Both Knockouts, but one seems to have the advantage

It was a constant refrain from federal health officials after the coronavirus vaccines were cleared: These injections are just as effective.

This turned out to be wrong.

About 221 million doses of the Pfizer-BioNTech vaccine have been distributed so far in the United States, compared to about 150 million doses of Moderna’s vaccine. In half a dozen studies published in the past few weeks, Moderna’s vaccine appeared to be more protective than the Pfizer-BioNTech vaccine in the months after vaccination.

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Research released by the Centers for Disease Control and Prevention on Friday found that the effectiveness of the Pfizer-BioNTech vaccine against hospitalization increased from 91% to 77% after a four-month period following the second shot. The Moderna vaccine showed no decline over the same period.

If the efficacy gap continues to widen, this may have implications for the booster debate. Federal agencies are this week assessing the need for a third injection of the Pfizer-BioNTech vaccine for certain high-risk groups, including the elderly.

Scientists who were initially skeptical of the reported differences between Moderna and Pfizer-BioNTech vaccines have slowly become convinced that the disparity is small but real.

“Our basic assumption is that mRNA vaccines work the same way, 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.”

But the gap is small and the real-world consequences are uncertain, as both vaccines are still very effective in preventing serious illness and hospitalizations, they warned with others.

“Yes, probably a real difference, probably reflecting the contents of the two vials,” said John Moore, virus expert at Weill Cornell Medicine in New York City. “But really, how much does this difference matter in the real world?” “

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“It is not appropriate for people who have taken Pfizer to panic that they have received an inferior vaccine.”

Even in the original clinical trials of the three vaccines eventually cleared in the United States – conducted by Pfizer-BioNTech, Moderna, and Johnson & Johnson – it was clear that the J&J vaccine was less effective than the other two. Research since then has confirmed this trend, although J&J announced this week that a second dose of its vaccine increases its effectiveness to levels comparable to others.

The Pfizer-BioNTech and Moderna vaccines are based on the same mRNA platform, and in early clinical trials they had remarkably similar efficacy against symptomatic infections: 95% for Pfizer-BioNTech and 94% for Moderna. This is partly why they have been described as more or less equivalent.

The subtleties have appeared over time. Vaccines have never been directly compared in a carefully designed study, so data indicating that effects vary is mostly based on observations.

The results of these studies can be skewed by a number of factors, including location, age of the vaccinated population, when they were immunized and the time between doses, Dean said.

For example, the Pfizer-BioNTech vaccine was rolled out weeks before Moderna’s vaccine to priority groups – the elderly and healthcare workers. Immunity declines more rapidly in the elderly, so a decline observed in a group of predominantly elderly people may give the false impression that the protection of the Pfizer-BioNTech vaccine is declining rapidly.

Given these caveats, “I’m not convinced there really is a difference,” said Dr. Bill Gruber, senior vice president at Pfizer. “I don’t think there is enough data to make this claim.”

But to date, observational studies have provided results in a number of places – Qatar, the Mayo Clinic in Minnesota, several other states in the United States – and among healthcare workers, hospitalized veterans or the general population.

The effectiveness of Moderna against serious illness in these studies ranged from 92% to 100%. Pfizer-BioNTech’s figures were trailing 10 to 15 percentage points.

The two vaccines diverged more strongly in their effectiveness against infection. Protection against both declined over time, especially after the arrival of the delta variant, but Pfizer-BioNTech vaccine values ​​declined. In two of the recent studies, the Moderna vaccine was more successful at preventing the disease by more than 30 percentage points.

A few studies have found that the levels of antibodies produced by the Pfizer-BioNTech vaccine are one-third to one-half of those produced by the Moderna vaccine. Still, this decrease is insignificant, Moore said: For comparison, there is a more than 100-fold difference in antibody levels in healthy individuals.

Still, other experts have said the body of evidence points to a disparity worth exploring, at least in people who respond poorly to vaccines, including the elderly and those who are immunocompromised.

“Ultimately, I think there are subtle but real differences between Moderna and Pfizer,” Dr. Jeffrey Wilson, immunologist and physician at the University of Virginia in Charlottesville, co-authored one of these studies, published in JAMA Network Open this month. “In high-risk populations, this might be relevant. It would be nice if people watched closely.

“Pfizer is a big hammer,” Wilson added, but “Moderna is a hammer.”

Several factors could explain the discrepancy. Vaccines differ in dosage and in the time between the first and second dose.

Vaccine makers would usually have enough time to test a range of doses before choosing one – and they have performed such tests for their trials of the coronavirus vaccine in children.

But in the midst of a pandemic last year, companies had to guess at the optimal dose. Pfizer went with 30 micrograms, Moderna with 100.

Moderna’s vaccine relies on a lipid nanoparticle, which can deliver the highest dose. And the first and second injections of this vaccine are delayed by four weeks, against three for the Pfizer-BioNTech vaccine.

The extra week can give immune cells more time to proliferate before the second dose, said Dr Paul Burton, Moderna’s chief medical officer. “We need to continue to study this and do more research, but I think it’s plausible.”

The Moderna team recently showed that half a dose of the vaccine further skyrocketed antibody levels. Based on that data, the company this month asked the FDA to allow 50 micrograms, the half dose, as a booster shot.

There is limited evidence showing the effect of this dose, and none on the duration of higher antibody levels. Federal regulators are reviewing Moderna’s data to determine whether there is sufficient data available to authorize a half-dose booster.

Ultimately, both vaccines remain stable against serious illness and hospitalizations, especially in people under 65, Moore said.

Scientists had initially hoped that the vaccines would be 50% or 60% effective. “We would all have seen this result as a great result and we would have been happy with it,” he said. “Fast forward to now, and we wonder if the vaccine effectiveness of 96.3% for Moderna versus 88.8% for Pfizer is a big deal. “

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