— “We wouldn’t say yes on the promise that three doses [will be] of value”

by Kristina Fiore

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) is facing a very difficult decision.

Members are being asked to consider whether a three-dose COVID-19 vaccine series should be authorized when there are only data available on two doses, and so far, all that’s known about those data is that noninferiority was not met in a prespecified immunogenicity analysis for kids ages 2 to under 5.

Will VRBPAC see some type of vaccine efficacy data in this age group, rather than just immunobridging data? A Pfizer spokesperson confirmed to MedPage Today that the study did include a placebo group, and the New York Times reported, citing an anonymous source, that vaccine efficacy was 57% in this age group.

Perhaps members will get an early glimpse at data with a third dose in this age group?

“We’re all reading the tea leaves,” said Paul Offit, MD, of Children’s Hospital of Philadelphia and a VRBPAC member who will be tasked with making a decision at the February 15 meeting. He said it’s likely that committee members would only give a thumbs up “if we felt comfortable that two doses offered something significant to those children.”

“I can only imagine we would say yes if there’s clear evidence that two doses is of value,” Offit told MedPage Today. “We wouldn’t say yes on the promise that three doses [will be] of value.”

Federal officials appear keen to push the application through. In a press release, Pfizer noted that they began their rolling emergency use authorization (EUA) submission “following a request from” the FDA.

Previously, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during a National Press Club briefing that Pfizer “decided that they believe this is really a three-dose vaccine, and there’s no doubt if you give three doses you’re going to get an effective and safe vaccine. But they haven’t proven it yet, so that’s the delay.”

“I can guarantee you it’s going to be effective,” he added.

There is indeed good precedent for an improved antibody response with a third dose in this population, said Joseph Schwab, MD, a professor of pediatrics at Rutgers New Jersey Medical School in Newark.

“We’ve seen that a third dose helps increase the immune response in adults, and vaccines in general, when you give booster doses, they do step up the immune response and boost the immunity you got from the first dose or two,” he said. “So, as a general principle, it makes sense that this would be positive.”

However, “whether the 3-mcg dose for all three doses is going to be good enough — we don’t know until we start using it,” he cautioned.

Schwab also said that authorities are likely trying to balance the “ongoing surge of Omicron, and the potential for new variants to break out, coupled with the increased hospitalizations among children that we’ve seen in this surge.”

Janet Englund, MD, professor of infectious disease and virology at Seattle Children’s, and an investigator for the Pfizer pediatric vaccine trials there, said the dire need for a vaccine in this population is certainly driving the push for authorization.

“We need it because these kids, their whole lives are impacted by not having a vaccine,” she said, adding that publicly available data from the company’s dose-finding studies show that the vaccine is safe for kids under 5, and has minimal side effects.

But even if two doses are authorized — banking on the hopes that three doses will be effective — will parents get their kids vaccinated?

“I assume compliance will be low” in the under-5 age group, Offit said. “It gets progressively lower as you get to younger and younger people.”

Vaccination rates among kids ages 12 to 15 are around 55%, and rates for those ages 5 to 11 fall to around 20%, Offit said. “I suspect it’s going to be even less for under-5’s, but I hope I’m wrong.”

If compliance is expected to be low, is releasing a vaccine prematurely going to further erode confidence — especially if a third dose is found to be insufficient?

“I think the biggest risk [of authorization without third-dose data is] the damage it might do to confidence in using the vaccine,” Schwab said, adding it would be “unfortunate” if people get frustrated with future changes in the vaccination schedule in this age group.

Starting a trial from scratch — perhaps investigating a two-dose series of 5 or 7 mcg — seems valuable, but may be too resource-intensive, particularly during a surge in U.S. cases, Englund said.

There are a “couple hundred families” in Englund’s trials, who make multiple visits and take on the risk that they may be getting a placebo.

“They have to have their kids’ blood drawn, their noses swabbed and visits every 21 days,” she said. “That’s a lot of work and time for these very busy families. It’s really tough.”

Offit echoed that sentiment: “What human price do you want to pay for knowledge?” he asked.

Still, others are adamant that third-dose data are in hand before a vaccine is put on the market.

Jeremy Faust, MD, of Mass General Brigham in Boston, and MedPage Today’s editor-in-chief, wrote in his Bulletin newsletter Inside Medicine that he won’t vaccinate his 3-year-old daughter until third-dose data are available.

If she were under 2, he noted, she would be vaccinated if it were authorized because “that’s simply what the data show. And in this household, we go by the data.”

“I’m worried that if we rush now, there will be fewer young children vaccinated by next fall than if we wait a few more weeks,” Faust wrote. “I’m less interested in vaccination rates in the next 6 weeks, and more interested in vaccination rates in the next 6-12 months.”

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