Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages
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.
Authors
- Richard Acton (ORCID: https://orcid.org/0000-0002-2574-9611)
- Thomas Ulas (ORCID: https://orcid.org/0000-0002-9785-4197)
- Alvaro Koch (ORCID: https://orcid.org/0009-0003-1593-9715)
- Robert Hänsel‐Hertsch (ORCID: https://orcid.org/0000-0002-2835-4471)
- Andromachi Pouikli (ORCID: https://orcid.org/0000-0003-1868-6875)
- Jan Rybniker (ORCID: https://orcid.org/0000-0001-8351-2690)
- Ulrike Göbel
- Alexander Simonis (ORCID: https://orcid.org/0000-0003-2945-9897)
- Peter Tessarz (ORCID: https://orcid.org/0000-0002-6953-9835)
- Sebastian J. Theobald
- Manuel Koch (ORCID: https://orcid.org/0000-0002-2962-7814)
- Sandra Winter
- Julie M Mudler (ORCID: https://orcid.org/0000-0003-1378-9648)
- Michael J. Hallek (ORCID: https://orcid.org/0000-0002-7425-4455)
- Marie‐Christine Albert
- Henning Walczak (ORCID: https://orcid.org/0000-0002-6312-4591)
- Alexandra Albus (ORCID: https://orcid.org/0000-0002-4897-6972)
- Dmitriy Holzmann
- Ram Mummadavarapu (ORCID: https://orcid.org/0009-0009-4244-8982)
Institutions
- Babraham Institute (GB)
- University of Bonn (DE)
- Radboud University Nijmegen (NL)
- University of Cologne (DE)
- German Center for Neurodegenerative Diseases (DE)
- Radboud University Medical Center (NL)
- Radboud Institute for Molecular Life Sciences (NL)
- German Center for Infection Research (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- CRUK Lung Cancer Centre of Excellence (GB)
- University Hospital Cologne (DE)
- Max Planck Institute for Biology of Ageing (DE)
- University College London (GB)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Molecular Systems Biology
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1038/s44320-025-00093-6
- Citations
- 21
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 16.75
Funders
- Deutsches Zentrum für Infektionsforschung
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Fritz Thyssen Stiftung
- Max-Planck-Gesellschaft
- Universität zu Köln
- Universitätsklinikum Köln