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A recent study conducted by researchers from the University of Cologne and University Hospital Cologne highlights that the new mRNA-based COVID-19 vaccines do more than just elicit immune responses; they also induce long-lasting epigenetic changes in innate immune cells. The research, titled ‘Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages’, was spearheaded by Professor Dr. Jan Rybniker, who leads the Division of Infectious Diseases at University Hospital Cologne, alongside Dr. Robert Hänsel-Hertsch, a principal investigator at the Center for Molecular Medicine Cologne (CMMC). The findings were published in Molecular Systems Biology.
The immune system operates via two primary pathways: innate and acquired (adaptive) immunity. Innate immunity offers broad, immediate protection against pathogens, while acquired immunity develops specific responses over time. The relationship between these two systems is symbiotic. Researchers have identified that the observed biological alterations are linked to epigenetic modifications on DNA. These modifications involve the acetylation of histones, the proteins around which DNA is coiled, allowing for reversible changes in gene expression without altering the underlying DNA sequence. As a result, mRNA vaccination may enhance immune responses to future pathogens that are not directly targeted by the vaccine. “Our findings reveal that mRNA vaccines foster an epigenetic ‘training’ of innate immune cells, promoting a prolonged immune response,” states Dr. Alexander Simonis, the study’s first author. This could lead to durable innate immunity, potentially enhancing the protective capabilities of the adaptive immune system, which could be explored further in larger clinical trials.
The research team examined monocytes, a type of white blood cell that can mature into macrophages, in blood samples from vaccinated individuals at six different intervals. Macrophages are central to the innate immune system and play a vital role in identifying and eliminating pathogens. The study revealed that mRNA vaccines induce significant and lasting modifications through acetylation, which affects specific genes associated with immunity in these monocytes.
Results demonstrated that the epigenetic modifications persisted for up to six months post-vaccination, indicating that the vaccine effectively trains the immune system’s ‘long-term memory.’ Given that human monocytes have a lifespan of approximately three days in circulation, the researchers suggest that the epigenetic markers are likely also present in the monocyte precursor cells located in the bone marrow.
Crucially, a single dose of mRNA vaccine is inadequate to generate these lasting markers. “Achieving persistent epigenetic changes necessitates either two consecutive doses or a booster shot, emphasizing the importance of full vaccination schedules for maintaining long-term immunity,” remarks Jan Rybniker.
The identified epigenetic alterations resulted in heightened expression of pro-inflammatory genes, which promoted the release of cytokines—signaling molecules that activate various immune cells and enhance their pathogen-fighting capabilities. “Since this activation occurs within the innate immune system and broadly targets a variety of pathogens, mRNA vaccinations may also confer protective benefits against additional viruses and bacteria, at least temporarily,” explains Dr. Sebastian Theobald, another first author of the study.
“Our findings indicate that histone modifications in macrophages not only activate immune response genes but suggest that these genes may also create guanine quadruplex DNA structures, which could play a significant role in establishing persistent immunity,” adds Dr. Robert Hänsel-Hertsch, an expert in epigenetics.
The implications of this research are profound, paving the way for enhanced vaccination strategies that could address COVID-19 as well as other infectious diseases in future campaigns.
This study was part of a broader project exploring innate immunity in vaccination at the CMMC, supported by the COVIM—COllaboratiVe IMmunity Platform within the Network of University Medicine (NUM), funded by the Federal Ministry of Education and Research.
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