The recombinant zoster vaccine induces trained immunity in monocytes through persistent downregulation of TGFβ

Older adults have decreased vaccine efficacy, but the adjuvanted recombinant VZV-gE zoster vaccine (RZV) is highly efficacious. We investigated memory-like innate immune responses after RZV and after the zoster vaccine live (ZVL), which is much less efficacious. RZV increased NK, monocyte, and DC activation in response to in vitro VZV-gE stimulation for up to 5 years post-vaccination, while ZVL increased only DC responses to VZV for up to 90 days. In purified monocyte and NK cell cocultures, RZV recipients showed increased responses to VZV-gE, HCMV and HSV antigenic stimulation post-vaccination. ATAC-seq analysis of purified monocytes revealed decreased accessibility in areas of the TGFβ1 gene. scRNA-seq and immunoproteomics confirmed decreased TGFβ1 transcription and translation, respectively. Exogenous supplementation and inhibition of TGFβ1 modulated in vitro monocyte responses to VZV-gE. In conclusion, RZV generated homologous (VZV-gE) and heterologous (HCMV, HSV) trained immunity in monocytes through genomic repression of the regulatory cytokine TGFβ-1. Cytokine modulation may represent a novel mechanism of generating trained immunity in myeloid cells.