Science in the Triangle

Construction workers are swarming the two-story building in Research Triangle Park where Medicago plans to start vaccine production in January. In the adjacent greenhouse engineers are testing equipment and some of the first 38 employees are working on trays with 13-day-old wild tobacco plants about 1 inch tall.

Medicago is close to finish building its one-of-a-kind production plant. The French Canadian biotech company, which does its research and development in Quebec City, uses nicotiana benthamiana, a wild tobacco species from Australia, to make influenza vaccine.

The process to extract the vaccine from the leaves of the wild tobacco plants promises to be four times faster than traditional, egg-based vaccine production and require 10 percent of the capital. The RTP production plant will show how well Medicago’s approach is working.

Test runs will start in November and continue in December, said Todd Talarico, senior director of industrial process at the production plant.

By January, Talarico projected to have another 40 temporary and permanent employees hired to produce the first 10 million doses of flu vaccine in 30 days.

“We’ll be able to tell whether we’re on track,” Talarico said.

Construction of the plant started in October 2010. Medicago received a $21 million grant from the U.S. Department of Defense to prove it can ramp up production to 10 million doses per month. Alexandria Real Estate, which builds facilities for life science companies, invested $13.5 million. Medicago contributed the remaining $7.5 million.

The plant is one of three built in the past 10 years to make commercial vaccines in North Carolina’s Research Triangle.

New Jersey-based Merck operates a $400 million plant north of Durham that has already undergone one expansion. The $500 million Novartis plant in Holly Springs is projected to start making flu vaccines from cell cultures in 2013. The Triangle is also home to most of North Carolina’s more than two dozen companies in vaccine research and development. (More on the Triangle vaccine hub here and here.)

Unlike Merck, Novartis and Pfizer, which acquired a vaccine plant in Sanford with the purchase of Wyeth in 2009, Medicago will grow its flu vaccine.

Flu vaccines are protein vaccines and proteins can be generated by cells, yeast, bacteria or eggs. Medicago uses a combination of agrobacteria and wild tobacco plants. The technology is the brainchild of Louis-Philippe Vézina, the company’s co-founder and chief scientific officer.

Starting with alfalfa and then switching to nicotiana benthamiana, Vézina was able to coax the plants to make virus-like particles, proteins called hemagglutinin, that prevent flu viruses from binding to and consequently infecting cells.

Hemagglutinin comes in 16 different types, including H1, H2 and H3, which are found on human flu viruses such as the H1N1 virus. H5 is part of the avian flu virus, or H5N1.

The virus-like particle, or VLP, the wild tobacco leaves produce is not an inactivated virus. It does not contain genetic material, is unable to replicate and is non-infectious. But in preclinical studies VLPs produced a strong and broad immune response in mice and ferrets.

In 2010, Medicago researchers published a report detailing the benefits of VLPs and their production in wild tobacco plants.

The company has also tested different vaccines in humans, including one for seasonal flu and one for pandemic avian flu. Results from Phase I and II clinical trials, which involved healthy volunteers, suggested the vaccines were safe and effective.

A lot remains to be done before Medicago can gain regulatory approval to produce vaccine for sale. Larger clinical trials to further test how well the VLPs work and whether they cause any side effects are among the requirements.

One step toward regulatory approval is for Medicago to prove that the plant-based process can crank out 10 million doses of vaccine per month. That would amount to about 120 million doses of single-strain pandemic flu vaccine or 40 million doses of triple-strain seasonal flu vaccine per year, a production capacity that comes close to the about 150 million annual doses of flu vaccine Novartis projected to manufacture at its Holly Springs plant.

Medicago’s approach combines botany, biotech and robots used in the Dutch tulip industry.

Talarico explained the production process during a tour of the greenhouse that will be fully automatic once all the equipment is tested and running smoothly. For now, greenhouse specialists like Tanya Blankenship are doing much of the thinning, transplanting and placing of the plants on large growing tables by hand.

In full operation, the greenhouse will be able to accommodate about 90,000 plants.

Each plant will start as a seed that germinates in a plug tray. When the plants are a few days old, they will begin a two-week trip through the greenhouse.

A robot will transplant each little plant with its plug of dirt into a plastic pot filled with soil. A conveyer belt will transport the pots down the line to get watered and then placed on a growing table.

Lined up one after another, the growing tables will slowly move on rollers through the greenhouse. Machines will make sure the plants get watered and fertilized regularly.

“Nobody has to touch plants,” Talarico said.

When the trip through the greenhouse ends, the potted tobacco plants will be transferred into an enclosed chamber or tank and placed into a solution containing agrobacteria that carry the genetic blueprint to make a particular VLP.

A vacuum will suck the air out of the tank, which will prompt the leaves of the tobacco plants to take up the agrobaceria. This infusion will not alter the genetic makeup of the plant, but within an incubation time of about five days the cells in the leaves will start producing VLPs.

Then, machines will strip the leaves off the stalks, cut them in pieces and placed them into a solution to extract the VLPs.

Medicago already used this process at its R&D facility in Canada to make vaccine for the clinical trials. Now, Talarico said, the company is preparing to repeat the accomplishment at its RTP plant, which has the capacity to produce 25 times more and is 50 percent bigger than originally planned.