After COVID killed off a flu strain, annual flu shots are in for a redesign

Vaccine advisors for the Food and Drug Administration voted unanimously (12 to 0) Thursday to remove, "as soon as possible," a component of annual flu shots that targets a strain of the virus that appears to have gone extinct amid the COVID-19 pandemic.

 

The vote follows a similar recommendation from the World Health Organization last week, which stated that "every effort should be made to exclude this component as soon as possible."

Exactly how soon that removal could happen is unclear, though, and some advisors on the FDA's panel expressed frustration that plans for the removal appear to have been slow-walked in the last couple of years, as it only became more apparent that the strain may be gone for good.

 

The missing strain is the influenza type B Yamagata lineage (aka B/Yamagata), one of only four flu viruses targeted by annual vaccines. There have been no confirmed detections of B/Yamagata worldwide since March 2020, when the pandemic coronavirus, SARS-CoV-2, erupted onto the global scene, dramatically disrupting the lives of people and other viruses everywhere. The subsequent 2020-2021 flu season was virtually nonexistent.

 

While other strains and lineages of influenza have since rebounded and are moving back to their normal seasonal cycles, B/Yamagata is still unaccounted for. Still, it's rather difficult to determine with absolute certainty if a virus has truly gone extinct—particularly a lineage that had previously circulated worldwide. For this reason, flu experts have been cautious about declaring it "extinct" and retooling annual shots.

 

But now, after more than three years since its disappearance, experts are confident in saying it presents a low risk of infection, and it's time to move on. In fact, keeping the vaccines as is may be riskier than taking the B/Yamagata component out. That's because some flu vaccines include inactivated or weakened viruses, requiring vaccine manufacturers to grow live viruses. Thus, keeping B/Yamagata in vaccines poses a risk of reintroducing the virus to people if a mishap occurs during production.

“Room for improvement”

But moving on from B/Yamagata is easier said than done. There are two formulations of flu vaccines: trivalent vaccines and quadrivalent ones. The trivalent shots only target three strains and don't need reformulating; they target two type A strains (H1N1 and H3N2) and another type B lineage called B/Victoria. But many of the vaccines in high-income countries, like the US, are quadrivalent, targeting four strains—the two type As and both B/Victoria and B/Yamagata—and thus need reformulating.

 

The simplest thing to do would be to take the B/Yamagata out of the current vaccines, dropping quadrivalent vaccines to trivalent ones. But the makers of quadrivalent vaccines largely only have licenses to make quadrivalent vaccines—not trivalent ones. In the US, all currently distributed, licensed vaccines are quadrivalent. Makers of those quadrivalent vaccines still technically have licenses for trivalent formulas, an FDA official said in the meeting today. But, the trivalent licenses have been moved to a "Discontinued" status and would have to go through a regulatory procedure to be revived.

 

Another hurdle is timing. Flu vaccines for the 2023-2024 season in the Northern Hemisphere are out now (with a B/Yamagata component in quadrivalent formulations)—far too late for a retool. (To find where to get a flu shot, you can check out vaccines.gov.) Now, vaccine experts, like the panel of FDA advisors who met today, are selecting flu strains for the 2024 season in the Southern Hemisphere, which usually spans April to September. But, there too, it is too late for to switch manufacturing processes from quadrivalent to trivalent formulations. In the meeting today, a representative for one flu vaccine maker, Sanofi, suggested the company would see what it could do to reformulate shots for the 2024-2025 season in the Northern Hemisphere, but still, there are no guarantees.

 

Beyond the problems of less-than-nimble manufacturing and licensing, experts are also unsure what an ideal reformulated flu vaccine would be. One possibility is to keep a quadrivalent formula but use three type A viruses and one type B instead of the previous even split. Another possibility is to drop to a trivalent formula but boost the dosage of one of the targeted flu strains—the most dominant in circulation—or boost the dosage for all three.

 

Between 2010 and 2023, seasonal flu vaccine efficacy has ranged from a dismal 19 percent to 60 percent, so there's "room for improvement," Jerry Weir, director of the Division of Viral Products in the FDA’s Office of Vaccines Research and Review, noted in today's meeting.

“We are where we are”

However, there's virtually no data to guide advisors on how best to redesign flu shots. Weir left the meeting today saying that the FDA would work with manufacturers and experts to update shots as soon as possible and figure out how to improve the vaccines.

 

But some FDA advisors expressed frustration that it appeared this work was just starting now and not a year or two ago. Hana El Sahly, chair of the FDA's advisory panel and an infectious disease expert at Baylor University, noted that today's meeting was the fourth in which advisors had discussed the disappearance of B/Yamagata. In past meetings, many had made clear that they mainly supported keeping the strain in flu shot formulations thus far to buy the FDA and manufacturers time to figure out reformulations.

 

"What I'm concerned about is that it seems like we are going to begin the discussion about it now with manufacturers and regulatory agencies," El Sahly said. "I wonder why this has not taken place so far."

 

The Sanofi representative responded that the company has not had "substantive meetings" with the FDA on the topic. "Here we are, and we've listened and we're ready to act, but I can't reverse the past. We are where we are," he said.

 

Weir, meanwhile, acknowledged the frustration and assured El Sahly that, despite the slow progress, their advice was "moving the conversation forward," and there would be "tangible results" in "the near future."