Trained Immunity Generated by the Recombinant Zoster Vaccine

Abstract

Trained immunity may play a role in vaccine-induced protection against infections. We showed that the highly efficacious recombinant VZV-gE zoster vaccine (RZV) generated trained immunity in monocytes, natural killer (NK) cells, and dendritic cells (DCs) and that the less efficacious live zoster vaccine did not. RZV stimulated ex vivo gE-specific monocyte, DC and NK cell responses that did not correlate with CD4 + T-cell responses. These responses were also elicited in purified monocyte and NK cell cocultures stimulated with VZV-gE and persisted above prevaccination levels for ≥ 4 years post-RZV administration. RZV administration also increased ex vivo heterologous monocyte and NK cell responses to herpes simplex and cytomegalovirus antigens. ATAC-seq analysis and ex vivo TGFβ1 supplementation and inhibition experiments demonstrated that decreased tgfβ1 transcription resulting from RZV-induced chromatin modifications may explain the development of monocyte trained immunity. The role of RZV-trained immunity in protection against herpes zoster and other infections should be further studied.

Keywords: adaptive NK cells; monocyte immunologic memory; older adults; recombinant zoster vaccine; trained immunity; zoster; zoster vaccines.

Figure 1. Peripheral blood innate and adaptive T cell responses to zoster vaccines.

Data were derived from 10 RZV recipients who received 2 doses of vaccine on Days 0 and 60 and 10 ZVL recipients who received a single dose of vaccine on Day 0. The graphs show means and SEM of the frequencies of activated innate and T cells in peripheral blood from pre-vaccination (D0) and up to 30 days after each dose of vaccine. p values shown on the graphs for the comparison of pre- and post-vaccination responses were generated using Friedman test for repeated measures. RZV participants showed transient increases of activated immune cells in blood after each dose of vaccine. ZVL administration generated increases of activated CD4+ effector memory T cells (Tem) only.

Figure 2. Innate and adaptive immune cell activation in response to ex vivo antigenic stimulation in RZV recipients.

Data were derived from 10 participants who received 2 doses of RZV at enrollment and 60 days later. PBMC were stimulated overnight with VZV-gE peptides (gE pp) or recombinant VZV-gE (rgE) and medium control as indicated on the graphs. The graphs show mean and SEM of the frequency of activated cells in antigen-stimulated conditions after subtraction of medium control from pre-vaccination up to 1 year post-vaccination. p values for the comparison of pre-vaccination with post-vaccination results were calculated using ANOVA for repeated measures. Responses of adaptive and innate immune cells followed similar trajectories except for gd T cells. See also Figure S4 for responses in ZVL recipients.

Figure 3. 5-year persistence of innate immune responses after RZV administration.

Data were derived from 14 RZV recipients who received 2 doses of vaccine at enrollment and 60 days later. The graphs show mean and SEM of the frequency of activated cells in rgE-stimulated conditions after subtraction of medium control. p values were calculated by ANOVA for repeated measures and FDR-adjusted.

Figure 4. Monocyte and NK cell trained immunity after RZV administration.

Data were derived from 10 RZV recipients. Monocytes and NK cells were purified using magnetic bead separation kits, combined, and incubated overnight with rgE, HSV or CMV lysate, or medium background control. Graphs show background-subtracted results before (D0) and after (D90) vaccination. p values were calculated by Wilcoxon matched-pairs signed rank test.

Figure 5. Epigenetic modifications of monocytes and NK cells obtained after RZV administration.

Panel A. The heatmap shows the 16 genes whose accessibility significantly changed in monocytes between Days 0 and 90 after vaccination (FDR p<0.1) in 8 participants. Panel B The heatmap shows the 13 genes whose accessibility significantly changed in NK cells between Days 0 and 90 after vaccination (FDR p<0.1) in 10 participants.

Figure 6. Effect of ex vivo treatment with rhTGFb1 or its inhibitor on monocyte responses to rgE stimulation.

Monocytes and NK cells purified from PBMC collected from 10 RZV recipients before vaccination (D0) and 90 days post-vaccination (D90) were combined ex vivo and stimulated with rgE. A subset of D0 monocyte & NK co-cultures was also treated with the TGFb1 inhibitor LY (D0 LY), and a subset of D90 cultures were supplemented with rhTGFb1. The graph shows individual data points, means and p values calculated by ANOVA for repeated measures. LY treatment of cells collected on D0 significantly increased their activation to levels similar to D90 activation. Conversely, treatment of D90 cells with rhTGFb1 significantly decreased their activation to levels similar to D0.