On May 10, the Food and Drug Administration extended its Emergency Use Authorization (EUA) of Pfizer’s COVID-19 shots to children 12 and up, but decided June 23 to add a warning to both Pfizer BNT162b2 and Moderna mRNA-1273 about an elevated risk of myocarditis, particularly in men age 30 and younger.

Concern about myocarditis and other unknown risks to young shot recipients pervaded the June 10 meeting of the FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC) and the June 23 meeting of the CDC Advisory Committee on Immunization Practices (ACIP). This article describes the risks and benefits discussed by government officials and medical researchers regarding these experimental products.

In general, the FDA is responsible for reviewing requests for emergency use authorization and biological license applications (BLAs). The Centers for Disease Control and Prevention, on the other hand, promotes the use of vaccines and other public health measures aimed to control the spread of infectious disease. Both FDA and CDC are part of the federal Department of Health and Human Services (HHS).

Dr. Doran Fink, Center for Biologics Evaluation and Research deputy director at the Clinical Division of Vaccines and Related Products Applications, described the content of myocarditis warnings to be added to mRNA COVID-19 shots authorized for emergency use by FDA.

“We thought it would be important to hear the ACIP discussion,” Fink said, “before finalizing the warnings, which would likely include information stating that these events have occurred in some recipients, that onset of symptoms has typically been several days to a week following vaccination, that limited information is available about potential long-term sequelae, and that symptoms suggesting myocarditis or pericarditis should result in recipients seeking medical attention.”

Dr. Tom Shimabukuro of the CDC COVID-19 Task Force presented surveillance data showing a high level of adverse events among young people receiving mRNA shots. The federal government is using a variety of methods to pick up vaccine side effects, including a new opt-in text messaging service called v-safe; the Vaccine Adverse Event Reporting System, which is passive and voluntary; and the Vaccine Safety Datalink, an electronic health records-based system of data collection that uses EHRs from eight hospital systems in Washington, Oregon, California, Colorado, Minnesota, Wisconsin and Massachusetts.

V-safe sends “check-in” text messages to participants, who are asked whether they have experienced specific vaccine side effects, such as headache and fever. After the second dose of the Pfizer mRNA product, more than 25 percent of 12- to 15-year-olds and a similar proportion of 16- to 25-year-olds reported that they were “unable to do normal daily activities.”

In the first month after the Pfizer EUA was expanded to middle-schoolers, 2,540 adverse events were reported by this group, including 144 serious adverse events. CDC emphasizes that adverse events reported to VAERS following vaccination have not been causally linked to the shots, but can be an indicator of safety signals.

To date, in people of all ages who have received mRNA COVID-19 shots, there have been 1,226 reports of myocarditis filed with VAERS. According to Shimabukuro, myocarditis after an mRNA shot is most common in men age 30 and younger, and happens more often after the second shot.

Recommendations spark

disagreement

Basing its June 23 recommendations on projected deaths and hospitalizations avoided in the entire U.S. population, and comparing those figures with the myocarditis burden borne by younger vaccinees, ACIP stood by its May 10 endorsement of COVID-19 shots for kids 12 and up, including recommending a second mRNA shot for kids who develop myocarditis or pericarditis after their first shot.

The latter recommendation drew criticism from Dr. Pablo Sánchez of Nationwide Children’s Hospital in Ohio. Speaking about pericarditis, Sánchez told his fellow committee members, “Whatever triggered it the first time – I think we just don’t have enough information for me to be saying, point blank, that I’m going to be giving the second dose of that vaccine. I’m a little hesitant to make that recommendation in my practice.”

Sánchez also focused on the issue of informed consent: “I think we need to be very up-front about mentioning this potential risk of vaccination, and hopefully the parents are aware of this before vaccination, rather than from the sheets that are given to them after vaccination.”

Of the nine members of the public selected by lottery to speak during the comment time, six spoke out against the use of COVID-19 shots in children. Another commenter urged the committee to recommend against using scarce vaccine doses for people who have already recovered from COVID-19. One pro-vaccine advocate delivered a three-minute rant about pending legislation in Ohio, calling an Ohio osteopath a “grifter.” Dr. Kelly Moore of the Immunization Action Coalition used her time to thank several members of ACIP for their work in promoting vaccines.

Researchers ask FDA to maintain high BLA standards

ACIP’s decision to stick with its recommendation of COVID-19 shots for children ages 12 and up comes just a few weeks after a June 1 citizen petition to FDA – signed by 27 physicians and medical researchers – urged caution with COVID-19 shot approvals.

The signatories appealed to FDA to require at least two full years of follow-up of the original clinical trial participants before approving a BLA for any COVID-19 shot. They also asked that FDA require “substantial evidence of clinical effectiveness that outweighs harms” in special populations, including infants, children and adolescents, prior to including them in the list of populations for which a vaccine is approved.

Dr. Robert M. Kaplan, a tenured professor at UCLA, is one of the signatories of the citizen petition. Kaplan is a long-term supporter of America’s vaccination programs who told the Press that he signed the petition because it “supports my beliefs: pro-vaccines, but also pro-high scientific standards for the FDA.” He was vaccinated as soon as his age group was eligible and explained that he is not opposed to continuing vaccination efforts under the existing EUAs.

However, he believes that “FDA should use a uniform standard for full approval. Using a lower standard because of the public health crisis is a bad precedent.” He notes that because of the EUAs, vaccines are available to those who want them, and points out that “the trials did not complete the two-year follow-up of treated and placebo subjects they had proposed. Our systems for post-marketing surveillance are inadequate, making it difficult to determine if there are longer term benefits and adverse events.”

VRBPAC commenters urge caution

in children

Another petition signatory, Dr. Peter Doshi, is a senior editor at “The BMJ” and an associate professor at the University of Maryland. Dr. Doshi spoke during the June 10 VRBPAC meeting, noting that in Pfizer’s trial data for 12- to 15-year-olds, “The placebo group was better off than the vaccine group […] efficacy benefits were rare, whereas side effects were common.”

“There were around 1,000 placebo recipients,” Dr. Doshi noted, “[and] just 2 percent [16 individuals] got COVID. Put another way, 2 percent of the fully-vaccinated avoided COVID, whereas 98 percent of the fully-vaccinated wouldn’t have gotten COVID anyway.”

Side effects among individuals receiving the active BNT162b2 product were high and included injection site pain in 90.5 percent of vaccine recipients, fatigue in 77.5 percent, headache in 75.5 percent, and joint pain in more than 20 percent.

More to the point, Dr. Doshi cautioned, “Then there are the long-term side effects, about which we still know nothing.” Pfizer followed the 12- to 15-year-olds in its trial for a median of two months, and no human of any age has received a COVID-19 mRNA product longer ago than March 2020.

The majority of the public commenters during the VRBPAC meeting expressed similar concerns. FDA Consumer Representative Kim Witczak, who runs the drug safety advocacy group Woody Matters, asserted that “Kids are neither in danger, nor dangerous,” questioning whether an emergency situation truly exists in the pediatric population.

Witczak pointed out the vast gap between what the public hears about vaccines distributed under an EUA and the actual authorization process at FDA: “Does the public truly understand how pediatric trials work? Like how many children are actually in these clinical trials?” she asked. “Like how efficacy/protection in pediatric trials is often determined by immunobridging, based on an assumption using adults’ experience?”

“Trust me,” Witczak told the advisory committee, “The average person doesn’t understand this. All they are being told is they are ‘safe and effective.’ These are just empty buzz words if the supporting data isn’t meaningful.”

“Four per million certainly does not constitute an emergency”

VRBPAC members debated what constitutes an “emergency” in children. Committee member Dr. H. Cody Meissner, director of Pediatric Infectious Disease at Tufts Medical Center in Boston, pointed to CDC data from April 24 that show the rate of hospitalization in pediatric patients to be just 0.4 percent – four in one million children. Meissner also noted that hospitalization rates have been decreasing nationwide since April 24.

“I very strongly believe we need a vaccine for adolescents and children,” Meissner said, “but I want to be sure that the risk of the vaccine is lower than the risk of hospitalization. Because four per million certainly does not constitute an emergency, and there are significant questions about the safety of this product.”

Meissner’s main safety concerns were myocarditis and potential sequelae. Rates of myocarditis in Americans between the ages 16 and 24 who received an mRNA product are from 3 to 27 times as high as researchers had anticipated, given the “background” rate in that population. There were 275 cases reported in vaccinated individuals from age 16 through 24 as of May 31, compared with 10 to 102 expected cases in this population.

Meissner framed the issue this way: “We don’t know what that [detection of post-vaccination myocarditis] means on a long-term basis. Will there be scarring of the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but we don’t know that. Before we start vaccinating millions of adolescents and children, it’s so important to find out what the consequences are.”

Whose risk?

Whose benefit?

During the public comment period, Doshi contended that “FDA can only indicate a product in a given population if the benefits outweigh the risks in that population.” However, VRBPAC members debated what the “known benefit” to the indicated population (children) might mean, as well as whether FDA could issue or expand an EUA for children based on a benefit to older demographic groups, rather than on a benefit to children themselves.

Dr. Ofer Levy, a professor at Harvard Medical School and researcher at the Broad Institute at MIT, asserted that “although we have to focus on benefits to the population of children, reaching herd immunity would be of benefit to children,” ostensibly because it might prompt the end of state and federal policies of social distancing, masking, reduced school attendance and the like.

Dr. Stanley Perlman, a VRBPAC member who holds the Mark Stinski Chair in Virology at the University of Iowa, asked for clarification – but didn’t receive it during the meeting-on whether Doshi was correct about the conditions for granting an EUA.

“We have to be in a good position to protect the general population in addition to children,” Perlman said, noting that “[o]ne of the public commenters said that we could only consider the effects on individuals themselves, rather than on society.” He asked, “Is that correct?”

No one at the VRBPAC meeting responded with an official interpretation of 21 US Code 360bbb-3, the authorization for medical products for use in emergencies, but ACIP’s June 23 recommendations were explicitly based on comparing benefits for all ages to risks for young people.

VRBPAC members also discussed the follow-up period for children younger than 12 in studies to support further EUA expansions. Two figures used as a starting point were 1,000 children under age 12, followed for a median of six months after receiving an experimental product.

Dr. David Kim of the US Public Health Service asked for longer follow-up, suggesting that public confidence in these new products would rise if parents were given safety data encompassing a period of two or even three years. Meissner was unwavering in his stance that EUA was the wrong avenue for children younger than 12.

Dr. Hayley Gans, professor of pediatrics at Stanford University Medical Center, recommended that FDA undertake proactive monitoring for the pediatric population currently receiving the experimental Pfizer product, with specific adverse events added to databases such as the Vaccine Safety Datalink (VSD), but no decisions were made at the meeting. Indicative of the overall paucity of data was the inability of Dr. Steven Anderson of the Center for Biologics Evaluation and Research (CBER) to tell Gans what percentage of the pediatric population receiving the experimental product is tracked “when we add in all the systems of surveillance that are going to be utilized moving forward.”

Note: The Press did not receive a response to multiple requests for comment from City of Bethlehem Bureau of Health Director Kristen Wenrich regarding COVID-19 shot clinics for children. The Press would welcome a statement from the Health Bureau regarding mass COVID-19 shot campaigns for children 12 through 15, as well as the issue of potential Pennsylvania mandates prior to an approved BLA.