Transient lung eosinophilia during breakthrough influenza infection in vaccinated mice is associated with protective and balanced Type 1/2 immune responses.

Eosinophils are versatile cells that participate in a multitude of homeostatic and inflammatory responses in the lung, ranging from allergic asthma to antiviral defense against respiratory viral infection. In the context of vaccination followed by viral infection, such as breakthrough infection, eosinophils have been linked to aberrant Th2 responses like vaccine-enhanced respiratory disease. Here, we demonstrate that the lung immune cell composition, cytokine and chemokine repertoire, histopathological profile, and systemic humoral response of breakthrough influenza infection in mice are distinct from those of primary influenza infection or allergic sensitization, canonical Type 1 and 2 immune responses, respectively. Longitudinal comparison of breakthrough infection with allergic sensitization and primary influenza infection demonstrated major differences in lung immunity between treatment groups in female BALB/c mice. Breakthrough infection mice exhibit lung eosinophil infiltration that peaks at 7-10 days post-challenge, enriched for the Siglec-F IMPORTANCE: Our findings reveal that eosinophilic recruitment during influenza breakthrough infection is non-pathological and represents a balanced immune response, distinct from highly inflammatory environments seen in primary influenza infection or allergic sensitization. We observed eosinophil enrichment in the lungs of vaccinated hosts following infection, which coincided with rapid viral clearance and minimal lung damage, challenging traditional associations of eosinophils with adverse outcomes in vaccinated hosts, like for respiratory syncytial virus. We identified a phenotypic shift toward Siglec-F