Temporal and Cellular Organization of Immune Responses to Live Attenuated Herpes Zoster Vaccination

Background: Cellular responses to live attenuated herpes zoster vaccination and their variation with age remain incompletely characterized. We aimed to define their temporal and cellular organization and identify immune features that differed between age groups. Methods: Using a nested cohort design, we evaluated conventional humoral and CD4 T cell responses in 100 adults at Day 0 and Day 30. Olink protein profiles were assessed in 50 participants at Day 0 and Day 1, and longitudinal single-cell RNA sequencing was performed in 18 participants at Day 0, Day 1, and Day 30. Results: Vaccination increased gE and VZV antibody levels by Day 30, whereas CD4 T cell cytokine responses were more variable. Olink profiling identified broad early changes shared by both groups and exploratory differences in selected immune and inflammatory proteins. At single-cell resolution, the broadest transcriptional response occurred at Day 1, led mainly by classical monocytes and naive CD4 T cells, followed by a more selective state at Day 30. Differences between age groups involved baseline plasmacytoid dendritic cell abundance and non-classical monocyte regulatory activity, the early conventional dendritic cell type 2 response, and later CD8 T cell and regulatory programs. Conclusions: These findings connect conventional immunogenicity with proteomic and cellular responses and identify selected immune states and pathways that differed between age groups across response phases.