Varicella-Zoster Virus-Specific Cellular Immune Responses to the Live Attenuated Zoster Vaccine in Young and Older Adults

The incidence and severity of herpes zoster (HZ) increases with age. The live attenuated zoster vaccine generates immune responses similar to HZ. We compared the immune responses to zoster vaccine in young and older to adults to increase our understanding of the immune characteristics that may contribute to the increased susceptibility to HZ in older adults. Young (25-40 y; n = 25) and older (60-80 y; n = 33) adults had similar magnitude memory responses to varicella-zoster virus (VZV) ex vivo restimulation measured by responder cell-frequency and flow cytometry, but the responses were delayed in older compared with young adults. Only young adults had an increase in dual-function VZV-specific CD4(+) and CD8(+) T cell effectors defined by coexpression of IFN-gamma, IL-2, and CD107a after vaccination. In contrast, older adults showed marginal increases in VZV-specific CD8(+) CD57(+) senescent T cells after vaccination, which were already higher than those of young adults before vaccination. An increase in VZV-stimulated CD4(+) CD69(+) CD57(+) PD1(+) and CD8(+) CD69(+) CD57(+) PD1+ T cells from baseline to postvaccination was associated with concurrent decreased VZV-memory and CD8(+) effector responses, respectively, in older adults. Blocking the PD1 pathway during ex vivo VZV restimulation increased the CD4(+) and CD8(+) proliferation, but not the effector cytokine production, which modestly increased with TIM-3 blockade. We conclude that high proportions of senescent and exhausted VZV-specific T cells in the older adults contribute to their poor effector responses to a VZV challenge. This may underlie their inability to contain VZV reactivation and prevent the development of HZ.