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The major antigenic component of licensed influenza vaccines, hemagglutinin (HA), elicits predominantly type-specific antibody responses, thus necessitating frequent antigenic updates to the annual vaccine. However, accumulating evidence suggests that influenza vaccines can also induce significant cross-reactive T-cell responses to highly divergent, heterosubtypic HA antigens not included in the vaccine. Influenza vaccines are less effective among the elderly and studies that characterize cross-reactive T-cell immunity in this vulnerable population are much needed. Here, we systematically compare the ex vivo frequency, cytokine profile and phenotype of vaccine-elicited HA-specific T-cell responses among a cohort of young (18–49 years old) and elderly (≥70 years old) vaccinees, as well as the maturation and activation phenotype of total CD4+ and CD8+ T-cells. IFN-γ production after in vitro expansion and HA-specific Ab titers were also determined. We find that vaccine-elicited ex vivo frequencies of CD4+ T-cells elicited by vaccination reactive to any given homo- or heterosubtypic Ag were comparable across the two age groups. While, no differences were observed between age groups in the phenotype of Ag-specific or total CD4+ T-cells, PBMC from young adults were superior at producing IFN-γ after short-term Ag-specific culture. Significantly, while vaccine-elicited T cell responses were durable among the younger vaccinees, they were short-lived among the elderly. These results have important ramifications for our understanding of vaccine-induced changes in the magnitude and functionality of HA-specific CD4+ T-cells, as well as age-related alterations in response kinetics.

Persistent antigenic drift in influenza hemagglutinin (HA) results in the emergence of serologically novel influenza viruses that result in seasonal epidemics globally. While the globular domain of the HA antigen is the primary repository of drift mutations, the viral-fusion domain is highly conserved. T cells are being increasingly recognized as a significant component of influenza immunity in humans and may target variant regions of HA that are not effectively targeted by type-specific antibodies. While a trivalent inactivated influenza vaccine (TIV) and a live-attenuated influenza vaccine (LAIV) are now licensed for use in humans, their comparative ability to elicit T cell responses against influenza HA is not well understood: specifically, the relative magnitude of T cell responses elicited by TIV and LAIV and their domain-specificity toward HA regions is unknown. In this study, we systematically compare immune responses elicited by TIV and LAIV in a cohort of healthy adults (18 to 49 years old) against the rapidly evolving H3N2 HA antigen. Data suggests TIV elicits higher geometric mean antibody titers than LAIV; whereas, LAIV elicits superior T cell responses. Importantly, the two vaccines vary significantly in their ability to elicit T cell responses targeting the variant and conserved regions of HA. These results have important implications for the deployment of influenza vaccines in years of antigenic mismatch and shift.