A third shot of Pfizer's coronavirus vaccine spurs a heightened immune response and helps to guard against waning immunity, data published Wednesday indicate, lending weight to the Biden administration's push for a large-scale booster program despite resistance from some Food and Drug Administration officials and the World Health Organization.
Publication of two separate analyses Wednesday in The New England Journal of Medicine comes two days ahead of a meeting of FDA advisers to discuss Pfizer's application for authorization of a third shot.
An endorsement from the panel isn't certain, however, as the issue has become controversial for a range of reasons. At least one of the agency's advisers has previously argued booster doses aren't necessary yet, and documents released Wednesday suggest a neutral, or even equivocal, view from agency staff.
Moreover, two top FDA vaccine officials recently announced plans to retire, reportedly due in part to disagreement with the White House's plans, and this week joined WHO officials in penning an editorial against widespread rollout of boosters.
The larger dataset published in NEJM on Wednesday comes from an analysis of more than 1 million people in Israel aged 60 or older who received at least two doses of the Pfizer vaccine, now called Comirnaty. The rate of confirmed coronavirus infection among those given a third shot was more than 11 times lower than those who received only two shots, measured beginning 12 days after the additional dose in the former group.
The authors of that review, who are all university or government researchers, also analyzed the rate of severe illness between the two groups and found it to be 20 times lower among those who were boosted.
As a retrospective review taken from Israel Ministry of Health records, this analysis won't be viewed to be as persuasive as the placebo-controlled Phase 3 trial that won the original emergency authorization and then approval of Comirnaty. However, with effective vaccines widely available, designing a large trial in which some volunteers are randomized to a control arm is more difficult now, making so-called real-world evidence like the Israel analysis more likely to be used by policymakers.
The researchers acknowledged a range of biases, such as differences in behavior between groups, that could have impacted their results, particularly around the reported reduction in infection rate. The booster group, for instance, had more men and more volunteers who were over 70, although the researchers tried to adjust for that imbalance.
New data from the Phase 3 trial of Moderna's vaccine, also released Wednesday, should provide FDA advisers and reviewers with additional data points on waning immunity. The Massachusetts-based biotech disclosed the data in a press release, not a peer-reviewed journal as the Pfizer data was.
Moderna looked at study participants who received its original two-dose vaccine sequence in 2020 and compared them to those who received a placebo and then later "crossed over" to receive the active vaccine following the trial's primary analysis. The nearly 11,000 crossover participants had their first dose a median of eight months earlier, while those in the initial vaccine group, totaling around 15,000, had their first dose 13 months earlier.
The researchers identified 162 breakthrough COVID-19 cases between July and August this year in the initial vaccination group versus 88 in the crossover group — a rate of 77 cases per 1,000-person years compared to 49. That translates to a 36% lower incidence rate, Moderna said, suggesting an association between time from vaccination and the risk of breakthrough infection, after adjusting for age and risk factors.
The second analysis published in NEJM on Wednesday, from Pfizer, studied immune response in 23 Phase 1 clinical trial volunteers who had been given a third shot. One month after the third dose, levels of "neutralizing antibodies" — which bind to virus particles and prevent them from entering cells — were more than five times higher than at one month following the second dose in enrollees aged between 18 and 55. Among those 65 to 85 years old, antibody levels were more than seven times higher.
The researchers said side effects were mostly mild or moderate in nature and similar to what was observed following the first and second doses.
Data from 210 participants in Pfizer's Phase 3 study, contained in briefing documents for Friday's FDA advisory committee, shows a more modest immune response to the third dose. Neutralizing antibody levels one month after the third dose were three times higher than they were one month following the initial two-dose regimen. Fewer of those participants saw a fourfold rise in neutralizing antibody levels following the third dose than did following the initial two-dose regimen, the FDA said.
The FDA noted a similar side effect profile to the booster dose and said no cases of cardiac muscle swelling or allergic reactions — two rare adverse events of special interest — were reported.
Extrapolating from such a small group of individuals, however, could overlook meaningful differences in safety between the first two shots and a third, additional dose. The FDA, for instance, said in its briefing documents that it's currently unclear whether a booster dose of Pfizer's Cominarty is associated with an increased risk of swelling in and around the heart.