Comparison of antibody and T-cell responses elicited by licensed inactivated- and live-attenuated influenza vaccines against H3N2 hemagglutinin.

T cells are being increasingly recognized as a significant component of influenza-specific immune responses in humans. Although an inactivated- and a live-attenuated influenza vaccine are now licensed for use in humans, their comparative ability to elicit T-cell responses against influenza is not well understood. Using the rapidly evolving H3N2 hemagglutinin (HA) as an antigenic model, we compared immune responses elicited by the trivalent inactivated influenza vaccine (TIV) and the live-attenuated influenza vaccine (LAIV) in a cohort of healthy adults 18-49 years of age. TIV elicited higher geometrical mean antibody titers than LAIV, whereas, LAIV elicited superior T-cell responses. Importantly, LAIV elicited higher magnitude T-cell responses toward the rapidly drifting variant region of HA that is prone to escape from antibody responses. These results have important implications for the deployment of influenza vaccines in years of antigenic mismatch and shift.

Age-related changes in durability and function of vaccine-elicited influenza-specific CD4(+) T-cell responses.

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.

Age-related changes in magnitude and diversity of cross-reactive CD4+ T-cell responses to the novel pandemic H1N1 influenza hemagglutinin.

Accumulating evidence suggests that T-cell responses play a significant role in controlling influenza disease. Although humoral responses to the major antigenic component hemagglutinin (HA) have been studied in considerable detail, our understanding of the cellular responses against this antigen is limited. Here, we systematically characterized the magnitude and diversity of immunity to pandemic H1N1 HA and its relationship to seasonal H1N1 HA responses in a cohort of healthy nonimmunized adults. We observed considerable diversity in the magnitude of crossreactive pandemic CD4+ T-cell responses among the subjects, with a subset of the individuals demonstrating higher magnitude T-cell responses against the pandemic antigen compared with the seasonal antigen. Importantly, the data suggest that age-related changes in CD4+ T-cell responses preferentially segregate to the antigenically drifting globular region of HA, more so than the conserved region involved in membrane fusion. These results have important ramifications for our understanding of influenza immunity in humans and development of vaccine strategies against this important pathogen.