Tobacco: More Efficient Flu Vaccine-Maker?

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Tobacco leaves are being used to produce flu vaccines.
Medicago Inc.

With flu season only a sneeze away, the vaccines that swell arms across North America this year will still be made with chicken eggs. However, a flu pandemic could call a Canadian biopharma company into action. In clinical trials now, their method uses tobacco plants to produce flu vaccines affordably in weeks rather than months.

"This one little plant can do 50 doses," said Andy Sheldon, CEO of the Canadian biopharma company Medicago that is developing tobacco-based vaccines. "Whereas when you're looking at one egg, which is what people use when they're making influenza vaccines, they can get about two doses."

Most flu vaccines remain egg-based, manufactured using living chicken embryos. This technique has limits, though. It makes vaccine production challenging to scale up and difficult to change when new viruses emerge. The 2009 swine flu pandemic had gone through a second wave before a vaccine was ready.

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Medicago, with help from U.S. defense grants, is one of several companies seeking a more effective replacement for eggs. Plants have been eyed as an alternative since the early 1990s, according to pioneering plant researcher Charles Arntzen. Currently the co-director for Arizona State University's Center for Infectious Diseases and Vaccinology, Arntzen said that several other plant species, including tomatoes, had initially been studied as possibilities.

Mega-Production Plants

Academic efforts to develop alternatives tended to get stuck in the lab due to the intense regulatory requirements for vaccine production, Arntzen explained. The typical flu vaccine must go through clinical trials before being approved, and another five to six months to become available, according to the U.S. FDA and the World Health Organization. Then, Antzen said, groups including German plant biotech company Icon Genetics started focusing on a tobacco strain called Nicotiana benthamiana.

"I just don't understand how this thing has ever evolved because it gets sick with every tobacco virus that comes along," he said. "When we infect the plant, it just produces massive amounts of our desired protein." This is the same tobacco strain that Medicago currently uses.

Although the exact process is proprietary, Medicago starts with tobacco plants grown in greenhouses. After about five weeks, the plants are suspended in a solution made from a human-safe bacteria found in soil. That solution in effect tells the tobacco plant to produce large quantities of an influenza viral protein. Once the plants take up that solution, they incubate for about five days.

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The leaves are then crushed and put through standard pharmaceutical steps to create a purified influenza vaccine. While Medicago's virus-like particle looks and behaves just like the real thing to elicit an immune response, Sheldon said, it lacks the DNA to replicate.

In addition, the company says its vaccine can be produced relatively inexpensively. A traditional egg-based facility would cost $350 to $400 million to produce between 40 and 50 million seasonal flu vaccine doses, a cell-culture facility can cost closer to $1 billion, while Medicago's facility in Research Triangle Park, North Carolina, can make as much as both combined using $36 million, Sheldon said.

Preparing for a Pandemic

Medicago received investment from the Defense Advanced Research Projects Agency (DARPA) as part of the agency's push to develop plant-based vaccines that could be made quickly in case of a pandemic. The biotech companies Kentucky BioProcessing LLC and Caliber Biotherapeutics also received DARPA grants for proof-of-concept scalable plant-based pharmaceuticals production. Starting in 2008, cigarette manufacturer Phillip Morris began investing in Medicago as well.

"What everyone's looking for is something faster," Sheldon said. He added that during the 2009 swine flu pandemic, once Medicago received the genetic sequence it only took 19 days to have a product with more than 95 percent purity in a vial. Last spring, Medicago produced 10 million doses of a swine flu vaccine candidate in one month, which DARPA called a "milestone development."

"Their vaccine is very nicely mimicking a portion of the flu virus," said Arntzen, who is independent of Medicago. He has seen their data and visited their North Carolina production facilities. "They're manufacturing something that really looks like what we make ourselves, in people."

The company is also working with the Infectious Disease Research Institute in Seattle, also a DARPA grant recipient. IDRI has been developing a vaccine ingredient called an adjuvant that stimulates better immunity. Together with IDRI and a device maker called NanoPass, Medicago began testing the plant-based vaccine administered with an intradermal microneedle device.

Medicago has already completed Phase I of clinical trials in the United States for its seasonal flu vaccine. That will likely be ready for the market in four to five years. Its avian flu vaccine is further along. The company has met all the regulatory requirements through to the end of Phase II clinical trials in Canada. Sheldon said the company would like to secure contracts for stockpiling its pandemic flu vaccine as soon as next year.

However, if a flu pandemic breaks out before then, Sheldon hopes they'll be called to help make vaccines for emergency use. "We have facilities in Quebec and facilities in North Carolina so we could help both sides of the border."

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