The WHO and drug regulators want to reformulate the flu vaccine. It’s easier said than done

Last fall, the World Health Organization and some national drug regulators urged influenza vaccine manufacturers to drop the component known as B/Yamagata from flu vaccines as quickly as possible, citing the fact that this lineage of flu B viruses appears to have been snuffed out during the Covid-19 pandemic.

It might seem like that request would be as simple as deciding to leave blueberries out of a mixed-fruit smoothie. It turns out it is not.

While some experts have claimed that this transition should be doable in time for next fall’s Northern Hemisphere flu vaccination campaigns, the International Federation of Pharmaceutical Manufacturers and Associations, an organization that represents vaccine manufacturers and other pharmaceutical entities, is calling for a longer lead time for the shift, saying it will take flu vaccine makers until the 2025-2026 Northern Hemisphere cycle to be able to make the change across the board. The Southern Hemisphere flu vaccines would follow in the 2026 winter, the IFPMA said.

“There’s a bit of a perception that, ‘Industry, you change the components of the vaccine twice a year. Why is this so complicated?’” said Paula Barbosa, the IFPMA’s associate director for vaccine policy.

“It’s widely different.”

Dozens of manufacturers around the world make hundreds of millions of doses of flu vaccine every year. Most of those products are quadrivalent, meaning they target four types of influenza — the influenza A viruses H1N1 and H3N2, and two lineages of flu B viruses, B/Victoria and B/Yamagata.

The protection against two flu B viruses is a relatively new feature of flu vaccines. Prior to 2012, the vaccines were trivalents — protecting against the two A viruses and one of the Bs. But the choice of which B to target wasn’t always correct, leading in some cases to reduced effectiveness of the vaccines. Over the past 15 years or so, most manufacturers transitioned to a four-in-one vaccine, hoping to improve the protection their products offer.

However, in the years preceding the start of the Covid pandemic, B/Yamagata viruses seemed to lose steam. They were detected less frequently than B/Victoria viruses, and didn’t appear to be evolving as quickly as B/Victoria viruses. (The viral target for B/Yamagata in current flu vaccines dates all the way back to 2013.) The reduction in global travel and social distancing measures taken in 2020 to minimize transmission of Covid-19 drove all flu activity to very low levels for a year or so. The other viruses eventually bounced back, but not B/Yamagata. The last confirmed detection of a B/Yamagata virus was in late March 2020. Hence the recommendation to take it out of the vaccines.

Though some virologists remain unconvinced the lineage is actually gone, increasingly flu experts believe there is no longer a need to include protection against B/Yamagata in flu vaccines.

“There’s no [B/Yamagata] virus circulating, so why include the antigen?” asked Scott Hensley, a University of Pennsylvania professor of microbiology who specializes in influenza. “I think it’s definitely time.”

In the main, the rationale for removing the B/Yamagata component is that it isn’t needed. Why stimulate the immune system to be able to fend off a viral enemy it isn’t going to face? But there is also, at least in theory, some risk involved in using one kind of flu vaccine — live-attenuated vaccines like AstraZeneca’s FluMist — that contains live but weakened B/Yamagata viruses. The concern is that the viruses in the vaccine could reassort — swap genes — with the remaining flu B viruses and reseed B/Yamagata in the world.

“I think specifically for the live-attenuated vaccine it is a bad idea to keep Yamagata in that vaccine,” said Ben Cowling, chair of epidemiology at the University of Hong Kong’s School of Public Health.

Experts who advise the Food and Drug Administration on vaccine policy, the Vaccines and Related Biological Products Advisory Committee, endorsed the idea of removing the B/Yamagata component from flu vaccines as quickly as possible at a meeting in early October. And several objected to the claim, raised during the autumn meeting by an industry representative, that it would take until the 2025-2026 vaccine cycle to accomplish this task.

Barbosa said whereas in some jurisdictions — such as the United States — there’s a reasonably uncomplicated regulatory pathway for making the change, in other countries the process is not as clear cut.

There are roughly 350 trivalent vaccine licenses that either need to be reactivated, updated, or in some cases, applied for from scratch, she said, adding that the transition involves an estimated 170 regulatory agencies that will need to sign off on a combined total of about 1,500 variations that need to be made to existing licenses.

Regulatory dossiers are voluminous and detailed. If a flu vaccine producer changed, for example, the location where it conducted some testing of its product, licensing dossiers need to be amended in all places where that testing is referenced to reflect the change. If new production facilities were built in the period after a company started marketing a quadrivalent flu vaccine — in other words, if trivalent products were never made in that location — the new facilities would need to go through approval for trivalent production.

“So the whole end-to-end manufacturing — including the components of quality and validation in many sites — are [quadrivalent] specific, and now will need to be revalidated and submitted for [trivalent],” Barbosa said. “From a regulatory and procedural standpoint, this is an extremely complex picture.”

Some of the manufacturers are in discussions with not just one regulatory agency, but multiple agencies. Some have production plants in a number of countries; major manufacturers sell flu vaccines to multiple countries.

Sanofi, the world’s largest manufacturer of flu vaccines, makes its products in France, Mexico, China, as well as at two U.S. facilities. CSL Seqirus makes flu vaccines in Australia, the United Kingdom, and the U.S., and sells them to at least 14 countries in North and South America, Europe, Australasia, and Asia. GSK makes flu shots in Canada and Germany that are sold in 30 different countries.

The complexity of the regulatory realities facing manufacturers explains why the industry feels the 2024-2025 flu season target can’t be met and that 2025-2026 is more realistic, Barbosa told STAT in an interview.

“This is evolving information, but that’s what we are working on,” she said. “This change presents companies with a number of practical and technical challenges in implementation.”

The IFPMA is advocating for a synchronized global shift, arguing that to make the change sooner in some but not all countries could jeopardize the ability of manufacturers to fill the orders they get from countries that buy the vaccines.

“To make it very clear, the companies are fully committed to supporting the transition,” Barbosa said. “We just feel that it’s critical that the companies are given the appropriate amount of time to operationalize the proposed changes.”

One of the experts at the October VRBPAC meeting who objected to the IFPMA’s timeline was veteran influenza epidemiologist Arnold Monto of the University of Michigan, who believes the shift can be made — at least for the U.S. market — in time for the 2024-2025 flu vaccine rollout.

“The U.S. is a major user of the vaccines. We may not be able to do it — to get rid of the B/Yamagata — globally. But there seems to be a possibility it could happen in the United States,” Monto said in an interview.

All of the licensed quadrivalent flu vaccines in the U.S. were previously marketed as trivalent formulations — which makes the transition much simpler than if a manufacturer had to apply for a whole new license. None of the manufacturers relinquished those trivalent licenses, FDA spokesperson Cherie Duvall-Jones said via email. Instead they were put on a list of “discontinued products” — a kind of a marketing limbo that keeps a license in play but doesn’t require the manufacturer to pay annual program fees for products it isn’t selling.

There is a process for reactivating such licenses. But the FDA wasn’t especially forthcoming about how that process works, saying simply that manufacturers have to submit official requests to have a product removed from the discontinued product list, after which the FDA will ask a manufacturer to submit “a prior approval supplement.” What is required of a company in this prior approval supplement wasn’t spelled out.

The agency sidestepped the question of whether the FDA would be willing to allow manufacturers supplying the U.S. market to take part in a synchronized transition, following the IFPMA timeline.

“The FDA is working with the influenza vaccine manufacturers to assess their readiness to make available a trivalent vaccine and the timing, but it is premature for FDA to provide specific answers to your questions at this time,” Duvall-Jones wrote.

Individual flu vaccine manufacturers were unwilling to talk much about the situation while in negotiations with the FDA about what they must each do to reactivate their trivalent licenses.

“Given this is an ongoing discussion, we don’t have anything to share at this time,” said Chelsea Tressler, a spokesperson for AstraZeneca.

A spokesperson for Sanofi said the company supports the timeline proposed by the IFPMA.

“While the U.S. FDA has a mechanism in place to speed this process, the majority of countries require us to file new license applications for trivalent products, which then have to be reviewed and approved,” the spokesperson said in an email. “It is important to remember that the continued use of quadrivalent inactivated vaccines presents no safety issue, nor is there any lesser efficacy than a trivalent vaccine.”

Barbosa said the IFPMA and its members are hoping for clearer guidance from the WHO and regulatory agencies when global influenza experts convene in February for the twice-annual meeting to select the strains to be included in the next iteration of flu vaccines. The February meeting picks the strains for the following Northern Hemisphere flu shot; the same experts meet in September to select the strains for the next Southern Hemisphere winter.

As to the question of whether some countries or regions could make the transition on a more accelerated schedule, Barbosa said: “It’s a possibility. And I guess we’ll know more in February.”