Annual? Bivalent? To all? Future of COVID shots unclear after FDA deliberations

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

But outside experts, including some on the FDA’s advisory committee, have questioned nearly 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 is a need to boost the young and healthy so often when current vaccines offer protection against serious disease but only short-term protection against infection.

One particularly outspoken member of the FDA’s committee, Paul Offit, a pediatrician and infectious disease expert at the Children’s Hospital of Philadelphia, has publicly attacked the bivalent booster, writing an op-ed 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 one of the two votes against.)

Still, despite the charged background to yesterday’s meeting, sparks of disagreement erupted over a calm discussion. The nine-hour meeting culminated in a unanimous vote by the committee to “harmonize” future formulations of covid-19 vaccines so that primary series and boosters become matched formulations. For example, the primary vaccines will match the updated bivalent boosters, which currently target both the original strain of SARS-CoV-2 that originated in Wuhan, China, as well as the omicron subvariants BA.4/5.

Streamlining

The FDA appeared 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 “simplification of the immunization schedule,” before arriving at the more dangerous but still mild discussion topic of considering “periodic updates of the COVID-19 vaccine formulation.”

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

“There is so much confusion around these different formulations that I think anything we can do to ease that confusion and simplify things is going to be a good thing,” said Archana Chatterjee, dean of the Chicago Medical School and member of the voting committee, said at the end of yesterday’s meeting. “I agree with my other colleagues that there is definitely still a need for these vaccines and for us to do our best to weaponize them. It is not sufficient to have vaccines, we must have them used… This is a step. in the right direction to get us there.”

But the bigger steps for future vaccines — deciding which formulation to use next, who should get them and when — remained elephant-in-the-room questions. And even among the relatively calm comments, it was clear that major disputes were bubbling beneath the surface.

Before the committee’s vote and discussion, the advisers listened to a series of presentations from vaccine manufacturers, the FDA and the Centers for Disease Control and Prevention, all of whom 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 at the meeting argued otherwise. Real-world observational data show an advantage for subjects boosted with the bivalent booster compared to the original (monovalent) vaccine – even against the newer subvariants. Data presented at the meeting show that it outperformed the original vaccine in terms of protection against symptomatic infection, ED visits or ED visits, and hospitalization.

In a CDC study published Wednesday, for example, 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 ages 18 to 18 years. 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 those ages 50 to 64, the relative effectiveness against BA.5-related infection was 43 percent, and it was 37 percent among those 65 and older.

In contrast to the newer 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, and 43 percent among those 65 and older.

There have also been a number of serological studies that have looked at how the antibody responses to the bivalent booster compare with those from the original booster when up against the spectrum of circulating omicron subvariants. The results are mixed and, in some cases, difficult to compare due to differences in intervals between vaccinations, the number of people involved and the types of assays used. But overall, the FDA asserted that it proposes that the bivalent booster produces better neutralizing antibody responses against currently and newly circulating omicron subvariants than the original vaccine.

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

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

Despite criticism from Offit and others before the meeting, committee members seemed comfortable with the bivalent data, accepting the FDA’s rosy outlook.

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