Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

ARS-CoV-2 variants have rapidly emerged in humans and supplanted ancestral strains [1][2][3][4][5] . Their proposed increased rates of interindividual transmission conferred a replication advantage at the population level. One of the first identified variants includes the D614G mutation in the gene encoding the spike (S) protein, which enhances viral infectivity and shifts S protein conformation toward an angiotensin-converting enzyme 2 (ACE2)-binding fusion-competent state, without significantly modifying sensitivity to antibody neutralization 1,6-8 . More recently, novel variants have appeared in multiple countries, with combinations of mutations and deletions in the receptor-binding domain (RBD) and N-terminal domain of S protein, as well as in other proteins. The B.1.1.7 variant emerged in the United Kingdom, the B.1.351 variant (also termed 501Y.V2) in South Africa and the P.1 and P.2 lineages in Brazil 2,3,5,9-12 . Although distinct, the variants share common characteristics, including known escape mutations that were previously identified under antibody pressure selection in vitro 2,3,[13][14][15][16][17] . Some of the mutations or deletions were also identified in immunocompromised individuals with prolonged infectious viral shedding and treated with convalescent plasma or S-protein Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351 variants to neutralizing antibodies