Jan 17, 2013 (CIDRAP News) – The US Food and Drug Administration (FDA) has approved the first influenza vaccine produced with the help of an insect virus and recombinant DNA technology, an approach the agency says may make it possible to start production faster in the event of a flu pandemic.

Flublok, a trivalent (three-strain) vaccine developed by Protein Sciences Corp. of Meriden, Conn., was approved for adults ages 18 through 49. The only flu virus component it contains is hemagglutinin, the active ingredient, which is produced by infecting cultures of insect cells with a baculovirus that turns them into hemagglutinin factories.

Most flu vaccines use viruses grown in chicken eggs. However, in November the FDA approved Novartis's Flucelvax, which uses flu viruses grown in mammalian cells, making it the first vaccine of its kind to gain US approval.

Karen Midthun, MD, director of the FDA's Center for Biologics Evaluation and Research, called Flublok a technological advance. "The new technology offers the potential for faster startup of the vaccine manufacturing process in the event of a pandemic, because it is not dependent on an egg supply or on availability of the influenza virus," she said in an FDA press release.

But the vaccine is similar to other licensed flu vaccines in that it uses hemagglutinin as the active ingredient or immune system target, according to a recent major report on flu vaccines. A number of flu experts have said that new kinds of flu vaccines with novel antigens are needed in order to provide broader, more enduring protection than today's vaccines, which must be reformulated each year to keep pace with viral mutations. Today's vaccines are generally about 60% effective in working-age adults.

In a press release, Protein Sciences called Flublok the first flu vaccine "to be made in a 100% egg-free system without growing influenza viruses—so the vaccine can be made quickly and without any of the infectious risk traditionally associated with vaccine manufacture." The vaccine contains no thimerosal (a preservative used in some vaccines), antibiotics, or adjuvants, the company said.

The product contains 45 micrograms (mcg) of hemagglutinin for each of the three targeted flu strains, which is three times what most other flu vaccines contain.

Manon Cox, PhD, MBA, the company's chief executive officer, told CIDRAP News that early studies of the vaccine showed that higher-than-standard doses induced better immune responses. The company eventually settled on 45 mcg as the optimal dose.

The FDA said Flublok was found to be about 44.6% effective against all flu strains in a controlled trial conducted at multiple US sites. The vaccine was given to about 2,300 people, while a similar number of volunteers received a placebo.

The vaccine's safety was tested in about 2,500 volunteers, the FDA said. The most common side effects were pain at the injection site, headache, fatigue, and muscle aches, which are also common in recipients of conventional egg-based flu vaccines.

Protein Sciences said Flublok will be widely available for the 2013-14 flu season. The company also hopes to provide a limited supply this season, but no doses are available yet, said Cox.

She said a problem with the fill-finish stage of production is holding up the vaccine right now. The product "is sitting in a big refrigerator in McPherson, Kansas, and we're waiting for the vials to be packaged and shipped to us," she told CIDRAP News, noting that the fill-finish step is handled by a subcontractor.

Cox said the company is considering a price of about $30 per dose for the vaccine, but no decision has been made yet. "We're very sensitive to the fact that most people feel vaccine should be provided for free," she commented.

Hemagglutinin for Flublok is produced by infecting insect cells with a baculovirus that has been altered to contain the gene for hemagglutinin. Baculoviruses infect a few insect species and are commonly found on green vegetables but do not grown in mammalian cells, according to previous reports.

Most conventional flu vaccines consist of whole, killed flu viruses or viral fragments that contain several proteins, not just hemagglutinin (though one vaccine uses a live, weakened virus).

Cox said it took a very long time to develop Flublok and gain FDA approval, in large part because the agency had many questions about the safety of the new production technology.

"It took 20 years to go from proof of concept to convincing the agency that this would work," she said.

Although the vaccine is highly purified, it contains some residual proteins of nonhuman origin, Cox noted. "All the evidence was that it was safe," she said. "There were no signs that our new cell line wasn't good enough. It's always very hard to prove a negative."

Early development of the vaccine was supported by the National Institute for Allergy and Infectious Diseases. In 2009, the company won a contract from the US Biomedical Advanced Research and Development Agency, part of the Department of Health and Human Services, for late-stage development.

Cox said the company is preparing to launch a trial of the vaccine in people 50 and older, with the hope of winning FDA approval for that age-group late this year. The agency had concerns about hypersensitivity reactions seen in some over-50 participants in a previous trial, although such reactions were twice as common in a comparison group that received a conventional flu vaccine, she explained.

Protein Sciences also plans to run a trial of Flublok in children ages 6 to 18 in the 2013-14 flu season, with the hope of winning FDA approval for that age-group the year after that, Cox said. Earlier, the vaccine was tested in very young children who had never had flu before, and it was found to be not very immunogenic, she noted.

As for the promise of faster production startups with Flublok, Cox said, "In 21 days after we have the genetic sequence [of the target virus], we are able to get it into production, so that's a substantially shorter time to do it than in cell culture or in eggs." But she noted that later steps, such as filling and finishing vaccine vials, can cause delays.

Nicholas Kelley, PhD, a coauthor of a lengthy analysis of flu vaccines published last year, agreed that the new vaccine promises to allow faster production startups.

"It can be produced and scaled up on a larger scale and faster than a mammalian cell culture vaccine," he said. But he added that in comparison with other flu vaccines, "there's no difference in how well it works."

Kelley is a research associate at the University of Minnesota's Center for Infectious Disease Research and Policy, which publishes CIDRAP News. He helped write The Compelling Need for Game-Changing Influenza Vaccines, a lengthy report on the whole flu vaccine landscape, published last October.

The report notes that alternative flu vaccine production platforms such as mammalian cell culture and insect cell culture improve on conventional egg-based technology in that they are likely to shorten the production time and are less prone to contamination. It cites Flublok as an insect-cell–based vaccine.

"However, as long as such vaccines continue to be directed toward the HA [hemagglutinin]-head antigen, they will have little potential to improve vaccine effectiveness or to provide broad, durable protection against disease," the report states.

The FDA noted that the shelf life for Flublok is 16 weeks from the data of manufacture. That compares with about 1 year for most flu vaccines.

Cox said the 16-week shelf life "has to do with our worst-case production lots in 2007,'" adding, "Since then we got data indicating it's feasible to get a shelf life of 9 to 12 months, but we didn't want to give new information to the agency [FDA] at this moment" for fear of causing further delays. She said the company hopes to get the listed shelf life changed soon.

See also:

Jan 16 FDA press release

Jan 16 Protein Sciences release

Apr 12, 2007, CIDRAP News story about earlier Flublok clinical trial

Aug 10, 2011, CIDRAP News item about phase 3 Flublok trial in 2007-08 season

Nov 21, 2012, CIDRAP News story about Novartis cell-based vaccine

Oct 15, 2012, CIDRAP News story "Report: Complacency, misperception stymie quest for better flu vaccines"