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

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.

Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia

“…We provide evidence that recessive and complete defects at these four loci can underlie ∼10% of cases of COVID-19 pneumonia in hospitalized children, but the possible role of the other 11 loci in COVID-19 pneumonia remains unclear. Recessive complete defects at the IFNAR2 , STAT1 , and IRF9 ( Levy et al, 2021 ) loci would also probably be causal, given the identification of patients with IFNAR1, TYK2, STAT2, and IRF7 deficiencies ( Abolhassani et al, 2022 ; Khanmohammadi et al, 2021 ; Zhang et al, 2020b ; this report), as would defects at the TBK1 locus, given the previous report ( Schmidt et al, 2021 ), and defects at the UNC93B1 , MYD88 , and IRAK4 loci, given the identification of patients with TLR7 deficiency ( Asano et al, 2021 ). It is also probable that recessive defects of MDA5, TLR3, and TRIF may underlie COVID pneumonia in children.…”

“…Inborn errors of type I IFNs should be considered in children hospitalized for COVID-19. Personalized treatment in the first days of infection, including therapeutic type I IFN ( Bastard et al, 2021b ; Vinh et al, 2021 ) and monoclonal antibody therapy ( Levy et al, 2021 ), should be considered in patients with defects upstream and downstream from type I IFN receptors, respectively ( Zhang et al, 2022 ). The human genetic and immunological determinants of disease in other children remain to be discovered.…”

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

“…The specific type I IFN to be used may be determined by the nature of the predisposition. IFN-α2 and IFN-β are good options in patients with a functional response pathway and without neutralizing auto-Abs against the IFN concerned, whereas mAbs neutralizing the virus would be a better option in patients with a defective type I IFN responsive pathway ( Lévy et al., 2021 ).…”

Impact of SARS-CoV-2 infection and COVID-19 on patients with inborn errors of immunity

“…Over the past 2 years, outcomes of SARS-CoV-2 infection have been reported for ∼1330 individuals with IEI. These studies range from reports of single cases or small numbers of patients 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 to cohort studies from Iran, 89 , 90 , 91 Turkey, 92 , 93 , 94 Brazil, 95 , 96 Israel, 97 Italy, 98 , 99 , 100 , 101 Spain, 102 the United Kingdom, 15 , 103 , 104 Mexico, 105 Denmark, 106 , 107 Poland, 108 …”