Tracking an FDA advisory panel meeting on Covid vaccines in children

Parents of America, you’re in the home stretch. In all likelihood, Covid-19 vaccines for children under the age of 5 are days away from being available to your little ones.

The Food and Drug Administration is widely expected to issue long-awaited emergency use authorizations of the pediatric formulations of both the Pfizer-BioNTech and the Moderna Covid vaccines within the next couple of days. Before it does, though, its independent vaccine advisers will weigh the evidence on the safety and efficacy of the vaccines at a meeting Wednesday.

My colleague Matt Herper and I will be live blogging the hearing of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, which begins at 8:30 a.m. ET. You can watch the meeting here. We will be posting our updates and analysis below in reverse chronological order, so check back often.

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— Helen Branswell

The Moderna vote

2:58 p.m.: The panel voted on the following question: Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine when administered as a 2-dose series (25 μg each dose) outweigh its risks for use in infants and children 6 months through 5 years of age?

Yes: 21
No: 0
Abstain: 0

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— Matthew Herper

Heading toward votes

2:25 p.m.: The afternoon session has started, with VRBPAC members given a final chance to ask Moderna and the FDA questions about the Moderna data. The question period should start shortly and then the panel will go into discussion of the voting question: Do the benefits of the vaccine outweigh any risks for this age group? An hour has been set aside for the discussion.

Once the Moderna vote is taken, the process will be repeated for the Pfizer vaccine: questions, then a discussion, then a vote.

The meeting is meant to end by 5 p.m.

— Helen Branswell

A parent pleads for a choice

1:40 p.m.: A number of parents who are tired of waiting for vaccines to be authorized for children under 5 years old were among the speakers in today’s public comment period.

Michael Baker, a father of a 1-year-old and a 3-year-old, posted an evocative slide showing all the things his children have not experienced while their parents are waiting for Covid vaccines to become available.

Baker noted he struggles with whether his family has made the right choice shielding their children from things that in other times would be a normal part of development, saying it will be years before the pandemic’s full impact on children’s social development is known.

He made a rather eloquent plea: “All I am asking is now that the rest of the country can choose not to care about Covid that I have the choice to vaccinate my children, and I have the choice to do it in the most timely fashion possible,” Baker said.

— Helen Branswell

The halftime report

1:10 p.m.: So where are we?

Right now the panelists are listening to comments from the public. But before they broke for lunch, Paul Offit, of Children’s Hospital of Philadelphia, asked the FDA a simple question that could be the main issue the panel will focus on for the rest of the day.

Until now, the Pfizer/BioNTech and Moderna Covid vaccines have appeared roughly equivalent. Why is it that, for the first time, they don’t? It appears that two doses of the Moderna shot provide some protection to children 23 months and younger. But it is not clear the same is true for two doses of Pfizer.

Susan Wollenshen, the FDA reviewer on the Pfizer data, said that it was difficult to answer that question with the data.

What’s more, the data for the Pfizer/BioNTech shot, in terms of the number of infections prevented, is preliminary, imprecise, and potentially unstable, in the words of the FDA’s Doran Fink, a deputy director in the office of vaccines. Forgive us all the talk of confidence intervals, but they basically show the range of possible results for a number. You want them to be as narrow as possible. And the confidence interval for the cases prevented by three doses of the Pfizer vaccine — it ranges from -369.1 to 99.6 — is extremely wide.

This probably makes things sound worse for the Pfizer/BioNTech shot than they are. There is other evidence, such as the levels of neutralizing antibodies, that the panel might feel are sufficient, given the strong track record of these vaccines, to justify an authorization. But there are other questions. The CDC’s Amanda Cohn keeps asking what data exist to determine how long the gap between the second and third shot of the vaccine series should be. Pfizer is suggesting eight weeks, but in its studies recipients waited longer, with the longest gap exceeding 30 weeks.

Fink, for his part, seemed to think that if the Pfizer vaccine is authorized more data can be collected though observational studies. Pfizer argued that the consistent picture given by all of its data shows that the vaccine is effective after three doses, and the FDA’s reviewers seemed to generally agree. But the panel will likely want to delve more into the differences between the two shots before they make a decision.

Discussion starts again at 2 p.m.

— Matthew Herper

And now we know

12:30 p.m.: With Covid cases in young children surging during the early part of the Omicron wave (remember the graph below?) the FDA came up with a rather startling plan.

Even though Pfizer and BioNTech had announced late last year that their two-dose trial hadn’t generated a strong enough response in little kids and they were adding a third dose, the FDA indicated in early February it was considering giving the vaccine a rolling authorization, letting parents start to vaccinate their kids before the third dose data became available.

As quickly as the idea emerged, it fizzled. The FDA announced it was going to wait for Pfizer’s third dose results before considering the company’s EUA application.

It wasn’t clear at the time what was behind the about-face, but the data presented to VRBPAC makes it crystal clear. The vaccine efficacy — how well the vaccine was actually protecting kids — was low, only 14.5% seven days after dose two, and the confidence intervals crossed zero, so they were not statistically significant. When you see a negative number — especially a big negative number — in the brackets under a vaccine efficacy estimate (far right column) in this graph, that means there’s a chance there was no benefit at all. I’ve added some arrows to show you what I’m talking about.

And in fact, that’s what FDA analyst Susan Wollersheim said as she presented the agency’s analysis on the vaccine.

“You don’t see a clear effect of dose two on the incidence of cases between the treatment groups,” Wollersheim said.

This chart represents what was seen in the youngest kids. The data for the kids aged 2 to 4 years weren’t much better. And though there is the 80% vaccine efficacy estimate seen in this group after dose 3, the confidence intervals are pretty wide and they cross zero.

— Helen Branswell

Pfizer bet on tolerability over efficacy

11:50 a.m.: William Gruber, Pfizer’s senior vice president for vaccine clinical research and development, told a clear story about the company’s decisions regarding a vaccine for toddlers and preschoolers: the company feels that parents will not adhere to a vaccine that makes their kids feel very sick, and focused on finding a dose that would be effective but would also mean fewer fevers.

The data on tolerability the company presented bear that out, with rates of adverse events that are similar to placebo. Compare this slide to the one on fevers with the Moderna shot.

The problem for Pfizer is that this appears to have resulted in less efficacy. Whereas the Moderna vaccine at two doses shows an efficacy against infection of more than 40%, Pfizer reported a vaccine efficacy at two doses in its briefing documents of 28.3%.  If that figure was in Pfizer’s presentation, I didn’t catch it.

What Pfizer did show was this slide, showing that at two doses the vaccine was less effective, based on how well antibodies neutralized virus, against Omicron.

Pfizer decided to add a third dose not as a booster, but as part of the primary series. At three doses, the company showed data that the neutralizing titers go way up — up to the same level seen here.

But many of the children in the company’s vaccine studies have not yet received a third dose. It’s not clear whether they have dropped out, or whether not enough time has passed from their second dose. The result is that although Pfizer is talking about the three dose vaccine having 80% efficacy, that estimate is based on very small numbers.

In the slide above, the estimate of 80.3% vaccine efficacy is based on only 7 cases in the placebo group and 3 in the vaccine group.  Before the panel, Jesse Goodman, a former FDA official, told Helen he’d be cautious about believing that result.

“I’ve had people ask me: ‘Well, one vaccine is 80%, the other is 50%, shouldn’t I use the one that’s 80%?’ And I would just be very careful uncritically reporting point estimates when they’re based on such few cases,” Goodman said.

After Pfizer presented, Amanda Cohn, a top CDC official, raised a concerns about this.  First, the recommended time to a third dose would not be the same as the time in the study. More than that, though, she worried that the efficacy might not kick in until that third dose. “It essentially means that these kids would not be protected at all for another eight weeks,” she said.

This could be an issue the panel will need to grapple with in its discussion.

— Matthew Herper

It’s Pfizer time

11:00 a.m.: Pfizer, which is asking FDA to give an EUA to its three-dose vaccine for children 6 months to 4 years of age, is presenting now.

This vaccine contains three micrograms of antigen in each shot. It’s a much smaller dose than the Moderna vaccine uses.

The second dose is given three weeks after the first; the third is given at least eight weeks after the second.

— Helen Branswell

Diving into the Moderna data

10:20 a.m.: The Moderna data show the shot was effective as a two-dose series. In findings that will not surprise anyone who knows people who have received the Moderna shot, it also made the small children feel sick and even feverish for a few days.

Below is a slide of the maximum temperatures of fevers for children in Moderna’s studies. As you can see, there were actually plenty of fevers in the placebo group – little kids get sick – but the fevers from the Moderna shot are clearly higher. But they also tend to resolve in a few days.

Moderna also presented several slides on the main efficacy goal of the study: the antibody levels produced, which are being used as a measure of the immune response generated by the vaccine. I actually think this slide, from Moderna’s review of all of the data its studies have produced, makes the point more clearly. No matter what age group one is looking at, the antibody levels look the same. In other words, the vaccine should work similarly to protect recipients regardless of their age.

But in the real world, facing Omicron, we don’t just care about how good a vaccine is at generating antibodies. We care how that translates into protecting people. And Moderna presented data here, too.

One of the tough things in these vaccine trials is what, exactly, counts as a case of Covid. The studies tend to test people only after they have symptoms. The so-called 301 definition, named after a previous Moderna study, only runs Covid tests if volunteers in the study have two symptoms. The definition from the Centers for Disease Control and Prevention runs a Covid test if there is even one symptom. The second results in more, less serious cases – and more statistical power. In kids 2 to 5, vaccine efficacy was 36.8% by the CDC definition and 46.4% by the 301 definition.

But there was also a problem researchers didn’t expect when they designed the study. The parents of very little children, those younger than 2 years old, didn’t want to bring them in for sick visits during the Omicron wave. That meant they couldn’t get the PCR results that Moderna was using as the main measure of Covid in the study. But Moderna did a second analysis, looking at the efficacy based on antigen test results that parents called in. That showed a vaccine efficacy of 53.5% by the CDC definition, and you can see those data above.

Moderna is continuing this study, and will assign children to receive either a booster dose of a current vaccine or one of the newer booster it is developing based on Omicron.

One of the big questions for the panel will be how to weigh these data against the Pfizer/BioNTech data, which will be presented later this afternoon. The efficacy there will be lower for two doses — about 28%. But as a three-dose series, efficacy will be more like 80%. Will the panel want to compare the vaccines? Will they just want to make both available? So far, there’s not a lot of indication about what the panelists are thinking.

— Matthew Herper

Important real-world question for parents of infants

9:50 a.m.: VRBPAC member Archana Chatterjee, a pediatric infectious diseases specialist at Rosalind Franklin University of Medicine and Science in Chicago, asked a question that will be of interest to parents of very young children.

Chatterjee wanted to know if the Covid vaccine was administered at the same time as other vaccines in the youngest children in the trial, those 6 months old.

Moderna’s senior vice president, Jacqueline Miller, said in the trial the kids who were 6 months old did not get the Covid vaccine at the same time as the other vaccines children that age get.

Miller said, though, that Moderna plans to soon start a trial to test giving the vaccine at the same time as other vaccines, to see if that will be doable.

— Helen Branswell

Moderna is up first

9:30 a.m.: Moderna, which made a case yesterday for emergency use authorization for its vaccine for children aged 6 to 17, is now making its case for authorization of its vaccine for children under the age of 6.

The Moderna vaccine was tested in more than 6,600 children under the age of 6 — 3,100 children aged 2 to 5 and 1,911 children aged 6 to 23 months. At least half the children were followed for at least two months after dose two, an FDA requirement.

The product is a messenger RNA vaccine, given in a two-dose regimen, four weeks apart. Each dose contains a quarter of the amount of vaccine contained in an adult dose of the Moderna vaccine.

Carla Vinals, Moderna’s vice president for regulatory affairs strategy, told the committee that the two doses met the bar the FDA set for pediatric vaccines — inducing in recipients antibody levels similar to what is seen in people 18 to 25 years old who have been vaccinated. That antibody level is presumed to be protective.

In terms of safety and tolerability, pain and headache were the most commonly reported side effects. Fever was reported in about a quarter of the children vaccinated, and was most common after the second dose. High fevers were rare.

There were 15 children who had fevers over 104F — 11 among children aged 2 to 5 and four among children 6 to 23 months. Six of these children had symptoms of other viral infections at the time they had fever. There were three fevers over 104F in children who received placebo.

— Helen Branswell

Covid hasn’t left little kids unscathed

8:55 a.m.: FDA’s Peter Marks, head of the Center for Biologics Evaluation and Research set the scene for the meeting by discussing the burden of Covid illness in children under the age of 5.

During the Omicron wave, hospitalizations of children soared, Marks noted. And as of May 28, there were 442 Covid deaths in children under the age of 5.

“We have to be careful we don’t become numb” to pediatric deaths to Covid just because they are overshadowed by the overwhelming number of deaths in older adults, Marks said.

— Helen Branswell

Declining demand

8:52 a.m.: Here’s a thing to keep in mind about the issue of young children and Covid vaccines: Some parents are champing at the bit to vaccinate their kids. But they are a minority of parents.

The phenomenon has been clear with each age group as vaccines have become available to first older teens, then adolescents, then children down to age 5. There are fewer adolescents vaccinated than older teens, and fewer children aged 5 to 11 vaccinated than kids 12 and older.

According to CDC statistics, 59% of kids 12 to 17 years old have received two doses of Covid vaccine. But only 29% of children aged 5 to 11 have received two doses. That trend isn’t likely to change with the youngest children, experts know. A fair number of parents have some concerns about vaccinating children against Covid.

— Helen Branswell

A multistep process

6:30 a.m.: The meeting of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, is the first in a four-step regulatory process that will play out between now and Saturday evening.

VRBPAC is being asked if the evidence of benefit of these vaccines outweighs any risk that might occur in this, the last group to become eligible for Covid-19 vaccination. Expect panelists to vote yes on both vaccines.

After VRBPAC votes, the FDA will rule. Then an expert panel that advises the Centers for Disease Control and Prevention will convene to study the data. The Advisory Committee on Immunization Practices meets Friday and Saturday, when it will vote on both of these vaccines.

If ACIP recommends use of the vaccines — this is a very safe bet — CDC Director Rochelle Walensky will need to formally sign off on the recommendations before they can be put into use. That is likely to happen within hours of the votes. And then parents who have been vaccinated for over a year and who have been anxiously waiting for their young children to be eligible for that same protection will be able to gain some peace of mind.

Even though the outcome is largely seen as a foregone conclusion, the two vaccines being considered are not identical, which likely will cause some confusion and make for some tough choices.

The Pfizer-BioNTech vaccine contains a smaller amount of antigen, 3 micrograms, rather than the 25 micrograms that make up a dose of Moderna vaccine for the youngest children.

Pfizer’s vaccine, which is for children ages 6 months to 4 years, is a three-dose vaccine. The company originally tested two doses, but found that the regimen didn’t provide adequate protection in the face of the Omicron variant.

Moderna’s product is a two-dose vaccine, for children ages 6 months to 5 years old.

— Helen Branswell

Some things to watch out for today

6 a.m.: There’s a reason why little kids are the last group to become eligible for Covid vaccine. They were the last group in which vaccines were tested. That fact has been frustrating for the vocal minority of parents keen to vaccinate their children under 5, but it is by design. New drugs and vaccines are always tested on an age de-escalation basis, so that by the time the products are tried in little children, there is evidence on their safety garnered through their use in adults.

Serious side effects from vaccines are rare, but because they’re rare it’s hard to detect them in clinical trials. Often it’s only when a vaccine goes into wide use that issues come into focus — say, the anaphylaxis sometimes reported after the Pfizer or Moderna vaccines, or the clotting disorder linked to the Johnson & Johnson or the AstraZeneca vaccines. Proponents of testing vaccines in children last argue that finding out what the risks are needs to be done in adults before new vaccines are used in young children.

“From a safety perspective, you just don’t want to jump into young children … without any experience in an older population,” Norman Baylor, a former head of the FDA’s Vaccines Office, said earlier this week in a Georgetown University briefing for journalists.

With that in mind, look for a lot of discussion about safety and tolerability of these vaccines in this age group, particularly in regards to concerns that in adolescents these vaccines — both of which are made using messenger RNA — are associated with an elevated risk of myocarditis and pericarditis, inflammation of the heart muscle and tissue surrounding the heart, respectively.

Myocarditis wasn’t seen in the clinical trials, but because of the small size of the pediatric trials, that’s not proof that the risk isn’t there.

“It makes you feel better that they didn’t see it commonly, but it certainly didn’t put it to bed,” VRBPAC member Paul Offit, an infectious diseases expert at Children’s Hospital of Philadelphia, said at the same briefing.

Other things to expect: Discussion about how to communicate to parents about the choice they’ll face and whether Moderna’s two-dose vaccine is likely to become a three-dose vaccine somewhere down the road.

— Helen Branswell