Type I interferon signaling is required for resistance to primary influenza virus infection and vaccine-induced long-term immunity.

Type I interferons (IFNs) are critical for early antiviral defense, yet their role in shaping vaccine-induced immunity remains incompletely understood. Here, we investigated the impact of type I IFN receptor (IFNαβR) deficiency on immune responses to influenza virus infection and vaccination in IFNαβR-deficient (AB6) mice. AB6 mice exhibited profound susceptibility to influenza virus infection, characterized by accelerated weight loss, elevated lung viral loads, and severe histopathology. Despite inducing short-term IgG antibodies and protection against weight loss after H5 hemagglutinin virus-like particle (H5 VLP) vaccination, AB6 mice were less effective in controlling lung viral loads and inflammation after lethal influenza virus infection, compared to the wild-type (B6) mice. IFNαβR deficiency dysregulated chemokines and numerous innate immune cells, particularly neutrophils, contributing to lung pathology after H5 VLP vaccination and influenza virus infection. AB6 mice exhibited a faster kinetics of waning IgG antibodies and lower efficacy of long-term protection after vaccination than wild-type B6 mice.IMPORTANCEType I interferons (IFNs) are essential mediators of antiviral defense, but their contribution to vaccine-induced immunity remains unclear. This study reveals that type I IFN receptor signaling is dispensable for the initial antibody induction but is critical for sustaining long-term humoral immunity and balanced immune regulation after influenza vaccination and infection. Loss of IFNαβR signaling leads to impaired viral control, excessive neutrophil-driven inflammation, and disrupted immune cell homeostasis. These findings highlight type I IFN signaling as a key integrator of innate and adaptive immune responses required for adequate and durable antiviral protection.