Way back in February, when COVID-19 vaccines were still largely restricted to the most vulnerable among us, public-health leaders were determined to send a unified message: Don't worry about the differences among the vaccines. "All three of them are really quite good, and people should take the one that's most available to them," Anthony Fauci said on Meet the Press.
Now that hundreds of millions of vaccine doses have been distributed in the United States, we have plenty of 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 A recent (but not yet peer-reviewed) study of more than half a million U.S. veterans showed that the Johnson & Johnson shot's protection against infection (whether or not that leads to disease or hospitalization) had plummeted from 88 percent to 3 percent by mid-August, while the other vaccines' effectiveness had declined much less. Research published in the past few months also signals that Moderna's shot beats out Pfizer's in terms of both antibody count and hospitalizations prevented, while a National Institutes of Health study released earlier this month found that Moderna's booster shot lifted participants' antibody levels a bit more than Pfizer's, and that both mRNA boosters were miles ahead of J&J's.
In light of all these data, it's tempting to rank the vaccines by brand name: Moderna is better than Pfizer is better than J&J. But the same numbers hint at a different pattern: Maybe what matters most is not which vaccine you get, but how much of it.
Consider how the vaccines differ in their dosing. J&J, the least effective in the studies, has only one shot in its primary series; the mRNA vaccines have two. So anyone who got J&J (and hasn't yet gotten a booster) received half as many doses total. Comparing Pfizer with Moderna, you see another dose difference: Each shot of Pfizer contains 30 micrograms of mRNA, while each one of Moderna contains 100. (Doses for children could also differ in size: Pfizer has proposed 10-microgram shots, while Moderna is going with 50.) Just how much of the difference in the shots' performance can be summed up by saying "More vaccine is better"?
"More vaccine" is not a simple proposition. For one thing, 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 that each one contains (about 50 billion). You can't really compare lipid nanoparticles with viral particles, several experts told me. According to Michael Arand of the University of Zurich's Institute of Pharmacology and Toxicology, you shouldn't even assume that each 50-billion-particle dose of J&J will be equivalent in size to the next one, since, depending on the details of production, some particles can be more infectious than others. A better dosage measure for adenovirus-based vaccines, he argued in a recent opinion paper, would be "infectious units." When I asked him via email whether developing a standard measure that works across different vaccine platforms might be possible, he said, "I do not think so."
Comparing doses of the Pfizer and Moderna vaccines is much easier, since their mechanisms are so similar. Each shot of Moderna delivers more than three times as much of the active ingredient, compared with Pfizer, and seems to induce a higher antibody count and lead to more durable protection against infection and hospitalization. "Over time, that higher dose might be what is driving the difference in protective efficacy," John Moore, a microbiology and immunology professor at Weill Cornell Medicine, told me.
The vaccines have differed in their dosing schedules too. Vaccinated (and un-boosted) Americans have received 60 micrograms of Pfizer over a period of three weeks, 200 micrograms of Moderna over four weeks, or 50 billion particles of J&J in one sitting. It's apples and oranges, except you have to wolf down the apple all at once, and some of the oranges are tangerines, and you can eat only a few slices at a time.
Even the one-week difference between Pfizer's schedule and Moderna's could be important. Mark Slifka, an immunologist at Oregon Health and Science University, told me that it could play into Moderna's slightly longer-lasting protection. Angela Rasmussen, a virologist at the University of Saskatchewan's Vaccine and Infectious Disease Organization, pointed out that the AstraZeneca vaccine--an adenovirus-vector design like J&J's--also seems to provide more protection when its doses are spaced further apart.
The number of vaccine doses you receive also matters, no matter their specific size and schedule. Slifka thinks that the number of times you get a vaccine is far more important than the amount of it delivered in each syringe. Getting more than one dose "is actually the great equalizer among vaccinations," he said, because it teaches the immune system that a particular threat should be taken seriously. Having multiple rounds of a moderately sized 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," Slifka said.
American public-health agencies haven't yet come out and said it, 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 that J&J may turn out to be "every bit as good as the mRNA vaccines" when compared 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 shot speculate that its protection against hospitalization and death could last longer than the other vaccines', thanks to the way it tickles a particular set of immune-system actors called T cells, which help prevent infections from progressing into severe disease. "There's a sort 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 vigor as J&J's. He says that 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. Slifka, for example, thinks that the differences between the adenovirus and the mRNA formulas--the ways they target our cells, the nature of the immune response they raise in us--might not be particularly relevant to the protection they provide. "Both of them are nanoparticles. One is a virus nanoparticle and the other one is a lipid nanoparticle, but they're both doing the same thing," he said: delivering genetic material into human cells so those cells can produce the coronavirus's distinctive spike protein and give the immune system target practice for when the real invader arrives.
We'll likely never know for sure how much of the difference among vaccines can be chalked up to their formulas, and how much comes from other factors. In theory, researchers could untangle those questions by running enormous randomized controlled trials of slightly larger and smaller doses of each shot, and of different intervals between (same-size) shots. But with half of the world still yet to receive a single dose of any COVID-19 vaccine, and plenty of good-enough regimens already identified, no one is going to devote resources to such fine-grained questions.
"If last year hadn't been such a shitstorm," Moore said, "all of these issues would have been ironed out." For now, we'll have to keep bumbling forward with our clunky toolbox of boosters and waiting periods and half-doses--and count our blessings to live in a country where we have the luxury of asking how much vaccine is the best amount.