Committee raises concerns over unknown risk of myocarditis in this age group

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted almost unanimously that the benefits of authorizing Pfizer/BioNTech’s Covid-19 vaccine, BNT162b2, for use in kids ages 5-11 years old outweigh the risks.

With 17 “yes” votes and one abstention, the committee voted in agreement of the following question:

“Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech Covid-19 vaccine when administered as a 2-dose series (10 μg each dose, 3 weeks apart) outweigh its risks for use in children 5-11 years or age?”

Now that VRBPAC has cast its vote, the FDA can move forward with issuing an emergency use authorization (EUA) to give two shots of BNT162b2 to younger kids; however, those who were hoping to get their kids vaccinated before Halloween will have to wait until next month. The CDC’s Advisory Committee on Immunization Practices is slated to discuss any pending EUA for this age group on Nov. 2, after which CDC director Rochelle Walensky, MD, can issue a final recommendation.

Once that happens, the White House plans to kick off a full-scale pediatric vaccination program to get shots into as many kid’s arms as possible. And, in the coming weeks, more Covid-19 vaccines may join the BNT162b2 shot in the pediatric immunization armamentarium. One day before VRBPAC’s meeting, Moderna announced it’s intention to request an EUA for its own vaccine, mRNA-1273, for kids ages 6-11 years old based on positive interim findings from the phase II/III KidCOVE trial.

To date, there have been at least 1.9 million confirmed Covid-19 cases among children, according to a CDC presentation given during the VRBPAC meeting—and, CDC medical officer Fiona Havers, MD, MHS, noted that given that many children have asymptomatic illness or mild symptoms, that number is likely an underestimate. What’s more, during the most recent spike in Covid-19 cases, kids ages 5-11 made up a larger proportion of all Covid infections compared to earlier in the pandemic, accounting for 10.6% of cases in the week ending Oct. 10. And, while children generally experienced lower overall Covid-related mortality and lower incidence of long Covid compared to adults, more than 5,200 children have been diagnosed with Covid-related multisystem inflammatory syndrome post-infection, and kids are also losing large amounts of school time, with over 2,000 unplanned school closures so far this school year impacting over one million students.

Breaking Down the Data

The committee’s decision was based on interim findings from a phase II/III study that were announced by the vaccine’s manufacturers in early October, as previously reported by BreakingMED.

“In participants 5-11 years of age without evidence of SARS-CoV-2 infection prior to Dose 2, the observed [vaccine efficacy] VE against confirmed Covid-19 occurring at least 7 days after Dose 2 was 90.7% (95% CI: 67.4%, 98.3%), with 3 Covid-19 cases in the BNT162b2 group compared to 16 in the placebo group (2:1 randomization BNT162b2 to placebo),” the FDA explained in a briefing document released prior to VRBPAC’s Oct. 26 meeting. “All cases of Covid-19 occurred in children without prior history of infection. None of these cases met the criteria for severe infection. Most of the cases occurred in July-August 2021. Comorbidities at baseline (including obesity) were present in total of 20.1% of cases. No virus sequence analyses were available to determine whether these cases were caused by the Delta variant or another variant.”

The most common adverse events reported after a second dose in this population included injection site pain, fatigue, and headache—most local and systemic reactions were mild to moderate in severity, with median onset two days post-vaccination and resolution within 1-2 days after symptom onset.

“The most frequently reported unsolicited AE in BNT162b2 recipients was lymphadenopathy (n=13; 0.9%),” the FDA noted. “More BNT162b2 recipients (n=14; 0.92%) reported hypersensitivity-related AEs (primarily rash and dermatitis) than placebo recipients (n=4; 0.53%).” And, notably, there were no reports of myocarditis/pericarditis among these patients.

This last point is important, given the rare risk for both myocarditis and pericarditis associated with receipt of the mRNA Covid-19 vaccines, particularly among adolescents and young adults. Since these vaccines have not yet been made available for children ages 5-11, there is no data on the incidence of excess myocarditis post-vaccination in this age group. As a result, the FDA’s Center for Biologics Evaluation and Research (CBER)’s benefit-risk analysis for use of BNT162b2 in younger children was forced to use myocarditis rates from vaccine recipients ages 12-17 years old.

In a presentation to the VRBPAC panel, CBER’s Hong Yang, PhD, noted that while the benefit of vaccination for kids ages 5-11 seems to outweigh the risk, the benefit-risk balance changes based on the prevalence of Covid-19 infection, vaccine efficacy, and whether the risk of myocarditis is comparable to that for older groups:

  • At current rates of Covid infection, assuming ages 5-11 have the same myocarditis risk as older patients, the benefit of vaccination with BNT162b2 in this age group greatly outweighs the risk.
  • If Covid-19 cases and hospitalizations drop to 5% and 10%, respectively, of rates as of Sept. 11, 2021, the number of prevented Covid-19 cases would still outweigh the incidence of myocarditis, but excess myocarditis hospitalizations, ICU stays, and deaths would outweigh those from Covid-19 infections.
  • If the rate of myocarditis incidence proves to be 50% lower than for older patients, the benefits of vaccination would again outweigh the risks of myocarditis.

Several of VRBPAC members noted that it is very unlikely that the incidence rate for myocarditis will be as high for children ages 5-11 post-vaccination as it is for older patients, especially considering that the recommended vaccine dose for these younger kids is one-third the dosage recommended for ages 12 and up.

However, they also acknowledged that lower incidence is not a sure thing, and several committee members raised concerns that recommending the shot for young kids might open them up to unexpected risks, especially considering that many kids may have natural immunity due to previous infection or exposure—according to a presentation by the CDC, Covid-19 seroprevalence was estimated to be just over 40% from May-June 2021 in kids ages 5-11.

Moreover, some committee members—and some public commenters—expressed concerns that a blanket recommendation to give the BNT162b2 vaccine to all kids ages 5-11 may prompt school-level vaccine mandates, which could increase Covid-19 disparities or prevent certain groups of students from attending school.

Ultimately, the committee concluded that it cannot vote based on adverse event data it doesn’t have, and it will ultimately be up to ACIP to decide whether or not the vaccine should be available to all kids or only to specific subsets of patients at higher risk for infection.

“I certainly believe that in hindsight, we can look back on this decision—giving parents the option to make that decision [to vaccinate] for themselves—in history, we will be glad that we were able to do that, and to look at the risk-benefit ratio and say that the benefits of this option far outweigh the unknown risk,” said VRBPAC member A. Oveta Fuller, PhD, of the University of Michigan Medical School in Ann Arbor, Michigan. “We can’t see the disease. We certainly cannot anticipate all the risk ahead. But we know we have systems in place that can help us do that, so I think we have to take a step and say we want to make this option available for what it might do to help the children, as well as others in the pandemic.”

John McKenna, Associate Editor, BreakingMED™

Cat ID: 31

Topic ID: 79,31,730,933,31,926,138,44,561,927,151,725,928,925,934