Annual? Bivalent? For all? Future of COVID shots murky after FDA deliberations

The US Food and Drug Administration's committee of independent vaccine experts gathered Thursday to discuss the future of COVID-19 shots. The meeting seemed primed for explosive debate. Earlier in the week, the FDA released documents that made clear the agency is holding steadfast to its idea that COVID vaccines will fit the mold of annual flu shots—with reformulations decided in the first half of each year, followed by fall rollouts in anticipation of winter waves.

But outside experts, including some on the FDA's advisory committee, have questioned almost every aspect of that plan—from the uncertain seasonality of COVID-19 so far, to the futility of chasing fast-moving variants (or subvariants, as the case may be). Some have even questioned whether there's a need to boost the young and healthy so frequently when current vaccines offer protection against severe disease, but only short-lived protection against infection.

One particularly outspoken member of FDA's committee, Paul Offit, a pediatrician and infectious disease expert at Children’s Hospital of Philadelphia, has publicly assailed the bivalent booster, writing a commentary piece in the New England Journal of Medicine earlier this month titled: Bivalent Covid-19 Vaccines — A Cautionary Tale. (The FDA's advisory committee voted 19-2 in support of the bivalent boosters last year, with Offit being one of the two votes against.)

Yet, despite the charged background of yesterday's meeting, the sparks of disagreement fizzled over a calm discussion. The nine-hour meeting culminated with a unanimous vote by the committee in favor of "harmonizing" future formulations of COVID-19 vaccines so that primary series and boosters are matched formulations. For example, the primary series vaccines would match the updated bivalent boosters, which currently target both the original strain of SARS-CoV-2 that came out of Wuhan, China, as well as omicron subvariants BA.4/5.

Streamlining

The FDA seemed to soften the ground with questions and discussion topics focused on "harmonizing" and simplifying COVID vaccines. After the single vote, the agency directed the committee to discuss "simplifying the immunization schedule," before getting to the more perilous, but still gentle discussion topic of considering "periodic updates to COVID-19 vaccine composition."

Overall, the committee members favored streamlining vaccines where possible—making primary series shots match booster doses, and potentially whittling down regimens to one dose for adults and two for children and high-risk adults.

"There's so much confusion about these different formulations that I think anything we can do to ease up on that confusion and simplify things, it's going to be a good thing," said Archana Chatterjee, Dean of Chicago Medical School and a voting committee member, said at the end of yesterday's meeting. "I concur with my other colleagues that there definitely remains a need for these vaccines and for us to do our best to get them into arms. Having vaccines is not sufficient, we need to have them be used. ... This is a step in the right direction in getting us there."

But, the bigger steps for future vaccines—deciding what formulation should be used next, who should get them, and when—remained elephant-sized questions in the meeting room. And even among the relatively placid comments, it was clear that large disputes were bubbling under the surface.

Before the committee's vote and discussion, the advisors listened to a series of presentations from vaccine makers, the FDA, and the Centers for Disease Control and Prevention, which all provided updates on the state of COVID-19 and the performance of the vaccines so far.

Data dive

Although Offit and others have criticized the bivalent boosters for not being better than the previous boosters, the data presented in the meeting argued otherwise. Real-world observational data shows an advantage for people boosted with the bivalent booster compared with the original (monovalent) vaccine—even against the more recent subvariants. Data presented during the meeting shows it has outcompeted the original vaccine in terms of protection against symptomatic infection, visits to the emergency department or urgent care visits, and hospitalization.

In a CDC study published Wednesday, for instance, researchers found that the bivalent booster's relative vaccine effectiveness against symptomatic infection with a BA.5-related omicron sublineage (which includes BQ.1 and BQ.1.1) was 52 percent among people from 18 to 49 years old. In other words, people in this age group had 52 percent more protection against infection with BA.5-related strains than people who received the original booster. For ages 50 to 64, the relative effectiveness against BA.5-related infection was 43 percent, and it was 37 percent among those 65 years and older.

Against the more recent XBB/XBB.1.5-related omicron subvariants, relative effectiveness against infection was 49 percent among people  18 to 49, 40 percent among people 50 to 64 years, and 43 percent among those 65 years and older.

There's also been a slew of serology studies looking at how the bivalent booster's antibody responses compare with those from the original booster when up against the gamut of currently circulating omicron subvariants. The results are mixed and, in some cases, hard to compare due to differences in intervals between vaccination, the number of people involved, and the types of assays used. But overall, the FDA argued that they suggest that the bivalent booster provides better neutralizing antibody responses against currently and recently circulating omicron subvariants than the original vaccine.

"The important thing is that the results all trend in the same direction," Jerry Weir, director of the FDA's Division of Viral Products, said in the meeting Thursday. "In other words, with all of these studies just like those from the manufacturers, there is improved variant-specific neutralization following administration of the bivalent BA.4/5 vaccine compared with the monovalent… I find it somewhat remarkable to see that level of uniformity."

For instance, one of the most recently published studies, released Wednesday in the New England Journal of Medicine, found that a bivalent boost led to a roughly threefold increase in neutralizing antibody levels against XBB.1 compared with people boosted with the original booster. That increase was roughly the same (3.6-fold and 2.7-fold) among people without and with previous SARS-CoV-2 infection, respectively.

Despite criticism by Offit and others before the meeting, committee members seemed comfortable with the bivalent data, accepting the FDA's rosy retrospective.

"I'm totally convinced that the bivalent vaccine is beneficial as a primary series and its boosters," committee member David Kim, an infectious disease expert at the Department of Health and Human Services, said.