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

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^hi eosinophil subset in breakthrough infection mice. Additionally, we highlight preservation of alveolar macrophages and absence of neutrophil and eosinophil extracellular traps in vaccinated hosts, key features that distinguish breakthrough infection from both Type 1- and Type 2-skewed disease models. These insights have broad implications for exploring eosinophil plasticity and cell-cell interactions in the lung, which could inform the development of strategies to harness the benefits of balanced Type 1/2 immune responses across different vaccine/respiratory virus pairs.