Epigenetic memory upon Covid19 vaccination
Innate immune memory plays a crucial role in the development of durable cell-mediated immune responses. How precisely mRNA vaccines train innate immune cells for shaping antigen specific adaptive immunity remains unknown. Here we show that SARS-CoV-2 mRNA vaccination leads to profound epigenetic histone modifications driving pro-inflammatory reprogramming of human blood derived monocytes. However, two consecutive vaccinations were required for histone 3 lysine 27 acetylation (H3K27ac) modifications specifically translating into innate immune associated transcriptional changes and Spike-protein mediated inflammasome activation in monocyte derived macrophages. While histone modifications were lost over time, we found that a single mRNA booster vaccine applied six months after two priming vaccines restored H3K27ac promoter modifications associated with potent inflammasome mediated secretion of pro-inflammatory cytokines. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a rapid and sustained pro-inflammatory immune response towards foreign antigens. Overall design: time course across first, second and booster vaccination against SARS-CoV2 using CUT&RUN for H3K27ac in patient-derived macrophages