A highly-anticipated Food and Drug Administration review of evidence on whether a booster shot of the Pfizer-BioNTech coronavirus vaccine is widely necessary struck a noncommittal tone Wednesday, setting the stage for a potentially fractious debate among expert advisers to the agency this week.

Pfizer and government officials have relied heavily on data from Israel in making the case to the public that boosters are necessary six months after full vaccination. One of the studies from Israel, published Wednesday in the New England Journal of Medicine, showed that people 60 and older who were given a booster shot had an 11-fold lower risk of contracting an infection than people who did not receive the additional shot. But FDA reviewers cautioned that a raft of studies with clear limitations have emerged in the last few months, pointing out that “biases can affect their reliability.” The reviewers stated that “US-based studies . . . may most accurately represent vaccine effectiveness.”

Some studies have suggested the efficacy of the vaccines declines against symptomatic infections, but some have not, agency reviewers wrote.

“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,” they wrote. “There are many potentially relevant studies, but FDA has not independently reviewed or verified the underlying data or their conclusions.”

The documents were released in advance of the FDA’s full-day meeting with its vaccine advisory committee Friday. The outside experts will weigh whether the agency should approve a booster for the Pfizer-BioNTech shot. Pfizer was the first vaccine maker to file its application and data with the agency.

The experts will vote on whether a booster should be approved by FDA, but their recommendation is not binding. The agency typically follows the recommendations of its advisers.


Infectious-disease experts are united in regarding vaccination as the critical weapon for fighting the pandemic, but the booster issue has opened fissures within the scientific and medical communities. The debates are numerous, and go beyond who should get a booster and when.

While there is widespread agreement that certain populations, such as people with compromised immune systems or older people in nursing homes, will probably need boosters, some medical experts feel it is unclear whether third shots should be recommended for all healthy younger adults at this juncture. Pfizer is seeking approval of a booster for people 16 years and older six months after completing the two-shot regimen.

Boosters have become embroiled in controversy and mired in public confusion. In mid-August, senior Biden administration officials, worried about data showing waning vaccine efficacy, announced boosters would be available beginning the week of Sept. 20, pending sign-offs from the FDA and the Centers for Disease Control and Prevention.

Health officials later warned the White House that only the Pfizer-BioNTech product had a chance of being approved by then. Reviews of two other authorized vaccines, from Moderna and Johnson & Johnson, are further behind.

“They have made a mess of this” by telling the public boosters would be available before scientific reviews, said John P. Moore, an immunologist at Weill Cornell Medicine in New York.

In San Francisco, people who received the Johnson & Johnson one-shot vaccine and attest that they have spoken with their health-care provider can already get a booster shot with one of the mRNA vaccines from Pfizer and Moderna. The CDC has not recommended such boosters. And experts say they know people are taking matters into their own hands, without waiting for regulatory approvals.


“There are already doctors recommending booster doses, and there are patients who have gone out there, through hook or crook, and have received boosters already,” said William Schaffner, an infectious-diseases professor at Vanderbilt University School of Medicine. “The average patient and the average doctor think a recommendation with a capital R has already been made. Washington got out ahead of its skis a little bit.”

Schaffner, who serves as a liaison to the CDC’s Advisory Committee on Immunization and Practices, which plays a key role in the agency’s recommendations, said there is a growing push among the panel to prioritize boosters for people in the first groups to receive vaccines – front-line health-care workers, people in nursing homes and then the elderly – before working down the age ladder. The Biden administration had suggested boosters for everyone 18 and older.

Pfizer officials have repeatedly made the case that a booster will be needed six to 12 months after full vaccination.

Pfizer presented data to the FDA showing that virus-blocking antibodies increased more than fivefold after a third dose of its original vaccine.

Those antibodies neutralized known variants of the coronavirus, including the highly transmissible delta. Pfizer has been developing a delta-specific booster, but because known variants remain susceptible to a third shot of the original formulation, it may simply be a trial run. The company’s goal is to be able to switch strains within 100 days, in the event variants capable of eluding existing vaccines emerge.

Pfizer’s call for boosters relies in part on the company’s follow-up of its 44,000-person clinical trial, which showed the vaccine’s ability to prevent any symptomatic infection declined gradually during six months. Initial protection was 96 percent in the first two months after vaccination, which fell to 90 percent during the next two months, and then to about 84 percent.


The vaccine’s protective effects against any symptomatic infection appeared to fall about 6 percentage points every two months, according to the company’s analysis, but protection against serious cases of disease remained robust at 97 percent. Even as protection against infections eroded, the vaccine remained highly effective. The FDA initially set the bar for a successful vaccine at a minimum of 50 percent efficacy.

The case for boosters is highly dependent on evidence from real-world use of vaccines in Israel, particularly data anticipated to show a drop in protection against serious cases of illness. Israeli health officials are scheduled to present data Friday.

Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, said last week in a lecture at the London School of Hygiene & Tropical Medicine that personal communications with Israeli health officials revealed a “significant diminution” in the Pfizer-BioNTech vaccine’s protection against hospitalization. He acknowledged that American data so far showed only an “early inkling” of such a drop.

But he showed a slide showing an uptick in severe cases in vaccinated people in Israel starting in July and August, and called it a “profound change.”

Fauci said his interpretation of the data is that a third dose is not a booster, but could be thought of as a key part of the original vaccine regimen, akin to other regimens requiring three shots – hepatitis B, for example.

Research on the durability of immunity provides a bewildering array of evidence that could be used for or against boosters.


Israeli data released last month showed a significant drop in protection against illness among people who received their vaccinations early in the year. But some experts have cautioned against leaning too much on one country’s data. Much of the research in the United States has indicated an erosion in protection against mild disease but little to no drop in protection against severe disease and death.

Laboratory research published Tuesday in the journal Science showed that even a low dose of the Moderna vaccine – just 25 micrograms, a quarter of the typical dose – provides long-lasting immunity. The data showed that antibodies waned seven- to tenfold during seven months, but there was a much less significant waning of other critical elements of the immune system that can keep an infection in the nose and mouth from spreading to the lungs and triggering a potentially severe or fatal illness. Those elements include “helper” and “killer” T cells, and B memory cells that can generate new antibodies when the immune system detects an infection.

“We were surprised that even with the lowest dose, we still see a very robust immune response even seven months out,” lead author Daniela Weiskopf, a La Jolla Institute for Immunology researcher, said. “What we don’t know so far is what’s the level of immune response that you need.”

She and co-author Shane Crotty favor boosters at some point, because they should boost antibodies dramatically. This is where the booster debate gets enmeshed with questions of pandemic strategy. Is the goal simply prevention of severe disease or would it make sense to boost everyone’s antibodies in an attempt to suppress the virus by trying to prevent even mild infections?

“It makes sense to have a booster,” Crotty said. “It’ll probably keep those antibody titers higher for longer.”