Future Covid-19 booster vaccinations should be 100% Omicron.

...or whatever is actually circulating at the time.

The promise of mRNA-based vaccines was not just that they might work better, but that they’d be easy to alter if new Covid-19 variants appeared. Putting aside the question of who needs a booster how often and why, I think we can all agree that if we are going to offer boosters to the public, they should be as effective as our best science permits. At the moment, we’re not achieving that mandate.

The next round of boosters can and should be based solely on the genetic sequence of the predominant variant at the minute production begins. How’d I get to this?

During the initial vaccine rollout two years ago, the circulating variants of SARS-CoV-2 were still similar to the “Ancestral” strain first isolated in Wuhan, China. But by the summer of 2021 the Delta variant had emerged. Even though Delta was markedly different from the ancestral strain, boosting with the vaccines we had on hand worked. Boosters kept older people out of the hospital, and temporarily decreased infections in everyone—albeit transiently in both cases. Pretty soon it became clear that if you wanted to use boosters to curb infections, you’d need to be boosting every 4-6 months. For some people, that might be important, and for others it could be unsustainable or even eventually backfire. (I’ll say more on imprinting below, and in a future Inside Medicine).

Omicron appeared in late 2021 and early 2022. Our vaccines still prevented severe disease and mortality (and a recent booster does helped keep higher risk people out of the hospital), but the protection against infection offered by the ancestral vaccine was becoming smaller. The time to convert on the promise of mRNA vaccines had come.

Last winter and spring, Pfizer and Moderna considered new vaccines. They could have chosen to completely replace the ancestral strain epitopes—the part of the vaccine that triggers the immune system to make antibodies)—with Omicron variant ones. Instead, they went halfsies and made a “bivalent” booster: 50% Ancestral, 50% Omicron.

My colleagues Dr. Céline Gounder and Dr. John Moore argued recently that a monovalent Omicron-only booster may have been the wiser choice, even given the information the FDA had at the time of its decision last summer. Two new papers out in the New England Journal of Medicine suggest that Dr. Gounder and Dr. Moore were probably right.

Paper #1: More stellar data from my collaborators in Qatar Dr. Hiam Chemaitelly, Dr. Laith Abu-Raddad, and their colleagues. They found that when people were infected with the Omicron BA.2.75 Subvariant (which appeared last summer), the risk of a subsequent reinfection was higher if a person had already been infected with a Delta or earlier variant as compared to someone who had already been infected with an Omicron variant. That said, hybrid immunity was most protective.

However, if you look closely, you’ll find that immune systems that have seen the spike protein of Covid-19 from pre-Omicron variants on too many occasions (i.e., from vaccinations plus a pre-Omicron first-time infection) may not “remember” Omicron well enough to prevent future infections. The good news, though, is that prior infection of any kind appears so protective against severe disease (at least among the rather young and healthy demographics of Qatar), that severe cases among the vaccinated or previously infected are simply not happening there. Long story short: an immune system that kept getting reminded of the original version of Covid-19 shrugged off Omicron when it first encountered it. To me, this argues for removing anything but Omicron epitopes from future Covid vaccines.

Paper #2: Laboratory data from the US (funded by Pfizer, I should mention) looked at various combinations of boosters among participants in a clinical trial ages 55 and up. Researchers tried different doses and different versions of the booster. Both the monovalent Omicron and bivalent boosters were somewhat better than another boost with the original vaccine, albeit not by a lot. But comparing the monovalent Omicron booster against the bivalent in neutralizing early Omicron (BA.1) revealed no real improvement. A higher dose of monovalent Omicron looks promising—but at such doses, we might be tempting fate with side effects, especially in young males, where we’ve had some problems in the past. Meanwhile, all booster versions triggered similar neutralization of the Ancestral strain. We don’t yet know how these boosters fare against the more recent subvariants, which will be important information.

However, I don’t see the point in keeping Ancestral epitopes in our boosters since a) the Ancestral strain is not around and is probably never coming back, and; b) the monovalent Omicron boosters are basically as good at neutralizing the Wuhan strain as the Ancestral-only vaccine is. So, what’s the point?

One question lingered in my mind looking at the data in the second paper: why did the monovalent Omicron vaccine not do far better against Omicron? Many of us are worried that the answer is that everyone in this trial had already received three doses of Ancestral strain-only vaccine. Imprinting may be happening here. What that means is that immune systems that kept seeing the Ancestral strain got used to it after three exposures (plus and infections they may have had along the way, which would have have either something or a lot in common with the Ancestral strain). It might be that to overcome that, we’ll need a couple (or a few) Omicron exposures. Most people have had one by now. But it may take a couple of Omicron-only boosts for some people’s immune system to wake up to the fact that its 2023 and we’re living in an Omicron world.

Of course, if something replaces Omicron, we might come to regret over-boosting with Omicron now or in the future, thereby recreating the same problem we are facing now. That’s why figuring out who truly benefits from these vaccines above and beyond a short-term reduction in infections is becoming increasingly important.