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

Significance Life-threatening COVID-19 pneumonia can be caused by rare inborn errors of type I interferon (IFN) immunity, or by autoantibodies neutralizing IFN-α2 or IFN-ω. In 2018, we reported a girl with critical influenza pneumonia due to inherited IRF9 deficiency, a component of the ISGF-3 transcription factor. We report the course of COVID-19 in the same patient. She was admitted on day 1 of upper respiratory tract infection with viremia. Administration of SARS-CoV-2–specific neutralizing monoclonal antibodies on day 2 prevented the development of pneumonia. SARS-CoV-2–specific monoclonal antibodies were sufficient to overcome a lack of ISGF-3– and IRF9-dependent type I and type III IFN immunity to the virus. They should be considered in selected children at high risk of life-threatening COVID-19.
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.