IRF7 variants in fully vaccinated Iranian patients with severe COVID-19: a pilot observational study

Severe and critical cases of COVID-19 infections have been reported in healthy and fully vaccinated individuals, raising concerns about host genetic factors that may contribute to disease severity despite full vaccination. The type I interferon (IFN) signaling pathway plays a crucial role in antiviral immunity, and rare and deleterious mutations in its regulatory genes, including IRF7 and TLR7 , have been associated with severe SARS-CoV-2 infections. This study aims to investigate rare or functionally relevant variants in IRF7 and TLR7 in patients who developed severe or critical COVID-19 despite full vaccination. Thirteen patients aged up to 65 years with severe or critical COVID-19 were enrolled between December 1, 2021, and December 30, 2023. All had received at least two doses of the SARS-CoV-2 vaccine. Patients with underlying comorbidities or known immunodeficiencies were excluded from the study. In addition, 30 mild or asymptomatic COVID-19 patients were included in the study as a control group. Genomic DNA was extracted, and PCR was performed to amplify selected exons of IRF7 (exons 1–3, 8–9) and TLR7 (exon 3 in males). Variants were annotated and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Nine patients (69%) carried at least one IRF7 variant. Common benign polymorphisms were observed in several patients and controls. In contrast, the rare variants, including rs386749598, rs746951093, rs201036875, and c.381G > C, were detected only in patients with severe or critical COVID-19. The recurrent rs386749598 variant was identified in 38.5% of patients but was absent in all control subjects. No variants were detected in TLR7 in either group. Our preliminary findings suggest a possible association between rare IRF7 variants and severe COVID-19 despite full vaccination. However, larger studies and functional analyses are required to confirm their biological and clinical significance.