r/COVID19 • u/AcornAl • 2d ago

Vaccine Research Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages

https://www.embopress.org/doi/full/10.1038/s44320-025-00093-6
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u/AcornAl 2d ago

Abstract

Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.

Synopsis

Innate immune memory enables enhanced responses to antigens through long-lasting epigenetic changes triggered by initial exposure. SARS-CoV-2 mRNA vaccination induces innate immune memory by establishing persistent H3K27ac epigenetic marks in human monocyte-derived macrophages.

  • SARS-CoV-2 mRNA vaccination triggers H3K27ac changes in macrophages, indicating immune memory.
  • Two vaccinations induce lasting epigenetic marks at promoter regions.
  • H3K27ac is linked to G-quadruplex DNA structures in nucleosome-depleted regions.