Should you mix and match your COVID vaccine booster?

In this week’s edition of the Booster Chronicles, the plot is picking up speed. An FDA advisory committee began a two-day meeting today to formulate recommendations on whether the agency should allow additional doses of the Johnson & Johnson and Moderna COVID-19 vaccines. (The FDA still has to approve every new use of boosters, and the CDC still has to recommend them before they’re readily available.) Committee members have already voted yes 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 yet untapped) clinical trial on the “mix-and-match” approach to booster vaccines, in which people receive a different dose of a vaccine than they received had started. The FDA committee should also discuss this idea before this meeting ends.

The 458 people NIH study showed that mix-and-match – aka heterologous– Boosting is safe and leads to an increase in the relevant antibody numbers, regardless of the combination of vaccines. This is not particularly surprising when you consider that data is already available from countries like United Kingdom. and Spainwho have been researching the mix-and-match approach to initial shooting regimes for months. In general, these have shown it to be about as good, and in some cases even better, than homologous therapy. This week’s report extends this finding for booster age and adds another one: When boosters were directly compared, the mRNA vaccines blew J & J’s out of the water.

When vaccines first hit the market last winter, Americans were told that each one was excellent, so we should all get the most accessible of the three. With mix-and-match boosters authorized, we may be faced with a more confusing decision: there are nine different paths in total, depending on where you started. Assuming all options are on the table soon, which should people choose?

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The NIH study tested and compared every possible combination, and here’s the gist: If you need a refresher, don’t take J&J. Two weeks after the booster, people who had followed J&J → Moderna treatment registered mean antibody levels that were 9.8 times higher than those who had received two J&J injections; Antibody levels in J&J → Pfizer recipients were just below this. Overall, the highest antibody levels were found in subjects given all three doses of Moderna; Pfizer → Moderna produced the second highest levels, then Moderna → Pfizer.

Moderna’s boosters seemed a little more effective than Pfizer’s in general, but that doesn’t mean Americans who have already received Pfizer boosters are missing out. The differences between these mRNA schemes were relatively small; More precisely, they are absolutely dwarfed by the differences between the two mRNA options and the J&J → J&J approach. Saad Omer, who heads the Yale Institute for Global Health, told me that “we can’t be too specific in interpreting this data,” because the study is so small. (There were only about 50 people in each of the nine experimental groups.) But the obvious benefit of using the mRNA vaccines as boosters over J & Js is so great that it is unlikely to be a mistake.

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Other factors could also limit the importance of the apparent Moderna-Pfizer divide. In one Paper was released earlier this week, a team that Omer was part of and led by colleague Akiko Iwasaki, found those who have recovered from COVID-19 infection and was vaccinated, could approach a plateau of immune protection, after which “the juice” [of a booster shot] is not worth the pressure, ”said Omer. That suggests that the differences between the mix-and-match combinations might be even less meaningful for this population (although Omer said he would need to see clinical data to be sure). The spiciness of Moderna could also be blunted, given today’s recommendation by the committee for the use of half a dose of booster. (The NIH study tested Moderna full-dose boosters.) Still, previous research suggests that half a dose of Moderna for the first or second shots were “generally comparable” in effect to the original regime. “I would be very surprised if it didn’t work as well as a booster,” said Paul Sax, Harvard professor and clinical director of the Infectious Diseases Division at Brigham and Women’s Hospital.

All of the results described above can only tell part of the story. Keep in mind that the NIH study used antibody counts, which are a proxy measure of actual immunity. Antibodies are the body’s first line of defense against the coronavirus, but they’re not our only weapon. Immune cells like B and T cells are also important, especially in the long term. (Sax told me that some researchers suspect that J&J might be particularly good at inducing the latter, longer-lasting form of immunity.) The best way to determine which of the nine combination options would provide the best protection against disease would be to recruit thousands of volunteers for a randomized controlled trial and then count how many people get sick over an extended period of time on each regimen. But other than that, antibody levels provide the best and most convenient information that can be quickly gathered from the largest number of people.

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Omer would like to see such long-term clinical outcomes data, along with more data on the effects of mix-and-match strategies on different age groups and duration of booster protection. This type of data is lacking in many booster studies, and not just mix-and-match. By the time we get it, we’ll be stuck where we are right now, knowing more about it than ever how to increase, but still unsure when exactly this is best.