As adults around the world scramble to get vaccinated against COVID-19, pharmaceutical companies are turning their attention toward one quarter of the population that still has no available shots: kids.

Several pharmaceutical companies are doing clinical trials in adolescents or young children. Pfizer was already testing its vaccine in kids aged 12 to 15, and it just announced results showing that its vaccine works very well at preventing COVID in this age group.* Moderna has been testing its vaccine in those aged 12 to 17. And this month both companies began trials in children aged six months to 11 years. Johnson & Johnson recently described plans to test its vaccine in young children and adolescents, too.

Given that most kids are at low risk for complications from COVID, the need for a pediatric vaccine for the disease may not seem pressing. But scientists say the pandemic may never be fully controlled until kids are inoculated. When we only vaccinate adults, we leave vulnerable “an enormous, immunologically naive population,” says James H. Conway, a pediatrician and associate director for health sciences at the Global Health Institute at the University of Wisconsin School of Medicine and Public Health. Without a pediatric vaccine, “the disease, even if our kids don't get super sick with it, is going to be there and continue to circulate routinely.”

Indeed, recent research suggests infections among kids are more common than public health authorities realized. In a Centers for Disease Control and Prevention paper published earlier this month, researchers tested blood samples routinely collected from people younger than 18 in Mississippi between May and September 2020. Although the state had only received reports of about 9,000 COVID infections in kids through September, analyses of coronavirus antibodies in the blood suggested that roughly 114,000 of them had actually had the pathogen—meaning the virus had infected nearly 13 times more children and adolescents than the state had recorded.

The upshot of such findings is that the U.S. must inoculate kids if it ever wants to reach herd immunity. “If we think about the fact that [people] 18 and under actually make up 25 percent of the population of the United States and probably a bigger proportion of the world population, we really need to make sure that children are part of the population that are immune by vaccine,” says Yvonne Maldonado, a pediatric infectious disease physician at the Stanford University School of Medicine and chair of the American Academy of Pediatrics (AAP) Committee on Infectious Diseases.

And although kids are generally at low risk for COVID complications, some are not so fortunate. More than 13,500 kids in the U.S. have been hospitalized with the disease, and 268 have died, according to AAP data released on March 18. Some of these children may have had asthma, diabetes, heart conditions, obesity, or a genetic, neurological or metabolic condition, all of which place people at increased risk for COVID complications, the CDC says. Race and ethnicity shape risk, too: according to an August 2020 CDC study, the rate of COVID-19 hospitalization is five times higher for Black children and eight times higher among Latino or Hispanic children than it is among white kids. Since last May, around 2,600 U.S. children and adolescents have also developed a rare condition called multisystem inflammatory syndrome in children, or MIS-C, weeks after having had COVID, and 33 of them have died.

It is therefore crucial to have vaccines available for kids to curb the spread of the coronavirus and to protect young people who are high-risk. But “when you’re talking about putting a vaccine in children, everyone wants to make sure that it’s safe,” says Jennifer Nayak, a pediatric infectious disease physician at the University of Rochester Medical Center, who is helping to run one of Moderna’s clinical trials in kids. This means that careful clinical trials are essential, she says. Researchers also have to take special care to minimize the risks to kids who enroll in these trials. Children do not always understand the risks involved in participating in trials, so they cannot provide informed consent, Nayak says.

This is one reason why pharmaceutical companies waited so long to begin testing their vaccines in kids. They wanted to have months’ worth of data showing that the vaccines were safe in adults first, Conway says. They also wanted to see what happened to vaccinated adults who were then exposed to the coronavirus to “make sure that if you’d been vaccinated and then got infected, that you didn’t have a bizarre, enhanced immune response to the disease,” which can be dangerous, he explains. This kind of reaction was, for instance, observed in some children who were vaccinated with a new dengue vaccine in the Philippines in 2016 and 2017 and then exposed to the dengue virus.

Researchers also want to be sure that the COVID vaccines do not elicit a reaction similar to MIS-C. They do not expect that result because the immune responses seen in kids with MIS-C differ from the kinds of immune responses the vaccines elicit in adults. But they still want to be sure. “Are we particularly concerned about this? No, but it’s one of the really very important reasons that the vaccines need to be studied in the pediatric population,” Nayak says. As for whether kids might have more side effects from COVID vaccines than adults do, no one yet knows. “Children may have more reactions, meaning either more fever or sore arms,” Maldonado says, “but they could be very similar.”

To conduct the trials, researchers will first test various doses of the vaccines in small groups of kids of a particular age to determine the dose that provides protection without causing many side effects. “It's Goldilocks, essentially: this one’s too hot, this one’s too cold, this one’s just right,” Conway says. Then they will give the dose they deem best to several thousand kids and track them, along with a similar group of kids who will get a placebo shot, over time to see how likely they are to develop COVID.

The pharmaceutical companies began trials in adolescents first because they are most similar to adults. The firms are slowly turning to younger age groups. Starting with teenagers is good from a public health standpoint, too: they are more likely than younger kids to spread the virus and are also more likely to get seriously ill, Nayak says. Still, the American Academy of Pediatrics maintains that even without vaccines available for young children and teens, it can be safe to reopen schools if safety measures are taken and if community spread is limited. That recommendation was made, in part, because not having in-person school poses mental, emotional and educational risks, and when it comes to overall spread of COVID in communities, kids “don't seem to be a major driver,” Conway says.

Researchers are not sure when vaccines for kids will be widely available because that will depend on the results of the clinical trials and the Food and Drug Administration’s approval process. But Conway says he expects them to be ready for adolescents aged 12 to 16 this summer, for five- to 11-year-olds by early 2022, and for babies and toddlers sometime after that. Maldonado hopes the vaccine for the youngest group will also be available in early 2022.

Conway says he is pleased with how the COVID clinical trials in young people have been designed and organized in that they balance the need for both safety and speed. Children deserve to be kept safe—both in clinical trials and the real world, where they may be exposed to the disease. “We need to advocate for kids,” he says. “They deserve to be protected.”

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*Editor’s Note (3/31/21): This sentence was updated to include results of Pfizer and BioNTech’s trial of their COVID-19 vaccine in adolescents.