Sept. 17, 2020 -- An expert panel that advises the FDA on its regulatory decisions voted Friday against recommending third doses of Pfizer’s COVID-19 vaccine for younger Americans.

But they didn’t kill the idea of booster shots completely.  

In a dramatic, last-minute pivot, the 18 members of the FDA’s Vaccines and Related Biological Products Advisory Committee unanimously voted to recommend the FDA make boosters available for seniors and others at high risk of severe outcomes from COVID-19, including health care workers.

The 16-2 vote was a rebuttal to Pfizer’s initial request. The company had asked the FDA to allow it offer third doses to all Americans over the age of 16 at least six months after their second shot.

The company requested an amendment to the full approval the FDA granted in August. That is the typical way boosters are authorized in the U.S., 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 its vaccine was granted full approval.

The committee’s actions were also a rebuff to the Biden administration, which announced before the FDA approved them that boosters would be rolled out to the general public this coming Monday. The announcement triggered the resignations of two of the agency’s top vaccine reviewers, who both participated in Friday’s meeting.

After initially voting against Pfizer’s request to amend its license, 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.

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, a pediatric infectious 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 almost certainly will, though regulators said they may still make some changes.

“We are not bound at FDA by your vote, we can tweak this,” said Peter Marks, MD, director of the Center for Biologics Evaluation and Research at FDA. Marks participated in the meeting and helped to draft the revised proposal.

If the FDA issues the recommended emergency use authorization, a council of independent advisors to the CDC will make specific recommendations about how the third doses should be given. After the CDC director weighs in, boosters will begin rolling out to the public.

Moderna submitted data to the FDA on Sept. 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 White House briefing earlier Friday.

"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."

He added, "We've used this time since our August announcement to communicate and coordinate with pharmacy partners, nursing homes, states and localities."

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 its risk. Teens have the highest risk of rare heart inflammation after vaccination, a side effect known as myocarditis. It is not known how the vaccines are causing these cases of heart swelling. Most who have been diagnosed with the condition have recovered, though some have need 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,  who is editor-in-chief of the New England Journal of Medicine.

Much of the data on the potential benefits and harms of third Pfizer doses comes 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 Israel’s experience with boosters.

Israel began to see a third surge of COVID-19 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 vaccinations as soon as the FDA approved it, 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. Delta arrived in March. By June, their cases were doubling every 10 days, despite about 80% of their most vulnerable adults being fully vaccinated, she 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,” she said.

People who had originally been first in line for the vaccines, seniors and health care workers, were having the highest rates of breakthrough infections. People further away from their second dose were more likely to get a breakthrough infection.

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 2,000 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 shows 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 U.S.

The benefit of slowing down explosive spread of a highly contagious virus was tantalizing, but many members noted that circumstances in Israel are very different than in the U.S. 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 U.S. used a different mix of vaccines – Pfizer, Moderna and Johnson & Johnson -- and doesn’t have the same high level of vaccination coverage of its population.

In the U.S., 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 those with underlying health conditions.

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 noted.

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,” he said.

At the same time, the primary benefit for third doses would be in preventing severe disease, and overall, data from the U.S. 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, a disease detective with the CDC, said it was probably due to a mix of factors including the fact that Israel defines severe cases a little differently.

In the U.S., 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 U.S., 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 the University of California at San Diego said he voted yes on the first question because he though full approval was the best way to give doctors 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 health care provider.