In a perspective published Jan. 11 in the New England Journal of Medicine, vaccine expert Dr. Paul Offit says it’s time to rethink booster recommendations.
In the third year of the pandemic, the population’s immune situation is vastly different from what it was in 2019 when SARS-CoV-2 emerged. Now, most people have been vaccinated against the virus, been infected with it (once or multiple times), or both. And the latest data show that the newest booster shot, which targets the Omicron BA.4/5 strain and original virus variants in a bivalent formulation, isn’t that much more effective in generating virus-fighting antibodies than the original vaccine when used as a booster.
“The experience of the past year has taught us that chasing these Omicron variants with a bivalent vaccine is a losing game,” says Offit, director of the vaccine education center at the Children’s Hospital of Philadelphia and a member of the U.S. Food and Drug Administration’s vaccine advisory committee. Offit also developed the rotavirus vaccine.
In his perspective piece, Offit cites data from two leading virologists—Dr. David Ho, director of the Aaron Diamond AIDS Research Center at Columbia University, and Dr. Dan Barouch at Harvard Medical School—who reported that when serum from people boosted with the bivalent Omicron booster was compared to that from people boosted with a dose of the original vaccine, their levels of neutralizing antibodies against BA.4/5 were comparable. Ho’s work also showed that the bivalent booster did not produce appreciably different antibody responses against newer Omicron variants, such as BQ.1, BQ.1.1, XBB, and now XBB.1.5, which together account for 83% of new infections in the U.S. as of the first week of January.
Antibodies are the immune system’s first line of defense, and serve as the front line for blocking viruses from infecting cells. But as most people know, either from personal experience or anecdotally through reports from friends and family, even those who are vaccinated and have received the Omicron BA.4/5 booster have gotten infected with the virus. While their vaccination and boosting protected them from getting seriously sick, they weren’t immune to infection. So why are these infections occurring if the bivalent vaccine was supposed to zero in on the BA.4/5 variant better than the original booster?
The reason has to do with how the immune system is trained against new viruses. Similar to the way newborn animals of some species imprint to recognize their mothers, immune cells dedicate energy and resources to recognizing and familiarizing themselves to any new agents they encounter. Most of the resulting defensive activity is geared toward this original invader, in a phenomenon virus experts call original antigenic sin, in which these immune cells continue to generate virus-fighting antibodies against the original pathogen even if more recent variants of the viruses vary from that template.
The important end result, says Offit, is that as the studies found, chasing variants of the virus with new boosters may not always produce appreciably better responses in the form of a barrage of antibodies. And it’s not just the bivalent BA.4/5 booster that resulted in this pattern. An earlier bivalent shot, aimed at another Omicron variant, BA.1, produced levels of BA.1-neutralizing antibodies that were just under two times those generated by a dose of the original shot.
It boils down to what we expect the booster shots to accomplish. At the beginning of the pandemic, the role of boosters was to maintain a certain level of antibodies as their numbers from the primary vaccinations waned, in order to slow spread of the virus. The idea was to protect the world’s population, which at that time was completely unprotected, with no immunity to the novel SARS-CoV-2 coronavirus, from getting severely sick with COVID-19 — sick enough to end up in the hospital and need ICU care. The first boosters fulfilled that mission as hospitalization rates went down in 2021, the first year after the vaccines were released.
But COVID-19, and the population’s ability to combat it, has changed since then. For one, the variant of the virus now infecting people—XBB.1.5—is different from the original. Through a combination of the fact that many people now have higher levels of protection from vaccines or having recovered from infections, and the fact that the Omicron variants as a group, BA.4/5 and XBB.1.5 included, do not seem to cause serious disease in most healthy people, the job of booster doses has also evolved. Now, boosting everyone with an Omicron shot is “trying to prevent, in otherwise healthy people, mild illness for a few months,” says Offit, until the next variant comes along to replace it. “That doesn’t make sense.”
It was reasonable to think that a bivalent booster targeting BA.4/5 would produce more robust levels of antibodies against BA.4/5, but it turns out that’s not necessarily the case, and that the protection is only slightly better when compared to the original booster. “[The bivalent booster] was sold as better, and better at preventing mild disease and transmission,” says Offit, “when there was no evidence for that.”
Now that there’s evidence showing that the bivalent booster isn’t necessarily more effective, the question becomes who should be getting it and why. The bivalent booster is still important for people at highest risk of getting severely ill, such as the elderly and immunocompromised, whose immune systems may not produce as strong of an immune response—even the small increase in additional antibodies could be important for them.
But for the rest of the population, it may be time to consider whether the bivalent booster is necessary, or if continuing to boost with the original vaccine would be sufficient. “I think the [U.S. Centers for Disease Control and Prevention] needs to answer that question,” says Offit. And to do that, Offit is calling on the CDC to provide more detailed data on who is being hospitalized for COVID-19 (not just people who are hospitalized and incidentally test positive for the infection), their age, whether they have immune-compromising conditions, whether they have other health issues, and their vaccination and booster status. “Give us those data, and we can then figure out who really needs to be boosted,” says Offit. “Initially, everybody benefited from getting vaccinated and boosted. But we need to learn who benefits now.”
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