Should You Mix and Match Your Booster Shot?

We know more than ever about how to use boosters, but still very little about when to use them.

In this week’s installment of the booster chronicles, the plot is picking up. An advisory committee to the FDA began a two-day meeting today to formulate recommendations for whether the agency should authorize additional doses of the Johnson & Johnson and Moderna COVID-19 vaccines. (The FDA still has to authorize, and the CDC still has to recommend, any new use of boosters before they’ll be readily available.) Committee members have already voted yes on giving boosters to people over 65 and other high-risk adults who received the Moderna vaccine. Meanwhile, the NIH released the results of a long-awaited (and not yet peer-reviewed) clinical trial on the “mix and match” approach to booster shots, in which people receive a dose of a different vaccine from the one they started with. The FDA committee is scheduled to discuss that idea, too, before this meeting ends.

The 458-person NIH study showed that mix-and-match—also known as heterologous—boosting is safe and induces an increase in the relevant antibody counts, no matter the combination of vaccines. This isn’t particularly surprising, given the data that have already emerged from countries such as the U.K. and Spain, which have been studying the mix-and-match approach to initial shot regimens for months. In general, these have shown it’s about as good as, and in some cases better than, a homologous regimen. This week’s report expands that finding for the booster age, and adds one more: When boosters were compared head-to-head, the mRNA vaccines blew J&J’s out of the water.

When the vaccines first debuted last winter, Americans were told that each one was excellent, so we should all get whichever of the three was most accessible. If mix-and-match boosters are authorized, we might find ourselves with a more bewildering decision: Nine different paths will be available in total, depending on where you started. Assuming that every option will soon be on the table, which one should people take?

The NIH study tested and compared every possible combination, and here’s the gist: If you need a booster, don’t take J&J. Two weeks after boosting, people who had followed a J&J → Moderna regimen registered average antibody levels that were 9.8 times higher than those who had gotten two J&J shots; antibody levels among J&J → Pfizer recipients hovered just behind. Overall, the highest antibody levels were found among people for whom all three doses were Moderna; Pfizer → Moderna produced the second-highest levels, then Moderna → Pfizer.

Moderna’s boosters seemed to be slightly more effective than Pfizer’s in general, but that doesn’t mean that Americans who have already gotten Pfizer boosters are missing out. The differences between those mRNA regimens were relatively small; more to the point, they’re absolutely dwarfed by the differences between either mRNA option and the J&J → J&J approach. Saad Omer, who directs Yale’s Institute for Global Health, told me that “we can’t be too precise” in interpreting these data, given the study’s small size. (There were only about 50 people in each of the nine trial groups.) But the apparent advantage of using the mRNA vaccines as boosters, compared with J&J’s, is so large, he said, that it’s unlikely to be an error.

Other factors might also limit the significance of the apparent Moderna-Pfizer divide. In a paper published earlier this week, a team including Omer and led by his colleague Akiko Iwasaki found that those who have recovered from a COVID-19 infection and been vaccinated might be approaching a plateau of immune protection after which “the juice [of a booster shot] is not worth the squeeze,” Omer said. That suggests that the differences between the mix-and-match combinations could be even less meaningful for that population (though Omer said he’d have to see clinical data to be certain). Moderna’s edge might also be dulled, given today’s recommendation from the committee for the use of a half-dose booster. (The NIH study tested full-dose boosters of Moderna.) Still, prior research suggests that a half dose of Moderna for the first or second shots were “generally comparable” in effect to the original regimen. “I’d be very surprised if it didn’t work quite well as a booster,” says Paul Sax, a Harvard professor and the clinical director of Brigham and Women’s Hospital’s infectious-disease division.

All the findings described above may be telling just part of the story. Remember, the NIH study used antibody counts, which are a proxy measure of actual immunity. Antibodies represent the body’s first line of defense against the coronavirus, but they’re not our only weapon. Immune cells, such as B and T cells, are also important, especially in the long run. (Sax told me that some researchers guess that J&J might be especially good at inducing the latter, longer-lasting form of immunity.) The best way to determine which of the nine mix-and-match options produces the best protection from disease would be to recruit thousands of volunteers for a randomized controlled trial, and then count how many people on each regimen get sick over an extended period. But short of doing that, antibody levels provide the best and most convenient information that can be garnered quickly from the greatest number of people.

Omer would like to see such long-term data on clinical outcomes, along with more data on mix-and-match strategies’ effects on different age groups and how long booster protection lasts. These sorts of data are missing from plenty of booster studies, not just mix-and-match. Until we get them, we’ll be stuck where we are right now, knowing more than ever about how to boost, but still unsure of when, exactly, it’s most appropriate to do so.