STANFORD, Calif. – Researchers at the Stanford University School of Medicine have identified two key proteins-CXCL10 and IFN-gamma-that appear to drive the rare instances of myocarditis, or heart muscle inflammation, linked to mRNA COVID-19 vaccines. The findings, published this week, detail a molecular mechanism involving communication between immune cells, specifically macrophages and T cells, and offer potential avenues for mitigating this vaccine-related side effect while preserving the critical protective benefits of vaccination against COVID-19. The study builds on mounting evidence demonstrating a considerably higher risk of myocarditis from COVID-19 infection itself compared to vaccination.
A rare side effect of mRNA COVID-19 vaccines – heart inflammation – has been linked to a specific biological process, according to new research from Stanford Medicine.
ATLANTA – Researchers at Stanford Medicine have identified a two-step process by which mRNA COVID-19 vaccines can, in some young men and adolescents, cause inflammation of the heart muscle, known as myocarditis. The study, published in Science Translational Medicine, also suggests potential avenues for reducing the risk.
Using advanced laboratory techniques and existing data from vaccinated individuals, the researchers discovered that the vaccines activate a specific type of immune cell, which then stimulates another type of immune cell. This resulting inflammatory activity directly damages heart muscle cells and triggers further inflammation.
“mRNA vaccines have been critical in mitigating the COVID-19 pandemic,” said Joseph Wu, director of the Stanford Cardiovascular Institute. “Without these vaccines, more people would have become sick, more would have experienced severe outcomes, and more would have died.” mRNA vaccines represent a significant advancement in medical technology due to their rapid production capabilities and adaptability to emerging pathogen strains.
“mRNA vaccines have been fundamental to mitigating the COVID pandemic,” Wu noted. “Without these vaccines, more people would have gotten sick, more people would have had severe outcomes, and more people would have died.”
A rare, but real, risk associated with mRNA COVID-19 vaccines is myocarditis, or inflammation of the heart muscle. Symptoms – including chest pain, shortness of breath, fever, and palpitations – typically appear one to three days after vaccination and occur without evidence of a viral infection. Many affected individuals exhibit elevated levels of cardiac troponin in their blood, a well-established clinical indicator of heart muscle injury. (Cardiac troponin is normally found exclusively in heart muscle; its presence in the bloodstream signals damage to heart cells.)
Myocarditis linked to the vaccine occurs in approximately one in 140,000 vaccinated individuals after the first dose, increasing to one in 32,000 after the second dose. The incidence peaks among vaccinated males aged 30 and under, affecting roughly one in 16,750. Fortunately, most cases have a favorable outcome, with cardiac function either fully preserved or restored, and recovery is often rapid, Wu said.
“This isn’t a heart attack in the traditional sense,” Wu explained. “There’s no blockage of blood vessels as seen in most common heart attacks. When symptoms are mild and inflammation hasn’t caused structural damage to the heart, we simply observe these patients to ensure recovery.”
However, Wu cautioned that severe inflammation can lead to significant heart damage, potentially requiring hospitalization, intensive care, and, rarely, death. “But COVID is worse,” he emphasized. A COVID-19 infection is approximately 10 times more likely to induce myocarditis than an mRNA COVID-19 vaccine, in addition to causing a range of other health problems.
In the study, researchers first analyzed blood samples from individuals vaccinated against COVID-19, some of whom developed myocarditis. Comparing those who developed the condition to those who did not, they observed elevated levels of two proteins in the blood of those who experienced myocarditis.
“We found two proteins, called CXCL10 and IFN-gamma. We believe these two are the main drivers of myocarditis,” Wu said.
Both CXCL10 and IFN-gamma belong to a class of proteins called cytokines – signaling substances that immune cells secrete to communicate chemically with each other. To better understand these communications, scientists generated human immune cells called macrophages (first-responder cells of the immune system) in a lab setting and incubated them with mRNA vaccines.
The macrophages responded by releasing various cytokines, most notably significant amounts of CXCL10. Furthermore, their response mirrored that of macrophages observed in vaccinated humans, based on comparisons with published data.
“We found two proteins, called CXCL10 and IFN-gamma. We believe these two are the main drivers of myocarditis,” Wu explained.
When scientists added another type of immune cell – T cells, mobile sentinels capable of recognizing and organizing immune attacks against specific pathogens, but also capable of inciting a general activation of the immune system – to the plate, or simply immersed the T cells in the solution in which the vaccinated macrophages had been incubated, they observed a marked increase in IFN-gamma production by the T cells. However, T cells incubated with the mRNA vaccine in the absence of macrophages or the incubation fluid produced only standard amounts of IFN-gamma. These results demonstrated that macrophages are the primary source of CXCL10 and T cells are the primary source of IFN-gamma in response to mRNA vaccination.
Researchers then investigated whether both cytokines contributed directly to heart damage. To answer this question, they vaccinated young male mice and detected elevated levels of cardiac troponin, the widely used clinical marker for heart muscle damage.
The researchers also observed infiltration of macrophages and another type of first-responder immune cell, neutrophils (short-lived first-response cells that survive to die in a glorious battle, usually against bacterial or fungal pathogens and the main component of pus) into the heart tissue of the mice. This also occurs in patients with post-vaccination myocarditis.
This infiltration of macrophages and neutrophils into the heart – which comes at a cost, as these first-shooting, ask-questions-later immune cells often cause collateral damage to healthy tissue, including heart muscle – could be minimized by blocking the activity of CXCL10 and IFN-gamma.
The researchers also observed an increase in populations of cell surface molecules in the mice’s hearts that trap macrophages, neutrophils, and other types of white blood cells, causing them to adhere to endothelial cells, which line all blood vessels, including those in the heart.
Thus, CXCL10 and IFN-gamma did contribute directly to heart damage in these mice. Blocking their activity largely preserved the immune response to vaccination while reducing vaccine-induced troponin levels.
Wu’s lab specializes in a technology that involves transforming human skin or blood cells into white blood cells, which can then be guided to differentiate into cardiomyocytes, macrophages, and endothelial cells, and fused into spherical structures that mimic the rhythmic contractions of the heart.
The researchers treated these “heart spheroids” with bathing fluid enriched with CXCL10 and IFN-gamma, derived from macrophages and T lymphocytes stimulated by the vaccine, respectively. They observed a significant increase in markers of cardiac stress, which were reversed by inhibitors of both cytokines.
The contractile ability of the heart spheroids, the rate of their beats, and other measures of healthy heart function were affected, but again were partially restored by cytokine inhibitors.
The research also revealed that elevated signaling of inflammatory cytokines may be a class effect of mRNA vaccines. Wu noted that IFN-gamma signaling is a fundamental defense mechanism against foreign DNA and RNA molecules, including viral nucleic acids.
The body needs these cytokines to protect itself from viruses. They are essential for the immune response, but can become toxic in large quantities, he explained. IFN-gamma secreted in large amounts, however noble its purpose, can trigger symptoms similar to myocarditis and degradation of the structural proteins of heart muscle.
That risk likely extends beyond COVID-19 mRNA vaccines. “Other vaccines can cause myocarditis and inflammatory problems, but the symptoms tend to be more diffuse,” Wu said. “Also, the risks of mRNA COVID-19 vaccines have received intense public scrutiny and media coverage. If you experience chest pain after a COVID-19 vaccine, you go to the hospital to get checked out, and if your serum troponin is positive, you’re diagnosed with myocarditis. If you experience muscle aches or joint pain after a flu vaccine, you just ignore it.”
