Background: Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Methods: Blood samples were taken pre-, 14 days, 28 days, and 1 year after a primary VZV vaccination (Zostavax) at middle age (N = 53, 50-65 years of age). VZV-specific IFN gamma-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Results: Robust short-term enhancement of the VZV-specific IFN gamma-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFN gamma-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFN gamma-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFN gamma-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFN gamma-producing cells. Conclusion: These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFN gamma-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.