Feature Article — COVID-19 Vaccines: Clinical Trials in Children

As schools prepare to reopen, parents and children alike are experiencing a range of emotions and concerns. On one hand, the need for in-person learning and socialization has become clear. On the other hand, the virus that causes COVID-19 continues to spread rapidly throughout many communities, and for most children, the best defense we have against this threat — the vaccine — is not yet an option. As a result, interest in the ongoing vaccine clinical trials in children has been high. With this in mind, we thought it was a good time to provide more information about the trials, the timeline and what it might mean for the upcoming school year.

COVID-19 vaccine and children: Where things stand by age

Depending on the age of your children, you may be in a situation in which one or more of your children can get vaccinated and others cannot yet get vaccinated. Currently, those 12 years and older can get two doses of the Pfizer mRNA vaccine, separated by at least 21 days. Those 11 and younger remain ineligible.

• Children 12 years and older — Because protection requires both doses, the sooner you get your child’s first dose, the better. At this point, some primary care providers are stocking the COVID-19 vaccine. However, if your child’s provider does not yet have it, check with local pharmacies and health departments or watch for announcements of special vaccination events in your area.
  
  This age group generally handles the vaccine well, but like adults, they may experience pain at the injection site, fatigue, headache, fever, chills, muscle pain or joint pain in the first day or two after vaccination. These symptoms tend to occur more commonly after the second dose. For this reason, you may want to schedule their dose for a day when they will not have camp, work or school the next morning.
  
  A very small number of teens and young adults have experienced an inflammation of the heart, called myocarditis. This tends to occur in about 1 of 50,000 recipients and is usually experienced within the first four days after vaccination. Symptoms include chest pain or shortness of breath. If your child experiences these symptoms following vaccination, contact their healthcare provider or seek emergency medical care. Fortunately, this problem appears to be generally short-lived and self-resolving.
  
  You can find out more in these related resources:
  • Animation: How COVID-19 mRNA vaccines work
  • PDF: What can teens expect when getting a COVID-19 vaccine?
  • Video: What Should I Know About COVID-19 Vaccine and Myocarditis in Teens?
• Children 11 years and younger — Because these children cannot be vaccinated, those between 2 and 11 years of age should mask when they are in situations with large numbers of people, particularly if they are indoors or in areas where viral transmission is high. While most children who get COVID-19 experience only mild symptoms or no symptoms at all, a small number can become severely ill, requiring hospitalization or dying. By the end of July 2021, COVID-19 had led to the hospitalization of about 3,330 children up to 17 years of age and caused 340 deaths in this age group.
• Homes with children of mixed ages — If you have both older and younger children in the home, it is important for older vaccinated children, and even vaccinated adults, to realize that they could get infected and expose unvaccinated members of the home. Recent data with the delta variant suggest that vaccinated people who get infected can have equal amounts of virus in their noses compared with unvaccinated counterparts. However, because symptoms are often mild or nonexistent, vaccinated individuals might not realize they have the virus. As such, vaccinated members of the household might also wish to mask and social distance when they go out to decrease the chance of bringing the virus home and infecting unvaccinated family members. This will be particularly important in communities with widespread transmission, so keeping track of what is happening in your community or checking ahead if you are traveling can be useful.
  
  You can track community spread data using the “COVID-Lab: Mapping COVID-19 In Your Community” tool from the Children's Hospital of Philadelphia’s PolicyLab.

COVID-19 vaccine and children: How the clinical trials are being done

Clinical trials tell us different things depending on how they are designed. As such, the way that one company designs their trial is likely to differ from that of another company. Understanding how the trials are designed is important for understanding the results. One current example of how these differences can affect the use of a vaccine is apparent in that the Pfizer vaccine can be used in those 12 years and older, but Moderna’s is currently only available for those 18 years and older. This does not tell us anything about how safe or effective the Moderna vaccine is in children; it is just this way based on the age groups each company chose to include in their original phase 3 clinical trials.

The clinical trials for children are important for determining three things:

• Dose: Doses of vaccine are different from doses of medications in that the latter are often prescribed based on the relative size of a person. On the other hand, vaccine doses are determined based on finding “the sweet spot” between generating immunity and causing the lowest rate of side effects. As a result, children and adults get the same dose of some vaccines (e.g., MMR and chickenpox vaccines), but different doses for others (e.g., hepatitis B, diphtheria, pertussis, and some influenza vaccines). Because our immune systems tend to be stronger when we are younger, children and young adults may not need as high of a dose compared with older adults. With COVID-19 vaccines, we have some evidence that younger people’s immune systems are responding more strongly because of the greater occurrence of side effects in younger people. However, the determination of optimal dose needs to be studied in a clinical trial, so both Pfizer and Moderna vaccines are being evaluated to determine the best dose for children.

• Safety: Safety is typically determined by evaluating both the kinds of side effects participants experience as well as the frequency with which they experience them. Participants, or their caregivers, will be asked to keep a diary explaining what the person experienced in the days after vaccination, be interviewed by the study team, or both. They will be asked about side effects that would be expected, but they will also be asked to report anything else that happens. In this manner, if something unexpected is occurring at a high enough frequency following vaccination, the study is designed to uncover it. To determine the frequency of side effects, the reports of all study participants who received vaccine will be compared with the frequency of the same side effect in the group that received a placebo. By keeping everyone “blinded,” meaning the participant, caregivers and study team do not know if a person received vaccine or placebo, the side effect rates will be less likely to be biased by knowledge of which group a participant was assigned to.
• Immune response: Scientists try to identify a “correlate of protection,” meaning some measurement, often antibody levels in the blood, that can be used to determine whether someone is protected against future infection. For example, if someone has hepatitis B surface antigen antibody levels of at least 10 international units per liter (IU/L), they are considered protected against hepatitis B. Unfortunately, a correlate of protection is not always identified, and currently, that is the case for the virus that causes COVID-19. However, we do know what levels of antibodies people who had COVID-19 tend to have, and we know what levels of antibodies vaccinated teens and adults tend to have. We also know that vaccinated people are less likely to become severely ill or die when infected. As such, the immune responses in children can be compared with this information from vaccinated people, most likely older teens or young adults, to ensure that they develop similar immune responses.

COVID-19 vaccine and children: What clinical trials are occurring

Clinical trials are described on a website overseen by the U.S. National Institutes of Health and the National Library of Medicine, clinicaltrials.gov. Website visitors can search by a variety of factors, such as condition, recruitment status and location, to find out what clinical trials are available and how they are being conducted. A recent search for COVID-19 vaccine trials in children identified five trials recruiting participants and three active trials that are not currently recruiting participants. So, let’s take a closer look:

Recruiting

Of the five trials currently recruiting participants, three are studies of the Pfizer vaccine. One is a study of the Moderna vaccine, and one is a study that includes both vaccines. See below for more details about each.

• Pfizer study of dosing, safety and immunologic response:
  • Participant ages: 6 months to 11 years of age (three different age cohorts — 6 months to less than 2 years, 2 years to less than 5 years, and 5 years to less than 12 years).
  • Three quantities of vaccine being evaluated: 10 micrograms, 20 micrograms, and 30 micrograms; the latter is the dose given to older teens and adults.
  • Comparison groups: Side effect rates (by dose and compared with placebo) and immune response (compared to those found in studies of 16- to 25-year-olds).
  • Study type: The dosing part of the study is not blinded, but the safety and immunologic responses portions of the study are blinded.
  • Study size: About 4,500 children.
  • Number of study locations: 101 sites.
• Pfizer study of dosing, manufacturing lots and boosters:
  • Participant ages: 12 and 50 years of age (dosing); 18- to 50-year-olds (booster dose 3 months after getting dose 2).
  • Four lots of vaccine, including one produced in the European Union, will be compared for similarity of immune responses generated.
  • Two different booster formulations: Original vaccine formula and a second version based on the South African variant.
  • Two doses: The regular 30 microgram dose and one lower dose of 20 micrograms.
  • Comparison groups: immunologic responses (across lots, booster formulations and doses); side effect rates.
  • Study type: Randomized, blinded study.
  • Study size: About 1,500 participants.
  • Number of study locations: 17 sites.
• Pfizer study of safety and immunologic response following booster dose:
  • Extension of the original Pfizer vaccine trial.
  • Participant ages: 12 years and older.
  • Booster dosing with one of the following: The original vaccine formulation, a lower dose of the original formulation, or an adaptation based on the South African (beta) variant.
  • This extension also includes recruitment of new, previously unvaccinated or uninfected participants who will get two doses of the revised formulation based on the beta variant to compare immunologic responses.
  • Comparison groups: Side effect rates and immune responses (after third dose compared with after second dose).
  • Study type: Randomized, blinded.
  • Study size: About 44,000 from all phases of the study.
  • Number of study locations: 162 sites.
• Moderna study of dosing, safety and immunologic response:
  • Participant ages: 6 months to 11 years of age (three age cohorts — 6 years to less than 12 years, 2 years to less than 6 years, and 6 months to less than 2 years; staggered starts beginning with oldest group); placebo group receives saline (salt solution) injections rather than vaccine (offered vaccine after study is unblinded).
  • Three quantities of mRNA vaccine (quantities not specified in clinicaltrial.gov posting).
  • Comparison groups: Side effect rates and immune responses.
  • Study type: Not blinded (dosing); randomized, blinded (safety and immunologic response).
  • Study size: About 7,000 participants.
  • Number of study locations: 69 sites.
• National Institute of Allergy and Infectious Diseases (NIAID) study of allergic reactions:
  • Participant ages: 12 to 69 years of age are being recruited with a preference toward non-pregnant females since women are more likely to experience an anaphylactic reaction following vaccination against COVID-19 compared with men.
  • Goal: To estimate the occurrence of systemic allergic reactions in a group of individuals with a condition known as high allergy/mast cell disorder.
  • Participants will receive a first dose of either the Pfizer vaccine, Moderna vaccine or placebo. The second dose will be either Pfizer or Moderna for all participants. Individuals who originally received a first dose as placebo will receive the second dose at a later visit.
  • Comparison groups: Rates of increased risk for group with allergies compared with a control population of individuals that do not have severe allergies or mast cell disorders.
  • Study type: Blinded.
  • Study size: About 3,400 participants.
  • Number of study locations: 29 sites.

Active, but not recruiting

Typically, “active, but not recruiting” status indicates that enough participants have been recruited for the study, but data are still being collected and evaluated. In the current review, one of these was a Pfizer vaccine trial looking at booster doses in those 16 years and older. One was a Moderna trial looking at vaccine safety and effectiveness in those 12 years of age to younger than 18 years of age, and a third trial was evaluating a vaccine that contains the spike protein with adjuvant in a lipid nanoparticle, sponsored by Novavax. This latter study included two phases. In the first phase they evaluated adults. Later, they extended the study to include those 12 years to younger than 18 years of age.

Note of caution

One final note about clinical trials if you are interested in participating or having your children participate. Unfortunately, the Federal Trade Commission (FTC) has identified scams related to fake clinical trials. The scammers are using the guise of COVID-19-related clinical trials to get people’s personal information and money. As such, before you decide to participate in any clinical trial, check the FTC’s tips for determining whether a clinical trial is real.

COVID-19 vaccine and children: The timeline

One of the questions we receive most commonly is when children younger than 12 years of age will be able to get COVID-19 vaccines, and the short answer is that we don’t know for sure. While the clinicaltrials.gov website includes dates, these are based on when all data and follow-up should be completed. These dates can change for reasons such as longer or shorter than anticipated recruiting timelines, unanticipated trial delays or temporary stops, or study sites not being recruited or approved in the expected time. However, it is also important to realize that companies can often submit data when they get to a certain point of follow-up post vaccination. For example, during the first approvals for adults, the companies were able to submit their data after they compiled eight weeks of follow-up data even though they were still following those vaccine recipients.

Currently, it is anticipated that the first data in children younger than 12 years of age may be submitted for review later this year; hopefully, sometime in the fall, but only time will tell.

COVID-19 vaccine and children: The takeaways

Parents wondering what this means for their families, can take away three important considerations:

1. Schools will open this fall, but most children will not be vaccinated. As such, it will be important to continue monitoring rates of disease in your area and teaching your children how to protect themselves based on the situation.
2. COVID-19 vaccines for children are coming, but the studies are needed to provide important information to ensure safe and effective vaccination of this group.
3. Flexibility will remain critical. If cases rise or outbreaks occur in schools, changes to schedules or protection strategies may be necessary.

The best way through this pandemic is together. So even if your family is tired of the masks and limitations, try to remind them that we all need to work together in our homes, schools and communities to put this behind us!

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