T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months. Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T-cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1. A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Medical Research Council UK, NIHR BMRC Oxford. •Heterologous prime-boost vaccination regimens of MVA/ChAdOx1 NP+M1 are safe and immunogenic in young and older adults•All MVA/ChAdOx1 NP+M1 regimens tested significantly increased cross-reactive T-cells•Responses were durable and were maintained 18 months after vaccination•The fold-increase after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1 Current seasonal influenza vaccines induce antibody responses to external glycoproteins, which are highly susceptible to the accumulation of mutations within antigenic sites, allowing escape from serological immunity conferred by prior infection or vaccination. In this phase I clinical study, we present the results of using two replication-deficient viral vectors expressing conserved influenza A antigens in four different vaccination regimens, administered at intervals of either 8weeks or one year. We found that vaccination was safe and boosted T cell responses to influenza antigens substantially, with a further increase after the second vaccination, both in young and older adults.