The two sides of the bivalent booster debate, broken down and explained.

Staying up-to-date on boosters matters for high-risk people. But it's not clear that the new Omicron-containing bivalent formulation changed the game as was hoped.

Is the bivalent Covid-19 vaccine booster better than the monovalent booster it replaced? We still don’t know. If it improves things, the available evidence says that it’s not the game changer many had hoped it might be. Still, for at-risk people in particular, a recent dose of a Covid-19 booster decreases rates of infection, and with it, lowers hospitalization rates, at least for a time.

How might we determine if the bivalent booster is better than the monovalent one? There are two ways:

1. Clinical data.

2. Laboratory data.

In yesterday’s Inside Medicine, we discussed new clinical data out of Israel (and some from the US) which show that staying up-to-date on Covid-19 vaccines remains important for high-risk older individuals who want to avoid hospitalization. We also know that the new boosters decrease the short-term odds of getting infected for everyone.

But these studies did not pit bivalent against monovalent boosters. They just looked at whether the bivalent booster recipients fared better than people who had not been boosted in a while.

It’s likely that a head-to-head clinical study comparing bivalent to monovalent booster effectiveness will never happen. However, one piece of clinical data we can expect to get in the coming months, is whether the protection offered by the new bivalent version of the boosters lasts longer than that offered by the previous one. That would be great news, and I await the answers.

Other than that, we’re basically left with laboratory data as the lens through which we can judge the new bivalent booster. This week, two relevant studies were published in The New England Journal of Medicine. Both tested whether patients who were boosted with bivalent formulations had better immune responses than those who received monovalent ones. In both studies, there was no appreciable difference between the formulations.

Both the bivalent and monovalent boosters increased antibody responses nicely. In one of the studies, antibody levels spiked to 1,500% of pre-booster levels (among monovalent recipients) and 1,700% of pre-booster levels (bivalent recipients). That difference is not meaningful. Scientists had been looking for orders of magnitude of difference between the two formulations. That said, the 1,500%-1,700% difference in both from pre-booster levels is meaningful, and it explains why the Israeli clinical data from yesterday look good, at least temporarily. (Yes, we expect the effect to wane.) It’s clear that staying up-to-date on vaccines is important for high-risk people and others who want to limit their short-term risk of infection. It’s just that the new-and-improved bivalent vaccine is not changing the game that much.

T cell responses, which are indicative of longer-term protection against severe disease, were not augmented significantly by either the monovalent or the bivalent boosters, one of the studies showed. The monovalent vaccine increased T cell responses by 180%-210% (again, not much; we wanted at least 1000%). Meanwhile, the bivalent vaccine increased T cell responses by just 140%-190%. One might think this means the bivalent did worse. But in reality, the differences are so small at this level, that it makes these results interchangeable. Again, we’re looking for order-of-magnitude differences (1000% if not 10,000% increases, not “merely” 2-fold increases).

Over the last couple of days, an intellectual brawl has erupted over whether all the available data indicate that the bivalent booster outperforms the monovalent.

You’ve got two sides: Team Offit and Team Topol.

Dr. Paul Offit argues that the bivalent booster is a bust. He points out that Covid-19 vaccines are great for decreasing severe, critical, and fatal cases, but only prevent infections for a short period. He feels that boosters have been overplayed since the start, although he is supportive of boosters for older and high-risk people. He’s also worried that bivalent booster’s relatively low value-add may be because the population is already somewhat overboosted—that is, the immune systems of patients who received 3, 4, or even 5 doses of the Wuhan variant (original) vaccine prior to receiving a bivalent vaccine are more-or-less ignoring the new parts of the bivalent vaccine, because they’ve been “trained” to look for the old parts they keep seeing. This phenomenon is called “imprinting.” Data from my collaboration with epidemiologists in Qatar suggests that this indeed is happening. (We’ll discuss this in the future, but what this means is that some people, ironically, may need more boosting, while some would actually do better with less.)

Dr. Eric Topol argues that the bivalent is better. The crux of Dr. Topol’s argument is that there are a handful of other studies that show the bivalent booster does elicit higher antibody responses, and that the two New England Journal of Medicine (NEJM) studies are outliers. Because both research teams used a kind of viral assay called a pseudovirus, he believes the NEJM data are inferior to other studies that used live virus.

I asked the lead authors of the two NEJM studies about this point. Both Dr. David Ho (Columbia University) and Dr. Daniel Barouch (Harvard University) disagreed with Dr. Topol.

“We also do live virus studies. The results generally parallel pseudovirus results,” Dr. Ho told Inside Medicine via email. He also strongly implied that scientists with domain expertise in this area tend to agree that the differences between these assays are not meaningful.

“We have also numerous times shown comparability between the pseudovirus and live virus assay,” Dr. Barouch said to Inside Medicine, also via email.

Dr. Barouch also mentioned that in the past, Moderna had generated some flashy data using pseudovirus. (He was more-or-less implying that it was cherry-picking to make a complaint or distinction about the assays now.)

But why did those other studies Dr. Topol mentioned have slightly better results, if the difference was not the assay being used?

Dr. Barouch has thoughts. He believes it comes down to major differences in how far the study participants were from their prior dose when they were most recently boosted.

“The major issue, in my view, is skewed populations.  The Moderna and Pfizer studies that showed 4-6 fold increased [antibody] titers of their bivalent boosters compared with their monovalent boosters are based on skewed populations that are not equivalent.  The companies looked at their monovalent boosters in individuals in February, 2022 who received their last vaccine 4-6 months previously, but looked at their bivalent boosters in individuals in August, 2022 who received their last vaccine 9-11 months previously.  The differences in the calendar dates and the times from prior vaccination skew their data (substantially) in favor of the bivalent booster.  This is particularly true since the BA5 surge occurred in summer 2022, and so many people in the bivalent booster group were seeing BA5 for the second time (due to prior BA5 infection), whereas no one in the monovalent group had seen BA5 previously (as that was before the BA5 surge).  Negative [antibody tests indicative of prior infection] does not exclude all infections and cannot be used to claim these two populations are equivalent.” —Dr. Dan Barouch.

Dr. Céline Gounder, an infectious diseases specialist, also pointed out that in the studies where the bivalent booster elicited higher antibody levels, those increases were modest, rather than the 10-100 fold differences scientists believe would be meaningful.

In my view, Dr. Topol is not wrong about the fact that bivalent boosters help high-risk populations. The problem I’m having is that most of the graphs and data shown in his essay simply indicate that high-risk people need to stay up-to-date on their vaccines. That’s not the same thing as proof that bivalent boosters are superior.

I also tend to agree with Dr. Gounder and Dr. John Moore, who published a piece in MedPage Today (Disclosure: I am medical editor-in-chief of that publication, though I did not have involvement in that piece). Researchers should have tested a full-on Omicron-only booster, instead of playing cute with half doses of the old and half doses of the new variants. (Dr. Offit feels the same way).

All of this said, whether or not the bivalent booster is similar or better than the monovalent one it replaced is not terribly important for any decisions you might have to make right now. If you’re at risk of a bad outcome from Covid-19, boosting will decrease the short-term chances of an infection, and with it the odds of hospitalization. While imprinting can’t be ignored, that’s a question scientists and researchers will have to sort out going forward.

For what it’s worth, I’d be far more interested in an Omicron-only booster in the future than the half-dose Omicron and half-dose Wuhan preparation we have now. I suspect many feel the same way.