Researchers at the University of Cologne have found that mRNA-based COVID-19 vaccines have a lasting impact on the innate immune system. These mechanisms could enhance the body’s ability to defend itself against future infections.
Researchers from the University of Cologne and University Hospital Cologne have demonstrated that novel mRNA-based COVID-19 vaccines not only trigger adaptive immune responses, such as the production of antibodies, but also induce long-lasting epigenetic changes in innate immune cells.
The study was led by Professor Dr. Jan Rybniker, Head of the Division of Infectious Diseases at University Hospital Cologne and principal investigator at the Center for Molecular Medicine Cologne (CMMC), along with Dr. Robert Hänsel-Hertsch, also a principal investigator at the CMMC. The findings were published in Molecular Systems Biology.
The immune system consists of two main components: the innate immune system, which provides immediate, broad protection against pathogens, and the adaptive (or acquired) immune system, which develops specific responses to new threats. These two arms of the immune system work in concert.
According to the researchers, the observed changes in innate immune cells are driven by epigenetic modifications, specifically, chemical changes to histone proteins. Histones act like spools around which DNA is wound. Acetylation of histones is a reversible process that alters how genes are expressed, without changing the DNA sequence itself.
These findings suggest that mRNA vaccination may enhance the long-term responsiveness of innate immune cells, potentially improving the body’s defense not only against the targeted virus, but also against unrelated pathogens.
Epigenetic Training of Immune Cells
“Our findings show that mRNA vaccines induce an epigenetic ‘training’ of innate immune cells, enabling a sustained immune response,” says Dr. Alexander Simonis, first author of the study. The epigenetic changes may provide the basis for long-lasting innate immunity that broadens the protection mechanisms of the acquired immune system. This can now be tested in larger clinical trials based on these study results.
The researchers analyzed monocytes – a type of white blood cells that can differentiate into macrophages in humans – in blood samples of vaccinated participants at six different time points. Macrophages are classical cells of the innate immune system that are crucial for the rapid detection and digestion of pathogens. They found that mRNA-based COVID-19-vaccinations cause a significant and persistent change through acetylation, i.e. the binding of a chemical group to specific, immunologically relevant genes of these monocytes.
Moreover, the findings showed that these epigenetic changes were preserved for six months after the vaccination, suggesting that the vaccine trains the ‘long-term memory’ of the immune system. Since human monocytes only circulate for about three days in the body, the researchers assume that the precursor cells of monocytes in the bone marrow also carry the epigenetic markers.
However, a single mRNA-vaccination is not sufficient to potently induce the markers. “Two consecutive vaccinations or a single booster vaccination are required for these persistent epigenetic changes, highlighting the need for multiple vaccinations to maintain a long-term immune response,” says Jan Rybniker.
Broad Immune Activation and Future Potential
The observed epigenetic changes led to increased ‘reading’ of pro-inflammatory genes, which in turn led to the production of messenger substances, so-called cytokines, that can activate numerous immune cells and thus increase their ability to fight pathogens.
“Since this is an activation of the innate immune system, which targets various pathogens in a relatively broad and unspecific manner, the mRNA vaccinations could also offer protection against other viruses and bacteria, at least for a certain period of time,” explains Dr. Sebastian Theobald, who is also first author of the study.
“These findings suggest that histone modifications in macrophages not only activate genes involved in the immune response, but that these genes additionally form guanine quadruplex DNA structures, which may be crucial to persistent immunity,” says Dr. Robert Hänsel-Hertsch, who is an expert in the field of epigenetics.
These findings have far-reaching implications for the development of future vaccination strategies, both against COVID-19 and other infectious diseases.
Reference: “Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages” by Alexander Simonis, Sebastian J Theobald, Anna E Koch, Ram Mummadavarapu, Julie M Mudler, Andromachi Pouikli, Ulrike Göbel, Richard Acton, Sandra Winter, Alexandra Albus, Dmitriy Holzmann, Marie-Christine Albert, Michael Hallek, Henning Walczak, Thomas Ulas, Manuel Koch, Peter Tessarz, Robert Hänsel-Hertsch and Jan Rybniker, 25 March 2025, Molecular Systems Biology.
DOI: 10.1038/s44320-025-00093-6
The study was conducted within the framework of a research project on deciphering innate immunity in vaccination at the CMMC and the platform COVIM – COllaboratiVe IMmunity Platform of the Network of University Medicine (NUM), funded by the Federal Ministry of Education and Research.
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