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Drivers Found for Rare Myocarditis in Young Males After Second SARS-CoV-2 mRNA Vaccine

Insights could help optimize the delivery of SARS-CoV-2 mRNA vaccines to deter very uncommon instances of vaccine-linked cardiac inflammation.

transmission electron microscope image shows SARS-CoV-2
Transmission electron microscope image of SARS-CoV-2. | NIAID

Over the past three years, the safety of SARS-CoV-2 mRNA vaccines has been thoroughly demonstrated. Yet, like with most medicines, these vaccines can come with uncommon side effects for some people.

Now, a study in Science Immunology identifies two processes behind one such side effect called myopericarditis. The work, involving an analysis of blood samples from 23 young patients, finds that vaccine-related myopericarditis does not come from autoimmune responses or allergic reactions. Rather, the disease likely comes from signaling from inflammatory chemicals, called cytokines, and an expansion of activated white blood cells.

“Our findings really point towards the inflammation-induced heart damage and rule out the development of autoantibody or excessive anti-SARS-CoV-2 antibodies in mediating the disease,” said Akiko Iwasaki, corresponding author of the study, Sterling Professor of Immunobiology and Molecular, Cellular, and Developmental Biology at Yale University, and an investigator of the Howard Hughes Medical Institute.

Myocarditis and pericarditis, or myopericarditis, have been observed very rarely in a subset of adolescent and young adult males following a second dose of a SARS-CoV-2 mRNA vaccine. This new research provides results that support other work that has explored how to best fine-tune vaccine strategies for this subset.

“Our results fit with what others have found in clinical data, thinking about the timing of the vaccine,” said Carrie Lucas, corresponding author of the paper, and associate professor of immunobiology at Yale University. That clinical research, she explained, has indicated that “when you space out the second dose of vaccine, you will reduce that amount of cytokine and bystander immune activation and potentially reduce the risk of myocarditis.”

Beyond mRNA vaccines, myocarditis and pericarditis can also emerge during viral infections, such as COVID-19 itself, where they typically cause much more serious damage.

“[This study is] important not just for basic understanding, but for how we might detect and treat these events earlier in future – not just vaccine – but even viral-induced myocarditis,” said Iwasaki at a press briefing for the study held by AAAS that was also attended by Lucas.

Finding Patients

The development of mRNA vaccines began many decades ago, starting with the discovery of mRNA in the 1960s. Around the 21st century, scientists began to investigate how they could safely inoculate people with modified viral mRNA as an alternate immunization strategy for training the immune system to recognize pathogenic viruses. As the COVID-19 pandemic began, these research efforts paid off, leading to today’s FDA-approved SARS-CoV-2 mRNA vaccines. In the three years since, countless studies on the Moderna and Pfizer/BioNTech vaccines have established their safety.

Due to this safety, it’s been difficult for scientists to find enough patients that experience vaccine-related myopericarditis. Past research that has been able to track this rare phenomenon has noted that patients are primarily male and, on average, span adolescence to young adulthood. From these observations, researchers theorized that age – especially youth – plays a role.

This hypothesis is supported by already existing evidence that children and adolescents have unique immune systems that respond differently to pathogens than adults do.

“They're not just small adults,” said Lucas, echoing a refrain that she noted is common among pediatric specialists.

Sex-based differences, like levels of testosterone production, as well as genetic factors were also suspected to contribute to instances of vaccine-associated heart inflammation in this mostly male subset.

“Testosterone has been tested in myocarditis animal models to worsen myocarditis and cardiac dilation,” said Iwasaki. “Testosterone may be driving some of these sorts of hyperactivation of the innate immune response as well as many other factors.”

By undertaking this new study, Iwasaki and her colleagues in the fields of immunology, pediatrics and cardiology hoped to gather information that could make uncommon instances of vaccine-associated myopericarditis, and myopericarditis at large, even more rare.

Pathways to Disease

To learn more about how myopericarditis may arise after a second SARS-CoV-2 mRNA vaccine, Lucas and the team analyzed blood samples from 23 previously healthy patients, 20 of whom were male, ranging from 13 to 21 years old. Those patients initially presented symptoms including, but not limited to, chest pain, palpitations, muscle pain and headaches. Those symptoms started one to four days after their second dose. Once hospitalized, the patients received treatments including NSAIDs and steroids and began to recover within one to six days.

By examining blood serum from these patients, the researchers saw that these patients’ immune systems showed increased cytokine signaling. This uptick in signaling – marked by inflammatory protein factors like IL-15 and IL-1 – encouraged white blood cells to proliferate. Those factors could one day be used as diagnostic biomarkers for myopericarditis.

“If we could go back in time and look at these patients prior to even coming to the hospital, we may have been able to detect these factors even earlier. And that would give us some sort of biomarkers to detect potential development of myocarditis after vaccinations or even exposure to viruses and such,” said Iwasaki. “It’s possible that we could extrapolate this in the future to [create] an earlier detection method. That's a study that needs to happen.”

The authors also noted an expansion of macrophages that were predisposed to causing fibrosis, a condition that involves tissue scarring. When it happens to heart tissue, it can seriously affect the organ’s health. Despite this surge in all of these immune cell populations, there was no evidence suggesting that vaccine-induced antibodies were to blame.

“It’s more of the innate immune system being revved up in these healthy young males who produce too many of these cytokines that make cytotoxic T-cells overreact and cause tissue inflammation,” said Lucas.

In the coming years, more mRNA vaccines will likely continue to be developed for a variety of pathogens, potentially including a universal vaccine for influenza. This new research could help public health experts improve strategies to administer those future mRNA vaccines across many demographics. It could also inform efforts to better treat myopericarditis caused by other triggers.

“We basically used every immunology tool to be able to examine what is going on. And I think our findings are informative and hopefully will help with the future detection and treatment and therapy of these cases should they arise in the future,” said Iwasaki. “And also hopefully will inform the myocarditis that occurs after a virus infection or other pathogen infection.”


Abigail Eisenstadt

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