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Data from an ongoing clinical trial showed that a booster dose of Pfizer/BioNTech's COVID-19 vaccine (Comirnaty) produced an immune response and no increased risk of severe adverse events, FDA staff said in .

The FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) is slated to meet on Friday to evaluate whether a booster dose of Pfizer's vaccine is safe and effective 6 months after the primary two-dose series.

Absent from FDA's documents were real-world data from Israel on booster doses, which White House officials, including NIAID director Anthony Fauci, MD, have touted in recent press briefings. In Pfizer's own ahead of the VRBPAC meeting, the company said the experience in Israel suggests the booster "restores" the 95% vaccine effectiveness rate seen earlier in the pandemic.

Primary support for the boosters comes from a immunobridging analysis from the phase II/III participants of the ongoing Pfizer study, , which was the basis for the vaccine's initial emergency use authorization and recent approval. The analysis compared neutralizing antibody titers against the reference strain 1 month following the booster dose versus those at 1 month following the two-dose primary series.

FDA stated that "effectiveness of the booster dose against the reference strain is being inferred" with the immunobridging data. The agency added that the vaccine met "immunobridging success criteria for the reference strain" for two co-primary immunogenicity endpoints: both geometric mean titers (GMT) ratio and difference in seroresponse rates among seronegative study participants prior to 1 month following the booster dose.

Pfizer amended its protocol in February and March 2021 to evaluate the safety, immunogenicity, and (yet unseen) efficacy of a booster dose. The cohort was comprised of 11 adults ages 18-55 and 12 adults ages 55 and older from the phase I trial about 7-9 months after a two-dose primary series, and 306 participants from the phase II/III trial about 6 months after the primary series. Most were white, with the FDA noting that phase I excluded individuals with comorbidities that put them at risk for severe COVID-19, and 20% of the phase II/III booster cohort were those high-risk individuals.

In the phase II/III booster cohort, "the 50% neutralizing GMTs at 1 month after booster dose were approximately 3-fold higher than those observed at 1 month post-primary series," agency staff wrote.

A post-hoc analysis requested by the FDA found that "the booster dose seroresponse rate, with seroresponse defined as at least 4-fold rise relative to the pre-booster titer, was 93.9%," the agency said.

FDA also reported the results of Pfizer's post-hoc analysis of vaccine efficacy during the Delta variant surge, noting, however, that this had not been "independently verified" by agency staff. FDA staff seemed dismissive of this analysis, noting the small sample size (23 participants from phase I) and that "the data were generated using non-validated SARS-CoV-2 plaque reduction neutralization assays with the reference strain ... and the Delta variant; the relative sensitivity of the two assays is not known."

Examining safety, among the 306 participants in the phase II/III cohort ages 18-55, there was one serious adverse event, a myocardial infarction, unrelated to the booster dose. In the 23 participants from phase I, none reported adverse events or serious adverse events up to 1 month after the booster. There were no deaths in either cohort.

As with the initial two-dose series, reactogenicity was more frequently reported in younger versus older adults. Injection site pain, fatigue, and headache were most commonly reported. FDA staff noted an imbalance in lymphadenopathy among booster recipients (5.2% vs 0.4%), which was described as mild to moderate and lasting about 2-8 days. Two cases were reported as ongoing at the time, FDA staff noted.

There were no cases of myocarditis, pericarditis, anaphylaxis, appendicitis, or Bell's palsy reported by any booster dose recipient through the study cutoff dates, FDA staff added.

At a briefing at the 2021 National Health Research Forum on Wednesday, Peter Marks, MD, PhD, director of FDA's Center for Biologics Evaluation and Research, spoke of the "scientific" need for booster doses.

"There is a scientific issue of what is the right thing to do to maximally protect against further circulation of COVID-19, and one can think that if one does not adequately deal with this in the population, we could end up with, unwittingly facilitating getting to that Omega variant more quickly," he said.

Marks added that "breakthrough infections against vaccines create issues with vaccine confidence."

"We have a vaccine confidence problem in this country, and we don't need to exacerbate it any further," he noted.

Whither Israeli Data?

The real-world evidence on the booster experience in Israel, included in Pfizer's briefing documents, involved data from over 1 million individuals ages 60 and older from July 30 to August 22. Infection rates at least 12 days after the booster were compared between individuals who received a booster dose and those who received only the primary series.

Detailed data published in the New England Journal of Medicine (NEJM) showed a greater number of new infections in the non-booster group compared to the the booster group (4,439 vs 934, respectively), for an adjusted rate ratio (aRR) of 11.3 (95% CI 10.4-12.3). And more cases of severe illness in the non-booster group (294 vs 29; aRR 19.5, 95% CI 12.9-29.5).

Pfizer said that this translates to approximately a 95% vaccine effectiveness rate, similar to the rate seen against the Alpha variant earlier in the year.

In addition, within the booster group, the rate of confirmed infection was lower at least 12 days after vaccination versus 4-6 days later by a factor of 5.4 (95% CI 4.8-6.1), the NEJM data showed.

Pfizer also noted that no new safety signals or adverse events were identified, and that reactogenicity profiles were similar to those in the primary series.

Israeli researchers are slated to present these data at Friday's VRBPAC meeting.

Another interesting wrinkle in the meeting will be that Marion Gruber, PhD, FDA's director of the Office of Vaccines Research and Review, will introduce the topic of booster doses at the meeting on behalf of the agency. Gruber is leaving the FDA after rumored friction over the FDA's role in boosters, and recently stating that they were unnecessary.

Washington Correspondent Shannon Firth contributed to this story.

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