Why it’s so tricky to get vaccines right for the littlest kids

Pre-K students at the Immanuel United Church of Christ in Shillington, Pennsylvania, line up to go outside on January 18, 2021. | Ben Hasty/MediaNews Group/Reading Eagle via Getty Images

The FDA could authorize Pfizer/BioNTech shots for children under 5 this month.

Children under 5 years old, who make up one of the largest unvaccinated groups in the US, could soon become eligible to receive Covid-19 shots. The US Food and Drug Administration will consider whether to authorize two small doses of Pfizer/BioNTech vaccines for these children on an emergency basis, the companies announced this week.

Approval could come as soon as this month. But Pfizer and the FDA have a tricky needle to thread, moving quickly while trying to maintain public trust in the process.

Vaccines for young children would help constrain the spread of the virus, relieve stress on hospitals, and help schools stay open. They would also provide peace of mind to parents, caregivers, and teachers whose lives have been repeatedly disrupted as the highly transmissible omicron variant continues to rage. More than 20 million children in the United States fall into this age group, so an emergency-use authorization (EUA) would close one of the biggest remaining gaps in vaccine eligibility.

But Pfizer’s own data showed that its vaccine generated less robust protection in some very young children with the first two doses. The company is still studying the impact of a third shot administered at least eight weeks later. Filing for approval at this stage is unusual, but company officials say they aim to give parents the option of starting to vaccinate kids sooner. That way they’re ready to receive a third dose by the time it’s greenlit.

“Ultimately, we believe that three doses of the vaccine will be needed for children 6 months through 4 years of age to achieve high levels of protection against current and potential future variants,” said Albert Bourla, chairman and CEO of Pfizer, in a press release. “If two doses are authorized, parents will have the opportunity to begin a COVID-19 vaccination series for their children while awaiting potential authorization of a third dose.”

It’s a different process than what’s been used for vaccines in other age groups. Some doctors are concerned that if public health officials fumble the approval process and messaging, it could create more confusion and hesitancy around vaccines.

Health officials are already trying to reassure the public that regulators will not relax their standards. “This is the same rigorous process that was used to assess numerous vaccines long before the pandemic began,” said US Surgeon General Vivek Murthy at a press conference this week.

The Pfizer/BioNTech announcement comes at a time when new Covid-19 infections driven by the omicron variant are declining across the United States, but children are forming a larger share of infections and hospitalizations. Since the beginning of the pandemic, 10.6 million US children have tested positive for the virus. Children under 4 have accounted for 1.6 million of those cases, leading to 287 deaths in that age group as of January 29.

However, parents have shown so far that they are not as motivated to vaccinate kids — only about one-third of parents say they’ve started vaccinating their 5- to 11-year-olds, according to one poll — and physicians worry that Pfizer and BioNTech’s unusual vaccine approval application could deter them further. While closing gaps in eligibility is a key step toward more widespread immunity, this round of shots can only help bring the pandemic under control if people take them.

Why the Pfizer/BioNTech’s latest application to the FDA is different

The FDA approval process usually aims to ensure that vaccines perform similarly across all ages. Since some very young children showed a weaker immune response than adults after two doses of their Covid-19 vaccine, Pfizer and BioNTech added a third dose to their study and expected to file for approval pending those results.

But the towering winter peak of Covid-19 cases may have spurred regulators themselves to get the ball rolling sooner, with the expectation that data would soon show that three Pfizer/BioNTech doses provide immune protection in kids that matches that in adults.

“Frankly, everybody in my field was a little surprised,” said Kristin Moffitt, an infectious disease physician at Boston Children’s Hospital. “It sounds like the FDA did outreach to Pfizer, likely driven by how much omicron transmission we’re seeing and the unbelievable impacts on all age groups.”

Xinhua News Agency via Getty Images

Kindergarten children play in a classroom at Montara Avenue Elementary School in Los Angeles on August 16, 2021.

In clinical trials of more than 8,000 children between 6 months old and 12 years old, researchers saw that different age groups had varying immune responses, suggesting that not all were equally protected against the coronavirus. Children between 6 months and 2 years old showed stronger responses, Pfizer noted in December, comparable to the levels seen in 16- to 25-year-olds. But the response was weaker in 2-, 3-, and 4-year-olds.

Why the youngest children had a stronger immune response than older kids is a mystery. “I don’t know how that happens, but it happens,” said Janet Englund, a professor of pediatric infectious diseases at Seattle Children’s Hospital, who is helping administer the Pfizer study. “If you would’ve asked me would I have predicted that, I would have said ‘no.’”

Researchers are now investigating whether a third dose in young children would bolster the immune response. The results may be ready in March, at which point regulators will begin the review process again.

Why did it take so long to get here? One reason is the nature of Covid-19 itself, a disease that exacted its dearest toll from older adults while children faced a much lower rate of hospitalization and death. That made vaccine approval for adults a higher priority than for younger children.

Moving down in age groups also takes time. There’s an adage in medical research that children are not little adults. Their bodies respond in different ways to drugs, and researchers can’t just assume the same protocol will work as well or be just as safe across all ages. So clinical trials are conducted in stages by age groups, doses are tweaked, and the youngest children are almost always the last to be tested.

“Vaccine doses have historically been age-dependent,” Moffitt said. “It really has to do with the maturity of the immune system.”

For the Pfizer/BioNTech vaccine, the adult dose is 30 micrograms, children between 5 and 11 receive 10 micrograms, and children under 5 receive 3 micrograms.

Conducting research in younger age groups has additional complications. Children are much more finicky test subjects than adults. “As a pediatrician, I can tell you it’s incredibly difficult,” Englund said. Not only do children have to receive their shots spaced weeks apart, but in a clinical trial, they also have to show up for blood tests and follow-up exams. Attrition rates in clinical trials of kids can be high.

It gets even trickier to study children under 5 years old and keep track of their complications or concerns. “Five- to 11-year-olds can talk and complain,“ Englund said. “Doing this in kids less than 5 is more work.” So it’s that much harder to collect the amount and quality of data needed to satisfy the FDA.

Children are at lower risk, but they’re getting infected in large numbers

Thankfully, children have generally faced much lower rates of severe illness and death from Covid-19 compared to adults. But the rates are not zero, and with the spread of the highly transmissible omicron variant, more children are being hospitalized.

According to the American Academy of Pediatrics, children accounted for almost 23 percent of new Covid-19 cases by the end of January. More than 17 percent of all Covid-19 cases in children under 18 occurred in the last two weeks of January. Across the US, children made up between 1.6 percent and 4.4 percent of hospitalizations.

“The sheer number of cases of omicron has been associated with more pediatric hospitalizations than we have seen at any other time during this pandemic,” Moffitt said. “We were absolutely feeling this, and families were feeling this. A lot of these were otherwise healthy kids.”

Even if children don’t get severely ill, pediatric Covid-19 cases have ripple effects: They can shut down schools, disrupt learning, and require parents to take time off work to care for sick children. Infected kids can also transmit the disease.

Still, caregivers of children don’t seem to be racing to vaccinate kids. In November 2021, an emergency use authorization made 28 million children between the ages of 5 and 11 eligible to receive the Pfizer/BioNTech Covid-19 vaccine. But the uptake has been slow.

“In my community, we’ve been a little disappointed with the uptake,” Englund said. “In our 5- to 12-year-olds, we’re barely at 50 percent, despite the fact the vaccine is widely available at schools and vaccine clinics.”

The Kaiser Family Foundation reports that as of February 1, about 33 percent of US parents of 5- to 11-year-olds say their kids have received at least one dose of a Covid-19 vaccine. Only 30 percent of parents of kids under age 5 say they will vaccinate their kids as soon as possible.

Kaiser Family Foundation

Parents appear more hesitant to vaccinate children under 5 years old against Covid-19.

Moffit said she’s encountered parents of very young children who are eager to have their kids vaccinated, and others who are hesitant and want to wait a while. Some want to wait for the vaccine to “graduate” from an EUA to full FDA approval, which could take months.

If the FDA approves two pediatric doses of the Pfizer/BioNTech vaccine, with the expectation that young children won’t get full protection until a third dose is approved down the road, health officials will have to be proactive about explaining this clearly to the public. Otherwise, the process could sow confusion and fuel hesitancy.

“I do worry if that approach ends up being taken, it may make it an even harder sell for vaccine uptake,” she said. “I think the FDA is going to have a tough call here.”

Researchers are also studying the Pfizer/BioNTech Covid-19 vaccine in babies as young as 2 months old. “We do see kids under 6 months hospitalized at our hospital,” Englund said. Scientists are also studying immunity in vaccinated pregnant people and their babies, to see how much immunity carries over to newborns. Whether babies under 6 months old will need Covid-19 shots will also depend on what variants are in circulation and the rate of transmission of the virus.

The FDA’s upcoming decision won’t be the last word on Covid-19 shots for young children. In time, doctors are hoping to see more Covid-19 vaccines authorized for use in children. “I think we need to have multiple vaccines available. ... I’d like to have three or four,” Englund said. “Maybe another vaccine might work better, or have less side effects, or be cheaper, or be more available in some places.”