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A US Food and Drug Administration (FDA) advisory panel voted unanimously today to recommend a booster dose of Pfizer’s mRNA COVID-19 vaccine for those 65 and older, and for those at high risk of severe outcomes from the disease, including healthcare workers.
This followed an earlier 16-2 vote by the FDA’s Vaccines and Related Biological Products Advisory Committee rejecting a booster dose for American age 16 and over.
Pfizer initially wanted the FDA to amend the Biologics License Application (BLA) for its Comirnaty vaccine to allow all Americans over the age of 16 get a booster dose at least 6 months after their second dose.
A supplemental BLA is the typical way boosters are authorized in the US, but it requires a higher bar of evidence and more regulatory scrutiny than the agency had been able to give since Pfizer filed for the change just days after it was granted full approval for its COVID vaccine.
The committee’s actions were also a rebuff to the Biden administration, which had prematurely announced that boosters would be rolled out to the general public by September 20. The announcement triggered the resignations of two of the agency’s top vaccine reviewers, who both participated in Friday’s meeting.
Marion Gruber, PhD, director of the FDA’s Office of Vaccines acknowledged that today’s meeting would be her last, and she thanked the American public.
“It has been a privilege to serve you. All of my actions and decisions over my 32-year career have been grounded in science, with you in mind, and in the best interest of your health and safety. And I will continue to hold fast to these principles moving forward,” she said.
After initially voting against Pfizer’s request to change its BLA, the committee then worked on the fly with FDA officials to craft a strategy that would allow third doses to be offered under an Emergency Use Authorization (EUA).
An EUA requires a lower standard of evidence and is more specific. It will restrict third doses to a more defined population than a change to the license would. It will also require Pfizer to continue to monitor the safety of third doses as they begin to be administered.
“This should demonstrate to the public that the members of this committee are independent of the FDA and that we do, in fact, bring our voices to the table when we are asked to serve on this committee,” said Archana Chattergee, MD, PhD, a pediatric infections disease specialist who is dean of the Chicago Medical School at Rosalind Franklin University in Illinois.
The FDA doesn’t have to follow the committee’s recommendation, but it typically does, while retaining the right to make changes.
“We are not bound at FDA by your vote, we can tweak this,” said Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research at the FDA. Marks participated in the meeting and helped to draft the revised proposal.
After the FDA issues the anticipated EUA, a council of independent advisors to the Centers for Disease Control and Prevention (CDC) will meet to make specific recommendations about how the third doses should be given. After the CDC director weighs in, third doses will begin rolling out to the public.
Moderna submitted data to the FDA on September 1 in support of adding a booster dose to its regimen. The agency has not yet scheduled a public review of that data.
The Biden administration is prepared to administer shots as soon as they get the green light, Surgeon General Vivek Murthy, MD, said at a Friday White House briefing.
“This process is consistent with what we outlined in August where our goals were to stay ahead of the virus,” Murthy said. “Our goal then and now is to protect the health and well-being of the public. As soon as the FDA and CDC complete their evaluations, we will be ready to move forward accordingly.”
“We’ve used this time since our August announcement to communicate and coordinate with pharmacy partners, nursing homes, states and localities,” he said.
White House COVID-19 Response Coordinator Jeff Zients said vaccine supply is “in good shape for all Americans to get boosters as recommended.”
Taking Cues From Israel
In considering Pfizer’s original request, the committee overwhelmingly felt that they didn’t have enough information to say that the benefits of an additional dose of vaccine in 16 and 17-year-olds would outweigh their risk.
Adolescents have the highest risk of a rare side effect of myocarditis after vaccination. It is not known how the vaccines are causing this heart swelling. Most teens who have been diagnosed with the condition have recovered, though some have needed hospital care.
Pfizer didn’t include 16 and 17-year-olds in its studies of boosters, which included about 300 people between the ages of 18 and 55. The company acknowledged that gap in its data but pointed to FDA guidance that said evidence from adults could be extrapolated to teens.
“We don’t know that much about risks,” said committee member Eric Rubin, MD, PhD, who is editor-in-chief of the New England Journal of Medicine.
Much of the data on the potential benefits and risks of third Pfizer doses come from Israel, which first began rolling out boosters to older adults in July.
In a highly anticipated presentation, Sharon Alroy-Preis, Israel’s director of public health services, joined the meeting to describe the nation’s experience with boosters.
Israel began to see a third surge of COVID cases in December.
“This was after having two waves and two lockdowns,” Alroy-Preis said. By the third surge, she said, Israelis were tired.
“We decided on a lockdown, but the compliance of the public wasn’t as it was in the previous two waves,” she said.
Then the vaccine arrived. Israel started vaccinating soon after the FDA approved it in the US, and they quickly vaccinated a high percentage of their population, about 3 months faster than the rest of the world.
All vaccinations are reported and tracked by the Ministry of Health, so the country is able to keep close tabs on how well the shots are working.
As vaccines rolled out, cases fell dramatically. The pandemic seemed to be behind them. Then Delta arrived in March. By June, Israel’s cases were doubling every 10 days, despite about 80% of their most vulnerable adults being fully vaccinated, Alroy-Preis said.
Most concerning was that about 60% of severe cases were breakthrough cases in fully vaccinated individuals.
“We had to stop and figure out, was this a Delta issue,” she said. “Or was this a waning immunity issue.… We had some clue that it might not be the Delta variant, at least not alone.”
People who had originally been first in line for the vaccines, seniors and healthcare workers, were having the highest rates of breakthrough infections since they were farther away from their second dose.
Alroy-Preis said that if they had not started booster doses in July, their hospitals would have been overwhelmed. They had projected that they would have 2000 cases in the hospital each day.
Boosters have helped to flatten the curve, though they are still seeing a significant numbers of infections.
Data from Israel presented at the meeting show boosters are largely safe and effective at reducing severe outcomes in seniors. Israeli experience also showed that third doses, which generate very high levels of neutralizing antibodies — the first and fastest line of the body’s immune defense — may also slow transmission of the virus.
Key Differences in the US
The benefit of slowing down explosive spread of a highly contagious virus was tantalizing, but many panel members noted that circumstances in Israel are very different than in the US.
Israel went into its current Delta surge already having high levels of vaccination in their population. They also relied on the Pfizer vaccine almost exclusively for their campaign.
The US used a different mix of vaccines and doesn’t have the same high level of vaccination coverage of its population.
In the US, transmission is mainly being driven by unvaccinated people, Rubin noted.
“That really means the primary benefit is going to be in reducing disease,” he said, “And we know the people who are going to benefit from that … and those are the kinds of people the FDA has already approved a third dose for,” he said, referring to an August authorization for immunocompromised people.
But Israel only began vaccinating younger people a few weeks ago. Most are still within a window where rare risks like myocarditis could appear, Rubin said.
He and other members of the committee said they wished they had more information about the safety of third doses in younger adults.
“We don’t have that right now, and I don’t think I would be comfortable giving it to a 16 year old,” Rubin said.
At the same time, the primary benefit for third doses would be in preventing severe disease, and overall, data from the US and other countries show that two doses of the vaccines remain highly effective at preventing hospitalization and death.
Asked why Israel began to see more severe cases in fully vaccinated people, the CDC’s Sara Oliver, MD, said it was probably due to a mix of factors including the fact that Israel defines severe cases a little differently.
In the US, a severe case is generally a person who has to be hospitalized or who has died from their infection. In Israel, a person with a severe case is someone who has an elevated respiratory rate and someone who has a blood oxygen level less than 94%. In the US, that kind of patient wouldn’t necessarily be hospitalized.
In the end, one of the two committee members who wanted full approval for Pfizer’s third doses said he was satisfied with the outcome.
Mark Sawyer, MD, a professor of pediatrics and infectious disease at the University of California at San Diego said he voted yes on the first question because he thought full approval was the best way to give physicians the flexibility to prescribe the shots to vulnerable individuals.
“I’m really glad we authorized a vaccine for a third dose, and I plan to go out and get my vaccine this afternoon,” Sawyer said, noting that he was at high risk as a healthcare provider.