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Need to mix and match your booster shot?

This week’s episode of the booster chronicles gets the plot going. An FDA advisory committee has begun 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 has yet to approve, and the CDC has yet to recommend, any new use of boosters before they will be readily available.) Committee members have already voted yes to giving boosters to people over 65 and other high-risk adults who received boosters. the Moderna vaccine. Meanwhile, the NIH has released the results of a highly anticipated (and not yet peer-reviewed) clinical trial on the “mix and match” approach to booster shots, in which people receive a dose of a different vaccine than they started with. . The FDA committee will also discuss that idea before this meeting ends.

The 458-person NIH study showed that mix-and-match—also known as heterologous—boosting is safe and leads to an increase in the relevant antibody counts, regardless of the combination of vaccines. This is not particularly surprising, given the data that has already emerged from countries such as the UK. and Spain, who have been studying the mix-and-match approach to initial withdrawal regimens for months. Overall, these have been shown to be about as good as, and in some cases better than, a homologous regimen. This week’s report expands on that finding for booster age and adds another: When boosters were compared directly, the mRNA vaccines blew J&Js out of the water.

When the vaccines first hit the market last winter, Americans were told they were all excellent, so we’d all have to pick which of the three was the most accessible. If mix-and-match boosters are allowed, we might be faced with a more perplexing decision: there are a total of nine different paths available, depending on where you started. Assuming all options are soon 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 been on a J&J → Moderna regimen recorded mean antibody levels 9.8 times higher than those who had received two J&J injections; antibody levels among J&J → Pfizer recipients hovered just behind. Overall, the highest antibody levels were found in people for whom all three doses were 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’ve already gotten boosters from Pfizer are missing out. The differences between those mRNA regimens were relatively small; In fact, they are absolutely dwarfed by the differences between both mRNA options and the J&J → J&J approach. Saad Omer, director of Yale’s Institute for Global Health, told me that “we can’t be too precise” in interpreting this data, given the small size of the study. (There were only about 50 people in each of the nine study groups.) But the apparent benefit of using the mRNA vaccines as boosters, compared to J&Js, is so great, he said, that it’s unlikely to be a mistake. .

Other factors may also limit the significance of the apparent division between Moderna and Pfizer. In a paper published earlier this week, a team with Omer and led by his colleague Akiko Iwasaki found that those who have recovered from a COVID-19 infection and vaccinated may approach a plateau of immune protection, after which “the juice” [of a booster shot] isn’t worth pinching,” said Omer. That suggests the differences between the mix-and-match combinations could be even less meaningful for that population (although Omer said he’d need to see clinical data to be sure). Moderna’s lead may also be blunted, given today’s committee recommendation for using a half-dose booster. (The NIH study tested boosters with a full dose of Moderna.) Still, previous research suggests that: half a dose of Moderna for the first or second shots were “generally comparable” in effect to the original regimen. “I’d be surprised if it didn’t work as well as a booster,” said Paul Sax, a Harvard professor and clinical director of the infectious disease division at Brigham and Women’s Hospital.

All the findings described above may only tell part of the story. Remember, 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 are not our only weapon. Immune cells, such as B and T cells, are also important, especially in the long term. (Sax told me that some researchers suspect J&J is especially good at inducing the latter, longer-lasting form of immunity.) The best way to determine which of the nine mix-and-match options gives the best protection against disease is is to recruit thousands of volunteers into a randomized controlled trial, and then count how many people on each regimen get sick over an extended period of time. But instead, antibody levels provide the best and most useful information that can be quickly obtained from the largest number of people.

Omer would like to see such long-term data on clinical outcomes, along with more data on the effects of mix-and-match strategies on different age groups and how long booster protection lasts. This kind of data is lacking in many booster studies, not just mix-and-match. Until we have them, we’ll be stuck where we are now, and know more than ever about it how to give a boost, but still not quite sure when it would be most appropriate.