June 14, 2021 -- Testing COVID-19 vaccines in young children is going to be tricky. Deciding how to approve them and who should get them may be even more difficult.

So far, the vaccines available to Americans ages 12 and up have sailed through the FDA’s regulatory checks, taking advantage of an accelerated clearance process called an Emergency Use Authorization (EUA).

EUAs set a lower bar for effectiveness, saying the vaccines may be safe and effective based on just a few months of data.

But with COVID cases plummeting in the United States and children historically seeing far less serious cases than adults, a panel of expert advisors to the FDA was asked to discuss whether the agency could consider vaccines for this age group under the same standard.

Said another way: Is COVID an emergency for kids?

There's another wrinkle in the mix, too — heart inflammation, which appears to be a very rare side effect tied to vaccination. It seems to happen more often in teens and young adults. To date, cases of myocarditis and pericarditis appear to be happening in 16 to 30 people for every 1 million doses given.

But if it is conclusively linked to the shots, some wonder whether it might tip the balance between benefits and risks for kids.

That left some of the experts who sit on the FDA's advisory committee for vaccines and related biological products urging the FDA to take its time and more thoroughly study the shots before they're given to millions of children.

Vaccine Studies Different in Children?

Clinical studies of the vaccines in teens and adults have relied on some straightforward math. Researchers take two groups of similar people, giving half of them the vaccine and the other half a placebo, then wait to see which group has more symptomatic infections. To date, the vaccines have dramatically cut the risk of getting severely ill with COVID for every age group tested.

But COVID infections are falling rapidly in the US, and that may make it more difficult for researchers to conduct a similar kind of experiment in children.

The FDA is considering different approaches to decide whether a vaccine would be effective in kids, including something called an "immunobridging trial."

In bridging trials, researchers don't look for infections; rather, they look for proven signs that someone has developed immunity, like antibody levels. Those biomarkers are then compared to the immune responses of younger adults who have demonstrated good protection against infection.

The main advantage of bridging studies is speed. It's possible to get a snapshot of how the immune system responds to a vaccine within weeks of the final dose. The drawback? Researchers don't know exactly what to look for to judge how well the shots are generating protection.

That's made even more difficult because kids' immune systems are still developing, so it may be tough to make direct parallels to adults.

"I have so much sympathy for the FDA because these are enormous problems and you have to make a decision," says said H. Cody Meissner, MD, chief of the division of pediatric infectious disease at Tufts Medical Center in Boston and a member of the FDA's vaccines and related biological products advisory committee.

Speed Vaccines to Market, or Gather More Data?

The plummeting rate of infections in the U.S. also means that it may be more difficult for the FDA to justify allowing a vaccine on the market for emergency use for children under age 12.

In its recent advisory committee meeting, the agency asked the panel whether it should consider COVID vaccines for children under an EUA or a biologics license application (BLA), aka full approval.

A BLA typically means the agency considers a year or 2 of data on a new product, rather than just 2 months' worth. Emergency use also allows products on the market under a looser standard — they "may be" safe and effective, instead of has been proven to be safe and effective.

Several committee members said they didn't feel the U.S. was still in an emergency with COVID, and couldn't see the FDA allowing a vaccine to be used in kids that wasn't given the agency's highest level of scrutiny, particularly with reports of adverse events like myocarditis coming to light.

"I just want to be sure the price we pay for vaccinating millions of children justifies the side effects, and I don't think we know that yet," Meissner says.

Others acknowledged that there is little risk to kids now with infections on the decline. But that picture could change as variants spread, schools reopen, and colder temperatures force people indoors.

The FDA must decide whether to act based on where we are now or where we could be in a few months.

"I think it's the million-dollar question right now," says Hannah Kirking, MD, a medical epidemiologist with the CDC who presented new and unpublished data on COVID's impact on children to the FDA's advisory committee.

Prospective studies tracking the way COVID moves through a household with weekly testing from New York City and Utah have found that children catch and transmit COVID almost as readily as adults, she says But they don't usually get as sick as adults do, so their cases are easy to miss.

Kirking also presented the results of blood tests from samples around the country looking for evidence of past infection. In these studies, about 27% of children under the age of 17 had antibodies to COVID — the most of any age group. So more than 1 in 4 kids already has some natural immunity.

That means the main benefit of vaccinating children might be the protection of others, while they still bear the risks — however tiny.

Some experts felt that wasn't enough reason to justify mass distribution of the vaccines to kids, and from a regulatory standpoint, might not be permissible.

"FDA can only approve a medical product in a population if the benefits outweigh the risks in that population," says Peter Doshi, PhD, assistant professor of pharmaceutical health services research in the University of Maryland's School of Pharmacy.

"If benefits don't outweigh risks in children, it can't be indicated for children. Full stop," adds Doshi, who is also an editor at the BMJ.

There’s another way to give children access to vaccines, he says: through an expanded access or compassionate use program. Since most pediatric COVID deaths have been in children with underlying health conditions, Doshi and others say it might make sense to allow expanded access — which would get vaccines to children at high risk for complications — lbefore turning them loose on millions before they are more thoroughly studied.

"It's not a particularly attractive option for industry, because there's no money to be made. Your medicine can't be commercialized under expanded access. The most you can reap is manufacturing cost, which is not a lot," he says.

Art Caplan, a professor of bioethics at New York University's Langone Medical Center, in New York City, said the argument for vaccinating children for flu falls along the same lines. The benefit-to-risk ratio is finely balanced in children. The main value of protecting them is to protect others.

"Flu rarely kills young folks. But you're really trying to protect old folks and that's the classic example," he says.

What's more, the idea that children would take on some risk with a vaccine for little personal benefit is oversimplified, he says

"Yes, you might get vaccinated to prevent harm to others, but those others are providing benefits to you. It's not a one-way street. I think that's a little morally distorted," Caplan says.. "Being able to keep society open benefits kids and adults alike."

Other committee members felt like it was too early to sound the all-clear on COVID, and said the FDA should authorize vaccines for children as quickly as it had for other age groups.

"We are still, I believe, in an emergency situation. I think that when this virus goes into our children, which is what it's going to do, that will give it an incubator to change," says Oveta Fuller, PhD, associate professor of microbiology and immunology at the University of Michigan Medical School.

For the good of the world, Fuller says, Americans needs to vaccinate children to prevent the virus from mutating and creating new and potentially more dangerous variants.

Weighing Risk Over Safety

Beth Thielen, MD, pediatric infectious disease specialist and virologist at the University of Minnesota Medical School, says she did not follow the committee's discussions, but about once a month she treats kids who are very sick because of the virus — either because of a COVID infection or because of multisystem inflammatory syndrome (MIS-C), an inflammatory reaction that strikes after infection.

She worries about how the virus has already changed, noting that the kind of disease she's seeing in kids now is different than what she saw in the early months of the pandemic.

"In the last couple of months, I've actually seen a few cases of severe pulmonary disease, more similar to adult disease in children," Thielen says. "I see on the horizon that we could start seeing more significant disease in young people, and then the risks of being unvaccinated go up substantially."

But she also knows nobody has a crystal ball, and right now, everything seems to be trending in the right direction with COVID. That makes the risk-to-benefit consideration murkier.

"The question in my mind is, what is the risk of side effects from the vaccine?" she says. . "I think we really need to know what the safety profile of vaccine looks like in children because we do have a decent understanding now what risk from disease looks like, because it's small, but we are seeing it."

For now, Thielen says she'll be keeping an eye on the next meeting of the CDC's Advisory Committee on Immunization Practices for more answers.