Journal Article

DZNE-2025-00501

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.

Simonis, A. ; Theobald, S. J. ; Koch, A. E. ; Mummadavarapu, R. ; Mudler, J. M. ; Pouikli, A. ; Göbel, U. ; Acton, R. ; Winter, S. ; Albus, A. ; Holzmann, D. ; Albert, M.-C. ; Hallek, M. ; Walczak, H. ; Ulas, T.DZNE* ; Koch, M. ; Tessarz, P. ; Hänsel-Hertsch, R. ; Rybniker, J.

2025
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44320-025-00093-6

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.

Keyword(s): Humans (MeSH) ; Macrophages: immunology (MeSH) ; Macrophages: metabolism (MeSH) ; Epigenesis, Genetic (MeSH) ; SARS-CoV-2: immunology (MeSH) ; SARS-CoV-2: genetics (MeSH) ; COVID-19: immunology (MeSH) ; COVID-19: prevention & control (MeSH) ; Histones: metabolism (MeSH) ; Histones: immunology (MeSH) ; Histones: genetics (MeSH) ; Immunologic Memory (MeSH) ; Promoter Regions, Genetic (MeSH) ; Acetylation (MeSH) ; COVID-19 Vaccines: immunology (MeSH) ; Immunity, Innate (MeSH) ; Cytokines: metabolism (MeSH) ; Vaccination (MeSH) ; RNA, Messenger: immunology (MeSH) ; mRNA Vaccines: immunology (MeSH) ; Epigenetic Memory (MeSH) ; Epigenetic Memory ; G-quadruplex ; H3K27ac ; SARS-Cov-2 mRNA Vaccination ; Trained Innate Immunity ; Histones ; COVID-19 Vaccines ; Cytokines ; RNA, Messenger ; mRNA Vaccines

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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