A study published Wednesday in The New England Journal of Medicine is the latest to show that Moderna's vaccine appears to be more protective than the Pfizer-BioNTech vaccine in the months after immunization.
The study evaluated the real-world effectiveness of the vaccines at preventing symptomatic illness in about 5,000 health-care workers in 25 states. It found that the Pfizer-BioNTech vaccine had an effectiveness of 88.8%, compared with Moderna's 96.3%.
Research published Friday by the Centers for Disease Control and Prevention found that the efficacy of the Pfizer-BioNTech vaccine against hospitalization fell from 91% to 77% after a four-month period. The Moderna vaccine showed no decline over the same period.
Roughly 221 million doses of the Pfizer-BioNTech vaccine have been dispensed thus far in the United States, compared with about 150 million doses of Moderna's vaccine.
Scientists who were initially skeptical of the reported differences between the Moderna and Pfizer-BioNTech vaccines have slowly become convinced that the disparity is small but real.
"Our baseline assumption is that the mRNA vaccines are functioning similarly, but then you start to see a separation," said Natalie Dean, a biostatistician at Emory University in Atlanta. "It's not a huge difference, but at least it's consistent."
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But the discrepancy is small and the real-world consequences uncertain, because both vaccines are still highly effective at preventing severe illness and hospitalization, she and others cautioned.
"Yes, likely a real difference, probably reflecting what's in the two vials," said John Moore, a virus expert at Weill Cornell Medicine in New York. "But truly, how much does this difference matter in the real world?"
"It's not appropriate for people who took Pfizer to be freaking out that they got an inferior vaccine."
Even in the original clinical trials of the three vaccines eventually authorized in the U.S. -- made by Pfizer-BioNTech, Moderna and Johnson & Johnson -- it was clear that the Johnson & Johnson vaccine had a lower efficacy than the other two. Research since then has borne out that trend, although Johnson & Johnson announced this week that a second dose of its vaccine boosts its efficacy to levels comparable to the others.
The Pfizer-BioNTech and Moderna vaccines rely on the same mRNA platform, and in the initial clinical trials, they had remarkably similar efficacy against symptomatic infection: 95% for Pfizer-BioNTech and 94% for Moderna. This was in part why they were described as more or less equivalent.
The subtleties emerged over time. The vaccines have never been directly compared in a carefully designed study, so the data indicating that effects vary are based mostly on observations.
Results from those studies can be skewed by any number of factors, including the location, the age of the people vaccinated, when they were immunized and the timing between the doses, Dean said.
For example, the Pfizer-BioNTech vaccine was rolled out weeks before Moderna's to priority groups -- older adults and health care workers. Immunity wanes more quickly in older adults, so a decline observed in a group consisting mostly of older adults may give the false impression that the protection from the Pfizer-BioNTech vaccine falls off quickly.
Given those caveats, "I'm not convinced that there truly is a difference," said Dr. Bill Gruber, a senior vice president at Pfizer. "I don't think there's sufficient data out there to make that claim."
But by now, the observational studies have delivered results from a number of locations -- Qatar, the Mayo Clinic in Minnesota, several other states in the U.S. -- and in health care workers, hospitalized veterans and the general population.
Moderna's efficacy against severe illness in those studies ranged from 92% to 100%. Pfizer-BioNTech's numbers trailed by 10 to 15 percentage points.
The two vaccines have diverged more sharply in their efficacy against infection. Protection from both waned over time, particularly after the arrival of the delta variant, but the Pfizer-BioNTech vaccine's values fell lower. In two of the recent studies, the Moderna vaccine did better at preventing illness by more than 30 percentage points.
"At the end of the day, I do think there are subtle but real differences between Moderna and Pfizer," said Dr. Jeffrey Wilson, an immunologist and physician at the University of Virginia in Charlottesville who was a co-author of one such study, published in JAMA Network Open this month. "In high-risk populations, it might be relevant. It'd be good if people took a close look."
"Pfizer is a big hammer," Wilson added, but "Moderna is a sledgehammer."