Inside a 97,000-square-foot greenhouse in North Carolina, thousands of small tobacco plants are growing in individualized containers.
In the heart of tobacco country, they are grown year round by Medicago, which is 40 percent owned by tobacco maker Philip Morris and based in Quebec, Canada — but the plants are not being grown for future use in cigarettes. Instead, they’re being grown for use in testing and production of the flu vaccine.
The tobacco plants being grown in Durham’s Research Triangle Park, the leading and largest high technology research and science park in North America, are a cousin of Nicotiana tabacum. The thousands of plants Medicago is growing are Nicotiana benthamiana, a flowering plant that is native to Australia.
The hope is that scientists will be able to make more of the vaccine faster. The plants, and vaccine, grow in five to six weeks, as opposed to the five or six months it takes to prepare the vaccine in chicken eggs, which is how most doses of it are currently produced.
Available in two to three years
Medicago, founded in 2000, is in the midst of a phase 3 clinical trial for its flu vaccine, with hopes to put it on the market for the 2020-21 influenza season.
Researchers have already enrolled 10,000 people aged 18 to 64 in the study, including 4,000 in the United States, as part of a Food and Drug Administration trial. Testing of the single quadrivalent doses began in 18 states last August and is scheduled to wrap up in April.
The tobacco-grown vaccine has been approved for trials in seven other countries around the world as well, including Canada. Researchers say the results so far are promising — no side effects for people with allergies to tobacco, unlike people with allergies to poultry, which is a concern for the current flu vaccine.
“The plant has been known by plant biologists for many years,” Nathalie Charland, senior director of Scientific and Medical Affairs at Medicago, told UPI. “They have a capacity to produce protein. We’re not using the plant to make cigarettes, but in the same family.”
Turning tobacco into the flu vaccine
The North Carolina facility opened in 2011. Researchers first experimented with alfalfa, which is part of the medicago genus, the plant family the company is named for. But they found tobacco was much better because it’s hearty and grows quickly. The big leaves are ideal, they say.
Clinical grade plant material is produced in a little more than a month. A vacuum sucks the air out and then they are placed in an inoculum solution. Then, the plants grow for another week and finally the brownish leaves are picked off by hand.
The company believes this process is a better way to cultivate the vaccine than from chicken eggs.
“Plants don’t need a live virus,” Charland said. “With plants all you need is a genetic scheme of one protein. It’s much more rapid. You don’t need to wait for live viruses. It’s five to six weeks instead of five to six months.”
Chicken eggs vs. tobacco plants
Growing vaccines in chicken eggs is a process that dates to the 1940s, in which a small amount of live flu virus is injected into a chicken egg.
“Every step of the process brings delay,” she said about the eggs. “They may not be growing well. You are killing embryos. There may not be enough viruses with egg-based manufacturers.”
Also, one egg produces up to four vaccines — but for one tobacco plant, up to 50 vaccines can be produced.
In addition, egg viruses sometimes cause problems with mutation, especially in the H3N2 viruses, which cause the worst outbreaks.
“Plants are highly efficient at producing proteins of varying complexity, serving as mini factories for our vaccines,” the company said in a fact sheet. “Greenhouse manufacturing can quickly scale to meet urgent needs.”
DARPA-funded production test
Because of these attributes, the U.S. Department of Defense awarded the company a $21 million grant in 2010 to see if 10 million doses of flu vaccine could be produced in 30 days.
The project was part of the Defense Department’s DARPA research program, which used a grant as part of its Blue Angel project. The project is designed to overhaul instability in vaccine supplies.
“We were successful in showing that 10 million doses in 30 days can be produced,” Charland said of the effort, which were achieved in 2012. “That was the goal of the DARPA project. We are the only one who led the market.”
Motivation to move past chicken eggs
Other companies have been testing vaccines in tobacco, but Medicago is farther along in the process and the others are not involved in Phase 3 trials.
The FDA is especially interested in non-egg vaccines. That interest only grew as this season’s vaccine has only been about 25 percent successful.
Earlier this month, FDA Commissioner Dr. Scott Gottlieb told Congress that one influenza vaccine made in cell culture was about 20 percent better this year than the one made in eggs.
The vaccine, sold under the brand Flucelvax, is made by Seqirus. The only other non-egg vaccine, Sanofi Pasteur’s FluBlock, is made from insect cells.
The National Institute of Allergy and Infectious Diseases is pushing for a safe and effective universal influenza vaccine that is at least 75 percent effective, protects against group I and II influenzas, protects for at least one year and works for all age groups.
With the tobacco vaccine, it’s getting close to reaching those criteria — especially with the ability to adapt quickly to new strains, Charland said, because of the rapid production process.
“The holy grail will take a lot of years,” Charland said. “They will have to demonstrate many seasons.”
In the meantime, the tobacco method is moving in the right direction.
Tobacco, pharmaceutical industries making it possible
When the vaccine goes on the market, Medicago will have control of the vaccine from start to finish unlike pharmaceutical companies that rely on egg manufacturers.
“We handle everything,” Charland said. “We control everything. We grow the plants. We produce materials, the virus-like product. It’s a purified form of vaccine. We are doing the whole process from A to Z.”
She said the company likely will eventually outsource some of the production because of what they anticipate to be large demand.
That’s good news for Philip Morris Investments, a part of cigarette-maker Philip Morris International, and Mitsubishi Tanabe Pharma, a Japanese company which acquired 60 percent of Medicago for $357 million in 2013.
Philip Morris, which initially invested $20 million in the company in 2008, and another $22 million in 2011, owns the other 40 percent of the company.
Charland said, however, that it is unlikely the company would start growing the flu vaccine in Philip Morris’s tobacco fields, saying “they are just investing in our company. Our technology won’t be grown in the fields. Always in a controlled environment. It is really a separate activity.”
She said the ownership is really a “sideline for them,” though Philip Morris is trying to move away from traditional cigarettes as it, like other tobacco companies, turns to non-burning and vaping products. The investment also may be good publicity for Philip Morris as public opinion has made a hard turn against smoking in general.
“I think people like the idea of creating something positive from a plant with such negative stigma,” Dave Henry, Medicago’s manufacturing director, told Modern Farmer in 2014.
Charland agrees that the potential of turning a plant that has been harmful to human health into one with the potential to preserve life is a good one — especially in an area that the healthcare industry has had a tough time in during recent years.
“I really believe our technology will make a difference compared with existing vaccine,” she said.
By Allen Cone