Case Reports

. 2021 Nov 9;118(45):e2114390118.

doi: 10.1073/pnas.2114390118.

Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Romain Lévy^{1

2

3

4}, Peng Zhang⁴, Paul Bastard^{1

2

4}, Karim Dorgham⁵, Isabelle Melki^{2

3

6}, Alice Hadchouel^{7

8}, George C Hartoularos⁹, Bénédicte Neven^{2

3}, Martin Castelle³, Charlotte Roy⁷, Tom Toin⁷, Laureline Berteloot¹⁰, Lucy Bizien^{1

2}, Hanène Abid¹¹, Marianne Burgard¹¹, Nadhira Houhou-Fidouh¹², Flore Rozenberg¹³, Emmanuelle Jouanguy^{1

2

4}, Chun Jimmie Ye^{9

9

14

15

16

17}, Guy Gorochov⁵, Qian Zhang^{1

2

4}, Jean-Laurent Casanova^{18

2

4

19}

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children 75015 Paris, France.
² Imagine Institute, University of Paris, Paris 75015, France.
³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
⁵ Sorbonne Université, INSERM, Centre for Immunology and Microbial Infections-Paris, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France.
⁶ General Pediatrics, Infectious Disease and Internal Medicine Department, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75019, France.
⁷ Pediatric Pulmonary Department, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
⁸ Institut Necker-Enfants Malades, INSERM U1151, Paris 75015, France.
⁹ Institute for Human Genetics, University of California, San Francisco, CA 94143.
¹⁰ Pediatric Radiology, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
¹¹ Department of Virology, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
¹² Department of Virology, INSERM, Infection, Antimicrobiens, Modélisation, Evolution, UMR 1137, Bichat-Claude Bernard Hospital, University of Paris, Assistance Publique-Hôpitaux de Paris, Paris F-75018, France.
¹³ Department of Virology, Cochin Hospital, University of Paris, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
¹⁴ Departments of Epidemiology and Biostatistics and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143.
¹⁵ Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143.
¹⁶ Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129.
¹⁷ Chan Zuckerberg Biohub, San Francisco, CA 94158.
¹⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children 75015 Paris, France; casanova@rockefeller.edu.
¹⁹ HHMI, The Rockefeller University, New York, NY 10065.

PMID: 34702736
PMCID: PMC8609338
DOI: 10.1073/pnas.2114390118

Case Reports

Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Romain Lévy et al. Proc Natl Acad Sci U S A. 2021.

. 2021 Nov 9;118(45):e2114390118.

doi: 10.1073/pnas.2114390118.

Authors

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children 75015 Paris, France.
² Imagine Institute, University of Paris, Paris 75015, France.
³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065.
⁵ Sorbonne Université, INSERM, Centre for Immunology and Microbial Infections-Paris, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75013, France.
⁶ General Pediatrics, Infectious Disease and Internal Medicine Department, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris, Paris 75019, France.
⁷ Pediatric Pulmonary Department, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
⁸ Institut Necker-Enfants Malades, INSERM U1151, Paris 75015, France.
⁹ Institute for Human Genetics, University of California, San Francisco, CA 94143.
¹⁰ Pediatric Radiology, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
¹¹ Department of Virology, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris, Paris 75015, France.
¹² Department of Virology, INSERM, Infection, Antimicrobiens, Modélisation, Evolution, UMR 1137, Bichat-Claude Bernard Hospital, University of Paris, Assistance Publique-Hôpitaux de Paris, Paris F-75018, France.
¹³ Department of Virology, Cochin Hospital, University of Paris, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
¹⁴ Departments of Epidemiology and Biostatistics and Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143.
¹⁵ Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA 94143.
¹⁶ Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129.
¹⁷ Chan Zuckerberg Biohub, San Francisco, CA 94158.
¹⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker Hospital for Sick Children 75015 Paris, France; casanova@rockefeller.edu.
¹⁹ HHMI, The Rockefeller University, New York, NY 10065.

PMID: 34702736
PMCID: PMC8609338
DOI: 10.1073/pnas.2114390118

Abstract

We describe an unvaccinated child at risk for life-threatening COVID-19 due to an inherited deficiency of IRF9, which governs ISGF-3-dependent responses to type I and III interferons (IFN). She was admitted, with a high nasal SARS-CoV-2 load on day 1 of upper respiratory tract infection. She was viremic on day 2 and received casirivimab and imdevimab. Her clinical manifestations and viremia disappeared on days 3 and 4, respectively. Circulating SARS-CoV-2 virus induced the expression of IFN-stimulated genes in leukocytes on day 1, whereas the secretion of blood type I IFNs, which peaked on day 4, did not. Antibody-mediated SARS-CoV-2 neutralization is, therefore, sufficient to overcome a deficiency of antiviral IFNs.

Keywords: COVID-19; RNA-seq; SARS-CoV-2; inherited primary immunodeficiency; interferon.

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Conflict of interest statement

The authors declare no competing interest.

Figures

**Fig. 1.**
(A) RT-PCR for SARS-CoV-2 on nasal swabs and blood on the day of symptom onset (day 1), and at various time points following treatment with casirivimab and imdevimab (mAbs), prescribed on day 2 of symptoms. (B) CT of the lungs of the patient on day 1, showing bilateral curvilinear subpleural opacities. (C) Decrease in viral load, in log₁₀ copies per milliliter, in nasal swabs and decrease in N-antigenemia (in pg/mL) following treatment with mAbs. (D) IFN-α2 determination by Simoa, on plasma collected from the patient on day 1, and at various time points after mAb treatment. (E) Serological results for SARS-CoV-2 anti-nucleocapsid protein (N) and spike protein (S) antibodies in the patient’s serum at various time points after the initiation of mAb treatment.

**Fig. 2.**
(A) RNA-seq comparison of gene expression between day 1, day 3, day 4, and day 14 in the patient, with expression assessed as the normalized and log-transformed read count (red: type-I IFN genes; purple: ISGs known to have antiviral functions; yellow: other ISGs; gray: other protein-coding genes). (B) Heatmap of RNA-seq gene expression z-scores for 44 ISGs with known antiviral functions in the patient on day 1, day 3, day 4, and day 14.

See this image and copyright information in PMC

References

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Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Affiliations

Monoclonal antibody-mediated neutralization of SARS-CoV-2 in an IRF9-deficient child

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous