Vaccine immunity can drive eosinophil recruitment in influenza breakthrough infection with mouse strain-specific outcomes

Eosinophils are pleiotropic cells and can respond to a wide array of inflammatory stimuli, including respiratory viral infection. Although they are historically associated with adverse outcomes in vaccinated hosts after breakthrough infection, such as during vaccine-associated enhanced respiratory disease (VAERD) for respiratory syncytial virus (RSV), eosinophils can also help mediate antiviral immunity. We previously observed mild, nonpathological lung eosinophilia in vaccinated mice experiencing influenza breakthrough infection, distinct from VAERD. Here, we investigated the factors driving this eosinophil recruitment and their contribution to host outcomes during influenza breakthrough infection. Vaccine-elicited Abs partially mediate eosinophil recruitment to the lungs during infection but do not confer full protection against viral replication or disease. Live viral replication was needed for robust eosinophil recruitment. Furthermore, both CD4 and CD8 T cells were required for optimal eosinophil accumulation in the lungs. Intramuscular vaccination resulted in the induction of a balanced type 1/2 response in the spleen and mainly a type 2 response in the lung upon infection, whereas a type 1 immune response dominated in the lungs of unvaccinated mice upon infection. Eosinophil depletion studies revealed strain-dependent effects: in BALB/c mice, eosinophil depletion did not significantly affect morbidity, viral load, lung inflammation, or lung lesion severity. However, in C57BL/6 mice, eosinophil depletion improved viral control and reduced pro-inflammatory cytokine expression. Our findings highlight the complex interplay among vaccine-induced immunity, eosinophil recruitment, and host genetic background in shaping outcomes during influenza breakthrough infection, with implications for vaccine strategies and immunopathology mitigation in diverse populations.