Future Tense

The Differences Between the Moderna and Pfizer Vaccines Are Starting to Matter

A pile of empty vials of Moderna, Pfizer, and AstraZeneca vaccines
The Moderna vaccine comes in a bigger bottle, too. Christof Stache/Getty Images

A version of this article first appeared in Katelyn Jetelina’s newsletter, Your Local Epidemiologist.

Last week, the Food and Drug Administration’s external review board voted against a third Pfizer dose for the general public. They did recommend a third shot for older adults and some other higher-risk groups. But the question of who needs booster shots and when is still open.

As we look at the possibility of a third mRNA dose, another important question has risen to the surface: Do Pfizer and Moderna people need a third dose? Or just Pfizer people? In other words, is there a meaningful difference between Moderna’s and Pfizer’s protection against COVID-19?

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Throughout the pandemic, I’ve always lumped Moderna and Pfizer together. For example, if there was evidence that Pfizer worked against a variant, then Moderna surely worked too. These mRNA vaccines are incredibly similar, but they’re not identical. There are a few subtle differences between the two. First, the formulation: The fat bubbles that carry the mRNA are a bit different in their chemical structure. The dose of RNA encapsulated in those fat bubbles is different too: Moderna has a much higher dose (100 micrograms) compared with Pfizer (30 micrograms). The vaccines are also given on a different schedule, with Moderna doses four weeks apart and Pfizer three. And finally, a situational difference that still affects the data with which we’re making decisions: Pfizer was approved in the United States (and around the world) a few weeks (or in some cases months) prior to Moderna.

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At first, these small differences didn’t affect vaccine effectiveness. Both vaccines were extremely great at protecting against asymptomatic, mild, moderate, and severe disease. But the story might be changing.

Last month, the Mayo Clinic released a preprint of a very large study of 645,109 patients who were followed after vaccination (January–July 2021). The scientists wanted to describe breakthrough rates among those vaccinated with Moderna and with Pfizer, compared with COVID-19 rates among unvaccinated people. How were the vaccines holding up?

They found that both vaccines continued to work great against hospitalization, ICU admission, and death (there were no deaths in the study). This was the case in January 2021 and this was the case in July 2021. It didn’t change.

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Effectiveness against any infection (so, mild to moderate disease), though, was lower for both vaccines in July (76 percent effectiveness) compared with January (86 percent effectiveness). Interestingly, Pfizer’s effectiveness decreased faster over time (i.e., more breakthrough cases) compared with patients vaccinated with the Moderna vaccine (i.e., fewer breakthrough cases). Nonetheless, both vaccines were much better at preventing infections compared with no vaccine (unvaccinated patients).

We saw this in another study, too, which tested 196 elder nursing home residents in Canada after vaccination. Interestingly, residents with Pfizer mounted 3.89 times fewer neutralizing antibodies than residents with Moderna. This was most apparent with the beta variant (first discovered in South Africa, also called B.1.351).

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On Aug. 30, a Belgian study was published in JAMA. The scientists looked at antibody levels against the spike protein in 1,647 workers at a hospital in Belgium. Levels among those who got two doses of the Moderna vaccine averaged 2,881 units per milliliter, compared with 1,108 units per milliliter among those who received two Pfizer doses. The immune response was even greater for vaccinated people who had been previously infected. So the number of antibodies was higher, but as you may know, those numbers aren’t really meaningful. We don’t know what antibody number you need to say “you’re protected.”

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A Qatar study largely found the same thing.

And, finally, the most recent study was released on Friday from the Centers for Disease Control and Prevention. The CDC published a study that assessed vaccine effectiveness across all three vaccines: Moderna, Pfizer, and Johnson & Johnson. They analyzed data from 3,689 hospitalized adults at 21 hospitals across 18 states during March–August 2021. Immunocompromised patients were excluded. What did they find? Moderna’s effectiveness against hospitalization was 93 percent. Pfizer’s effectiveness was significantly lower at 88 percent. Pfizer’s effectiveness against hospitalization was also decreasing over time, while Moderna’s effectiveness held steady.

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So is there really a difference? Maybe. But we don’t know why yet. It could be due to the higher dosage of RNA in Moderna compared with Pfizer. The higher dosage may possibly explain the longevity of the response (or strength against delta). It could be the four weeks between doses in Moderna compared with the three weeks in Pfizer—the more time between doses, the stronger the response. We’ve seen this time and time again (and it may explain why we need a third dose). It could be timing. Moderna was offered later than Pfizer. That time difference, on a population level, may be influencing this difference. In other words, Moderna may start decreasing too; it just hasn’t had the time yet like Pfizer has.

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Or this could be nothing. The aforementioned studies had limitations (as all studies do), which may bias the conclusions. We need more studies showing the same thing among different populations to be more confident. We also need to figure out why. What’s driving the difference, and why does effectiveness seem to worsen?

Both vaccines continue to work against hospitalization and death. Will Moderna’s effectiveness eventually start to decline like Pfizer’s? Will Pfizer’s effectiveness against severe disease continue to decline among the general population like we saw in Israel? This, ladies and gentlemen, is causing the heated scientific debate among scientists. We cannot possibly stop all breakthrough infections, so is there a need for a booster for the general public? And if so, when?

Future Tense is a partnership of Slate, New America, and Arizona State University that examines emerging technologies, public policy, and society.

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