-10% of unvaccinated patients with these auto-Abs died of COVID-19 (23), suggesting that although insufficient to prevent hypoxemic pneumonia, vaccination may have protected these patients from a fatal outcome. Overall, auto-Abs to type I IFNs can underlie hypoxemic breakthrough COVID-19 infection in previously healthy individuals who developed normal antibody responses after SARS-CoV-2 mRNA vaccination.

**Antibodies neutralizing SARS-CoV-2 in all 10 patients**

To further test the hypothesis that the hypoxemic breakthrough cases were driven by the auto-Abs neutralizing type I IFNs and not by an insufficient antibody response to the vaccine, we assessed the neutralizing activity in all 10 patients' plasma against SARS-CoV-2. Although we did not collect blood samples prior to COVID-19 diagnosis, we collected them in the first 3 days of hospitalization. As we did not determine with which viral strain the patients had been infected, we performed the neutralization assay with pseudoviruses representing both the previously globally dominant D614G strain and the Delta variant (B.1.617.2), which was dominant when and where the patients were infected. We compared the patients' results with the neutralization titer of healthy vaccinated donors 2-8 weeks after the 2nd dose of the mRNA vaccine. All 10 individuals tested had a neutralization capacity, when compared with the healthy vaccinated controls, although it was slightly reduced for 2 individuals (P4 and P6) for the D614G strain and for 3 individuals (P1, P4 and P6) for the Delta variant (Fig. 2A, B, S1D, E). Although P1 neutralized 10 ng/mL of type I IFNs, P4 and P6 only neutralized low concentrations of type I IFNs. Specifically, P4 neutralized both IFN-α2 and IFN-ω but only at 100 pg/mL, while P6 neutralized only IFN-ω at 100 pg/mL. This observation suggests that in patients whose auto-Abs neutralized only low concentrations of type I IFNs, sub-optimal antibody response to the vaccine may have also contributed to hypoxemic pneumonia. Overall, this suggested that hypoxemic COVID-19 pneumonia can occur in individuals with a normal antibody response to two doses of mRNA vaccine (42 of 48 patients tested). Moreover, in about 20% of the breakthrough cases (10 of 42 cases), hypoxemic pneumonia was probably due to auto-Abs neutralizing IFN-α2 and/or IFN-ω (and typically at high concentration of both IFNs). Finally, 70% of the latter cases (7 of 10 cases), plasma neutralization of two viral strains was normal, while one had a lower neutralization against the delta strain, and the remaining 2 had a subnormal neutralization of both viral strains (D614G, and Delta).

**DISCUSSION**

The pathogenesis of life-threatening COVID-19 pneumonia involves two steps, with a deficiency of respiratory type I
IFN immunity in the first days of infection resulting in viral
spread, which triggers excessive systemic and pulmonary in-
flammation (30, 33, 34). The vaccination of billions of indi-
viduals has efficiently reduced the number of critical cases.
Nevertheless, breakthrough hypoxemic COVID-19 pneumo-
nia can occur in previously healthy individuals who are vac-
cinated against SARS-CoV-2, which is assumed to be due to a
poor antibody response to the vaccine (31). Our findings sug-
gest that most breakthrough hypoxemic cases (42 of 48
tested) did not have a known B cell deficiency and also had a
normal antibody response to the vaccine, although no sam-
ples were available before SARS-CoV-2 infection. Moreover,
we showed that about 20% (10 of 42) of these breakthrough
cases with normal antibody response to the vaccine also car-
ried auto-Abs neutralizing IFN-α2 and/or IFN-ω (10 ng/mL
for 7 patients and 100 pg/mL for 3 patients). In addition, the
plasma of 7 of the 10 patients with auto-Abs to type I IFNs
efficiently neutralized SARS-CoV-2 in vitro, while one had a
lower neutralization against the delta strain, and plasma
from the remaining 2 neutralized the two viral strains tested
sub-optimally. Both patients had auto-Abs neutralizing only
100 pg/mL of type I IFNs. Plasma (diluted 1/10) from seven
of the 10 individuals with these auto-Abs neutralized a high
concentration (10 ng/mL) of both IFN-α2 and IFN-ω, con-
sistent with unvaccinated individuals carrying such auto-Abs
being at the greatest risk of critical COVID-19 among individ-
uals carrying any combinations of auto-Abs to type I IFNs (22,
23, 30). The proportion of individuals with hypoxemic
COVID-19 due to neutralizing both IFN-α2 and IFN-ω at the
high dose (10 ng/mL) is even higher in the breakthrough co-
hort reported here (7 of 42, 16%) than in the previously de-
scribed unvaccinated cohort (175 of 3,136, 7.1%) (P = 0.015)
(22). Two of the 3 patients neutralizing only 100 pg/mL of
type I IFNs, also had a slightly diminished neutralization ca-
pacity against SARS-CoV-2, suggesting in these individuals a
combination of 2 factors: the presence of auto-Abs to low con-
centration of type I IFNs, and a suboptimal antibody re-
sponse to the vaccine.

Nevertheless, as we were not able to identify and study
auto-Ab positive individuals who were vaccinated and effi-
ciently protected against severe infection, we cannot estimate
the percentage of breakthrough cases with hypoxemic pneu-
monia in individuals with auto-Abs neutralizing type I IFNs
infected with SARS-CoV-2. Until 70 years old, the proportion
of individuals from the general population sampled prior to
the pandemic that carry auto-Abs against both IFN-α2 and
IFN-ω is 0.02% and 0.03% for the neutralization of 10 ng/mL
and 100 pg/mL, respectively, while it reaches 0.6% and 1.6%
over 70 years old. As mRNA vaccines have high efficacy to
prevent critical pneumonia, it is probable that most patients
with auto-Abs against type I IFNs benefit from vaccination,
although the protection might not be sufficient in individuals

neutralizing high concentrations of multiple type I IFNs. It is
also not unreasonable to speculate that, despite an infection
with a vaccine-covered viral variant and a normal antibody
response to the vaccine, a small proportion of the patients
with such auto-Abs might not be fully protected by the vac-
cine, especially if infected with a high viral inoculum. By in-
ference from previous studies, the auto-Abs of the 8 patients
neutralizing IFN-α2 also probably neutralizes the 13 types of
IFN-α (10, 20, 22, 35, 36). These findings suggest that a potent
post-vaccine humoral immunity can be insufficient to fight
SARS-CoV-2 infection, especially in patients with auto-Abs
neutralizing both IFN-α2 and IFN-ω, and even more so at
high concentration.

Our results here suggest it may be beneficial to test for
auto-Abs to type I IFN in vaccinated patients diagnosed with
breakthrough COVID-19 pneumonia of varying severity. Test-
ing uninfected people, including vaccinated individuals, may
also be considered, especially in those over 70 years old given
the high prevalence of auto-Abs to type I IFNs in this popu-
lation (>4%) and their lower global type I IFN immunity (30,
36). One of the 10 patients suffered from APS-1 and thus most
likely harbored these auto-Abs since early childhood (20, 21,
37), while another patient had myasthenia gravis, which is
also commonly associated with these auto-Abs (38). Testing
patients with conditions known to be associated with these
auto-Abs may benefit these patients. All individuals with
auto-Abs to IFNs might benefit not only from vaccine boost-
ers but perhaps from recurrent vaccinations. Prospective
studies assessing vaccine-induced immunity before infection
in patients with auto-Abs to type I IFNs would be informa-
tive, for example in the setting of vaccine trials. Systematic
screening at hospital admission for auto-Abs to type I IFNs
would also be of help for the management of vaccinated or
unvaccinated individuals with hypoxemic pneumonia. In-
deed, monoclonal antibodies (mAbs) neutralizing the virus
could also be administered promptly (39), as shown for an
IRF9-deficient patient (40), especially in patients with the
highest titers of auto-Abs to type I IFNs. Anti-viral com-
pounds, such as remdesivir (41, 42) or molnupiravir (43), may
also benefit these patients if administered early in the course
of infection. Conversely, in ambulatory patients with these
auto-Abs, early recombinant IFN-β therapy may also be con-
sidered, to prevent the development of hypoxemic pneumo-
nia (44). In sum, our findings indicate that auto-Abs to type
I IFNs is a susceptibility factor for a severe clinical course of
COVID-19 even in vaccinated subjects with a breakthrough
infection.

MATERIALS AND METHODS

Study Design

We enrolled 48 patients with proven hypoxemic COVID-
19 pneumonia, 12 unvaccinated controls, and 11 vaccinated
controls from 6 countries in this study. We collected plasma
or serum samples for all these individuals to test for the presence of IgG Abs against SARS-CoV-2 and auto-Abs to type I IFNs by immuno-assay. All individuals were recruited according to protocols approved by local Institutional Review Boards (IRBs).

### COVID-19 classification

The severity of COVID-19 was assessed for each patient as follows (6, 10): “critical COVID-19 pneumonia” was defined as pneumonia developing in patients with critical disease, whether pulmonary, with high-flow oxygen, mechanical ventilation (continuous positive airway pressure, bilevel positive airway pressure, intubation), septic shock, or with damage to any other organ requiring admission to the intensive care unit. “Severe COVID-19” was defined as pneumonia developing in patients requiring low-flow oxygen (<6L/min). The controls were individuals infected with SARS-CoV-2 (as demonstrated by a positive PCR and/or serological test and/or displaying typical symptoms, such as anosmia/ageusia after exposure to a confirmed COVID-19 case) who remained asymptomatic or developed mild, self-healing, ambulatory disease with no evidence of pneumonia.

### Statistics

For comparison of groups in Fig. 1a, a two-sided *t* test was performed using a Python library (SciPy) for both Spike and RBD. Briefly, all groups were compared to the unvaccinated control group (n=12). In addition, the group of auto-Ab positive breakthrough cases were compared to the group of auto-Ab negative breakthrough cases.

### Detection of anti-cytokine auto-Abs by a high throughput automated ELISA (Gyros)

Cytokines, recombinant human (rh)IFN-α2 (Milteny Biotech, ref. number 130-108-984) or rhIFN-ω (Merck, ref. number SRP3061), were first biotinylated with EZ-Link Sulfo-NHS-LC-Biotin (Thermo Fisher Scientific, cat. number A39257), according to the manufacturer's instructions, with a biotin-to-protein molar ratio of 1:12. The detection reagent contained a secondary antibody Alexa Fluor 647 goat anti-human IgG (Thermo Fisher Scientific, ref. number A21445) diluted in Rexip F (Gyros Protein Technologies, ref. number P0004825; 1/500 dilution of the 2 mg/mL stock to yield a final concentration of 4 µg/mL). Buffer PBS-T 0.01% and Gyros Wash buffer (Gyros Protein Technologies, ref. number P0020087) were prepared according to the manufacturer's instructions. Plasma or serum samples were then diluted 1/100 in PBS-T 0.01% and tested with the Bioaffy 1000 CD (Gyros Protein Technologies, ref. number P0004253), and the Gyrolab X-Pand (Gyros Protein Technologies, ref. number P0020520). Cleaning cycles were performed in 20% ethanol.

### RLBA for anti-IFN-α2 auto-Ab detection

A DNA plasmid containing full-length cDNA sequence with a Flag-Myc tag (OriGene, #RC221091) was verified by Sanger sequencing and used as template in T7-promoter-

based in vitro transcription/translation reactions (Promega, #L1170) using [S35]-methionine (PerkinElmer, #NEG709A). IFN-α2 protein was column-purified using NAP-5 columns (GE Healthcare, #17-0853-01); incubated with 2.5 µl of serum, 2.5 µl of plasma, or 1 µl of anti-myc-positive control antibody (Cell Signaling Technology, #2272); and immunoprecipitated with Sephadex protein A/G beads (4:1 ratio; Sigma-Aldrich, #GE17-5280-02 and #GE17-0618-05) in 96-well polyvinylidene difluoride filtration plates (Corning, #EK-680860). The radioactive counts [counts per minute (cpm)] of immunoprecipitated protein were quantified using a 96-well Microbeta TriLux liquid scintillation plate reader (PerkinElmer). Antibody index for each sample was calculated as follows: (sample cpm value - mean blank cpm value)/(positive control antibody cpm value - mean blank cpm value). For the COVID-19 patient and CCP cohorts, a positive signal was defined as greater than 6 standard deviations above the mean of pre-COVID-19 blood bank non-inflammatory controls.

### Functional evaluation of anti-cytokine auto-Abs by luciferase reporter assays

The blocking activity of anti-IFN-α2 and anti-IFN-ω auto-Abs was determined with a reporter luciferase activity. Briefly, HEK293T cells were transfected with a plasmid containing the *Firefly* luciferase gene under the control of the human *ISRE* promoter in the pGL4.45 backbone, and a plasmid constitutively expressing *Renilla* luciferase for normalization (pRL-SV40). Cells were transfected in the presence of the X-tremeGene9 transfection reagent (Sigma-Aldrich, ref. number 6365779001) for 24 hours. Cells in Dulbecco's modified Eagle medium (DMEM, Thermo Fisher Scientific) supplemented with 2% fetal calf serum (FCS) and 10% healthy control or patient serum/plasma (after inactivation at 56°C, for 20 min) were either left unstimulated or were stimulated with IFN-α2 (Milteny Biotech, ref. number 130-108-984), IFN-ω (Merck, ref. number SRP3061), at 10 ng/mL or 100 pg/mL, or IFN-β (Milteny Biotech, ref. number: 130-107-888) at 10 ng/mL, for 16 hours at 37°C. Each sample was tested once for each cytokine and dose. Finally, cells were lysed for 20 min at room temperature and luciferase levels were measured with the Dual-Luciferase® Reporter 1000 assay system (Promega, ref. number E1980), according to the manufacturer's protocol. Luminescence intensity was measured with a VICTOR-X Multilabel Plate Reader (PerkinElmer Life Sciences, USA). *Firefly* luciferase activity values were normalized against *Renilla* luciferase activity values. These values were then normalized against the median induction level for non-neutralizing samples, and expressed as a percentage. Samples were considered neutralizing if luciferase induction, normalized against *Renilla* luciferase activity, was below 15% of the median values for controls tested the same day.

### SARS-CoV-2 serological studies

Serum collection
Control serum was collected under informed consent from healthy recipients of BNT162b2 vaccine (vaccines based on the Wuhan spike protein -S protein- sequence), which were confirmed to have no prior SARS-CoV-2 infection by anti-SARS-CoV-2 nucleocapsid (N protein) IgG assay (45). All serum samples were heat inactivated at 56°C for 30 min prior to neutralization experiments.

## Luminex Assay

Luminex immunoassays for SARS-CoV-2 serology studies were performed as previously described using proteins from the Wuhan strain of the virus (46). Briefly, whole N protein, trimeric Spike ectodomain (residues 1-1213) and receptor binding domain (residues 328-533, all generously provided by Dr. John Pak, Chan Zuckerberg Biohub) were each conjugated to a unique spectrally encoded bead using manufacturer instructions (Luminex Antibody Coupling Kit, #40-50016) with 5 µg of protein per 1 million beads. All beads were blocked overnight before use in PBST supplemented with 0.1% BSA and pooled on day of use. 2000-2500 beads per ID were pooled per replicate. Patient serum or plasma was incubated with beads at a final dilution of 1:250 for 1 hour, washed twice in PBST, stained with an anti-IgG (human) pre-conjugated to phycoerythrin (Thermo Scientific, #12-4998-82) for 30 min at 1:2000, then washed thrice in PBST. Primary incubations were done in PBST supplemented with 2% non-fat milk and secondary incubations were done in PBST. Beads were processed in duplicate in 96 well format and analyzed on a Luminex LX 200 cytometer. Median Fluorescence Intensity from each set of beads within each bead ID were retrieved directly from the LX200 after normalizing to the intra-assay negative controls (Bovine Serum Albumin (BSA) conjugated beads).

## Pseudovirus production

SARS-CoV-2 pseudoviruses were generated using a previously described recombinant vesicular stomatitis virus expressing GFP in place of the VSV glycoprotein (rVSV★G-GFP) (47). The SARS-CoV-2 spike gene bearing the D614G mutation or the set of mutations in the B.1.617.2/Delta variant (T19R, T95I, G142D, ★157-158, L452R, T478K, P681R, D614G, D950N) were cloned in a CMV-driven expression vector and used to produce SARS-CoV-2 spike reporter pseudoviruses. Pseudoviruses were titered on Huh7.5.1 cells overexpressing ACE2 and Transmembrane protease, serine 2 (TMPRSS2) (gift of Andreas Puschnik) using GFP expression to measure the concentration of focus forming units (ffu).

## Pseudovirus neutralization experiments

Huh7.5.1-ACE2-TMPRSS2 cells were seeded in 96-well plates at a density of 7000 cells/well one day prior to pseudovirus inoculation. Cells were verified to be free of mycoplasma contamination with the MycoAlert Mycoplasma detection kit (Lonza). Serum samples were diluted into complete culture media (DMEM with 10% FBS, 10mM HEPES, 1x

Pen-Strep-Glutamine) using the LabCyte Echo 525 liquid handler and 1500 ffu of SARS-CoV-2 pseudovirus was added to each well to reach final dilutions ranging from 1:20-1:10240, including no-serum and no-pseudovirus controls. Serum/pseudovirus mixtures were incubated at 37°C for 1h before being added directly to cells. Cells inoculated with serum/pseudovirus mixtures were incubated at 37°C and 5% CO₂ for 24h, resuspended using 10x TrypLE Select (Gibco), and cell fluorescence was measured with the BD Celesta flow cytometer. All neutralization assays were repeated for a total of three independent experiments with each experiment containing two technical replicates for each condition. Flow cytometry data was analyzed with FlowJo to determine the percentage of cells transduced with pseudovirus (GFP-positive). Percent neutralization for each serum dilution was calculated by normalizing GFP-positive cell percentage to no-serum control wells. Fifty percent neutralization titers (NT₅₀) were calculated from ten-point response curves generated in GraphPad Prism 7 using four-parameter logistic regression.

## SUPPLEMENTARY MATERIALS

www.science.org/doi/10.1126/sciimmunol.abp8966

Materials and Methods

Fig. S1

Table S1

Data file S1

## REFERENCES AND NOTES

1. P. Zhou, X. L. Yang, X. G. Wang, B. Hu, L. Zhang, W. Zhang, H. R. Si, Y. Zhu, B. Li, C. L. Huang, H. D. Chen, J. Chen, Y. Luo, H. Guo, R. D. Jiang, M. Q. Liu, Y. Chen, X. R. Shen, X. Wang, X. S. Zheng, K. Zhao, Q. J. Chen, F. Deng, L. L. Liu, B. Yan, F. X. Zhan, Y. Y. Wang, G. F. Xiao, Z. L. Shi, A pneumonia outbreak associated with a new coronavirus of probable bat origin. *Nature* 579, 270–273 (2020). doi:10.1038/s41586-020-2012-7 Medline

2. Worldometer. (2021), vol. 2021.

3. A. T. Levin, W. P. Hanage, N. Owusu-Boaitey, K. B. Cochran, S. P. Walsh, G. Meyerowitz-Katz, Assessing the age specificity of infection fatality rates for COVID-19: Systematic review, meta-analysis, and public policy implications. *Eur. J. Epidemiol.* 35, 1123–1138 (2020). doi:10.1007/s10654-020-00698-1 Medline

4. M. O'Driscoll, G. Ribeiro Dos Santos, L. Wang, D. A. T. Cummings, A. S. Azman, J. Paireau, A. Fontanet, S. Cauchemez, H. Salje, Age-specific mortality and immunity patterns of SARS-CoV-2. *Nature* 590, 140–145 (2021). doi:10.1038/s41586-020-2918-0 Medline

5. D. Bogunovic, M. Merad, Children and SARS-CoV-2. *Cell Host Microbe* 29, 1040–1042 (2021). doi:10.1016/j.chom.2021.06.015 Medline

6. Q. Zhang, P. Bastard, Z. Liu, J. Le Pen, M. Moncada-Velez, J. Chen, M. Ogishi, I. K. D. Sabli, S. Hodeib, C. Korol, J. Rosain, K. Bilguvar, J. Ye, A. Bolze, B. Bigio, R. Yang, A. A. Arias, Q. Zhou, Y. Zhang, F. Onodi, S. Korniotis, L. Karpf, Q. Philippot, M. Chbihi, L. Bonnet-Madin, K. Dorgham, N. Smith, W. M. Schneider, B. S. Razooky, H. H. Hoffmann, E. Michailidis, L. Moens, J. E. Han, L. Lorenzo, L. Bizien, P. Meade, A. L. Neehus, A. C. Ugurbil, A. Corneau, G. Kerner, P. Zhang, F. Rapaport, Y. Seeleuthner, J. Manry, C. Masson, Y. Schmitt, A. Schlüter, T. Le Voyer, T. Khan, J. Li, J. Fellay, L. Roussel, M. Shahrooeei, M. F. Alosaimi, D. Mansouri, H. Al-Saud, F. Al-Mulla, F. Almourfi, S. Z. Al-Muhsen, F. Alsohime, S. Al Turki, R. Hasanato, D. van de Beek, A. Biondi, L. R. Bettini, M. D'Angio', P. Bonfanti, L. Imberti, A. Sottini, S. Paghera, E. Quiros-Roldan, C. Rossi, A. J. Oler, M. F. Tompkins, C. Alba, I. Vandernoot, J. C. Goffard, G. Smits, I. Migeotte, F. Haerynck, P. Soler-Palacin, A. Martin-Nalda, R. Colobran, P. E. Morange, S. Keles, F. Çölkesen, T. Ozcelik, K. K. Yasar, S. Senoglu, S. N. Karabela, C. Rodríguez-Gallego, G. Novelli, S. Hraiech, Y. Tandjaoui-Lambiotte, X. Duval, C. Laouénan, A. L. Snow, C. L. Dalgard, J. D. Milner,
D. C. Vinh, T. H. Mogensen, N. Marr, A. N. Spaan, B. Boisson, S. Boisson-Dupuis, J. Bustamante, A. Puel, M. J. Ciancanelli, I. Meyts, T. Maniatis, V. Soumelis, A. Amara, M. Nussenzweig, A. García-Sastre, F. Krammer, A. Pujol, D. Duffy, R. P. Lifton, S. Y. Zhang, G. Gorochov, V. Béziat, E. Jouanguy, V. Sancho-Shimizu, C. M. Rice, L. Abel, L. D. Notarangelo, A. Cobat, H. C. Su, J. L. Casanova; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort; NIAID-USUHS/TAGC COVID Immunity Group, Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. *Science* **370**, eabd4570 (2020). doi:10.1126/science.abd4570 *Medline*

7. S. Y. Zhang, Q. Zhang, J. L. Casanova, H. C. Su; COVID Team, Severe COVID-19 in the young and healthy: Monogenic inborn errors of immunity? *Nat. Rev. Immunol.* **20**, 455–456 (2020). doi:10.1038/s41577-020-0373-7 *Medline*

8. S. Khanmohammadi, N. Rezaei, M. Khazaei, A. Shirkani, A Case of Autosomal Recessive Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency with Severe COVID-19. *J. Clin. Immunol.* (2021). *Medline*

9. Q. Zhang, P. Bastard, A. Cobat, J. L. Casanova; COVID Human Genetic Effort, Human genetic and immunological determinants of critical COVID-19 pneumonia. *Nature* **603**, 587–598 (2022). doi:10.1038/s41586-022-04447-0 *Medline*

10. P. Bastard, L. B. Rosen, Q. Zhang, E. Michailidis, H. H. Hoffmann, Y. Zhang, K. Dorgham, Q. Philippot, J. Rosain, V. Béziat, J. Manry, E. Shaw, L. Haljasmägi, P. Peterson, L. Lorenzo, L. Bizien, S. Trouillet-Assant, K. Dobbs, A. A. de Jesus, A. Belot, A. Kallaste, E. Catherinot, Y. Tandjaoui-Lambiotte, J. Le Pen, G. Kerner, B. Bigio, Y. Seeleuthner, R. Yang, A. Bolze, A. N. Spaan, O. M. Delmonte, M. S. Abers, A. Aiuti, G. Casari, V. Lampasona, L. Piemonti, F. Ciceri, K. Bilguvar, R. P. Lifton, M. Vasse, D. M. Smadja, M. Migaud, J. Hadjadj, B. Terrier, D. Duffy, L. Quintana-Murci, D. van de Beek, L. Roussel, D. C. Vinh, S. G. Tangye, F. Haerynck, D. Dalmau, J. Martinez-Picado, P. Brodin, M. C. Nussenzweig, S. Boisson-Dupuis, C. Rodríguez-Gallego, G. Vogt, T. H. Mogensen, A. J. Oler, J. Gu, P. D. Burbelo, J. I. Cohen, A. Biondi, L. R. Bettini, M. D'Angio, P. Bonfanti, P. Rossignol, J. Mayaux, F. Rieux-Laucat, E. S. Husebye, F. Fusco, M. V. Ursini, L. Imberti, A. Sottini, S. Paghera, E. Quiros-Roldan, C. Rossi, R. Castagnoli, D. Montagna, A. Licari, G. L. Marsseglia, X. Duval, J. Ghosn, J. S. Tsang, R. Goldbach-Mansky, K. Kisand, M. S. Lionakis, A. Puel, S. Y. Zhang, S. M. Holland, G. Gorochov, E. Jouanguy, C. M. Rice, A. Cobat, J. D. Notarangelo, L. Abel, H. C. Su, J. L. Casanova; HGID Lab; NIAID-USUHS Immune Response to COVID Group; COVID Clinicians; COVID-STORM Clinicians; Imagine COVID Group; French COVID Cohort Study Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; COVID Human Genetic Effort, Autoantibodies against type I IFNs in patients with life-threatening COVID-19. *Science* **370**, eabd4585 (2020). doi:10.1126/science.abd4585 *Medline*

11. R. Koning, P. Bastard, J. L. Casanova, M. C. Brouwer, D. van de Beek; with the Amsterdam U.M.C. COVID-19 Biobank Investigators, Autoantibodies against type I interferons are associated with multi-organ failure in COVID-19 patients. *Intensive Care Med.* **47**, 704–706 (2021). doi:10.1007/s00134-021-06392-4 *Medline*

12. J. Troya, P. Bastard, L. Planas-Serra, P. Ryan, M. Ruiz, M. de Carranza, J. Torres, A. Martínez, L. Abel, J. L. Casanova, A. Pujol, Neutralizing Autoantibodies to Type I IFNs in >10% of Patients with Severe COVID-19 Pneumonia Hospitalized in Madrid, Spain. *J. Clin. Immunol.* **41**, 914–922 (2021). doi:10.1007/s10875-021-01036-0 *Medline*

13. S. E. Vazquez, P. Bastard, K. Kelly, A. Gervais, P. J. Norris, L. J. Dumont, J. L. Casanova, M. S. Anderson, J. L. DeRisi, Neutralizing Autoantibodies to Type I Interferons in COVID-19 Convalescent Donor Plasma. *J. Clin. Immunol.* **41**, 1169–1171 (2021). doi:10.1007/s10875-021-01060-0 *Medline*

14. D. Goncalves, M. Mezidi, P. Bastard, M. Perret, K. Saker, N. Fabien, R. Pescarmona, R. Lombard, T. Walzer, J.-L. Casanova, A. Belot, J.-C. Richard, S. Trouillet-Assant, Antibodies against type-I Interferon: detection and association with severe clinical outcome in COVID-19 patients. *medRxiv*. (2021). doi:10.1172/JCI150867 *Medline*

15. E. Y. Wang, T. Mao, J. Klein, Y. Dai, J. D. Huck, J. R. Jaycox, F. Liu, T. Zhou, B. Israelow, P. Wong, A. Coppi, C. Lucas, J. Silva, J. E. Oh, E. Song, E. S. Perotti, N. S. Zheng, S. Fischer, M. Campbell, J. B. Fournier, A. L. Wyllie, C. B. F. Vogels, I. M. Ott, C. C. Kalinich, M. E. Petrone, A. E. Watkins, C. Dela Cruz, S. F. Farhadian, W. L. Schulz, S. Ma, N. D. Grubaugh, A. I. Ko, A. Iwasaki, A. M. Ring; Yale IMPACT Team, Diverse functional autoantibodies in patients with COVID-19. *Nature* **595**, 283–288 (2021). doi:10.1038/s41586-021-03631-y *Medline*

16. M. G. P. van der Wijst, S. E. Vazquez, G. C. Hartoularos, P. Bastard, T. Grant, R. Bueno, D. S. Lee, J. R. Greenland, Y. Sun, R. Perez, A. Ogorodnikov, A. Ward, S. A. Mann, K. L. Lynch, C. Yun, D. V. Havlir, G. Chamie, C. Marquez, B. Greenhouse, M. S. Lionakis, P. J. Norris, L. J. Dumont, K. Kelly, P. Zhang, Q. Zhang, A. Gervais, T. Le Voyer, A. Whatley, Y. Si, A. Byrne, A. J. Combes, A. A. Rao, Y. S. Song, G. K. Fragiadakis, K. Kangelaris, C. S. Calfee, D. J. Erle, C. Hendrickson, M. F. Krummel, P. G. Woodruff, C. R. Langelier, J. L. Casanova, J. L. Derisi, M. S. Anderson, C. J. Ye; UCSF COMET consortium, Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. *Sci. Transl. Med.* **13**, eabh2624 (2021). doi:10.1126/scitranslmed.abh2624 *Medline*

17. Y. Acosta-Ampudia, D. M. Monsalve, M. Rojas, Y. Rodríguez, J. E. Gallo, J. C. Salazar-Uribe, M. J. Santander, M. P. Cala, W. Zapata, M. I. Zapata, R. Manrique, J. M. Pardo-Oviedo, B. Camacho, C. Ramírez-Santana, J. M. Anaya; CP-COVID-19 group, COVID-19 convalescent plasma composition and immunological effects in severe patients. *J. Autoimmun.* **118**, 102598 (2021). doi:10.1016/j.jaut.2021.102598 *Medline*

18. X. Solanich, R. Rigo-Bonnin, V. D. Gumucio, P. Bastard, J. Rosain, Q. Philippot, X. L. Perez-Fernandez, M. P. Fuset-Cabanes, M. A. Gordillo-Benitez, G. Suarez-Cuartin, E. Boza-Hernandez, A. Riera-Mestre, A. Parra-Martínez, R. Colobran, A. Antolí, S. Navarro, G. Rocamora-Blanch, M. Filamil, L. Calatayud, X. Corbella, J. L. Casanova, F. Morandeira, J. Sabater-Riera; Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona. *J. Clin. Immunol.* **41**, 1733–1744 (2021). doi:10.1007/s10875-021-01136-x *Medline*

19. A. Chauvineau-Grenier, P. Bastard, A. Servajean, A. Gervais, J. Rosain, E. Jouanguy, A. Cobat, J. L. Casanova, B. Rossi, Autoantibodies neutralizing type I interferons in 20% of COVID-19 deaths in a French hospital. *Res Sq.* (2021). doi:10.1084/jem.20210554 *Medline*

20. P. Bastard, E. Orlova, L. Sozaeva, R. Lévy, A. James, M. M. Schmitt, S. Ochoa, M. Kareva, Y. Rodina, A. Gervais, T. Le Voyer, J. Rosain, Q. Philippot, A. L. Neehus, E. Shaw, M. Migaud, L. Bizien, O. Ekwall, S. Berg, G. Beccuti, L. Ghizzoni, G. Thiriez, A. Pavot, C. Goujard, M. L. Frémond, E. Carter, A. Rothenbuhler, A. Linglart, B. Mignot, A. Comte, N. Cheikh, O. Hermine, L. Breivik, E. S. Husebye, S. Humbert, P. Rohrlich, A. Coaquette, F. Vuoto, K. Faure, N. Mahlaoui, P. Kotnik, T. Battelino, K. Trebušak Podkrajšek, K. Kisand, E. M. N. Ferré, T. DiMaggio, L. B. Rosen, P. D. Burbelo, M. McIntyre, N. Y. Kann, A. Shcherbina, M. Pavlova, A. Kolodkina, S. M. Holland, S. Y. Zhang, Y. J. Crow, L. D. Notarangelo, H. C. Su, L. Abel, M. S. Anderson, E. Jouanguy, B. Neven, A. Puel, J. L. Casanova, M. S. Lionakis; Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. *J. Exp. Med.* **218**, e20210554 (2021). doi:10.1084/jem.20210554 *Medline*

21. C. Meisel, B. Akbil, T. Meyer, E. Lankes, V. M. Corman, O. Staudacher, N. Unterwalder, U. Kölsch, C. Drosten, M. A. Mall, T. Kallinich, D. Schnabel, C. Goffinet, H. von Bernuth, Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1. *J. Clin. Invest.* **131**, e150867 (2021). doi:10.1172/JCI150867 *Medline*

22. P. Bastard, A. Gervais, T. Le Voyer, J. Rosain, Q. Philippot, J. Manry, E. Michailidis, H. H. Hoffmann, S. Eto, M. Garcia-Prat, L. Bizien, A. Parra-Martínez, R. Yang, L. Haljasmägi, M. Migaud, K. Särekannu, J. Maslovskaja, N. de Prost, Y. Tandjaoui-Lambiotte, C. E. Luyt, B. Amador-Borrero, A. Gaudet, J. Poissy, P. Morel, P. Richard, F. Cognasse, J. Troya, S. Trouillet-Assant, A. Belot, K. Saker, P. Garçon, J. G. Rivière, J. C. Lagier, S. Gentile, L. B. Rosen, E. Shaw, T. Morio, J. Tanaka, D. J. P. L. Tharaux, D. Sene, A. Stepanian, B. Megarbane, V. Triantafyllia, A. Fekkar, J. R. Heath, J. L. Franco, J. M. Anaya, J. Solé-Violán, L. Imberti, A. Biondi, P. Bonfanti, R. Castagnoli, O. M. Delmonte, Y. Zhang, A. L. Snow, S. M. Holland, C. Biggs, M. Moncada-Vélez, A. A. Arias, L. Lorenzo, S. Boucherit, B. Coulibaly, D. Anglicheau, A. M. Planas, F. Haerynck, S. Duvlis, R. L. Nussbaum, T. Ozcelik, S. Keles, A. A. Bousfiha, J. El Bakkouri, C. Ramirez-Santana, S. Paul, Q. Pan-Hammarström, L. Hammarström, A. Dupont, A. Kurolup, C. N. Metz, A. Aiuti, G. Casari, V. Lampasona, F. Ciceri, L. A. Barreiros, E. Dominguez-Garrido, M. Vidigal, M. Zatz, D. van de Beek, S. Sahanic, I. Tancevski, Y. Stepanovskyy, O. Boyarchuk, Y. Nukui, M. Tsumura, L. Vidaur, S. G. Tangye, S. Burrel, D. Duffy, L. Quintana-Murci, A. Kloperk, N. Y. Kann, A. Shcherbina, Y. L. Lau, D. Leung, M. Coulongeat, J. Marlet, R. Koning, L. F. Reyes, A. Chauvineau-Grenier, F. Venet, G. Monneret, M. C. Nussenzweig, R. Arrestier, I. Boudhabhay, H. Baris-Feldman, D. Hagin, J. Wauters, I. Meyts, A. H. Dyer, S. P. Kennelly, N. M. Bourke, R. Halwani, N. S. Sharif-
Askari, K. Dorgham, J. Sallette, S. M. Sedkaoui, S. AlKhater, R. Rigo-Bonnin, F. Morandeira, L. Roussel, D. C. Vinh, S. R. Ostrowski, A. Condino-Neto, C. Prando, A. Bonradenko, A. N. Spaan, L. Gilardin, J. Fellay, S. Lyonnet, K. Bilguvar, R. P. Lifton, S. Mane, M. S. Anderson, B. Boisson, V. Béziat, S. Y. Zhang, E. Vandreakos, O. Hermine, A. Pujol, P. Peterson, T. H. Mogensen, L. Rowen, J. Mond, S. Debette, X. de Lamballerie, X. Duval, F. Mentré, M. Zins, P. Soler-Palacin, R. Colobran, G. Gorochov, X. Solanich, S. Susen, J. Martinez-Picado, D. Raoult, M. Vasse, P. K. Gregersen, L. Piemonti, C. Rodríguez-Gallego, L. D. Notarangelo, H. C. Su, K. Kisand, S. Okada, A. Puel, E. Jouanguy, C. M. Rice, P. Tiberghien, Q. Zhang, A. Cobat, L. Abel, J. L. Casanova; HIGD Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James's Hospital; SARS CoV2 Interest group; French COVID Cohort Study Group; Imagine COVID-Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19; Biobank Investigators; COVID Human Genetic Effort; CONSTANCES cohort; 3C-Dijon Study; Cerba Health-Care; Etablissement du Sang study group; Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths. *Sci. Immunol.* 6, eab14340 (2021). doi:10.1126/sciimmunol.abl4340 Medline

23. J. Manry, P. Bastard, A. Gervais, T. L. Voyer, J. Rosain, Q. Philippot, E. Michailidis, H. H. Hoffmann, S. Eto, M. Garcia-Prat, L. Bizien, A. Parra-Martinez, R. Yang, L. Haljasmagi, M. Migaud, K. Sarekannu, J. Maslovskaja, N. de Prost, Y. Tandjaoui-Lambiotte, C. E. Luyt, B. Amador-Borrero, A. Gaudet, J. Poissy, P. Morel, P. Richard, F. Cognasse, J. Troya, S. Trouillet-Assant, A. Belot, K. Saker, P. Garcon, J. G. Riviere, J. C. Lagier, S. Gentile, L. Rosen, E. Shaw, T. Morio, J. Tanaka, D. Dalmau, P. L. Tharaux, D. Sene, A. Stepanian, A. Megarbane, V. Triantafyllia, A. Fekkar, J. Heath, J. Franco, J. M. Anaya, J. Sole-Violan, L. Imberti, A. Biondi, P. Bonfanti, R. Castagnoli, O. Delmonte, Y. Zhang, A. Snow, S. Holland, C. Biggs, M. Moncada-Velez, A. Arias, L. Lorenzo, S. Boucherit, D. Anglicheau, A. Planas, F. Haerynck, S. Duvlis, R. Nussbaum, T. Ozcelik, S. Keles, A. Bousfiha, J. E. Bakkouri, C. Ramirez-Santana, S. Paul, Q. Pan-Hammarstrom, L. Hammarstrom, A. Dupont, A. Kurolap, C. Metz, A. Aiuti, G. Casari, V. Lampasona, F. Ciceri, L. Barreiros, E. Dominguez-Garrido, M. Vidigal, M. Zatz, D. van de Beek, S. Sahanic, I. Tancevski, Y. Stepanovskyy, O. Boyarchuk, Y. Nukui, M. Tsumura, L. Vidaur, S. Tangye, S. Burrel, D. Duffy, L. Quintana-Murci, A. Klocperk, N. Kann, A. Shcherbina, Y. L. Lau, D. Leung, M. Coulongeat, J. Marlet, R. Koning, L. Reyes, A. Chauvineau-Grenier, F. Venet, G. Monneret, M. Nussenzweig, R. Arrestier, I. Boudhabhay, H. Baris-Feldman, D. Hagin, J. Wauters, I. Meyts, A. Dyer, S. Kennelly, N. Bourke, R. Halwani, F. Sharif-Askari, K. Dorgham, J. Sallette, S. Mehlal-Sedkaoui, S. AlKhater, R. Rigo-Bonnin, F. Morandeira, L. Roussel, D. Vinh, C. Erikstrup, A. Condino-Neto, C. Prando, A. Bondarenko, A. Spaan, L. Gilardin, J. Fellay, S. Lyonnet, K. Bilguvar, R. Lifton, S. Mane, M. Anderson, B. Boisson, V. Beziat, S. Y. Zhang, E. Andreakos, O. Hermine, A. Pujol, P. Peterson, T. H. Mogensen, L. Rowen, J. Mond, S. Debette, X. deLamballerie, C. Burdet, L. Bouadma, M. Zins, P. Soler-Palacin, R. Colobran, G. Gorochov, X. Solanich, S. Susen, J. Martinez-Picado, D. Raoult, M. Vasse, P. Gregersen, C. Rodriguez-Gallego, L. Piemonti, L. Notarangelo, H. Su, K. Kisand, S. Okada, A. Puel, E. Jouanguy, C. Rice, P. Tiberghien, Q. Zhang, J. L. Casanova, L. Abel, A. Cobat, The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies. *Res Sq*, (2022).

24. F. P. Polack, S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. Pérez Marc, E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. Koury, P. Li, W. V. Kalina, D. Cooper, R. W. Frenck Jr., L. L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Şahin, K. U. Jansen, W. C. Gruber; C459100 Clinical Trial Group, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. *N. Engl. J. Med.* 383, 2603–2615 (2020). doi:10.1056/NEJMoa2034577 Medline

25. S. J. Thomas, E. D. Moreira Jr., N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. Pérez Marc, F. P. Polack, C. Zerbini, R. Bailey, K. A. Swanson, X. Xu, S. Roychoudhury, K. Koury, S. Bouguermouh, W. V. Kalina, D. Cooper, R. W. Frenck Jr., L. L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, Q. Yang, P. Liberator, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Şahin, W. C. Gruber, K. U. Jansen; C459100 Clinical Trial Group, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. *N. Engl. J. Med.* 385, 1761–1773 (2021). doi:10.1056/NEJMoa2110345 Medline

26. M. Bergwerk, T. Gonen, Y. Lustig, S. Amit, M. Lipsitch, C. Cohen, M. Mandelboim,

E. G. Levin, C. Rubin, V. Indenbaum, I. Tal, M. Zavitan, N. Zuckerman, A. Bar-Chaim, Y. Kreiss, G. Regev-Yochay, Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. *N. Engl. J. Med.* 385, 1474–1484 (2021). doi:10.1056/NEJMoa2109072 Medline

27. C. Kuhlmann, C. K. Mayer, M. Claassen, T. Maponga, W. A. Burgers, R. Keeton, C. Riou, A. D. Sutherland, T. Suliman, M. L. Shaw, W. Preiser, Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose. *Lancet* 399, 625–626 (2022). doi:10.1016/S0140-6736(22)00090-3 Medline

28. M. W. Tenforde, W. H. Self, K. Adams, M. Gaglani, A. A. Ginde, T. McNeal, S. Ghamande, D. J. Douin, H. K. Talbot, J. D. Casey, N. M. Mohr, A. Zepeski, N. I. Shapiro, K. W. Gibbs, D. C. Files, D. N. Hager, A. Shehu, M. E. Prekker, H. L. Erickson, M. C. Exline, M. N. Gong, A. Mohamed, D. J. Henning, J. S. Steingrub, I. D. Peltan, S. M. Brown, E. T. Martin, A. S. Monto, A. Khan, C. L. Hough, L. W. Busse, C. C. Ten Lohuis, A. Duggal, J. G. Wilson, A. J. Gordon, N. Qadir, S. Y. Chang, C. Mallow, C. Rivas, H. M. Babcock, J. H. Kwon, N. Halasa, J. D. Chappell, A. S. Lauring, C. G. Grijalva, T. W. Rice, I. D. Jones, W. B. Stubblefield, A. Baughman, K. N. Womack, J. P. Rhoads, C. J. Lindsell, K. W. Hart, Y. Zhu, S. M. Olson, M. Kobayashi, J. R. Verani, M. M. Patel; Influenza and Other Viruses in the Acutely Ill (IVY) Network, Association Between mRNA Vaccination and COVID-19 Hospitalization and Disease Severity. *JAMA* 326, 2043–2054 (2021). doi:10.1001/jama.2021.19499 Medline

29. E. Leshem, K. Nelson, B. A. Lopman, Severe breakthrough COVID-19 infections in Scotland-implications for immunisation programmes. *Lancet Respir. Med.* 9, 1354–1356 (2021). doi:10.1016/S2213-2600(21)00413-6 Medline

30. Q. Zhang, P. Bastard, A. Cobat, J. L. Casanova; COVID Human Genetic Effort, Human genetic and immunological determinants of critical COVID-19 pneumonia. *Nature* 603, 587–598 (2022). doi:10.1038/s41586-022-04447-0 Medline

31. M. Lipsitch, F. Krammer, G. Regev-Yochay, Y. Lustig, R. D. Balicer, SARS-CoV-2 breakthrough infections in vaccinated individuals: Measurement, causes and impact. *Nat. Rev. Immunol.* 22, 57–65 (2022). doi:10.1038/s41577-021-00662-4 Medline

32. J. Liu, M. T. Laurie, L. Rubio, S. E. Vazquez, S. Sunshine, A. M. Mitchell, M. Hapte-Selassie, S. A. Mann, G. Pilarowski, D. Black, C. Marquez, S. Rojas, M. S. Lionakis, M. Petersen, J. D. Whitman, V. Jain, M. Anderson, D. Havlir, J. DeRisi, SARS-CoV-2 transmission dynamics and immune responses in a household of vaccinated persons. *Clin. Infect. Dis.* 40c029 (2022). doi:10.1093/cid/ciac029 Medline

33. T. Carvalho, F. Krammer, A. Iwasaki, The first 12 months of COVID-19: A timeline of immunological insights. *Nat. Rev. Immunol.* 21, 245–256 (2021). doi:10.1038/s41577-021-00522-1 Medline

34. S. Stertz, B. G. Hale, Interferon system deficiencies exacerbating severe pandemic virus infections. *Trends Microbiol.* 29, 973–982 (2021). doi:10.1016/j.tim.2021.03.001 Medline

35. P. Bastard, E. Michailidis, H. H. Hoffmann, M. Chbini, T. Le Voyer, J. Rosain, Q. Philippot, Y. Seeleuthner, A. Gervais, M. Materna, P. M. N. de Oliveira, M. L. S. Maia, A. P. Dinis Ano Bom, T. Azamor, D. Araújo da Conceição, E. Goudouris, A. Homma, G. Slesak, J. Schäfer, B. Pulendran, J. D. Miller, R. Huits, R. Yang, L. B. Rosen, L. Bizien, L. Lorenzo, M. Chrabieh, L. V. Erazo, F. Rozenberg, M. M. Jeljeli, V. Béziat, S. M. Holland, A. Cobat, L. D. Notarangelo, H. C. Su, R. Ahmed, A. Puel, S. Y. Zhang, L. Abel, S. J. Seligman, Q. Zhang, M. R. MacDonald, E. Jouanguy, C. M. Rice, J. L. Casanova, Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. *J. Exp. Med.* 218, e20202486 (2021). doi:10.1084/jem.20202486 Medline

36. J. Manry P. Bastard, A. Gervais, T. Le Voyer, J. Rosain, Q. Philippot, E. Michailidis, H. H. Hoffmann, S. Eto, M. Garcia-Prat, L. Bizien, A. Parra-Martínez, R. Yang, L. Haljasmagi, M. Migaud, K. Sarekannu, J. Maslovskaja, N. de Prost, Y. Tandjaoui-Lambiotte, C. E. Luyt, B. Amador-Borrero, A. Gaudet, J. Poissy, P. Morel, P. Richard, F. Cognasse, J. Troya, S. Trouillet-Assant, A. Belot, K. Saker, P. Garçon, J. G. Rivière, J. C. Lagier, S. Gentile, L. B. Rosen, E. Shaw, T. Morio, J. Tanaka, D. Dalmau, P. L. Tharaux, D. Sene, A. Stepanian, B. Mégarbane, V. Triantafyllia, A. Fekkar, J. R. Heath, J. L. Franco, J. M. Anaya, J. Solé-Violán, L. Imberti, A. Biondi, P. Bonfanti, R. Castagnoli, O. M. Delmonte, Y. Zhang, A. L. Snow, S. M. Holland, C. M. Biggs, M. Moncada-Vélez, A. A. Arias, L. Lorenzo, S. Boucherit, D. Anglicheau, A. M. Planas, F. Haerynck, S. Duvlis, T. Ozcelik, S. Keles, A. A. Bousfiha, J. El Bakkouri, C. Ramirez-Santana, S. Paul, Q. Pan-Hammarström, L. Hammarström, A. Dupont, A. Kurolap, C. N. Metz, A. Aiuti, G. Casari, V. Lampasona, F. Ciceri, L. A.
Barreiros, E. Dominguez-Garrido, M. Vidigal, M. Zatz, D. van de Beek, S. Sahanic, I. Tancevski, Y. Stepanovskyy, O. Boyarchuk, Y. Nukui, M. Tsumura, L. Vidaur, S. G. Tangye, S. Burrel, D. Duffy, L. Quintana-Murci, A. Klocperk, N. Y. Kann, A. Shcherbina, Y. L. Lau, D. Leung, M. Coulongeat, J. Marlet, R. Koning, L. F. Reyes, A. Chauvineau-Grenier, F. Venet, G. Monneret, M. C. Nussenzweig, R. Arrestier, I. Boudhabhay, H. Baris-Feldman, D. Hagin, J. Wauters, I. Meyts, A. H. Dyer, S. P. Kennelly, N. M. Bourke, R. Halwani, F. S. Sharif-Askari, K. Dorgham, J. Sallette, S. M. Sedkaoui, S. AlKhater, R. Rigo-Bonnin, F. Morandeira, L. Roussel, D. C. Vinh, C. Erikstrup, A. Condino-Neto, C. Prando, A. Bondarenko, A. N. Spaan, L. Gilardin, J. Fellay, S. Lyonnet, K. Bilguvar, R. P. Lifton, S. Mane, M. S. Anderson, B. Boisson, V. Béziat, S. Y. Zhang, E. Andreakos, O. Hermine, A. Pujol, P. Peterson, T. H. Mogensen, L. Rowen, J. Mond, S. Debette, X. de Lamballerie, C. Burdet, L. Bouadma, M. Zins, P. Soler-Palacin, R. Colobran, G. Gorochov, X. Solanich, S. Susen, J. Martinez-Picado, D. Raoult, M. Vasse, P. K. Gregersen, L. Piemonti, C. Rodríguez-Gallego, L. D. Notarangelo, H. C. Su, K. Kisand, S. Okada, A. Puel, E. Jouanguy, C. M. Rice, P. Tiberghien, Q. Zhang, J. L. Casanova, L. Abel, A. Cobat; HGID Lab; COVID Clinicians; COVID-STORM Clinicians; NIAID Immune Response to COVID Group; NH-COVAIR Study Group; Danish CHGE; Danish Blood Donor Study; St. James's Hospital, SARS-CoV2 Interest Group; French COVID Cohort Study Group; Imagine COVID-Group; Milieu Intérieur Consortium; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank Investigators; COVID Human Genetic Effort; CP-COVID-19 Group; CONSTANCES cohort; 3C-Dijon Study; Cerba Health-Care; Etablissement Français du Sang Study group, The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies. Proc. Natl. Acad. Sci. U.S.A. 119, e2200413119 (2022). doi:10.1073/pnas.2200413119 Medline

37. A. Meager, K. Visvalingam, P. Peterson, K. Möll, A. Murumägi, K. Krohn, P. Eskelin, J. Perheentupa, E. Husebye, Y. Kadota, N. Willcox, Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLOS Med. 3, e289 (2006). doi:10.1371/journal.pmed.0030289 Medline

38. A. Meager, M. Wadhwa, P. Dilger, C. Bird, R. Thorpe, J. Newsom-Davis, N. Willcox, Anti-cytokine autoantibodies in autoimmunity: Preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin. Exp. Immunol. 132, 128–136 (2003). doi:10.1046/j.1365-2249.2003.02113.x Medline

39. A. Gupta, Y. Gonzalez-Rojas, E. Juarez, M. Crespo Casal, J. Moya, D. R. Falci, E. Sarkis, J. Solis, H. Zheng, N. Scott, A. L. Cathcart, C. M. Hebner, J. Sager, E. Mogalian, C. Tipple, A. Peppercorn, E. Alexander, P. S. Pang, A. Free, C. Brinson, M. Aldinger, A. E. Shapiro; COMET-ICE Investigators, Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N. Engl. J. Med. 385, 1941–1950 (2021). doi:10.1056/NEJMoa2107934 Medline

40. R. Lévy, P. Zhang, P. Bastard, K. Dorgham, I. Melki, A. Hadchouel, G. C. Hartoularos, B. Neven, M. Castelle, C. Roy, T. Toin, L. Berteloot, L. Bizien, H. Abid, M. Burgard, N. Houhou-Fidouh, F. Rozenberg, E. Jouanguy, C. J. Ye, G. Gorochov, Q. Zhang, J. L. Casanova, Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child. Proc. Natl. Acad. Sci. U.S.A. 118, e2114390118 (2021). doi:10.1073/pnas.2114390118 Medline

41. J. H. Beigel, K. M. Tomashek, L. E. Dodd, A. K. Mehta, B. S. Zingman, A. C. Kalil, E. Hohmann, H. Y. Chu, A. Luetkemeyer, S. Kline, D. Lopez de Castilla, R. W. Finberg, K. Dierberg, V. Tapson, L. Hsieh, T. F. Patterson, R. Paredes, D. A. Sweeney, W. R. Short, G. Touloumi, D. C. Lye, N. Ohmagari, M. D. Oh, G. M. Ruiz-Palacios, T. Benfield, G. Fåtkenheuer, M. G. Kortepeter, R. L. Atmar, C. B. Creech, J. Lundgren, A. G. Babiker, S. Pett, J. D. Neaton, T. H. Burgess, T. Bonnett, M. Green, M. Makowski, A. Osinusi, S. Nayak, H. C. Lane; ACTT-1 Study Group Members, Remdesivir for the Treatment of Covid-19 - Final Report. N. Engl. J. Med. 383, 1813–1826 (2020). doi:10.1056/NEJMoa2007764 Medline

42. R. L. Gottlieb, C. E. Vaca, R. Paredes, J. Mera, B. J. Webb, G. Perez, G. Oguchi, P. Ryan, B. U. Nielsen, M. Brown, A. Hidalgo, Y. Sachdeva, S. Mittal, O. Osiyemi, J. Skarbinski, K. Juneja, R. H. Hyland, A. Osinusi, S. Chen, G. Camus, M. Abdelghany, S. Davies, N. Behenna-Renton, F. Duff, F. M. Marty, M. J. Katz, A. A. Ginde, S. M. Brown, J. T. Schiffer, J. A. Hill, Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N. Engl. J. Med. (2021). Medline

43. A. Jayk Bernal, M. M. Gomes da Silva, D. B. Musungaie, E. Kovalchuk, A. Gonzalez, V. Delos Reyes, A. Martin-Quiros, Y. Caraco, A. Williams-Diaz, M. L. Brown, J. Du, A. Pedley, C. Assaid, J. Strizki, J. A. Grobler, H. H. Shamsuddin, R. Tipping, H. Wan, A. Paschke, J. R. Butterton, M. G. Johnson, C. De Anda, Molnupiravir for Oral

Treatment of Covid-19 in Nonhospitalized Patients. N. Engl. J. Med. (2021). Medline

44. P. D. Monk, R. J. Marsden, V. J. Tear, J. Brookes, T. N. Batten, M. Mankowski, F. J. Gabbay, D. E. Davies, S. T. Holgate, L. P. Ho, T. Clark, R. Djukanovic, T. M. A. Wilkinson; Inhaled Interferon Beta COVID-19 Study Group, Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir. Med. 9, 196–206 (2021). doi:10.1016/S2213-2600(20)30511-7 Medline

45. S. K. Elledge, X. X. Zhou, J. R. Byrnes, A. J. Martinko, I. Lui, K. Pance, S. A. Lim, J. E. Glasgow, A. A. Glasgow, K. Turcios, N. S. Iyer, L. Torres, M. J. Peluso, T. J. Henrich, T. T. Wang, C. M. Tato, K. K. Leung, B. Greenhouse, J. A. Wells, Engineering luminescent biosensors for point-of-care SARS-CoV-2 antibody detection. Nat. Biotechnol. 39, 928–935 (2021). doi:10.1038/s41587-021-00878-8 Medline

46. C. R. Zamecnik, J. V. Rajan, K. A. Yamauchi, S. A. Mann, R. P. Loudermilk, G. M. Sowa, K. C. Zorn, B. D. Alvarenga, C. Gaebler, M. Caskey, M. Stone, P. J. Norris, W. Gu, C. Y. Chiu, D. Ng, J. R. Byrnes, X. X. Zhou, J. A. Wells, D. F. Robbiani, M. C. Nussenzweig, J. L. DeRisi, M. R. Wilson, ReScan, a Multiplex Diagnostic Pipeline, Pans Human Sera for SARS-CoV-2 Antigens. Cell Rep. Med. 1, 100123 (2020). doi:10.1016/j.xcrm.2020.100123 Medline

47. M. Hoffmann, H. Kleine-Weber, S. Pöhlmann, A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol. Cell 78, 779–784.e5 (2020). doi:10.1016/j.molcel.2020.04.022 Medline

**Acknowledgments:** We thank the patients and their families for placing their trust in us. We warmly thank the members of both branches of the Laboratory of Human Genetics of Infectious Diseases. We warmly thank Y. Nemirovskaya, M. Woollett, D. Liu, S. Boucherit, C. Rivalain, M. Chrabieh and L. Lorenzo for administrative assistance. We warmly thank Helen C. Su for fruitful discussions. We warmly thank Yuna Myuyshondt and Suzanne Sandmeyer for their assistance. **Funding:** The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the program "Investissement d'Avenir" launched by the French Government and implemented by the Agence Nationale de la Recherche (ANR) with references ANR-21-RHUS-08 and ANR-10-IAHU-01, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR-GENVIR (ANR-20-CE93-003), ANR AABIFNCOV (ANR-20-C011-0001) and ANR GenMISC (ANR-21-COVR-0039) projects, the European Union's Horizon 2020 research and innovation program under grant agreement No 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM and the University of Paris. CRG, RPD and CF were funded by Instituto de Salud Carlos III (COV20_01333, COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), the Fundación Canaria Instituto de Investigación Sanitaria de Canarias (FIISC19/43), Grupo DISA (OA18/017), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19").EA is supported by the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574) and the European Commission's Horizon 2020 research and innovation program (CURE, grant no. 767015 and IMMUNAID, grant no. 779295). LR and LFP were supported by Singapore National Medical Research Council COVID-19 Research Fund (COVID19RF-001; COVID19RF-007; COVID19RF-0008; COVID19RF-060) and A\*STAR COVID-19 Research funding (H/20/04/g1/006). The UCSF COMET Consortium is supported by the University of California, San Francisco Clinical and Translational Science Institute and the National Institutes of Health (U19AI077439). AA, GRB and XS are funded by the 202115-31 project, funded by
La Marató de TV3. L.D.N. was supported by the intramural Research Program of the NIAID, NIH. J.L.D. is supported by the Chan Zuckerberg Biohub. The authors wish to acknowledge the support of the Chao Family Comprehensive Cancer Center Experimental Tissue Shared Resource, supported by the National Cancer Institute of the National Institutes of Health under award number P30CA062203. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020). PB and TLV were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller).

**Author contributions:** P.B. and J.-L.C. wrote the manuscript, with the assistance of S.V., Q.Z., S.-Y.Z., E.J., M.S.A and J.L.D. who edited the manuscript, tables and figures. P.B, S.V, J.L., L.M., A.G., T.L.V., J.R., Q.P., L.B., J.M., A.P., E.J., C.J.Y., A.C., L.T., performed the experiments, generated data or analyzed it. P.B., S.D., L.R., D.C.V., E.C., L.F.R., C.M., V.E., C.Z., E.C., A.W., A.M., G.W., R.B., A.F., S.S., I.T., P.G., Y.Z., S.D., D.A., E.P.A., L.R., L.R., D.C.V., L.F.R., M.G., N.H., D.B., Y.T.L., R.H., N.S.S.A., J.D., S.B., Y.S., O.B., C.M., M.N., B.N., K.S., O.A., A.A., E.J., G.R.B., C.T., M.L., P.L.T., T.B., K.D., G.G., G.R.G., L.F.P.N, L.R., A.P., A.B., F.R., T.O., S.K., J.M.P., L.D.N., J.T., X.S.M., S.T.A., L.M.A., and E.A. treated and recruited the patients. Y.A.J., S.A., S.B., S.A.C., S.C., Z.C., G.K.F., R.G., A.J., K.N.K., T.L., D.L., A.L., C.L., R.L., M.M., V.N., R.P., L.P., P.P., A.A.R., A.R., N.R., B.S., C.S., A.S., K.T. L.T.A., A.W., A.W., M.W. recruited patients, and collected and managed samples and data. C.S.C., D.J.E., C.M.H., M.F.K., C.R.L., P.G.W. founded and led the COMET Consortium. Q.Z., S.-Y.Z., E.J., M.S.A, J.-L.C and J.L.D. supervised the study. Competing interests: J.-L.C. reports being an inventor on patent application PCT/US2021/042741, filed 22 July 2021, submitted by The Rockefeller University, which covers the diagnosis of, susceptibility to, and treatment of viral disease and viral vaccines, including COVID-19 and vaccine-associated diseases. C.S.C., D.J.E., C.M.H., M.F.K., C.R.L., P.G.W. report funding from Genentech. C.S.C. reports funding from The National Heart, Lung, and Blood Institute (NHLBI), The U.S. Food and Drug Administration (FDA), U.S. Department of Defense (DOD), and Quantum Leap Healthcare Collaborative, and serves on consulting and advisory boards for Vasomune, Genle Life Sciences, Janssen, and Cellenkos. C.M.H. reports funding from NHLBI and consulting fees for clinical trial design with Spring Discovery. The other authors have no conflicts of interest to report. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using this material.

Submitted 4 March 2022
Accepted 26 May 2022
Published First Release 14 June 2022
10.1126/sciimmunol.abp8966
A

<figure><img src="image_2.png" /></figure>

B

<figure><img src="image_3.png" /></figure>

C

<figure><img src="image_4.png" /></figure>

D

<figure><img src="image_5.png" /></figure>

Fig. 1. Neutralizing auto-antibodies (Abs) against IFN-α2 and IFN-ω in patients with hypoxemic breakthrough COVID-19 despite a normal serological response to SARS-CoV-2 mRNA vaccine. (A) SARS-CoV-2 serology against spike(S)-protein and receptor binding domain (RBD) in hypoxemic breakthrough COVID-19 (N=43), patients with immune suppression (n=5), unvaccinated controls (N=12), and vaccinated and uninfected healthy controls (n=11). Mean fluorescence intensity is shown. The orange dots correspond to the 10 individuals with auto-Abs neutralizing type I IFNs. Empty circles represent either Spike or RBD serology, to outline the highest value for one patient. The arrow represents the patient without B cell deficiency but with an insufficient Ab response to the virus. (B) Radioligand binding assay (RLBA) results for auto-Abs against IFN-α2 in patients with hypoxemic breakthrough COVID-19 pneumonia without immune suppression or low Ab response to the vaccine (N=42), uninfected controls (N=96), and uninfected APS-1 patients (N=6). (C) Neutralization of 10 ng/mL IFN-α2, IFN-ω or IFN-β in the presence of plasma 1/10 from patients with hypoxemic breakthrough COVID-19 pneumonia with a good Ab response to the vaccine (N=42). Relative luciferase activity is shown (ISRE dual luciferase activity, with normalization against *Renilla* luciferase activity) after stimulation with 10 ng/mL IFN-α2 or IFN-ω in the presence of plasma 1/10. RLA: relative luciferase activity. (D) Neutralization of 100 pg/mL IFN-α2 or IFN-ω in the presence of plasma 1/10 from patients with hypoxemic breakthrough COVID-19 pneumonia with a good Ab response to the vaccine (N=42).
<figure><img src="image_6.png" /><figcaption>Fig. 2. Neutralization titers against SARS-CoV-2 in the patients with auto-Abs against type I IFNs. Neutralization titers against SARS-CoV-2 for healthy vaccinated donors 2-8 weeks after the second dose of mRNA vaccine (n=11), and patients with hypoxemic breakthrough COVID-19 pneumonia and auto-Abs to type I IFNs (n=10). The dashed line shows the geometric mean of healthy donor titers, the box shows interquartile range, and the shaded region is the full range. (A) Neutralization assay performed with pseudoviruses representing the D614G strain, and (B) the Delta variant (B.1.617.2).</figcaption></figure>
<table><caption>**Table 1.** Clinical and demographic information of the 10 patients with hypoxemic breakthrough COVID-19 infection and auto-Abs neutralizing type I IFNs. HTN: hypertension, AF: atrial fibrillation. APS-1: auto-immune polyendocrine syndrome type 1.</caption><thead><tr><th>Patient</th><th>Origin</th><th>Residence</th><th>Sex</th><th>Age</th><th>Comorbidities</th><th>Vaccine source</th><th>Doses number</th><th>Time of disease post vaccination (weeks)</th><th>ICU</th><th>Classification</th><th>Outcome</th></tr></thead><tbody><tr><td>P1</td><td>American</td><td>USA</td><td>M</td><td>80</td><td>Diabetes, asthma</td><td>Pfizer</td><td>2</td><td>2</td><td>Yes</td><td>Critical</td><td>Alive</td></tr><tr><td>P2</td><td>Greek</td><td>Greece</td><td>F</td><td>82</td><td>HTN, myasthenia gravis, hashimoto, dyslipidemia</td><td>Pfizer</td><td>2</td><td>4</td><td>Yes</td><td>Critical</td><td>Alive</td></tr><tr><td>P3</td><td>Greek</td><td>Greece</td><td>M</td><td>73</td><td>HTN, diabetes, dyslipidemia, glaucoma</td><td>Pfizer</td><td>2</td><td>2</td><td>Yes</td><td>Critical</td><td>Alive</td></tr><tr><td>P4</td><td>Greek</td><td>Greece</td><td>M</td><td>86</td><td>HTN, diabetes, dyslipidemi, AF, benign prostate hyperplasia, parkinson</td><td>Pfizer</td><td>2</td><td>12</td><td>Yes</td><td>Critical</td><td>Alive</td></tr><tr><td>P5</td><td>Greek</td><td>Greece</td><td>M</td><td>73</td><td>Diabetes, coronary heart disease</td><td>Pfizer</td><td>2</td><td>3</td><td>No</td><td>Severe</td><td>Alive</td></tr><tr><td>P6</td><td>Greek</td><td>Greece</td><td>F</td><td>77</td><td>HTN, diabetes, dyslipidemia</td><td>Pfizer</td><td>2</td><td>16</td><td>No</td><td>Severe</td><td>Alive</td></tr><tr><td>P7</td><td>Cambodian</td><td>France</td><td>M</td><td>71</td><td>HTN</td><td>Pfizer</td><td>2</td><td>15</td><td>Yes</td><td>Critical</td><td>Alive</td></tr><tr><td>P8</td><td>French</td><td>France</td><td>F</td><td>86</td><td>NA</td><td>Pfizer</td><td>2</td><td>6</td><td>No</td><td>Critical</td><td>Alive</td></tr><tr><td>P9</td><td>American</td><td>USA</td><td>M</td><td>80</td><td>NA</td><td>Pfizer</td><td>2</td><td>2</td><td>No</td><td>Critical</td><td>Alive</td></tr><tr><td>P10</td><td>French</td><td>France</td><td>M</td><td>43</td><td>APS-1</td><td>Pfizer</td><td>2</td><td>2</td><td>No</td><td>Severe</td><td>Alive</td></tr></tbody></table>
<table><caption>Table 2. Auto-Abs neutralized in the 10 patients. 1: neutralizing. 0: non-neutralizing.</caption><thead><tr><th>Patient</th><th>anti-IFN-α2 auto-Abs (10 ng/mL)</th><th>anti-IFN-β auto-Abs (10 ng/mL)</th><th>anti-IFN-ω, auto-Abs (10 ng/mL)</th><th>anti-IFN-α2 auto-Abs (100 pg/mL)</th><th>anti-IFN-ω, auto-Abs (100 pg/mL)</th></tr></thead><tbody><tr><td>P1</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P2</td><td>1</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P3</td><td>1</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P4</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P5</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P6</td><td>0</td><td>0</td><td>0</td><td>1</td><td>1</td></tr><tr><td>P7</td><td>0</td><td>0</td><td>0</td><td>0</td><td>1</td></tr><tr><td>P8</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P9</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr><tr><td>P10</td><td>1</td><td>0</td><td>1</td><td>1</td><td>1</td></tr></tbody></table>

Appendix: List of COVID HGE Consortium authors

Laurent Abel¹ Cristian Achille² Alessandro Aiuti³ Saleh Al-Muhsen⁴ Fahd Al-Mulla⁵ Mark S. Anderson⁶ Evangelos And-dreakos⁷ Micol Angelini⁸ Andrés A. Arias⁹ Gokhan Aytekin¹⁰ Fausto Baldanti¹¹ Hagit Baris Feldman¹² Alexandre Belot¹³ Feder-ica Bergami¹⁴ Catherine M. Biggs¹⁵ Dusan Bogunovic¹⁶ Alexandre Bolze¹⁷ Anastasiia Bondarenko¹⁸ Ahmed A. Bousfiha¹⁹ Petter Brodin²⁰ Yenan Bryceson²¹ Carlos D. Bustamante²² Manish J. Butte²³ Giorgio Casari²⁴ John Christodoulou²⁵ Antonio Condino-Neto²⁶ Stefan N. Constantinescu²⁷ Francesca Conti²⁸ Megan A. Cooper²⁹ Clifton L. Dalgard³⁰ Murkesh Desai³¹ Beth A. Drolet³² Jamila El Baghdadi³³ Recai Ergun³⁴ Dilek Ergun³⁵ Sara Espinosa-Padilla³⁶ Jacques Fellay³⁷ Carlos Flores³⁸ José Luis Franco³⁹ Antoine Froidure⁴⁰ Stefano Ghirardello⁴¹ Peter K. Gregersen⁴² Bodo Grimbacher⁴³ Filomeen Haerynck⁴⁴ David Hagin⁴⁵ Rabih Halwani⁴⁶ Lennart Hammarström⁴⁷ James R. Heath⁴⁸ Sarah E. Henrickson⁴⁹ Elena W.Y. Hsieh⁵⁰ Eystein Husebye⁵¹ Kohsuke Imai⁵² Yuval Itan⁵³ Erich D. Jarvis⁵⁴ Fikret Kanat⁵⁵ Timokratis Karamitros⁵⁶ Kai Kisand⁵⁷ Vasyl Kopcha⁵⁸ Mykhaylo Korda⁵⁹ Cheng-Lung Ku⁶⁰ Yu-Lung Lau⁶¹ Yun Ling⁶² Carrie L. Lucas⁶³ Tom Maniatis⁶⁴ Davood Mansouri⁶⁵ László Maródi⁶⁶ Isabelle Meyts⁶⁷ Joshua D. Milner⁶⁸ Kristina Mironska⁶⁹ Trine H. Mogensen⁷⁰ Francesco Mojoli⁷¹ Francisco Morandeira⁷² Tomohiro Morio⁷³ Lisa F.P. Ng⁷⁴ Luigi D. Notarangelo⁷⁵ Antonio Novelli⁷⁶ Giuseppe Novelli⁷⁷ Clona O'Farrelly⁷⁸ Satoshi Okada⁷⁹ Keisuke Okamoto⁸⁰ Tayfun Ozcelik⁸¹ Michele Pagani⁸² Qiang Pan-Hammarström⁸³ Jean W. Pape⁸⁴ Rebeca Perez de Diego⁸⁵ David S. Perlin⁸⁶ Graziano Pesole⁸⁷ Andrea Pession⁸⁸ Antonio Piralla⁸⁹ Anna M. Planas⁹⁰ Carolina Prando⁹¹ Aurora Pujol⁹² Lluís Quin-tana-Murci⁹³ Sathishkumar Ramaswamy⁹⁴ Laurent Renia⁹⁵ Igor Resnick⁹⁶ Raúl Rigo-Bonnin⁹⁷ Carlos Rodríguez-Gallego⁹⁸ Vanessa Sancho-Shimizu⁹⁹ Anna Sediva¹⁰⁰ Mikko R.J. Seppänen¹⁰¹ Mohammed Shahrooei¹⁰² Anna Shcherbina¹⁰³ Ondrej Slaby¹⁰⁴ Andrew L. Snow¹⁰⁵ Pere Soler-Palacín¹⁰⁶ András N. Spaan¹⁰⁷ Ivan Tancevski¹⁰⁸ Stuart G. Tangye¹⁰⁹ Ahmad Abou Tayoun¹¹⁰ Baykal Tulek¹¹¹ Stuart E. Survey¹¹² K M Furkan Uddin¹¹³ Mohammed Uddin¹¹⁴ Bénédicte Clément¹¹⁵

¹Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France. ²Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ³San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale San Raffaele, and Vita Salute San Raffaele University, Milan, Italy. ⁴Immunology Research Lab, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. ⁵Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Dasman, Kuwait. ⁶Diabetes Center, University of California San Francisco, San Francisco, CA, USA. ⁷Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. ⁸Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ⁹St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia; School of Microbiology, University of Antioquia UdeA, Medellín, Colombia. ¹⁰Department of Immunology and Allergy, Konya City Hospital ¹¹Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy ¹²The Genetics Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. ¹³Pediatric Nephrology, Rheumatology, Dermatology, HFME, Hospices Civils de Lyon, National
Referee Centre RAISE, and INSERM U1111, Université de Lyon, Lyon, France. ¹⁴Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ¹⁵Department of Pediatrics, BC Children's and St. Paul's Hospitals, University of British Columbia, Vancouver, BC, Canada. ¹⁶Icahn School of Medicine at Mount Sinai, New York, NY, USA. ¹⁷Helix, San Mateo, CA, USA. ¹⁸Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine. ¹⁹Department of Pediatric Infectious Diseases and Clinical Immunology, CHU Ibn Rushd and LICIA, Laboratoire d'Immunologie Clinique, Inflammation et Allergie, Faculty of Medicine and Pharmacy, Hassan II University, Casablanca, Morocco. ²⁰SciLifeLab, Department Of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. ²¹Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden. ²²Stanford University, Stanford, CA, USA. ²³Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics and the Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA. ²⁴Clinical Genomics, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy. ²⁵Murdoch Children's Research Institute and Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia. ²⁶Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. ²⁷de Duve Institute and Ludwig Cancer Research, Brussels, Belgium. ²⁸Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy ²⁹Washington University School of Medicine, St. Louis, MO, USA. ³⁰Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. ³¹Bai Jerbai Wadia Hospital for Children, Mumbai, India. ³²School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA. ³³Genetics Unit, Military Hospital Mohamed V, Rabat, Morocco. ³⁴Selcuk University, Department of Pulmonology, Konya, Turkey ³⁵Selcuk University, Department of Pulmonology, Konya, Turkey ³⁶Instituto Nacional de Pediatria (National Institute of Pediatrics), Mexico City, Mexico. ³⁷School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. ³⁸Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid; Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain. ³⁹Group of Primary Immunodeficiencies, University of Antioquia UDEA, Medellín, Colombia. ⁴⁰Pulmonology Department, Cliniques Universitaires Saint-Luc ; Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, Brussels, Belgium. ⁴¹Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ⁴²Feinstein Institute for Medical Research, Northwell Health USA, Manhasset, NY, USA. ⁴³Center for Chronic Immunodeficiency & Institute for Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ⁴⁴Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Laboratory, Jeffrey Model Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium. ⁴⁵The Genetics Institute Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. ⁴⁶Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates. ⁴⁷Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. ⁴⁸Institute for Systems Biology, Seattle, WA, USA. ⁴⁹Department of Pediatrics, Division of Allergy Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. ⁵⁰Departments of Pediatrics, Immunology and Microbiology, University of Colorado, School of Medicine, Aurora, CO, USA. ⁵¹Department of Medicine, Haukeland University Hospital, Bergen, Norway. ⁵²Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University (TMDU), Tokyo, Japan. ⁵³Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ⁵⁴Laboratory of Neurogenetics of Language and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA. ⁵⁵Selcuk University, Department of Pulmonology, Konya, Turkey ⁵⁶Bioinformatics and Applied Genomics Unit, Hellenic Pasteur Institute, Athens, Greece. ⁵⁷Molecular Pathology, Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu Estonia. ⁵⁸Horbachevsky Ternopil National Medical University ⁵⁹Horbachevsky Ternopil National Medical University ⁶⁰Chang Gung University, Taoyuan County, Taiwan. ⁶¹Department of Pediatrics & Adolescent Medicine, The University of Hong Kong, Hong Kong, China. ⁶²Shanghai Public Health Clinical Center, Fudan University, Shanghai, China. ⁶³Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. ⁶⁴Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA. ⁶⁵Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran. ⁶⁶Primary Immunodeficiency Clinical Unit and Laboratory, Department of Dermatology, Venereology and Dermatooncology, Semmelweis University, Budapest, Hungary. ⁶⁷Department of Pediatrics, University Hospitals Leuven; KU Leuven, Department of Microbiology, Immunology and Transplantation; Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium. ⁶⁸Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. ⁶⁹University Clinic for Children's Diseases, Department of Pediatric Immunology, Medical Faculty, University “ St.Cyril and Methodij” Skopje, North Macedonia. ⁷⁰Department of Biomedicine, Aarhus University, Aarhus, Denmark. ⁷¹Anesthesia and Intensive Care, Rianimazione I, Fondazione IRCCS
Policlinico San Matteo, Pavia, Italy ⁷²Department of Internal Medicine, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain. ⁷³Tokyo Medical & Dental University Hospital, Tokyo, Japan. ⁷⁴A*STAR Infectious Disease Labs, Agency for Science, Technology and Research, Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore. ⁷⁵National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ⁷⁶Laboratory of Medical Genetics, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. ⁷⁷Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy. ⁷⁸Comparative Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. ⁷⁹Department of Pediatrics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. ⁸⁰Tokyo Medical and Dental University, Tokyo, Japan. ⁸¹Department of Molecular Biology and Genetics, Bilkent University, Bilkent - Ankara, Turkey. ⁸²Anesthesia and Intensive Care, Rinanimazione I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ⁸³Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. ⁸⁴Haitian Study Group for Kaposi's Sarcoma and Opportunistic Infections (GHESKIO), Port-au-Prince, Haiti. ⁸⁵Institute of Biomedical Research of IdiPAZ, University Hospital "La Paz", Madrid, Spain. ⁸⁶Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA. ⁸⁷Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari A. Moro, Bari, Italy. ⁸⁸Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy ⁸⁹Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy ⁹⁰IIBB-CSIC, IDIBAPS, Barcelona, Spain. ⁹¹Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil. ⁹²Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. ⁹³Human Evolutionary Genetics Unit, CNRS U2000, Institut Pasteur, Paris, France; Human Genomics and Evolution, Collège de France, Paris, France. ⁹⁴Al Jalila Children's Hospital, Dubai, UAE. ⁹⁵A*STAR Infectious Disease Labs, Agency for Science, Technology and Research, Singapore; Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore. ⁹⁶University Hospital St. Marina, Varna, Bulgaria. ⁹⁷Department of Clinical Laboratory, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain. ⁹⁸Department of Immunology, University Hospital of Gran Canaria Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria; Department of Clinical Sciences, University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain. ⁹⁹Department of Pediatric Infectious Diseases and Virology, Imperial College London, London, UK; Centre for Pediatrics and Child Health, Faculty of Medicine, Imperial College London, London, UK. ¹⁰Department of Immunology, Second Faculty of Medicine Charles University, V Uvalu, University Hospital in Motol, Prague, Czech Republic. ¹¹Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland: Rare Diseases Center and Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. ¹²Specialized Immunology Laboratory of Dr. Shahrooei, Ahvaz, Iran; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium. ¹³Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. ¹⁴Central European Institute of Technology & Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. ¹⁵Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. ¹⁶Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain. ¹⁷St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands. ¹⁸Department of Internal Medicine II, Medical University of Innsbruck, Innsbruck, Austria. ¹⁹Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW, Australia. ¹¹⁰Al Jalila Children's Hospital, Dubai, UAE. ¹¹¹Selcuk University, Department of Pulmonology, Konya, Turkey ¹¹²BC Children's Hospital, The University of British Columbia, Vancouver, Canada. ¹¹³Centre for Precision Therapeutics, Genetics & Genomic Medicine Centre, NeuroGen Children's Healthcare and Lecturer, Holy Family Red Crescent Medical College Dhaka, Bangladesh. ¹¹⁴ Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE; GenomeArc Inc., Toronto, ON, Canada. ¹¹⁵ Service des Urgences, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France.

## Appendix: List of COMET Consortium authors

Yumiko Abe-Jones, MS¹, Saurabh Asthana, PhD²,³,⁴, Sharvari Bhide, BA⁵, Carolyn S. Calfee, M⁶,⁷, Sidney A. Carrillo, MPH⁶, Suzanna Chak, BA⁶, Zachary Collins, BA²,³,⁴, David J. Erle, MD³,⁴,⁷,⁸, Gabriela K. Fragiadakis, PhD³,⁴,⁹, Rajani Ghale, MS⁶, Carolyn M. Hendrickson, MD⁵,⁸, Alejandra Jauregui, BA⁶, Kirsten N. Kangelaris, MD¹, Matthew F. Krummel, PhD²,³,⁴, Charles R. Langelier, MD, PhD¹⁰,¹¹, Tasha Lea, MS², Deanna Lee, BA⁵,⁸, Aleksandra Leligdowicz, MD, PhD¹², Carolyn Leroux, BS⁶, Raphael Lota, BA¹³, Michael Matthay, MD⁷, Viet Nguyen, BA⁵,⁸, Ravi Patel, PhD³,⁴, Logan Pierce, MD¹, Priya Prasad, PhD¹, Arjun Arkal Rao, PhD²,³,⁴, Ahmad Rashid, BS¹³, Nicklaus Rodriguez, BA¹³, Bushra Samad, MS²,³,⁴, Cole Shaw, MSEE²,³,⁴, Austin Sigman, BS⁶, Kevin Tang, MS¹³, Luz Torres Altamirano, BA¹³, Alyssa Ward, PhD⁹, Andrew Willmore, BS⁶, Michael Wilson, MD¹⁴, Prescott G. Woodruff, MD⁶,⁷

1. Division of Hospital Medicine, University of California, San Francisco, CA, USA.
2. Department of Pathology, University of California, San Francisco, CA, USA.

3. UCSF CoLabs, University of California, San Francisco, CA, USA.

4. Bakar ImmunoX Initiative, University of California, San Francisco, CA, USA.

5. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, CA, USA.

6. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, USA.

7. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.

8. Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA

9. Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA.

10. Division of Infectious Diseases, University of California, San Francisco, CA, USA.

11. Chan Zuckerberg Biohub, University of California, San Francisco, CA, USA.

12. Division of Critical Care Medicine, Robarts Research Institute, University of Western Ontario, London, ON, Canada.

13. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.

14. Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.

**Appendix: List of French COVID study group authors**

Laurent ABEL¹, Clotilde ALLAVENA², Claire ANDREJAK³, François ANGOULVANT⁴, Cecile AZOULAY⁵, Delphine BACHELET⁶, Marie BARTOLI⁷, Romain BASMACI⁸, Sylvie BEHILILL⁹, Marine BELUZE¹⁰, Nicolas BENECH¹¹, Dehbia BENKERROU¹², Krishna BHAVSAR⁶, Laurent BITKER¹¹, Lila BOUADMA⁶, Maude BOUSCAMBERT¹³, Pauline CARAUX PAZ¹⁴, Minerva CERVANTES-GONZALEZ⁶, Anissa CHAIR⁶, Catherine CHIROUZE¹⁵, Alexandra COELHO¹⁶, Hugues CORDEL¹⁷, Camille COUFFIGNAL¹⁶, Sandrine COUFFIN-CADIERGUES¹⁸, Eric d'ORTENZIO⁷, Etienne DE MONTMOLLIN⁶, Alexa DEBARD¹⁹, Marie-Pierre DEBRAY⁶, Dominique DEPLANQUE²⁰, Diane DESCAMPS⁶, Mathilde DESVALLÉE²¹, Alpha DIALLO⁷, Jean-Luc DIEHL²², Alphonsine DIOUF¹⁶, Céline DORIVAL¹², François DUBOS²³, Xavier DUVAL⁶, Philippine ELOY⁶, Vincent ENOUF⁹, Olivier EPAULARD²⁴, Hélène ESPEROU¹⁸, Marina ESPOSITO-FARESE⁶, Manuel ETIENNE²⁵, Denis GAROT²⁶, Nathalie GAULT⁶, Alexandre GAYMARD¹³, Jade GHOSN⁶, Tristan GIGANTE²⁷, Morgane GILG²⁷, François GOEHRINGER²⁸, Jérémie GUEDJ²⁹, Alexandre HOCTIN¹⁶, Isabelle HOFFMANN⁶, Ikram HOUAS¹⁸, Jean-Sébastien HULOT²², Salma JAAFOURA¹⁸, Ouifiya KAFIF⁶, Florentia KAGUELIDOU³⁰, Sabrina KALI⁶, Younes KERROUMI³¹, Antoine KHALIL⁶, Coralie KHAN²¹, Antoine KIMMOUN²⁸, Fabrice LAINE³², Cédric LAOUÉNAN⁶, Samira LARIBI⁶, Minh LE⁶, Cyril LE BRIS³³, Sylvie LE GAC⁶, Quentin LE HINGRAT⁶, Soizic LE MESTRE⁷, Hervé LE NAGARD²⁹, Adrien LEMAIGNEN²⁶, Véronique LEMEE²⁵, François-Xavier LESCURE⁶, Sophie LETROU⁶, Yves LEVY³⁴, Bruno LINA¹³, Guillaume LINGAS²⁹, Jean Christophe LUCET⁶, Moïse MACHADO³⁵, Denis MALVY³⁶, Marina MAMBERT¹⁶, Aldric MANUEL³⁷, France MENTRÉ⁶, Amina MEZIANE¹², Hugo MOUQUET⁹, Jimmy Mullaert⁶, Nadège NEANT²⁹, Duc NGUYEN³⁶, Marion NORET³⁸, Aurélie PAPADOPOULOS¹⁸, Christelle PAUL⁷, Nathan PEIFFER-SMADJA⁶, Vincent PEIGNE³⁹, Ventzislava PETROV-SANCHEZ⁷, Gilles PEYTAVIN⁶, Huong PHAM⁶, Olivier PICONE⁸, Valentine PIQUARD⁶, Julien POISSY²³, Oriane PUÉCHAL⁴⁰, Manuel ROSA-CALATRAVA¹³, Bénédicte ROSSIGNOL²⁷, Patrick ROSSIGNOL²⁸, Carine ROY⁶, Marion SCHNEIDER⁶, Richa SU⁶, Coralie TARDIVON⁶, Marie-Capucine TELLIER⁶, François TÉOULÉ¹², Olivier TERRIER¹³, Jean-François TIMSIT⁶, Christelle TUAL⁴¹, Sarah TUBIANA⁶, Sylvie VAN DER WERF⁹, Noémie VANEL⁴², Aurélie VEISLINGER⁴¹, Benoit VISSEAUX⁶, ²⁹, Aurélie WIEDEMANN³⁴, Yazdan YAZDANPANAH⁶

¹Inserm UMR 1163, Paris, France. ²CHU Nantes, France. ³CHU Amiens, France. ⁴Hôpital Necker, Paris, France. ⁵Hopitál Cochin, Paris, France. ⁶Hôpital Bichat, Paris, France. ⁷ANRS, Paris, France. ⁸Hôpital Louis Mourier, Colombes, France. ⁹Pasteur Institute, Paris, France. ¹⁰F-CRIN Partners Platform, Paris, France. ¹¹CHU Lyon, France. ¹²Inserm UMR 1136, Paris, France. ¹³Inserm UMR 1111, Lyon, France. ¹⁴CH Villeneuve Saint Georges, France. ¹⁵CHRU Jean Minjoz, Besançon, France. ¹⁶Inserm UMR 1018, Paris, France. ¹⁷Hôpital Avicenne, Bobigny, France. ¹⁸Inserm sponsor, Paris, France. ¹⁹CHU Toulouse, France. ²⁰CIC 1403 Inserm - CHU Lille, France. ²¹Inserm UMR 1219, Bordeaux, France. ²²Hôpital Européen Georges Pompidou, Paris, France. ²³CHU Lille, France. ²⁴CHU Grenoble, France. ²⁵CHU Rouen, France. ²⁶CHU Tours, France. ²⁷F-CRIN INI-CRCT, Nancy, France. ²⁸CHU Nancy, France. ²⁹Inserm UMR 1137, Paris, France. ³⁰Hôpital Robert Debré, Paris, France. ³¹GH Diaconesses, Paris, France. ³²CHU Rennes, France. ³³CH Beziers, France. ³⁴Vaccine Research Insitute (VRI), Inserm UMR 955, Créteil, France. ³⁵Grand Hôpital de l'Est Francilien, Marne-la-Vallée, France. ³⁶CHU Bordeaux, France. ³⁷CH Annecy, France. ³⁸RENARCI, Annecy, France. ³⁹CH Métropole Savoie, Cambery, France. ⁴⁰REACTing, Paris, France. ⁴¹Inserm CIC-1414, Rennes, France. ⁴²Hôpital la Timone, Marseille, France.