FDA Analysis Chills the Rush to Approve Boosters

Brenda Goodman, MA

September 16, 2021

The US Food and Drug Administration (FDA) has posted its review of Pfizer's application for permission to market a third dose of its COVID-19 vaccine to the public, setting the stage for what is likely to be a hot debate on Friday among an independent panel of experts that advises that agency on its regulatory decisions.

"It's going to be a split vote. There's no way they're going to reach unanimity among the advisors," said John Moore, PhD, professor of microbiology and immunology at the Weill Cornell School of Medicine, New York City.

Moore said while there is evidence that third doses can benefit people who are immunocompromised or over the age of 65, Pfizer has asked the FDA to approve boosters, at 6 months after the second dose, for anyone over the age of 16. There's far less evidence to support of boosters for teens and younger adults.

"I just cannot see how everyone on the committee is going to buy into that idea," said Moore.

The meeting on Friday of the FDA's Vaccines and Related Biological Products Advisory Committee — a panel of experts convened by the agency to advise on its regulatory decisions — will be closely watched. Their vote is not binding, but the FDA typically follows their recommendations.

The FDA's analysis says that after assessing — but not independently reviewing or verifying — available evidence, the "overall data indicate that currently US-licensed or authorized COVID-19 vaccines still afford protection against severe COVID-19 disease and death in the United States."

The FDA's consideration of booster doses will likely delve into a complex stew of questions:

  • Should the agency base its regulatory actions on the efficacy of the vaccines as they stand today or act based on what could happen in the future as more variants emerge?

  • Do boosters add collective value by slowing transmission of the virus? Or do they mostly prevent infections on par with severe colds? 

  • Will the continued funneling of finite vaccine doses to wealthy countries hinder the rest of the world's ability to vaccinate against the virus.

The United States has largely looked to Israel, which has already rolled out third doses, for cluea as to what lies ahead with immunity. Critics say Israel has never released detailed data supporting its contention that the protection of the Pfizer vaccine against severe COVID outcomes has diminished over time. The FDA briefing document says some of that data will be reviewed at Friday's meeting.

The stakes are high. The United States, as with many other wealthy countries, has largely pinned its hopes for exiting the restrictions of the pandemic on having as-needed supplies of high-quality vaccines. 

At the same time, the focus on providing boosters to Americans and citizens of other countries has been called short-sighted when so much of the world's population is still unvaccinated. As long as the virus spreads anywhere, there's always the risk that it will change and become resistant to the antibodies the vaccines generate against it, drawing out the cycle of devastating surges capable of crippling whole countries and regions at a time.

Breakthrough Infections

An FDA-requested analysis of Pfizer's own study data should further fuel the controversy. The analysis looked at vaccine breakthrough infections during the Delta surge — from July through August of 2021. It showed that a person's risk depended upon when they were last vaccinated.

The more than 18,000 study participants originally assigned to get the vaccine — who are now about 10 months away from their last doses — had a higher rate of Delta-caused breakthrough infections compared with 18,000 study participants who were switched from placebo shots to the vaccines after the study was unblinded.

There were roughly 70 infections for every 1000 person-years in the originally vaccinated group compared to 51 infections for every 1000 person-years in the more recently vaccinated group, representing a 27% decrease in infections.

The more recently vaccinated study participants are about 5 months away from their last doses. There were only three serious breakthrough infections out of all the original study participants, however, they were all in the earliest vaccinated group.

And there's another twist. A further analysis that looked at breakthrough infections in very recently vaccinated people — those who were 4 months or less away from their second doses — found cases more than tripled during the Delta surge, rising from about 13 cases for every 1000 person-years before Delta compared with 43 infections per 1000 person-years during Delta.

The FDA reviewers write that this suggests that although waning immunity is one factor driving breakthrough infections, there's likely some quality of the Delta variant itself — the way it is transmitted or how well the vaccine protects against it — that's also at play.

The FDA review also concluded that third doses of the Pfizer vaccine, which was tested in about 300 people, seemed to be safe. Swollen lymph nodes were the most commonly reported adverse event, affecting about 5% of people who got third doses. 

There were no cases of Bell's palsy, myocarditis or pericarditis, or appendicitis.

The FDA's brief also notes that because 16- and 17-year-olds were not included in the booster studies, there's no direct evidence to support approval for this age group. Any approval for this age group would depend on extrapolation of data from adults.

Foregone Conclusion?

All these issues, and the questions they raise Friday, are not likely to change the ultimate outcome, Moore said.

The Biden administration announced in August that the booster doses would be offered to Americans starting on September 20, undercutting its regulatory agencies and prompting the resignations of two experienced vaccine reviewers at the FDA.

"The horse is out of the barn on this. There's going to be boosters," said Moore. "I think the debate will be whether it really is appropriate to go for everyone over the age of 16, which is what Pfizer is asking for," he said.

The CDC's Advisory Committee on Immunization Practices will meet next week to make recommendations on exactly who should get the boosters and how they should be given.


John Moore, PhD, professor of microbiology and immunology, Weill Cornell School of Medicine, New York, New York.

FDA, Briefing Document, Vaccines and Related Biological Products Advisory Committee, September 15, 2021.

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