It is well-past time for the biopharmaceutical industry to move away from the 70-year-old antiquated egg-based process of developing a flu vaccine and "graduate to the 21st century," the U.S. government's top infectious disease expert told lawmakers.
The flu vaccine was only 36% effective overall this season and 23% during the 2014-2015 season when the H3N2 virus was also the predominant strain.
"We can do better," Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, or NIAID, said during a March 8 hearing held by the House Energy and Commerce Subcommittee on Oversight and Investigations.
Fauci noted some companies are already using modern techniques to produce flu vaccines for the U.S. market, like CSL Ltd. unit Seqirus Inc.'s cell-based product Flucelvax and Sanofi subsidiary Protein Sciences Corp.'s recombinant protein-based vaccine Flublok.
But production for those products has been limited — with Flucelvax representing only 18% and Flublok only 3% of the total flu vaccine produced for the 2017-2018 season, said Rick Bright, director of the U.S. Biomedical Advanced Research and Development Authority.
Growing the virus in eggs and producing the vaccine can take about six months, while cell-based and recombinant products can be made much quicker and can provide more flexibility to rapidly shift to keep pace with changes in the virus, Bright told lawmakers. Those products may also prove to be more effective.
But for the most part, vaccine makers continue to rely on the egg-based manufacturing process, Fauci said.
Companies are reluctant to give up the egg-based process because "it works" and the vaccines are safe, Food and Drug Administration Commissioner Scott Gottlieb told the House members.
However, the biggest reason biopharmaceutical companies are sticking with eggs is because "it would require an enormous investment to fundamentally change their manufacturing," Gottlieb said.
"But we've got to go there," Fauci said. "We can't stay stuck in the old technologies," he said, adding that companies must get past their inertia.
While the NIAID leader said he believed cell-based vaccines "are better," the recombinant DNA technologies are "the way of the future" and would be the tool for getting to a universal flu vaccine — a product that could provide robust, long-lasting protection against multiple subtypes of influenza, rather than a select few.
Only recently have scientists understood the structural biology of the flu virus, which Fauci described as looking like broccoli or a mushroom.
The head part of the virus has many mutations that change from season to season, while the stem does not, he explained.
The challenge is inducing a response against the part of the flu virus that does not change from year to year, Fauci said.
He said scientists at the NIAID, which is part of the National Institutes of Health, or NIH, have been working on a number of approaches to achieve that goal.
Last week, Fauci and his colleagues published their strategic plan for pursuing a universal flu vaccine.
"We stand at a unique moment in time where we have tools and capabilities to dramatically enhance our fight against influenza," Bright told lawmakers.
Immediate steps to address the flu
While investing in and working toward the universal flu vaccine is "crucial," unfortunately "that reality is still many years off," Gottlieb said.
"We must also consider what immediate and intermediate steps we can take to enhance the production of existing licensed vaccines and what should be done to invest in and advance domestic manufacturing to ensure new and existing technologies are scalable so that manufacturers meet domestic and global demand," the FDA commissioner said.
He said the FDA was working to help develop more effective cell lines that may be better scaled through continuous manufacturing, which enables much faster production and more reliable products through an uninterrupted process.
The agency is also looking at how to develop a more robust recombinant manufacturing process to increase yield while reducing cost, Gottlieb added.
"We need to develop a science-based framework that includes the regulatory tools and guidelines for products to be developed in these systems and to be properly evaluated and our investment will provide regulatory clarity for this kind of new technology," he told lawmakers.
Greater investment in antivirals
The officials also stressed the need for new antivirals to treat the flu.
Bright emphasized there has not been a new class of influenza antivirals approved by the FDA for almost 20 years.
"We rely on a single class of influenza antivirals now and the virus continues to change and resistance to that class of antivirals continues to emerge," he said. "It's very concerning," particularly because of the potential for avian flu viruses, like H5N1 or H7N9, to eventually become transmissible from human to human and create a pandemic, Bright warned.
He noted the marketplace for antivirals has not always been profitable.
While Roche Holding AG's Tamiflu has remained popular, BioCryst Pharmaceuticals Inc. has had a more difficult time marketing its intravenous antiviral Rapivab, also known as peramivir, which was approved in 2014.
"I don't think there's a full appreciation and recognition of the impact and benefit that one can receive from getting an antiviral drug in a timely manner when they're infected with influenza," Bright said.
That lack of appreciation for the "power of that drug" may cause other companies to be hesitant to pursue antivirals, he said.
But the officials were optimistic about a new faster-acting antiviral, Xofluza, also known as baloxavir marboxil, from Shionogi & Co. Ltd. and Roche. The companies are expected to file an application with the FDA later this year.
Xofluza is a single-dose drug, versus the twice-daily, five-day regimen for Tamiflu, Bright noted.
Fauci pointed out that the NIH did the early research on Xofluza's mechanism of action, publishing a peer-reviewed journal article about it in 1979.
"It goes to show you that basic science is the root of everything we do" — even something that nearly 40 years later "turns into a product made by a Japanese company."