Inherited IFNAR1 structural deficiency in severe adverse events following yellow fever vaccination.

Yellow fever virus (YFV) infection is life-threatening but preventable by the live-attenuated YFV 17D/17DD vaccine. Rare Adverse Events Following Immunization (AEFI-YF) involve Inborn Errors of Immunity (IEI), and auto-antibodies against type I interferons (IFNs). We conducted an integrative genetics and functional investigation of a Brazilian family with three siblings presenting AEFI-YF (two deceased), using whole exome sequencing (WES), and qPCR, molecular modeling, in vitro YFV-17D stimulation of leukocytes, cytokine quantification, immunophenotyping, and RNAseq. A novel homozygous IFNAR1 copy number variation (CNV Δ3-4-5) in the proband (heterozygous in five of 11 unaffected relatives) caused receptor dysfunction, suppressing baseline IFN responses but triggering inflammasome-driven innate cell activation upon YFV-17D exposure. This study underscores IFNAR1 deficiency's causality in AEFI-YF pathogenesis and provides mechanistical insights. Our findings advocate for precision vaccinology by screening relatives of AEFI-YF cases for type I IFN EIIs and auto-antibodies prior to live-attenuated vaccination.