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Is Moderna really better than Pfizer, or is it just a higher dose?

Way back in February, when COVID-19 vaccines were still largely confined to the most vulnerable among us, public health leaders were determined to send a unified message: Don’t worry about the differences between vaccines. “All three of them are really really good, and people should take the one that’s most available to them,” Anthony Fauci said On Meet the press.

With hundreds of millions of vaccine doses distributed in the United States, we have reason to doubt that story. A recent (but not yet peer-reviewed) study of more than half a million U.S. veterans showed that the protection of the Johnson & Johnson shot against infection (whether or not leading to illness or hospitalization) plummeted from 88 percent to 3 percent in mid-August, while the effectiveness of the other vaccines had declined much less. Research published in recent months also indicates that Moderna’s shot beats Pfizer’s in both respects. number of antibodies and hospital admissions while a National Institutes of Health study published earlier this month found that Moderna’s booster injection increased participants’ antibody levels slightly more than Pfizer’s, and that both mRNA boosters were miles ahead of those. from J&J.

In light of all this data, it’s tempting to rank vaccines by brand name: Moderna is better than Pfizer is better than J&J. But the same numbers indicate a different pattern: Perhaps the most important thing isn’t which vaccine you get, but how much of it.

Consider how the vaccines differ in their dosage. J&J, the least effective in the studies, has only one shot in his primary series; the mRNA vaccines have two. So everyone who got J&J (and hasn’t gotten a booster yet) got a total of half the doses. If you compare Pfizer to Moderna, you see a different dose difference: each injection of Pfizer contains 30 micrograms of mRNA, while each dose of Moderna contains 100. (Doses for children can also vary in size: Pfizer has suggested injections of 10 micrograms, while Moderna will go with 50.) How much of the difference in the performance of the injections can be summed up by saying, “More vaccine is better”?

“More vaccine” is not an easy proposition. To begin with, doses of Pfizer and Moderna are measured in mass of mRNA lipid nanoparticles; J&J doses are measured by counting the number of harmless adenovirus particles each contains (about 50 billion). You can’t really compare lipid nanoparticles to viral particles, several experts told me. According to Michael Arand of the Institute of Pharmacology and Toxicology at the University of Zurich, you should not even assume that each dose of J&J of 50 billion particles will be the same size as the next, since, depending on the details of the production, some particles can be more contagious than others. A better dose measure for adenovirus-based vaccines, he argued in a recent opinion piece, would be “infectious units”. When I asked him via email if it would be possible to develop a standard measure that would work across different vaccine platforms, he said, “I don’t think so.”

Comparing doses of the Pfizer and Moderna vaccines is much easier because their mechanisms are so similar. Each injection of Moderna delivers more than three times as much of the active ingredient, compared to Pfizer, and appears to induce a higher number of antibodies and lead to more durable protection against infection and hospitalization. “Over time, that higher dose can make the difference in protective efficacy,” John Moore, a professor of microbiology and immunology at Weill Cornell Medicine, told me.

The vaccines also differ in their dosing schedules. Vaccinated (and unboosted) Americans have been given 60 micrograms of Pfizer over a three-week period, 200 micrograms of Moderna over four weeks, or 50 billion parts of J&J in one sitting. They are apples and pears, except you have to eat the apple in one sitting, and some oranges are tangerines, and you can only eat a few slices at a time.

Even the one-week difference between Pfizer’s schedule and Moderna’s can be significant. Mark Slifka, an immunologist at Oregon Health and Science University, told me it could help give Moderna’s slightly longer protection. Angela Rasmussen, a virologist at the Vaccine and Infectious Disease Organization at the University of Saskatchewan, pointed out that the AstraZeneca vaccine — an adenovirus vector design like J&J’s — also appears to provide more protection when doses are further apart.

The number of vaccine doses you receive also matters, regardless of their specific size and schedule. Slifka thinks the number of times you get a vaccine is much more important than the amount given in each syringe. Getting more than one dose “is actually the big equalizer among vaccinations,” he said, because it teaches the immune system that a particular threat should be taken seriously. Multiple rounds of a moderate dose may also be better than taking one megadose because the more vaccine you get at once, the worse your side effects are likely to be. “With the mRNA vaccines and the adenovirus vectors, there’s an upper limit to how much you can give [in one dose] before it’s just not a good idea,’ said Slifka.

U.S. public health authorities haven’t said it yet, but J&J “is really a two-dose vaccine,” Rasmussen told me. Paul Offit, who directs the Vaccine Education Center at the Children’s Hospital of Philadelphia, said J&J could be “just as good as the mRNA vaccines” when comparing two doses to two doses. He also suspects that a single dose of J&J would prevent more hospitalizations and deaths than a single dose of Pfizer or Moderna.

But that opinion is far from universal. “I have absolutely no doubt that adenoviruses are inferior technology to the mRNAs,” Moore said. Many fans of J&J’s injection speculate that the protection against hospitalization and death may last longer than the other vaccines’, thanks to the way in which tickles a certain series of immune system actors called T cells that help prevent infections from developing into serious disease. “There’s some kind of T-cell mafia around,” Moore said, but some studies have shown that the mRNA vaccines produce T cell responses with at least as much power as J&J’s. He says antibodies are a better proxy for protection anyway, and the Moderna and Pfizer options consistently produce more of them in the vaccinated.

A few experts continue to suspect that all three vaccines are somewhat interchangeable. For example, Slifka thinks that the differences between the adenovirus and the mRNA formulas– the way they attack our cells, the nature of the immune response they elicit in us – may not be particularly relevant to the protection they provide. “Both are nanoparticles. One is a virus nanoparticle and the other is a lipid nanoparticle, but they both do the same thing,” he said, delivering genetic material into human cells so that those cells can produce the coronavirus’ signature spike protein and give the immune system a response. can target. practice for when the real intruder arrives.

We will probably never know for sure how much of the difference between vaccines can be attributed to their formulas and how much comes from other factors. In theory, researchers could untangle those questions by conducting huge randomized controlled trials with slightly larger and smaller doses of each shot, and with different intervals between (of the same size) shots. But with half the world still to receive a single dose of a COVID-19 vaccine, and many good-enough regimens have already been identified, no one is going to spend resources on such granular questions.

“If last year hadn’t been such a shitstorm,” Moore said, “all these issues would have been ironed out.” For now, we’ll have to keep bumbling with our clunky toolbox of boosters and wait times and half doses – and count our blessings of living in a country where we have the luxury of asking how much vaccine is best.