Need to know:

  • Overall favourable mRNA vaccine safety and efficacy data in over-12s should be the same in younger vaccine recipients.
  • However, there is the risk of more severe or more frequent adverse events in kids owing to their reactive immune systems. Even then, similar side effects in children and adults may lead to severe clinical outcomes in kids.
  • It is logical to investigate lower doses in children. But there is still the possibility that the same or even a higher dose may be needed due to kids’ naïve immune systems. The key is to reach protective levels of vaccine-induced immune response.
  • Children have pre-established vaccination schedules, and it should be discussed how Covid-19 vaccines would be integrated. But delaying any vaccine jabs should be discouraged as this heightens the risk of non-Covid-19 outbreaks.

While mRNA vaccines for Covid-19 are likely to be overall safe and effective in recipients aged under 12 years old, experts are aware there are blind spots specific to this group that can lead to unexpected outcomes. Pfizer/BioNTech and Moderna are powering through with their plans in under-12s, with possible US authorisation and rollout in Q4.

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Regarding safety, it is possible that known mRNA vaccine-related side effects may be more profound or frequent in under-12s because their immune systems are more reactive. Even if side effects manifest in similar ways in adults and children, clinical outcomes could be more severe in kids.

It is logical to investigate lower mRNA vaccine doses in under-12s, as is being done by both companies, due to lower body mass. However, similar or higher doses as used in adults may still be needed to elicit the required immune response since younger recipients have a naïve immune system.

Since mRNA vaccines are a new technology, they require more caution when it comes to integrating them in regular inoculation schedules. But multidisease vaccines are common and delaying existing vaccines to make way for Covid-19 shots risks non-Covid-19 outbreaks.

On 14 September, Pfizer CFO Frank D’Amelio said he expects Phase I/II/III Comirnaty (BNT162b2) trial data in 5–11-year-olds by the end of September and a US authorisation application in early October. A Pfizer spokesperson added data readout and authorisation filing in the six months to 5-year-olds group will happen soon after. As for Moderna’s Phase II/III Spikevax (mRNA-1273) trial that is enrolling participants in three groups, the 6–11-year-old cohort is fully enrolled, as per a 9 September presentation. Moderna did not respond to a comment request.

Over-12s data relevant in children

Based on data in recipients over 12 years old, the overall favourable safety and efficacy of these mRNA vaccines should be similar in under-12s, Yale Medicine vaccinologist and pediatric infectious disease specialist Dr Inci Yildirim said. mRNA vaccines’ positive safety profile is based on millions of deployed doses and experience shows it can induce an immune response that leads to protection from symptomatic disease, University of Virginia professor of pediatrics Dr Steven Zeichner added.

In adults, common mRNA vaccine-related side effects include injection-site pain, tiredness, headaches and fever, among others. Rare events of heart inflammation are mostly observed in 16–18-year-olds and are much less common in 12–15-year-olds, which is reassuring for much younger recipients, Treuman Katz Center for Pediatric Bioethics director Dr Douglas Diekema noted. While Comirnaty is now fully approved in over-12s, thus opening the possibility of off-label use, the Centers for Disease Control and Prevention (CDC) strongly discourages this in under-12s, he added.

Risk of more frequent side effects in kids

Yet higher risk of severe or more frequent side effects may still be an issue in under-12s, Zeichner noted. Children have a more robust immune response than older people, and while this may be a positive for efficacy, it could be an issue with safety, experts explained. However, children have less severe Covid-19 symptoms, so mRNA vaccine-related side effects may also not be as severe in kids, Diekema, who is also an attending physician at Seattle Children’s Hospital in Washington, said. Studies show the difference in disease severity in children and adults could be due to pre-existing coronavirus antibodies, immunosenescence, or comorbidities, among other factors.

Severe side effects acceptable in adults may not be so for under-12s, Nikolai Petrovsky, PhD, said, a professor at Flinders University College of Medicine and Public Health in Adelaide, Australia. In 2010, certain seasonal influenza vaccines were not used in children aged 6 months to 8 years because of febrile seizure concerns due to fever, even though it was used in older recipients, Petrovsky added. Since Covid-19 disease severity is lower in under-12s, the vaccine safety bar is higher, Yildirim, who is also a professor in pediatrics and global health at Yale School of Medicine, said. On 3 September, the UK's Joint Committee on Vaccination and Immunisation noted it would not recommend universal vaccination of adolescents aged 12-15 years because the "margin of benefit is considered too small".

Eye on unique safety issues needed

Covid-19 can manifest in a distinct manner in children which could also mean unique vaccine-related side effects, Zeichner noted. Multisystem inflammatory syndrome in children (MIS-C) appears specifically in younger patients. This is caused by an immune response triggered by a SARS-CoV-2 infection which happens several weeks after an acute infection. The cause of MIS-C is still unclear and predicting who might have it is challenging as patients are previously healthy, University of Alabama professor of pediatrics Dr Randy Cron added. Indeed, very rare side effects may only surface once more are vaccinated, as is the experience with older recipients, Yildirim said.

The main concern for vaccine-hesitant parents is safety. Because mRNA vaccines use a relatively new technology, it is possible that parents may be more amenable to traditional technologies, added Baylor College of Medicine National School of Tropical Medicine associate dean Dr Maria Elena Bottazzi. In the US, there are no authorized Covid-19 vaccines that feature traditional approaches such as protein subunit or inactivated virus vaccines. Bottazzi and Petrovsky are involved in trials studying Covid-19 protein subunit vaccines.

Investigation of lower dose logical

Since under-12s have a lower body mass, these vaccine recipients are likely to need lower doses to induce the same level of immune response as adults, Yildirim noted. Fractional dosing in paediatric vaccines is not unusual, Bottazzi added. But there is also the possibility of under-12s requiring a higher dose than adults as their immune system is relatively naïve and may not respond the same way, Zeichner explained. Due to lockdown measures, children have been isolated from typical pathogen exposure in the past 18 months, which may or may not impact vaccine effectiveness, Yildirim said.

Comirnaty is approved in adults with a 30microgram dose, while the trial in kids is studying 10, 20 and 30 microgram doses in three age cohorts (5–11-year-olds, 2–5-year-olds, and 6-month-to-2-year-olds). The SpikeVax trial is studying the 50-microgram dose in 6–11-year-olds, and 25 and 50 microgram doses in 2–5-year-olds. An undisclosed dose and 25 micrograms will be investigated in 6-month-to-2-year-olds. While 100 microgram SpikeVax is authorized in adults, Moderna also has positive 50 microgram immune response data in adults. Paediatric trials are studying a two-dose schedule.

Repurposed adult vaccines for kids atypical

But it is also possible that under-12s may need the same dose as adults, Zeichner said. The antibody concentration needs to be the same in all recipients regardless of age or weight, he explained. Covid-19 vaccine development is atypical whereby research first happened in adults before being investigated in children, Diekema noted. This makes it more challenging to forecast if there should be any dosing changes in under-12s, he added.

mRNA vaccine trials in children may have recruited more participants than necessary to allow better safety evaluation, Emory University biostatistics and bioinformatics assistant professor David Benkeser, PhD, said. In turn, there should be plenty of participants to determine geometric mean titers, he added. Moderna plans to enroll 13,275 participants and Pfizer/BioNTech has 4,500 volunteers, both across age groups. Both trials’ primary efficacy endpoints are investigating vaccine-induced immune response, not number of vaccinated individuals who test positive for Covid-19, as was done in adults.

Vaccine schedule needs review for rollout

The best way to integrate Covid-19 vaccines into children’s existing routine schedule needs to be worked out. The different vaccines may negatively interact with each other, Yildirim said, adding caution is underscored by mRNA vaccines being a new technology. To assuage this issue, perhaps there should be a window between injections, but time durations are unclear, she noted.

But Zeichner said giving multiple vaccines to children is not unusual. Approved Tdap and MMR vaccines are designed to protect from multiple diseases. Delaying vaccines in the current schedule to make way for Covid-19 shots may have negative consequences and could lead to non-Covid-19 outbreaks, Zeichner added. Diekema agreed, noting overall vaccination rates in children are already lagging due to the pandemic. In adults, Covid-19 and influenza vaccines can be given the same day.