Flu vaccine makers have argued that despite being urged by the World Health Organisation and some national drug regulators to drop the component known as B/Yamagata from their shots as quickly as possible, it's not as simple as it sounds.
The WHO and others believe this lineage of flu B viruses died out during the Covid-19 pandemic and that it is now superfluous in the vaccines – but the manufacturers say the process of leaving out the component is far more complex than assumed.
While some experts say this transition should be doable in time for the next northern hemisphere flu vaccination campaigns, the International Federation of Pharmaceutical Manufacturers and Associations wants a longer lead time for the shift, saying it will take flu vaccine makers until at least the 2025-2026 northern hemisphere cycle to make the change.
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?’” Paula Barbosa, the IFPMA’s associate director for vaccine policy, told STAT News.
Dozens of manufacturers worldwide make hundreds of millions of doses of flu vaccine annually. Most are quadrivalent, targeting 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. Before 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, sometimes leading to reduced effectiveness of the jabs. Over the past 15 years or so, most manufacturers transitioned to a four-in-one vaccine, hoping to improve protection.
However, in the years before the Covid pandemic, B/Yamagata viruses seemed to lose steam. They were detected less frequently than B/Victoria viruses, and didn’t evolve as quickly. (The viral target for B/Yamagata in current flu vaccines dates back to 2013.)
The reduction in global travel and social distancing measures taken in 2020 to minimise 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 March 2020. Hence the recommendation to remove it from the vaccines.
Though some virologists remain unconvinced the lineage has actually gone, increasingly, flu experts believe there is no longer a need to include protection against it.
“There’s no [B/Yamagata] virus circulating, so why include the antigen?” asked Scott Hensley, a University of Pennsylvania professor of microbiology who specialises in influenza. “It’s definitely time.”
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 (swop 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 shot,” said Ben Cowling, chair of epidemiology at the University of Hong Kong’s School of Public Health.
Experts who advise the US 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 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 do this.
Barbosa said whereas in some jurisdictions, like the United States, there’s a reasonably uncomplicated regulatory pathway for making the change, in other countries the process is not as simple.
There are roughly 350 trivalent vaccine licences that either need to be reactivated, updated, or in some cases, applied for from scratch, she said, adding that the transition involves around 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 licences.
Regulatory dossiers are voluminous and detailed. If a flu vaccine producer changed, for example, the location where it conducted some testing of its product, licencing dossiers must be amended in all places where that testing is referenced to reflect the change.
If new production facilities were built after a company started marketing a quadrivalent flu vaccine – 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 need to be revalidated and submitted for (trivalent),” Barbosa said. “From a regulatory and procedural standpoint, this is complex.”
Some of the manufacturers are in discussions with not just one regulatory agency, but multiple agencies. Some have production plants in numerous 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 and at two US facilities. CSL Seqirus makes flu vaccines in Australia, the UK, and the US, 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 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 News.
“This is evolving information, but that’s what we are working on,” she said. “This change presents companies with various practical and technical challenges in implementation.”
The IFPMA is advocating for a synchronised global shift, arguing that to make the change sooner in some but not all countries could jeopardise manufacturers’ ability to fill the orders they get from countries buying the vaccines.
“To make it clear, the companies are fully committed to supporting the transition,” Barbosa said. “We just feel it’s critical they’re given the appropriate amount of time to implement the changes.”
All of the licensed quadrivalent flu vaccines in America were previously marketed as trivalent formulations, making the transition much simpler than if a manufacturer had to apply for a whole new licence. None of the manufacturers relinquished those trivalent licences, said FDA spokesperson Cherie Duvall-Jones.
Instead, they were put on a list of “discontinued products”, a marketing limbo that keeps a licence in play but doesn’t require the manufacturer to pay annual programme fees for products it isn’t selling.
There is a process for reactivating such licences. But the FDA wasn’t forthcoming about how that works, saying simply that manufacturers must submit official requests to have a product removed from the list, after which it would ask a manufacturer to submit “a prior approval supplement”.
The agency side-stepped the question of whether the FDA would be willing to allow manufacturers supplying the US market to take part in a synchronised transition, following the IFPMA timeline.
“The FDA is working with the manufacturers to assess their readiness to make available a trivalent vaccine and the timing, but it is premature to provide specific answers,” Duvall-Jones wrote.
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 vaccines.
The meeting picks the strains for the next northern hemisphere flu shot; the same experts meet in September to select the strains for the impending southern hemisphere winter.
On whether some countries or regions could make the transition on a more accelerated schedule, Barbosa said: “It’s a possibility… I guess we’ll know more in February.”
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