The Altered Neonatal CD8⁺ T Cell Immunodominance Hierarchy during Influenza Virus Infection Impacts Peptide Vaccination

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality and delayed clearance of the virus. Generating effective CD8⁺ T cell responses may be important for improving vaccination outcomes in vulnerable populations, but neonatal T cells frequently respond differently than adult cells. We sought to understand CD8⁺ T cell specificity and immunodominance during neonatal influenza infection and how any differences from the adult hierarchy might impact peptide vaccine effectiveness. Neonatal C57BL/6 mice displayed an altered CD8⁺ T cell immunodominance hierarchy during influenza infection, preferentially responding to an epitope in the influenza protein PA rather than the co-dominant adult response to NP and PA. Heterosubtypic infections in mice first infected as pups also displayed altered immunodominance and reduced protection compared to mice first infected as adults. Adoptive transfer of influenza-infected bone-marrow-derived dendritic cells promoted an NP-specific CD8⁺ T cell response in influenza-virus-infected pups and increased viral clearance. Finally, pups responded to PA (224–233), but not NP (366–374) during peptide vaccination. PA (224–233)-vaccinated mice were not protected during viral challenge. Epitope usage should be considered when designing vaccines that target T cells when the intended patient population includes infants and adults.