FDA advisers reject third shots for all, back them for vulnerable
The independent group cited concerns about inadequate safety data on a third shot for all
The Food and Drug Administration’s outside advisers on Friday voted unanimously, 18-0, in favor of third Pfizer COVID-19 shots for vulnerable people at high risk of severe disease and people ages 65 or older.
The vote came after the panel voted 2-16 against Pfizer’s request to approve a third shot for all Americans ages 16 or older.
The committee also voted, 18-0, to recommend that FDA include health care workers and other workers at high risk of exposure as part of the group that would qualify for a booster.
The endorsement of the panel of independent scientists was one of the highest hurdles to the White House’s plan to offer Americans a third shot.
President Joe Biden announced a target rollout date of around Sept. 20 in a national address in August. The announcement was backed by the administration’s top health officials, including FDA acting Commissioner Janet Woodcock and Centers for Disease Control and Prevention Director Rochelle Walensky.
But an endorsement from the FDA’s independent advisory committee was never guaranteed. The decision to announce a specific date for the rollout ahead of FDA approval raised eyebrows among infectious disease experts and confused public health authorities.
The independent group, made up of infectious diseases experts and vaccinologists, said they were concerned about inadequate safety data on a third shot, especially in younger people who will mount a strong immune response. A strong immune response can lead to myocarditis, or inflammation of the heart, in rare cases.
The FDA presented data from a study of about 300 people showing that antibodies surged by three times in people receiving a third shot and there were no significant safety signals.
“Is 300 people a large enough study?” said Hayley Gans, professor of pediatrics at Stanford University Medical Center. Gans said not incorporating safety data from people who opted for a third shot without FDA approval is a “missed opportunity.”
“I think it will be proven safe but we just don’t have that data yet,” said Harvard Medical School immunology professor Eric Rubin.
Some in the group of scientists questioned whether a third shot is necessary for all adults and older teens, given the nature of the immune system and longer lasting B- and T-cells that rev up when someone is exposed to the virus.
“It’s a little disappointing that there’s been very little reporting on the cellular immune responses and an entire focus on the neutralizing anti-sera,” said Michael Kurilla, director of clinical innovation at the National Center for Advancing Translational Sciences. “Clearly for that population that’s at high risk, that’s absolutely essential." But for the broad population, he said, their protection seems to be holding up well over time.
“It’s not clear everybody would need to be boosted other than a subset of the population that would clearly be at risk for high disease,” he continued.
The scientists also questioned the wisdom of relying on a third shot in already protected people to curb transmission, and expressed they thought getting first shots into more arms would be more beneficial.
They said because of the nature of coronavirus’ incubation period, creating a vaccine that could provide so-called "sterilizing immunity" that would prevent all infections, even asymptomatic ones, might be out of reach.
The CDC’s presentation on several vaccine efficacy studies showed enduring protection for most people, said Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, which was hard to reconcile with data from Israel showing declining immunity.
“The third dose of mRNA vaccine increases the number of neutralizing antibodies and will likely decrease asymptomatic or mildly symptomatic infection, which is associated with infectiousness,” Offit said. “So then the question then becomes how does that impact the arc of the pandemic? Which may not be all that much.”
The advisers also expressed a desire to see a booster tailored to more infectious variants like delta.
More vetting is required before federal officials permit a third dose. The next step is for the FDA to formally allow the third dose for everyone as Pfizer requested, or for a smaller subset of people under an emergency use authorization.
Next the CDC's own set of advisers, the Advisory Committee on Immunization Practices, will consider more details about who should get a third shot and who might qualify as at risk. Finally, the CDC will decide whether to support the recommendations.
The FDA does not always follow its advisory committee's recommendations, but generally does.
"We are not bound at FDA by your vote, just so you understand that," said Center for Biologics Evaluation and Research Director Peter Marks, who favors booster shots for all.
Tension at FDA
The meeting included peeks at behind-the-scenes tensions at the FDA on booster shots between Marks and that office’s top vaccine reviewers, Marion Gruber and Phil Krause.
Krause eviscerated Pfizer for not submitting more data for peer review or for independent analysis by the FDA’s scientists.
He contested one of the real-world studies Pfizer cited to support its application, a look at Kaiser Permanente patients in California. The drugmaker said it showed 61 percent efficacy against severe disease in people older than 65, while Krause said it showed 93 percent efficacy in that group.
After several critical and skeptical comments from members of the committee, Marks suggested backing off of a formal vote. But Gruber insisted on the vote.
The FDA also had asked Pfizer to look at a broader group of people with the following strategy: compare people in its massive clinical trial who received the placebo but later “crossed over” to receive the real vaccine.
Through this study, Pfizer found a 26 percent dip in the relative risk of a breakthrough infection in people vaccinated five months ago when compared to people vaccinated 10 months ago. The FDA calculated that is equivalent to a 1 to 5 percent difference in vaccine effectiveness.
The FDA also found the data used to support Pfizer's argument that a booster is effective against delta in 23 people was overwhelmingly in healthy white people. Data in about 300 people supporting the jump in antibody levels was more diverse.
The tumultuous eight-hour meeting, and the committee vote against a policy the Biden White House was clearly advocating, show the booster debate has not been handled well, experts say.
“I think the committee felt uncomfortable about how pressured it was. I see this as the committee trying to do the right thing for the public health. They wanted there to be some access to vaccines but they weren’t comfortable with the level of data to support an approval for boosters for the whole population,” said Jesse Goodman, an expert in pharmaceutical policy with Georgetown University and former FDA chief scientist. “The process clearly could have been much better managed.”
"I’ll be frank here, this meeting was rushed,” said Norman Baylor, a pharmaceutical consultant and former director of FDA’s Office of Vaccines Research and Review, who added more data should have been collected before boosters were discussed for all.