In January, Megan Egbert saw a post on her Facebook feed that COVID-19 vaccine manufacturer Moderna was recruiting volunteers for a clinical trial in adolescents. She quickly thought about her two daughters, ages 14 and 12.
Like most teenagers, the girls had been through a tough year of remote learning and missed activities. Egbert, a librarian from Boise, Idaho, hoped that participating in the clinical trial was a way for her daughters to get access to the vaccine, which so far has been authorized for use only in adults. (The Moderna vaccine is cleared for ages 18 and older; the age cutoff for the other vaccine authorized in the U.S., from Pfizer-BioNTech, is 16.)
Her daughters were taller than most adults, so she didn’t think they would be at risk to take the regular-size dose that was being tested. The girls quickly agreed to the idea; a few weeks later, they received their first shot, with a two-in-three chance that it was the real vaccine instead of a placebo.
A local television station interviewed the sisters, who had become “mini celebrities” at school for participating in the trial, says Egbert. The next day, she checked the link to the news report on Facebook and found hundreds of comments. While some hailed the sisters as “brave young ladies,” others questioned their parents’ judgment.
“People were saying we were using our kids as guinea pigs,” says Egbert. “They were saying it’s not for teens until it’s been tested.” But that raises a long-standing quandary of pediatric medicine: How can scientists know the vaccines are safe for children unless they test them on actual children? And if children can benefit from the vaccine and play an important role is establishing herd immunity, why have pharmaceutical companies waited to study them?
Different immune systems
The U.S. Food and Drug Administration requires that new vaccines be independently studied in children. Children’s immune systems are still maturing and are unpredictable, so they might react to the coronavirus differently or have side effects that don’t occur in adults.
“They might respond better or worse,” says James Campbell, professor of pediatrics at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health. “Until you do the study with the vaccine, you don’t know what will happen.”
Despite early perceptions that the pandemic has largely spared U.S. children, the cumulative data reveal a different story. As of February 11, up to 2.3 percent of the more than three million children who have tested positive for COVID-19 were hospitalized, and at least 241 children have died.
While vaccination can protect children from becoming infected with—and spreading—COVID-19, pediatricians also hope that it will prevent a dangerous and rare disorder known as Multisystem Inflammatory Syndrome in Children, which has been documented in coronavirus patients. The disorder can involve inflammation in several vital body parts, including the heart, lungs, and brain.
“I’m seeing these inflammatory conditions constantly in the hospital and am worried,” says Joseph Domachowske, professor of pediatrics at State University of New York Upstate University in Syracuse. “If we can prevent the onset of the infection itself, we can prevent the post-infection consequences.”
Last fall, the influential American Academy of Pediatricians called for children to be included in COVID-19 vaccine trials, and many parents are eagerly waiting to see if vaccinations will be available before the start of the school year.
Several trials of COVID-19 vaccines involving adolescents are already underway. Pfizer-BioNTech is testing its coronavirus vaccine on 2,259 children between 12 and 15. Moderna is enrolling 3,000 participants ages 12 to 17, and Johnson & Johnson has said it will launch a similar trial if its vaccine candidate receives emergency authorization from the FDA.
The initial vaccine data for the adolescent groups could come as early as the summer. Data for younger children could be available the following year. Once that data is in, the companies will conduct additional trials with children as young as six months.
Building on adult results
Despite the urgency, Campbell says the staggered approach is a prudent one for COVID-19 vaccines, because children aren’t in the highest risk group. One recent Icelandic study of 40,000 people found that children under 15 were half as likely to get the coronavirus as adults and half as likely to spread it.
So-called “age de-escalation” is a common strategy in drug development, especially when a disease is more severe in adults, according to Campbell. For example, he’s studying a universal influenza vaccine that was tested in adults first and yielded promising results. Now he’s starting trials with children in three staggered age groups so he can compare the side effects, dosage levels, and immune responses.
One advantage of studying adolescents immediately after adults is that researchers can build on the track record of adult volunteers. During the FDA review process of the Pfizer-BioNTech vaccine in December, the agency looked at data from 21,720 people who’d taken the vaccine as part of the phase three study. That data clearly showed that the vaccine is 94-percent effective at preventing COVID-19.
“We don’t need more efficacy data,” says Robert Frenck, director of the Vaccine Research Center at Cincinnati Children’s Hospital, who’s also the principal investigator for the Pfizer-BioNTech vaccine trial there. “We know it’s 94 percent. We think the immune response will translate.”
That’s why investigators are studying a far smaller number of adolescents to evaluate vaccine safety and validate the adult results. The concept is known as an immunological bridge: Since they know the vaccine’s efficacy from adult trials, they simply need to evaluate whether adolescents who received the vaccine also successfully produce antibodies to ward off future COVID-19 infections.
It also makes sense to target adolescents first, since they’re more likely to get infected than their younger peers. In one review of pediatric COVID-19 cases, children ages 12 to 17 made up 63 percent of cases, while children five to 11 accounted for just 37 percent.
Because children’s immune systems develop over time, evaluating COVID-19 vaccines in younger children will require a new strategy altogether to see if they need a different formulation or dosage, says Domachowske, who’s supervising pediatric trials for Pfizer-BioNTech at SUNY Upstate University.
“Children are most certainly not just small adults,” he says. Although children reach adult-like levels of immunity by age six, that pace differs from child to child based on genetics and environment.
In the Pfizer-BioNTech trial of children ages five to 11, which could begin as early as March, those participants will start off with a lower dose than the amount currently given to adults and adolescents. “It’s just to see side effects and demonstrate that they have a protective immune response,” Domachowske says. “Then, if needed, we try the next higher dose to see if that’s acceptable and to determine if the vaccine has a safety and efficacy profile that’s similar to adults.”
Next phases will include children as young as two years, and then for babies down to six months. Depending on the results, the vaccine makers could end up producing a different dose for younger children.
Domachowske said pediatricians often gave half the amount of a typical flu vaccine shot to children from six months to three years out of an abundance of caution, but recently started giving the full dosage after new data showed the full amount was tolerated just as well and even produced an equal—or better—antibody response.
This careful approach to pediatric research is a welcome contrast to the period from the 1900s until the 1970s, when some children were subjected to abuse in the name of medical progress, says Douglas Diekema, director of education for the Treuman Katz Center for Pediatric Bioethics at Seattle Children’s Hospital.
“Few people know about the kids in institutions that were involved in egregious research,” he says.
Take these shocking examples: In 1949, dozens of boys at the now-closed Fernald State School in Massachusetts were fed oatmeal laced with radioactive tracers as part of an experiment to see how nutrients traveled throughout the body. Another 14-year study started in 1956 at Willowbrook State School, a home for children with cognitive disabilities in Staten Island, New York. There, healthy children were purposely fed live hepatitis virus from stool samples of sick children to see if they would become ill.
Following widespread reforms in the 1970s, all research with human subjects must go through a hospital’s institutional review board. Children are also now specifically protected under legislation created in 1983, adds Liza-Marie Johnson, chair of the Hospital Ethics Committee at St. Jude Children's Research Hospital in Memphis, Tennessee.
“Some people have wondered why kids weren’t enrolled in COVID-19 trials earlier, but the purpose of these regulations is to protect kids from unnecessary risk,” says Johnson. For instance, children were enrolled only when there was enough data about the vaccines’ safety in adults. “Research is opened to minors when a trial is low risk and offers potential for benefit.”
However, researchers routinely struggle with convincing parents to enroll their children in pediatric trials. Not surprisingly, successful recruitment is directly related to how sick a child is. “Parents are extremely motivated to participate if their child has a rare disease,” says Erica Denhoff, education program manager of Institutional Centers for Clinical and Translational Research at Boston Children’s Hospital. “Oftentimes this drug might be their only hope whether their child survives or has a chance of having a normal life.”
Getting kids into trials becomes much more challenging if they’re not in immediate danger, and participation requires frequent appointments or monitoring. Parents are more likely to opt out if a study has rigid hours, or they’re juggling child-care or transportation issues, she says.
Even joining COVID-19 vaccine trials requires a significant commitment. Egbert says that for the Moderna study, her daughters had to agree to keep symptom diaries for a week following both injections, attend regular telemedicine visits, and submit to four coronavirus tests and four blood draws over 13 months. “I tell them this is like a job,” she says, adding that they will each be compensated $1600 by Moderna, paid in increments, as long as they stay in the trial.
A sense of purpose
The most effective way to enroll and retain study participants is to help them form an emotional connection to the trial’s purpose, says Tricia Barrett, senior vice president and managing director at Praxis Communications, a clinical trial recruitment firm.
“There’s a big sense of altruism. Parents think, I’m not only helping my child, but others as well,” she says. “For the kids, we help make them feel like part of something cool.”
Bob McDonnell is one of the nearly two million legendary “polio pioneers,” whose participation in the Salk trials helped stop the spread of the paralyzing disease. At age nine, he didn’t have much say in participating. But as a 76-year-old retiree in Loveland, Colorado, he’s grown more grateful of his role over time. “Now I’m glad I was part of something for the good of mankind,” he says.
Charles and Lara Mashek of Oklahoma City also considered the practical and magnanimous implications when they signed up their daughters, ages 14 and 12, in the Moderna trial at the Lynn Health Science Institute. Both physicians, they’d already been immunized against COVID-19 and were eager for their kids to have a chance at getting the shot. “We believe strongly in vaccines, and we see the value of testing and trials,” says Charles Mashek.
Fourteen-year-old Elizabeth Mashek agreed. “I’m proud to be in it,” she says. “I think it’s pretty cool.”