Tracking an FDA advisory panel meeting on Covid vaccines in young 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.:

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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

— 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.