Dr. Phlip McMillan, John McMillan
Broad population use of mRNA vaccines against COVID-19 has sparked growing interest in precisely how these vaccines trigger immunity and why is it so shortlived. While scientists initially focused on antibody production and T-cell responses, recent research has uncovered something unexpected: mRNA vaccines appear to create unexpected changes in our innate immune cells (macrophages) through epigenetic modifications. A remarkable study published in March 2025 titled “Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages” has revealed important new insights into how these vaccines work at a molecular level.
“There have been many statements claiming that mRNA can’t change your DNA because it’s RNA,” notes Dr. Philip McMillan, a clinician and researcher. “While it’s true that mRNA doesn’t integrate into DNA, recent findings clearly demonstrate that mRNA vaccines can alter how our DNA functions by changing its accessibility.”
What Are Epigenetic Changes?
To understand these findings, we need to grasp how our genetic material is organized within cells. Our DNA doesn’t simply float freely inside the nucleus. Instead, it’s carefully wrapped around protein structures called histones, similar to string wound around a yo-yo. This packaging system allows our cells to control which genes are accessible for reading at any given time.
One key epigenetic mechanism involves chemical tags attached to histones that can either tighten or loosen the DNA wrapping. When DNA is tightly wrapped, genes are inaccessible and remain inactive. When the wrapping loosens, genes become available for transcription into RNA, which can then make proteins.
“When chromatin is condensed and tightly wrapped, the DNA can’t make new RNA,” explains Dr. McMillan. “To make new RNA, you have to unwind the ‘yo-yo.’ If you imagine DNA as string wrapped around a yo-yo, there’s a section in the string that needs to be accessed. To access it, you must unwind the yo-yo string to reach that section.”
The Recent Research Breakthrough
The 2025 study by Alexander Simonis, Sebastian J. Theobald, and colleagues examined how SARS-CoV-2 mRNA vaccination affects human macrophages, a type of immune cell that helps fight infections. Their research revealed that the vaccines establish specific epigenetic modifications in these cells.
Specifically, they found increased histone H3 lysine 27 acetylation (H3K27ac) at gene promoters — the “starting points” for gene transcription. This acetylation effectively loosens the DNA wrapping around histones, keeping genes responsible for immune responses in an “accessible” state. The researchers discovered that these epigenetic changes persisted for at least six months after vaccination, suggesting a form of “memory” in these innate immune cells.
How mRNA Vaccines Create Immune Memory
Traditional understanding of vaccine memory has focused on antibody-producing B cells and virus-targeting T cells. However, recent papers have shown that mRNA vaccines don’t produce the expected long-lived plasma cells in bone marrow that typically maintain immunity after conventional vaccines.
Instead, these new findings suggest an alternative mechanism for immunity. mRNA vaccines also train macrophages to remember and respond to infection through epigenetic reprogramming. Importantly, the researchers found that two consecutive vaccinations were required for this persistent epigenetic memory to develop, explaining why the prime-boost strategy is important for mRNA vaccines to be effective.
The H3K27ac modifications were particularly concentrated at promoters of genes involved in immune responses, including those that produce cytokines (signaling molecules that coordinate immune responses) and innate immune receptors. When these macrophages later encountered pathogen components, they responded more vigorously than those from unvaccinated individuals.
The Role of G-Quadruplex DNA
The study revealed another fascinating discovery: the epigenetic marks were enriched in DNA regions containing G-quadruplex structures. These are unusual DNA configurations where guanine-rich sequences form four-stranded structures rather than the typical double helix.
The researchers found that these G-quadruplex regions were particularly common in the nucleosome-depleted regions of macrophage DNA where H3K27ac marks persisted. This suggests a potential relationship between these unique DNA structures and the maintenance of epigenetic memory after vaccination.
What This Means for Public Health
While the researchers present these findings as a positive discovery that helps explain vaccine effectiveness, Dr. McMillan raises serious concerns about the potential implications of macrophages remaining in an activated state for extended periods.
“On the surface, that may seem like a good thing, but it immediately raised red flags for me,” explains Dr. McMillan. “I knew instinctively there was something very important in this paper, but not necessarily from the angle they were examining.”
For instance, researchers in Israel found that within about three months of receiving an mRNA COVID vaccine, lymph nodes remained highly activated in some individuals, something not typically seen with other vaccines. The persistent epigenetic changes in macrophages might explain this prolonged activation of immune tissues. This unusual activation was so pronounced that PET scans couldn’t reliably distinguish between vaccine-related lymph node activity and potential cancer signals in some patients.
Another concerning observation is what some researchers have termed “Long Vax” – the appearance of long-term symptoms after vaccination that mirror those experienced after infection. While some scientists argue vaccines are protective against such conditions, the epigenetic macrophage activation could explain why some individuals experience worsening symptoms. If the immune system is already partially activated due to these epigenetic changes, additional triggers might prevent it from properly deactivating, potentially leading to chronic inflammation.
The findings also suggest that mRNA vaccines induce “trained immunity” in innate immune cells, potentially conferring broader protection beyond just the specific target pathogen. A single booster dose administered six months after the initial vaccinations potently restored the epigenetic marks and enhanced cytokine production, suggesting this mechanism contributes to the efficacy of booster shots.
Questions and Future Research
Several important questions remain about these epigenetic changes following mRNA vaccination. How long do these modifications truly last beyond six months? Do they differ between individuals based on age, sex, or pre-existing conditions? Could these persistent changes explain why some individuals experience extended inflammatory responses?
The findings raise particular concerns about potential long-term consequences of having immune cells locked in an activated state. Unlike traditional vaccines that primarily generate memory B and T cells, this epigenetic reprogramming of macrophages represents a fundamentally different mechanism that keeps innate immune cells in a heightened state of readiness.
Dr. McMillan notes: “While researchers view this as positive for immune memory, I’m concerned about the implications. Histones act like dimmer switches, they can turn gene expression up or down. If they’re locked in the ‘on’ position, those immune cells may never ‘go to sleep,’ potentially explaining some of the long-term effects we’re seeing.”
This constant state of activation in macrophages could potentially contribute to chronic inflammation in susceptible individuals. Macrophages that remain primed to produce inflammatory cytokines might over-respond to minor triggers, potentially creating a cascade of inflammatory responses disproportionate to the actual threat.
Future research will need to explore these questions and their implications for vaccine scheduling, development, and potential side effects. Scientists should investigate whether some individuals might be more susceptible to prolonged macrophage activation and whether there are ways to modulate this response in those experiencing adverse effects. While mRNA doesn’t change DNA sequences themselves, it appears to influence how certain genes are accessed and expressed, particularly those involved in immune responses.
These discoveries remind us that science constantly evolves, challenging prior assumptions and revealing new layers of biological complexity. Dr. McMillan concludes “These are complex, fascinating topics, and we’ve only begun to understand the implications. There’s still much more work needed to fully understand what’s happening at the molecular level.”
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