Researchers think they’ve figured out why the COVID vaccine causes heart inflammation in an extremely small number of teenage boys — and what might be done to avoid it.

The second dose of COVID vaccine appears to promote a severe inflammatory response in these teens, setting off a cascade of events that causes myocarditis (inflammation of the heart muscle), the researchers reported.

Such a reaction probably can be avoided by allowing more time between the first and second doses, noted senior researcher Carrie Lucas, an associate professor of immunobiology at the Yale School of Medicine, in New Haven, Conn.

“Our results fit with what others have found in clinical data thinking about the timing of the vaccine,” Lucas said. “When you space out the second dose of the vaccine, you will reduce that amount of cytokine and bystander immune activation, and potentially reduce the risk of myocarditis.”

The study also rules out two other possible reasons why the second shot might cause myocarditis.

Neither vaccine-induced antibodies nor an allergic reaction to the vaccine seems to be causing the heart inflammation, based on the evidence found in the blood samples studied, said co-researcher Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine.

“This study really sheds light on which of these three hypotheses is likely going on, which is the inflammation-induced myocarditis,” Iwasaki said.

The researchers emphasized that COVID vaccine-associated cases of myocarditis are very rare, with only 54 cases occurring in more than 2.5 million people vaccinated during the first year of vaccine rollout.

Myocarditis occurred in the highest-risk group, boys 12 to 17, in only 36 cases out of every 100,000 second doses of COVID vaccine, the investigators found. The risk is only 3 out of every 100,000 following a first dose in that age group.

Overall, teen boys and young men are at much greater risk from myocarditis caused by COVID-19 infection than from the vaccine, the study authors noted.

The team pointed to a 2022 U.S. Centers for Disease Control and Prevention report, which found that boys aged 12 to 17 had two to six times the risk of heart complications following COVID-19 infection compared to vaccination. Young men aged 18 to 28 had seven to eight times the risk following infection compared with vaccination.

The findings were published May 5 in the journal Science Immunology.

“By not getting vaccinated, you potentially expose yourself to COVID, where the risk of myocarditis is actually higher,” said Dr. William Schaffner, medical director of the National Foundation for Infectious Diseases.

To understand what is happening in these rare instances following vaccination, the Yale researchers analyzed blood samples taken from 23 males between the ages of 13 and 21 who developed myocarditis within one to four days after their second dose.

Their symptoms included chest pain, palpitations, fever, shortness of breath, headaches, muscle pain, sweating, fatigue, nausea and congestion.

“When it does occur, it’s a transient inflammatory response that happens in the heart muscle,” Lucas explained. “Typically, the patients are improving clinically with very simple treatments that reduce inflammation. They bounce back and can go home with improving clinical symptoms within one to six days after they present.”

The researchers found that in these teens and young men, the second dose of vaccine produced a powerful release of cytokines — chemicals that activate immune cells to go on the attack.

The cytokines in particular spur on “bystander” white blood cells called cytotoxic lymphocytes “that have potential to damage tissue,” Lucas said. “They’re elevated and activated.”

“Importantly, these lymphocytes don’t look like they’re responding to one specific antigen, but rather it’s a very broad activation likely driven by cytokine, and this leads to heart inflammation,” Lucas explained.

Scarring of the heart tissue can occur as a result of the repair process the body then induces in response to the inflammatory damage, the researchers added.

This over-response in some young men could be avoided by spacing out the second COVID vaccine dose and allowing the inflammation caused by the first dose to subside, Lucas noted.

Prior studies have suggested that giving eight weeks between doses rather than three or four weeks could reduce the risk of myocarditis, she added.

This also jibes with the fact that subsequent booster vaccine doses haven’t shown a similar risk of myocarditis, Iwasaki said, because enough time has passed between those doses to lower the risk of an inflammatory overreaction.

The researchers added that this sort of immune response is not unique to the messenger RNA vaccines developed for COVID-19.

“There are other vaccines and viruses and other pathogens that can cause similar myocarditis,” Iwasaki said, pointing to prior studies that showed an increased risk of heart inflammation from some live virus and virus-vectored vaccines.

Lucas and Iwasaki couldn’t say why certain young men are at particular risk for this reaction, but they noted that the male hormone testosterone has been shown to worsen myocarditis in animal studies.

“Testosterone may be driving some of this hyperactivation of the innate immune response, as well as many other factors,” Iwasaki said.

The good news is that any cases of myocarditis that do occur from the COVID vaccine can be effectively treated with drugs that reduce inflammation, including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, the researchers said.

It would be a lot tougher to treat myocarditis caused by either vaccine-induced antibodies or an allergic reaction, Iwasaki said.

“We were a little bit relieved that this is the kind of inflammation-induced myocarditis that we’re seeing,” Iwasaki said.

Schaffner agreed that “the main thing they have done is rule out a simple antibody response.”

“It’s a much more subtle immunological phenomenon, which involves the T-cell system and consequent immune phenomena,” Schaffner said.

Information like this will be important as the United States proceeds with development of a national vaccination strategy for COVID, Schaffner added.

“This has been telegraphed by the FDA [U.S. Food and Drug Administration] and the CDC of getting an annual updated COVID booster, similar to what we do with influenza vaccine. We update the vaccine and we get an annual booster both for influenza, and we’re moving in that direction for COVID,” Schaffner said.

More information

The U.S. Centers for Disease Control and Prevention has more about heart complications following COVID infection versus vaccination.

SOURCES: Carrie Lucas, PhD, associate professor, immunobiology, Yale School of Medicine, New Haven, Conn.; Akiko Iwasaki, PhD, professor, immunobiology, Yale School of Medicine; William Schaffner, medical director, National Foundation for Infectious Diseases, Bethesda, Md.; Science Immunology, May 5, 2023

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