The expected authorization soon of a COVID-19 vaccine by Pfizer and BioNTech will follow a revealing discussion about what the nation’s top vaccinology and infectious diseases experts know — and what is still uncertain — about its ability to protect people from the sometimes-fatal disease.
Although the Food and Drug Administration’s independent advisers agreed, 17-4, in its daylong meeting Thursday that the vaccine's benefits outweigh its risks, the group's conversation also raised some important questions.
Experts hope the view into the group's thinking will build confidence in the science behind the vaccine and convince people to get their shots.
The animated debate within the panel — known as the Vaccines and Related Biological Products Advisory Committee — will likely influence regulators and shape discussion about this vaccine in the months ahead, before the FDA considers it for full approval.
Here are some of the unanswered questions about the Pfizer/BioNTech vaccine, according to the country’s top experts.
Use in older teenagers
The four votes of committee members against the vaccine did not entirely indicate the vaccine should not be authorized under emergency use. There was broad agreement during the meeting that given the clear effectiveness of the vaccine, the lack of evidence of severe side effects and the urgency of the pandemic, the vaccine should be authorized.
The four panelists who voted against it were not given the opportunity to explain their decisions, but statements by three of them later to CQ Roll Call indicate that some objected to the wording of the language they voted on.
The question the committee considered was: “Based on the totality of scientific evidence available, do the benefits of the Pfizer-BioNTech vaccine outweigh its risks for use in individuals 16 years of age and older?”
Two of the four committee members voting “no” expressed concern in statements to CQ Roll Call about making the vaccine available to people as young as 16 or 17. The clinical trial only enrolled 103 children in this age bracket.
“There was a paucity of safety and efficacy data for 16 [and] 17-year-olds and I thought it was important, as has been repeated many times, that scientific evidence should drive decisions,” said HHS vaccination official and VRBPAC member David Kim, who voted no. “I would have voted ‘yes’ most enthusiastically had the language been… '18 years of age and older.’”
Kim said he had planned to explain his vote and propose alternative language, but the meeting was abruptly adjourned after the vote.
Archana Chatterjee, dean of the Chicago Medical School, also expressed disappointment she was not able to explain her vote.
"I am fully in support of the Emergency Use Authorization for the Pfizer/BioNTech vaccine for adults 18 years and older, along with any measures that are going to help us get this deadly pandemic under control,” said Chatterjee. “However, we currently have 16- and 17-year-olds who, as minors, are not able to make their own decisions on whether or not to take part in a vaccination program, and we have limited safety and efficacy data on how the vaccine affects the pediatric population. Since most of them will not be eligible to receive the vaccine in the near future, and because they are not in a high-risk group, I believe we have time to gather and analyze additional data in this and younger age groups.”
Chatterjee said she thought about abstaining, but that FDA was more likely to take note if she voted no.
Panel member A. Oveta Fuller said her no vote was not about whether to vaccinate teenagers, but instead about a lack of evidence about whether the vaccine prevents transmission and how long the protection might last.
“My ‘no’ vote was not about inclusion of the 16 [and] 17-year-olds,” said Fuller, an expert in immunology at the African studies center and medical school at the University of Michigan.
While heralding the vaccine’s efficacy, she suggested that people get the vaccine through a continuing Phase 3 “expanded access” study rather than an EUA so more data could be gathered.
“An [EUA] seems to me to be premature…. With a little more coordinated effort, we could fill gaps and have important, convincing data on mRNA vaccine use that would lead to broader, more confident public uptake,” she said, using a term for the vaccine's technology.
In addition to deciding whether to authorize the vaccine, the FDA must determine if the vaccine would pose a greater risk for some populations who should not get it without more research.
Some of the meeting's most contentious moments concerned the question of whether people who have severe allergies to vaccines or anything else should receive it.
Moncef Slaoui, the co-lead of the Trump administration's Operation Warp Speed COVID-19 vaccine and treatments initiative, said people with severe allergies should not be vaccinated, given that two people vaccinated in the United Kingdom this week had symptoms of anaphylactoid reaction. But FDA, not Operation Warp Speed, has the regulatory authority to make that decision. Details would be in the emergency use authorization.
FDA vaccine reviewer Susan Wollersheim said in a presentation that the agency did find in its own analysis that the trial participants who got the vaccine may have been slightly more prone to allergic reactions than those getting the placebo. Potential allergic reactions were seen in 137 people, or 0.63 percent of those getting the vaccine, compared to 111 people in the placebo group, or 0.51 percent. None of the apparent allergic reactions recorded was severe.
The FDA is finishing work on fact sheets to give to health care providers and patients informing them that until the vaccine receives full approval, it is still considered “investigational,” and detailing some common side effects, according to Marion Gruber, director of the FDA’s office of vaccines research and review. Those fact sheets will include information for people with a history of allergic reactions to vaccines and medicines.
Committee member Paul Offit, a Children’s Hospital of Philadelphia vaccinologist, suggested more studies should be done on whether people with common allergies react to the vaccine. While Offit said it is unlikely people with allergies would experience severe reactions, more research could help quell concerns.
“This issue is not going to die until we have better data,” Offit said.
Another potential side effect is Bell’s palsy, which occurred in four trial participants who received the vaccine and none in the placebo group.
FDA indicated the incidence was not higher among trial participants than in the general population.
But VRBPAC member Michael Kurilla, a National Center for Advancing Translational Sciences expert in immunology, raised concerns that it could be related to the vaccine, given that coronavirus has neurological effects, like the loss of control and taste.
“Given the small number of cases, it would be difficult to attribute causation at this time,” said Wollersheim.
This is unlikely to slow an authorization but will be something the FDA monitors during the vaccine rollout.
“Given the severity of the pandemic, I don’t think it’s a showstopper,” said M. Miles Braun, former epidemiologist with FDA’s Center for Biologics Evaluation and Research, not affiliated with the VRBPAC.
Call for more monitoring
One criticism of the way that the vaccine has been tested came up in the meeting. The clinical trial data indicates the vaccine prevents symptoms, but some experts want more data on the idea that the vaccine prevents severe disease.
Just 10 clinical trial participants experienced severe disease, and nine of them got the placebo. That suggests that efficacy in protection against more severe cases mirrors 95 percent efficacy of the vaccine overall.
Attorney Sheldon Toubman, VRBPAC’s designated consumer representative, pushed for more data on the vaccine’s ability to protect against severe COVID-19 cases.
The clinical trial stopped collecting data on Nov. 14 so the drugmakers could submit their paperwork to the FDA on Nov. 20.
Surely, Toubman said, more people in the study have gotten severely sick with COVID-19 since then.
“Is there data from Pfizer right now, as of yesterday, which shows additional cases that gives us more data [on severe disease]?” he said.
“Severe disease is what people really care about. Frankly, almost nobody cares whether the vaccine prevents you from getting a sore throat,” Toubman continued.
Doran Fink, an FDA official with the division of vaccines and related products applications, emphasized that in the history of vaccines, there is plenty of evidence that shots that protect against mild disease protect better against severe disease, and little evidence of a vaccine that would protect against mild disease but not severe disease.
There were also concerns about whether potential side effects had been studied long enough in Black and Latino patients, given a push by Pfizer to prioritize their recruitment toward the end of the trial.
“Do we have an adequate amount of follow-up data for that group?” asked VRBPAC member James Hildreth, Meharry Medical College chief executive officer.
William Gruber, Pfizer's head of vaccine clinical research and development, expressed confidence in the data, with some caveats.
“I feel confident that minority communities were recruited throughout, perhaps with a bit more toward the end,” Gruber said. “I’m convinced the data supports those minority communities were followed for a long enough time, certainly to demonstrate efficacy, within the limits of some of those groups having a smaller number of total cases.”