As older adults, health care workers, firefighters, and others roll up their sleeves for a COVID-19 vaccine, there’s a flurry of research to get shots to children, for whom no vaccine has yet been authorized. Even though young people are less likely to fall seriously ill, doctors and scientists agree that vaccinating them is crucial for their own protection and that of the broader population. And because companies already have solid data from adult trials, they are running smaller studies in children that focus on safety and immune responses to COVID-19 vaccines.
The first two vaccines to receive emergency use authorization in the United States for adults are now in clinical trials for young people, with initial results expected by summer. Pfizer and BioNTech have completed enrollment of more than 2200 volunteers ages 12 to 15, and Moderna is wrapping up recruitment of a planned 3000 volunteers with the same minimum age. Both vaccines are based on messenger RNA coding for the coronavirus spike protein, which prompts production of protective antibodies. Another three vaccines, which use a harmless virus to deliver a gene for the same protein, are also taking steps toward pediatric authorization. On 12 February, AstraZeneca and the University of Oxford announced they would begin to test their vaccine in 300 U.K. children ages 6 to 17. Johnson & Johnson, whose adult vaccine will be considered by U.S. regulators this week, says it’s moving toward testing in young people, and Sinovac Biotech is testing its product on children in China ages 3 to 17.
Adult deaths from COVID-19 dwarf those in children: In the United States, for example, young people make up about 250 of 500,000 total deaths. But for children, COVID-19 is still “causing more deaths than influenza does in a typical season,” says Douglas Diekema, a pediatrician and bioethicist at Seattle Children’s Hospital. “Those are unnecessary deaths and should be prevented.” In addition, more than 2000 children and teenagers have developed a severe inflammatory syndrome that can cause critical illness and damage organs. And some children report lingering symptoms such as intense fatigue, similar to the emerging “long COVID” in adults.
The hazards have convinced many doctors that children need access to vaccines before they can return to their pre-2020 routines. “I don’t think anybody wants to keep kids wearing masks for the rest of their childhood,” says Evan Anderson, a pediatric infectious disease specialist at Children’s Healthcare of Atlanta who helped lead adult clinical trials of Moderna’s vaccine and has pressed for prioritizing pediatric studies. Furthermore, because children can transmit the virus to adults—for whom vaccination isn’t 100% effective—protecting kids will be key to driving down infection rates.
For children and another special population, pregnant women, clinical trials are trending much smaller than the tens of thousands of participants in the adult trials that garnered initial authorization. Although these latest studies will, like their larger counterparts, track symptoms and count COVID-19 cases, they will primarily rely on immune markers as a proxy for vaccine effectiveness. One widely used marker is “neutralizing” antibodies to the virus as measured in the blood. Neutralizing antibodies stop viruses from entering cells and replicating. In Pfizer’s and Moderna’s adolescent trials, antibodies will be measured 1 month after the second dose of vaccine. The goal is to see whether in a younger crowd the vaccine spurs antibody levels that match those in adults, explains Robert Frenck, who directs the Gamble Vaccine Research Center at Cincinnati Children’s Hospital and is helping lead Pfizer’s adolescent trial.
One sticking point is that scientists are unsure how high a level of neutralizing antibodies to look for. “We don’t know the protective titer” of antibodies that someone needs to be shielded from illness, says John Moore, a vaccine researcher at Cornell University who isn’t involved in running vaccine trials. Still, he continues, “We have a pretty good feel.” If children produce somewhat fewer antibodies relative to adults that’s unlikely to be concerning, he says. But if “responses were down 50-fold, you’d be getting worried” that the vaccine wasn’t protecting them. (In the adult trials, elderly people developed about half as many neutralizing antibodies as younger adults but were well-protected from illness.) The U.S. Food and Drug Administration (FDA) would not comment about study designs, but in guidance to industry, it has indicated it’s open to considering a COVID-19 vaccine’s use based on immune responses that are “reasonably likely to predict clinical benefit.”
There’s precedent for focusing on these kinds of surrogate markers. Rabies vaccine studies, for example, relied on “indirect markers of protection,” says Grace Lee, a pediatric infectious disease specialist at Stanford Children’s Health who also sits on the Advisory Committee on Immunization Practices (ACIP), which develops recommendations for U.S. vaccine use. “You can’t wait for people to get rabies” in a clinical trial. To craft vaccines against human papillomavirus, researchers initially examined their ability to prevent symptoms of infection and then used immunologic markers as trials shifted into younger age groups.
Like other physicians eager for results of trials on children 12 and up, Lee thinks it’s unlikely that efficacy of COVID-19 vaccines will falter markedly in adolescents, whose immune responses are similar to those of adults. “The main thing I’m looking for is safety,” she says. With some 200 million people vaccinated worldwide so far, the vaccines appear very safe in adults. Still, because the risk of harm from COVID-19 to children is much lower than to adults, physicians and parents want assurances of safety and evidence that neutralizing antibodies and other markers of immunity persist, a sign that the protection will be durable.
In kids and adolescents, Pfizer, Moderna, and AstraZeneca are testing the same dose adults receive. As more trials of younger children open, however, companies may experiment with different doses. With drugs, “You want to have a certain level in the bloodstream,” says Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia who sits on a vaccine advisory committee for FDA. “So weight matters.” But for vaccines, which aim to trigger an immune response, the dose varies less—or not at all. The same dose of flu vaccine, for example, is generally given to 6-month-olds and 60-year-olds, and young children actually get a higher dose of diphtheria and pertussis vaccines than adults. At a January ACIP meeting, Emily Erbelding, an infectious diseases specialist at the National Institute of Allergy and Infectious Diseases, suggested half- and quarter-doses may be tried in infants and young children. “If you get the same immune response at a quarter of the dose and it decreases side effects, well then we would probably give a smaller dose,” Frenck says.
In the meantime, pediatricians, parents, and others have to wait. Pfizer, for example, has announced plans to submit its data on adolescents to regulators by June; it also expects to open a trial in 5- to 11-year-olds within a couple of months, and in under 5-year-olds later this year. Diekema, a volunteer cross-country coach at the local high school, is getting ready to head back to the field for the first time in a year. Even if he does his best to enforce social distancing among the teens, he imagines them playfully high-fiving between runs. Children are “like magnets” when near one another, he says. “That’s why we need the vaccines.”
https://www.sciencemag.org/news/2021/02/trials-ramp-doctors-stress-need-vaccinate-kids-against-covid-19
