Florida Surgeon General Joseph Ladapo ignited a furor this month when, based on a state analysis purporting to show COVID-19 vaccines were linked to cardiac deaths in young men, he advised men ages 18 to 39 to steer clear of the shots. Scientists slammed his warning and decried the eight-page analysis, which was anonymous and not peer reviewed, for its lack of transparency and flawed statistics.

Still, COVID-19 vaccines do have a rare but worrisome cardiac side effect. Myocarditis, an inflammation of the heart muscle that can cause chest pain and shortness of breath, has disproportionately struck older boys and young men who received the shots. Only one out of several thousand in those age groups is affected, and most quickly feel better. A tiny number of deaths have been tentatively linked to vaccine myocarditis around the world. But several new studies suggest the heart muscle can take months to heal, and some scientists worry about what this means for patients long term. The U.S. Food and Drug Administration (FDA) has ordered vaccinemakers Pfizer and Moderna to conduct a raft of studies to assess these risks.

As they parse emerging data and fret over knowledge gaps, scientists and doctors are divided over whether such concerns should influence vaccine recommendations, especially now that a new COVID-19 wave is looming and revamped boosters are hitting the scene. Nearly all urge vaccinating young people with the first two vaccine doses, but the case for boosters is more complicated. A key problem is that their benefits are unknown for the age group at highest risk of myocarditis, who are at lower risk of severe COVID-19 and other complications than older adults.

“I’m a vaccine advocate, I would still vaccinate children,” says Jane Newburger, a pediatric cardiologist at Boston Children’s Hospital who has cared for and studied postvaccine myocarditis patients. But Michael Portman, a pediatric cardiologist at Seattle Children’s Hospital who’s also studying patients, says he would hesitate to recommend boosters to healthy teens. “I don’t want to cause panic,” Portman says—but he craves more clarity on the risk-benefit ratio.

Earlier this month, a team from Kaiser Permanente Northern California and the U.S. Centers for Disease Control and Prevention (CDC) reported the risk of myocarditis or pericarditis—inflammation of the tissue surrounding the heart—was about one in 6700 in 12- to 15-year-old boys following the second vaccine dose, and about one in 16,000 following the first booster. In 16- and 17-year-olds, it was about one in 8000 after the second dose and one in 6000 after the first booster. Men ages 18 to 30 have a somewhat elevated risk as well.

Many scientists suspect vaccine-driven myocarditis is somehow triggered by an immune reaction following the COVID-19 shot. A study from Germany published last month in The New England Journal of Medicine suggested it may be driven by an inflammatory response associated with SARS-CoV-2’s spike protein, which the messenger RNA (mRNA) vaccines coax the body to produce. The group reported finding certain antibodies in both vaccine-induced myocarditis patients and patients with severe COVID-19, which itself can cause myocarditis. The same antibodies, which interfere with normal inflammation control, also turned up in children who developed a rare, dangerous condition called multisystem inflammatory syndrome (MIS-C) after a bout of COVID-19. “I think it’s really another mechanism,” says Karin Klingel, a cardiac pathologist at the University of Tübingen who helped lead the work. But whether the antibodies are directly causing myocarditis remains unclear.

Most postvaccine myocarditis patients are briefly hospitalized and their symptoms quickly abate. Newburger’s hospital has tracked 22 patients who developed the condition, and she is largely reassured by their healing. Portman agrees: “Many of these kids are asymptomatic after they leave the hospital.”

But what he sees in the youngsters during follow-up appointments nags at him: Although their heart rhythm is normal and they usually feel fine, MRI scans of their heart often show something called late gadolinium enhancement (LGE), which signifies injury to the muscle. In June, Portman and his colleagues reported in The Journal of Pediatrics that 11 of 16 patients had LGE about 4 months after their bout of myocarditis, although the area affected in the heart had shrunk since they were hospitalized. This month, a CDC team reported that among 151 patients who had follow-up cardiac MRIs after 3 months, 54% had abnormalities, mostly LGE or inflammation.

How much to worry about lingering scarring in vaccinated patients is a question mark. Right now, this “doesn’t seem to correlate to adverse clinical outcomes,” says Peter Liu, chief scientific officer of the University of Ottawa Heart Institute. Nonetheless, “We’re tracking these” patients over time, Liu says, in a registry study of about 200 affected people across Canada so far. “We need longer term data to reassure us and the public,” agrees Hunter Wilson, a pediatric cardiologist at Children’s Healthcare of Atlanta who supports boosters for young people. (He recently led a study comparing outcomes from myocarditis induced by vaccines, by “classic” myocarditis not caused by COVID-19, and by MIS-C, which is available as a preprint and under journal review.)

FDA is requiring six myocarditis studies each from Pfizer and Moderna, the makers of the two mRNA vaccines. Newburger, who’s also keen for longer term data, co-leads one of them in conjunction with the Pediatric Heart Network; the study, which Portman is involved in as well, aims to start recruiting up to 500 patients later this fall. The various studies will assess not only full-blown myocarditis, but also a shadow version called subclinical myocarditis, in which individuals remain symptom-free.

Subclinical myocarditis may be more common than thought. Christian Müller, director of the Cardiovascular Research Institute at University Hospital Basel, recently collected blood samples from almost 800 hospital workers 3 days after they got a COVID-19 booster. None met the criteria for myocarditis but 40 had high levels of troponin, a molecule that can indicate damage to the heart muscle. Chronic heart problems and other preexisting conditions might be to blame in 18 cases, but for the other 22 cases—2.8% of participants, women and men—Müller believes the vaccine caused troponin levels to rise. The findings, which he presented at a meeting in August, align with those of a recently published study from Thailand.

The good news: In both studies, troponin levels quickly fell to normal. And a brief troponin spike without symptoms doesn’t concern Müller: “If we’re healthy and we lose 1000, 2000 [heart muscle cells], that is irrelevant,” he says. What worries him is a potential cumulative effect of annual boosters. “I’m highly concerned if we consider this a recurrent phenomenon.”

The big question is whether any risk, however minimal, to the heart is outweighed by the benefits of a booster. Young people are rarely hospitalized for COVID-19, but the virus is not risk-free for them either. Last year, a study of nearly 1600 college athletes prior to vaccination found 2.3% had either clinical or subclinical myocarditis after a bout of COVID-19. Other lasting effects of infection include MIS-C and Long Covid. Studies in adults suggest vaccination reduces the risk of Long Covid by anywhere from 15% to 80%. “Because of that, I really think vaccination is worth it,” Liu says.

Müller does not: He’s glad his teenage daughters received their initial vaccine series but has no plans get them a booster. Paul Offit, an infectious disease specialist at the Children’s Hospital of Philadelphia, thinks that if the goal is to stave off severe illness, there’s little evidence healthy people under age 65 need a booster dose—and certainly not adolescents.

Countries are divided as well: In Switzerland, Germany, and Denmark, the new bivalent boosters are recommended mainly for older adults and vulnerable younger ones. In the United States, in contrast, CDC now recommends that everyone age 5 and up, regardless of health history, get boosted.

Complicating the risk-benefit analysis are the pandemic’s ever-changing currents. Omicron, now the dominant variant, “seems a whole lot milder” than its predecessors, Newburger says. CDC reports that as of August, at least 86% of children in the United States have been infected by SARS-CoV-2, which may reduce their risk of future infections. At the same time, “We’re seeing so much less vaccine myocarditis now” than last year, Newburger says. She doesn’t know why, but the trend might alleviate concerns about the side effect. “Everything is a moving target.”

The uncertainty is frustrating—but that’s the story of the pandemic, says Walid Gellad, a physician who studies drug safety at the University of Pittsburgh: “Everything that we need to know we end up learning after we needed to know it.”

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