Both Pfizer-BioNTech and Moderna announced in March they had begun clinical trials of their COVID-19 vaccines in children younger than age 12 years. Although public reaction was mixed, researchers and bioethicists now say the timetable for a pediatric vaccine and for the United States to possibly reach herd immunity is early 2022.

Moderna will study three doses of the vaccine for the youngest children, but two for older children (ages 2 to 12 years). The chosen dose from the first part of the study will be used in the study’s Part 2, which is the placebo-controlled expansion portion. “Vaccine effectiveness will either be inferred through achieving a correlate of protection, if established, or through immunobridging to the young adult (ages 18-25) population,” Moderna said in a statement. “Evaluation of vaccine safety and reactogenicity is also a primary endpoint of the study.”1

Pfizer says it is planning to study three different doses of its vaccine in small age groups of children. First, the vaccine will be tested in children ages 5-11 years, in children ages 2-4 years, and finally in ages 6 months to 2 years. Side effects and the ability of the doses to produce antibodies against the virus will be tested. The sample sizes will expand after doses are chosen for each age group. About two-thirds of participants will receive the vaccine, the other one-third will receive a placebo. After six months, all the children will receive the vaccine.2

Differences in Children

“We don’t think that the immune system is going to operate in a significantly different way in children vs. in adults,” says William J. Muller, MD, PhD, associate chief research officer for clinical trials in the department of pediatrics at Northwestern University’s Feinberg School of Medicine and an attending physician in the division of infectious diseases at the Ann & Robert H. Lurie Children’s Hospital of Chicago. “We do know that the responses to vaccines in kids can sometimes be a little bit different, meaning that they may need less of a dose to get an equivalent response or they might need more of a dose to get an equivalent response. That’s really one of the important things to find out from these kinds of trials — basically, the lowest dose that will give you protection and minimize any chances of safety problems. The biggest concern for studying vaccines and kids is to make sure that they’re safe.”

Children might react more strongly to vaccines, but they also have experienced milder disease response to COVID-19. “Probably half or more of children that get the infection really have minimal or no symptoms,” Muller said in an episode of Northwestern’s Breakthroughs podcasts. “Those who have symptoms will often have relatively mild symptoms that would be very consistent with respiratory illnesses in the wintertime in general … But we also know that there have been as many deaths in pediatric patients from COVID as there are in a typical flu season, so it’s not a benign disease in children. It’s something that we really need to take seriously from a treatment standpoint, and from a therapeutic standpoint.”3

However, some children, even those who did not experience disease symptoms, developed multisystem inflammatory syndrome after COVID-19 infection. These children present with what seems to be an overwhelming infection: low blood pressure, fever, and abdominal pain. “It’s not clear if this is just some response of their immune system that is dysregulated that causes them to have these symptoms that look like they have infection,” Muller said.

At Lurie, most children with this syndrome have recovered quickly. Others have required a long hospitalization. “It can be a pretty significant disease, and even though it’s very uncommon, it’s one that we are very concerned about,” he explained.

The Risk for Minors

Although safety is important in studies of adults, the emphasis is magnified in pediatric studies, Muller said. Younger children cannot give an accurate representation of how they are feeling or if they are experiencing any side effects after taking the vaccine. “Is there are more than a minimal risk to the patient who’s participating?” Muller asked. “In the case of a new agent, there is almost always going to be risks that we don’t know about when you introduce a new medical intervention, in this case, a vaccine, into a population.” A potential of benefit in children for some of these vaccines may reduce the regulatory burden and risk assessment for study teams.

A group of bioethicists recently addressed this question of when a vaccine trial is appropriate to study in younger children. Waiting too long can “unjustly deny minors and families the benefits of the vaccine,” while also pushing back an effective response such as herd immunity by a year or more, they noted. However, enrolling minors too soon can expose them to excessive risks, since younger minors are unable to understand and provide their own informed consent. To address the concern of excessive risk, enrolling minors in clinical trials requires the permission of their parents or legal guardians, along with the assent of minors who can provide it, the bioethicists wrote.4

At Lurie, Muller says, children over age 12 years provide a written assent, which is similar to the adults’ consent form. However, it is targeted more toward what the IRB thinks the children would want to know: Why are they involved in this study? What does it mean to be in a study? What are the risks of participating? What are the potential benefits? “There’s not as much detail on what goes on with each individual study visit,” he explains.

From ages eight to 12 years, investigators at Lurie obtain a verbal assent. “I know those are semiarbitrary ages, but the idea is that an eight- to 12-year-old might not be able to understand the details of the form that we create that describes the study, but they will understand what a study involves and that they have some choice as to what happens,” Muller says.

Children younger than eight years might be more likely to say no because of the intervention. “They don’t have a real sense of the risk of the disease. They just know the risk of intervention,” he explains. “That doesn’t mean we don’t talk to children who are younger than eight about being in a study and what’s involved, but it’s not a requirement.”

In addition to the parent or guardian consent and minor assent, children should be enrolled only when the trial poses low risks or offers a potential for participant benefit that justifies the risks, the bioethicists noted. “A common way to satisfy these requirements is to enroll minors only after there is evidence of safety and efficacy in adults, which may include evidence of immunogenicity in the case of vaccines,” they wrote. “By ensuring that there is evidence of safety and a potential for benefit prior to enrolling minors, this approach offers one way to protect minors from being exposed to excessive research risks.”4

However, this can lead to a delay in vaccines for minors. Instead, the bioethicists suggested enrolling minors after sufficient safety data in adults but before evidence of efficacy. “Enrolling minors, beginning with older, healthy adolescents, after there is sufficient evidence of safety in adults, addresses concerns over exposing children to excessive research risks,” they wrote. “Doing so before efficacy has been demonstrated in adults can speed the process of providing access to a safe and effective vaccine for children and their families, thereby reducing the time until the pandemic is effectively addressed.”

Since the COVID-19 pediatric trials began in March, minors should have an available vaccine early in 2022, Muller said. “It’s going to take three or four months just to get through the initial enrollment period. It will take another three or four months to get enough data analysis and enough follow-up to show that there might be some benefits.”3

On Feb. 25, the American Academy of Pediatrics (AAP) wrote a letter to White House leaders, asking for a faster timetable. The letter urged officials to “use every measure available to achieve authorization of COVID-19 vaccines in children as soon as can be done safely.”5

At this rate, the United States will not see a COVID-19 vaccine for children younger than 12 years until early next year, said Lee Ann Savio Beers, MD, FAAP, president of AAP. Herd immunity with COVID-19 vaccination is unlikely until younger Americans are vaccinated, since children 18 years of age and younger make up more than 20% of the U.S. population. “Having a COVID-19 vaccine available for children is essential for our nation to end the pandemic,” Beers said in a statement. “We must make sure that vaccine trials in children are equitable and include those at increased risk who could most benefit from a vaccine, particularly Black and Latinx children. We need to apply the same urgency to vaccinate children as we have for adults. Pediatricians stand ready to partner with the federal government to make this happen.”6

Parents Assessing Risk

Response to the announcement of the pediatric trials on social media was polarized, ranging from “Finally!” to “How dare they let children be guinea pigs?” Muller does not believe parents want their children to be unnecessarily exposed to something potentially dangerous. “That’s really the key,” he says. “Different people have different levels of risk tolerance and different assessments of what might be beneficial to them.”

Hoping to one day become a site for one of the trials, Lurie has developed a registry for parents or guardians to indicate they might be interested in enrolling their children in a vaccine trial. If a vaccine trial becomes available and has openings for participants, the hospital would contact the families.

More than 10,000 families have logged onto the registry, Muller says, although not everyone has completed the registry process. Still, he says, Lurie has “well over what we would need to do multiple studies in children.” During his podcast, Muller said most of those registered were from the Chicago area, but the registry has also received responses from 24 different states, including ones as far away as Arizona and Washington state.3

In general, the parents who have signed up on the registry seem to be enthusiastic about the vaccine becoming available to their children, Muller says. The reasons for their enthusiasm are varied. One is their children will be protected from disease. The second reason is the pandemic’s disruption on people’s lives. Current guidelines say most people who test positive for COVID-19 should isolate for 10 days after symptom onset. “Every time [children] get sick — even if they don’t get that sick — someone has to stay home with them. It’s already been a big disruption for people’s work lives.”

All those things should improve if there is more widespread uptake of the vaccine, and that includes children. “I don’t think you can reach herd immunity without including 20 to 25% of the population,” Muller says.

REFERENCES

  1. Moderna. Moderna announces first participants dosed in Phase 2/3 study of COVID-19 vaccine candidate in pediatric population. March 16, 2021. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-dosed-phase-23-study-0
  2. Pfizer. Pfizer/BioNTech announce positive topline results of pivotal COVID-19 vaccine study in adolescents. March 31, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-biontech-announce-positive-topline-results-pivotal
  3. Children and COVID-19 vaccines with William Muller, MD, PhD. Breakthroughs. March 2, 2021. https://breakthroughs.libsyn.com/children-and-covid-19-vaccines-with-william-muller-md-phd
  4. Mintz K, Jardas E, Shah S, et al. Enrolling minors in COVID-19 trials. Pediatrics 2021;147(3)e2020040717.
  5. American Academy of Pediatrics. AAP letter urging inclusion of children in COVID-19 trials. Feb. 25, 2021. https://downloads.aap.org/DOFA/AAP%20Letter%20Urging%20Inclusion%20of%20Children%20in%20COVID-19%20Trials_02_25_21.pdf
  6. American Academy of Pediatrics. As new COVID-19 vaccine nears authorization, American Academy of Pediatrics urges more children be included in clinical trials. Feb. 25, 2021. https://services.aap.org/en/news-room/news-releases/aap/2021/as-new-covid-19-vaccine-nears-authorization-american-academy-of-pediatrics-urges-more-children-be-included-in-clinical-trials/