How the risk of side effects could change with Covid-19 vaccine boosters

Additional doses of Covid-19 vaccines are likely rolling out in the United States later this year. It raises the question: What will the side effects from a booster shot look like? Is there a higher or lower risk of an adverse event, compared to the earlier regimens?

Overall, the Covid-19 vaccines are overwhelmingly safe and remarkably effective. But as the shots went into millions of arms starting late last year, researchers uncovered a handful of sometimes serious side effects, which were so exceedingly rare that the clinical trials that led to the shots’ authorizations — even with tens of thousands of participants — couldn’t capture them. Researchers don’t fully understand the root causes of some of the side effects, but they’ve also reported that the risk of some of them, including certain heart and blood clotting issues, is much higher after a Covid-19 infection itself than after receiving a Covid-19 vaccine.

STAT asked experts what the landscape of adverse events might look like following another dose, and they stressed that they were speculating. Because the additional doses haven’t gone into many arms yet, the amount of data is limited, so it’s impossible to forecast what will happen. (Whether boosters are necessary from a protection standpoint is another issue. Many experts argue there is not evidence to support adults broadly needing boosters, though certain groups of people, like those with compromised immune systems, do.)

“We’re reading the tea leaves,” said Mark Slifka of Oregon Health and Science University, an expert on immunology, viruses, and vaccines.

Better answers could arrive soon. Israel and some European countries are ahead of the United States in their version of booster plans. A study looking at the early days of Israel’s booster campaign, giving another dose of the Pfizer-BioNTech vaccine to people 60 or older, did not appear to turn up any new safety concerns. And statements from the companies about their small studies of boosters have indicated similar safety features to the earlier doses.

Since most issues tied to vaccination occur shortly after the shots are delivered, “if there was a dramatic increase in risk in terms of the safety profile, we’d start to see that soon,” Slifka said.

Below, STAT outlines some of the side effects tied to the different vaccines and what experts are considering at this point.

The more common, less worrisome issue: feeling sick after a shot

With the two-dose mRNA vaccines from Pfizer and Moderna, the second shot proved to be a real doozy for some who rolled up their sleeves. It wasn’t universal, but lots of people felt fluish, feverish, and achy for a day or two, typically after their second shot.

The culprit was the immune system really ramping up. If the first shot provided the body’s defenses with the scent of a key protein from the SARS-CoV-2 virus, then the immune system was ready to pounce when it saw that spike protein again with shot #2. It was all in the name of building up a lasting and robust blockade in the body, but it did mean some people had quite a hangover after the second dose.

“The immune system goes, ‘I know what this is,’ and attacks it more vigorously,” said Kawsar Talaat, a Johns Hopkins infectious disease physician and vaccine researcher.

Talaat said that it’s possible that, because the immune system is already primed to recognize and target the spike protein, some people could experience something similar after a third dose.

But Slifka offered another hypothesis, one where perhaps the third shot won’t be as bad, or won’t affect as many people. In the United States, second doses were given three to four weeks after the first dose, so the immune system was still in a heightened state from that first shot. Maybe, Slifka said, if people aren’t getting boosters until at least eight months later, their immune systems will have calmed, and the third shot won’t come with quite the kick the second shot did.

Anaphylaxis

Soon after the mRNA vaccines were authorized last year, it became clear that some people were having severe allergic reactions. The discovery led the United States and other countries to advise that people should be monitored for 15 minutes after receiving their shots — 30 minutes for people with a history of severe allergies — and that providers should be equipped to deliver epinephrine, which can treat anaphylaxis.

The initial estimate for the Pfizer shot was up to 11 cases of anaphylaxis per 1 million doses given, but more recent data suggests the rate for both the Pfizer and Moderna immunizations is about 5 per million doses administered. At a Centers for Disease Control and Prevention advisory panel meeting last month, experts noted that most cases occurred in women after the first dose, though they added that perhaps that was at least in part because people who had such a reaction to the first shot didn’t get their second dose — a move the CDC recommends.

Still, subsequent research has shown that people who appeared to have some form of allergic reaction after the first dose were able to safely receive a second dose.

As for people who haven’t had an allergic reaction to the vaccines, they’re probably at low risk for such a response to a third dose, Talaat said. “If you’ve tolerated two doses of a vaccine, you’re far less likely to have an anaphylactic reaction to a third dose.”

Myocarditis and pericarditis

Myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the tissue around the heart) have also been tied to the mRNA vaccines, with higher rates among men under 40 compared to older men and women overall, and the greatest risk in boys age 12 to 17, health authorities have said. Most cases have occurred soon after the second dose.

The vast majority of the cases investigated so far have been mild compared to cases of myocarditis tied to other causes, including viral infections. And a recent study from Israel found that there was a higher risk of myocarditis associated with a Covid-19 infection than with a Covid-19 vaccine.

To some experts, the clustering of cases soon after the second shot suggests that they are a result of the immune response, which, after being primed by the first dose, goes too far and causes the inflammation. One hypothesis for people who develop myocarditis or pericarditis after the first shot is that some had an initial Covid-19 infection, so the first shot was the equivalent of a second exposure, akin to the second dose in people who hadn’t had Covid-19.

David Juurlink, the head of the division of clinical pharmacology at the University of Toronto, has concerns that if it’s the immune response that’s triggering the inflammation, then it might occur at higher rates after the third dose. Beyond that, he also thinks it’s possible that cases could be more severe.

“I do worry that for young men who’ve had two doses and get a third, the risk might be higher,” Juurlink said.

In granting full approval to the Pfizer shot last month, the Food and Drug Administration said the rates of myocarditis and pericarditis in vaccinated boys 16 to 17 years old could be as high as 1 in every 5,000, but that the benefits of the shots still outweighed the risks.

But the possibility of a third dose could reignite the debate around the risk-benefit profile, particularly for boys and young men. If third doses wind up increasing the risk of myocarditis in those groups even higher — and it’s not clear that an extra shot is all that necessary to protect them from Covid-19 — should they broadly receive boosters? Or should it just be older people, who are at lower risk of developing myocarditis after the shots and whose immunity against Covid-19 might be waning in a more worrisome way than young people’s?

Data that could help settle those questions don’t exist yet. But boosters won’t be made available to everyone all at once. They’ll start going to people who had their initial regimens first, including older people and health workers. If researchers detect an increase in myocarditis among them after their third shots, Juurlink said, it could be a signal that health authorities should account for that elevated risk as they consider boosters for younger men.

On the other hand, Slifka raised the possibility that if third shots are given long enough after the second shot, perhaps the immune system will have had a chance to stabilize, and there won’t be any further increase in the risk of myocarditis or pericarditis.

The clotting question

Though U.S. officials are advancing the mRNA vaccines into booster programs first, a Johnson & Johnson booster could also eventually be made available. The J&J shot was authorized as a one-dose regimen, so the booster would be a second shot.

The most concerning adverse event tied to the J&J shot is what’s been named thrombosis with thrombocytopenia syndrome, or vaccine-induced immune thrombocytopenia and thrombosis (VITT), which is characterized by an unusual combination of widespread blood clots and low platelet counts. It appears to be extremely rare, but has also caused serious health crises and some deaths. (The condition, which could be the result of an aberrant immune response, has also been linked to the Oxford-AstraZeneca vaccine, which uses a similar design as the J&J shot. The AZ shot has not been authorized in the United States.)

Experts said they weren’t sure whether the risk of this particular side effect might change with a second shot of the J&J vaccine. The AZ vaccine is given as two doses, so it could shed some light on what might happen with a second dose of the J&J immunization, but analyses of VITT cases have typically detected them after the first dose. The risk appears to be higher for younger adults than older adults, according to a study published last month looking at 170 definite and 50 probable cases of VITT in the United Kingdom that occurred after the first dose of the AZ vaccine. Initially, VITT seemed to occur among women more frequently, though the recent U.K. study did not find a difference based on sex.

One possibility is that a tiny fraction of people have some sort of genetic factor that leaves them vulnerable to a condition like VITT developing. If that is the case, then people who safely got their first J&J dose might not face much risk in getting a second one.

The J&J shot has also been tied in rare cases to Guillain-Barré syndrome, which involves muscle weakness and sometimes temporary paralysis. Experts told STAT they weren’t sure whether or how the risk of that might change with a second dose of the shot.