Background <p>Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults; however, older adults remain significantly at risk for severe influenza-related illness. Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response.</p> Methods <p>In this study, we combined in vitro and ex vivo immune assays with human samples to investigate B cell, CD4⁺ T cell, and myeloid cell responses to influenza vaccine antigens at the serologic and single-cell level.</p> Results <p>We found that older adults mounted antibody titers equivalent to those of younger adults but had fewer influenza-reactive CD4⁺ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets.</p> Conclusions <p>These data suggest that with aging, transcriptional programming alterations in myeloid and T cells contribute to reduced antiviral responses, and formulating vaccines tailored to cellular immune responses is necessary to improve outcomes in older adults.</p>