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A month before the World Health Organization declared H1N1 a pandemic virus in June 2009, the Defense Advanced Research Projects Agency had a plan to address the crisis. The DARPA effort, called Blue Angel, has been working since May 2009 to develop a surge capacity for flu viruses.
Although the swine-origin H1N1 virus turned out to be fatal only for a small percentage of those infected, "the need to demonstrate a response to an urgent situation hasn't changed," Army Col. (Dr.) Alan Magill, a program manager in DARPA's defense sciences office, toldAmerican Forces Press Service.
"We've used H1 as an example, a proof of concept," he said. "We hope these technologies that are established will move on to address other issues besides influenza."
Eighteen months and $100 million later, Blue Angel and the companies it funds have created new technologies for developing, testing and quickly mass-producing new vaccines.
For the largest program, called AMP for Accelerated Manufacture of Pharmaceuticals, companies in four states are building facilities where they can quickly produce vaccine-grade proteins grown in the cells of tobacco plants. Once they produce the proteins, the goal is for each company to scale up its process to produce 100 million doses of H1N1 flu vaccine per month. Existing vaccine manufacturers worldwide produce a fraction of that -- about 300 million doses of vaccine in six months, Magill said.
Vaccines are produced in steps, beginning with getting a sample of the active virus. From the original virus, "seeds" are used to grow the virus in hundreds of millions of chicken eggs -- a time-consuming process developed more than 50 years ago. After the virus particles are grown, they're purified to make vaccine.
AMP set out to speed up the process by looking at a range of animals and plants whose cells could produce high-quality proteins that would work well in people, Magill said. What emerged from the first round of experiments were tobacco plants.
"Think about walking through the woods on a rainy day. You walk through on Tuesday and there's nothing there, and you take the same walk on Wednesday and suddenly there's a mushroom that's a foot high and it grew overnight," Magill said.
"Anything in nature that produces a tremendous amplification of biomass was of interest," he added. "Clearly these weeds -- that's really what tobacco plants are -- grow very fast, and that's what we captured."
Plants with the fastest-growing cells will be able to produce more proteins in a shorter time for vaccines, he explained.
Four companies are working to transform protein-producing tobacco plants from a proof of concept to a demonstration of the capability. The next step will be to develop full industrial processes for producing the proteins.
The companies are Fraunhofer USA Center for Molecular Biotechnology in Delaware, Kentucky Bioprocessing in Owensboro, a consortium called Project GreenVax, whose partners are the Texas A&M University system and a Texas company called G-Con, and Medicago USA in North Carolina.
"They're all using tobacco plants, and there's a little variation on the theme," Magill said. "But the approaches -- what do you put in the plants, how do you infect the plant cells, what kind of vectors [carriers] do you use, what is the nature of the protein, how is it purified -- all of these are actually quite different."
The companies all are making progress, he said. One of them, Fraunhofer, already has a product in Phase 1 clinical trials -- the first stage of testing in people.
"The final trial will go on for six months, because we have to do safety monitoring," Magill said. "But we'll know whether the technology worked probably about the end of January."
Another Blue Angel project is a technology called Modular Immune In Vitro Constructs, or MIMIC, which Magill calls "an immune system in a test tube." DARPA created MIMIC to quickly test new vaccines for safety and effectiveness.
Pharmaceutical companies that produce candidate vaccines initially don't actually know if the drug will improve a person's immunity or will be safe when administered. That's why in the United States the Food and Drug Administration requires companies to hold a series of clinical trials before drugs are approved for market.
As a pharmaceutical company with a candidate vaccine, Magill said, "all I can do is commit to a Phase 3 [effectiveness] study in which I will have to enroll 10,000 people over the course of about three years in order to ... show that my new vaccine in this case would be as good as the traditional egg-based vaccine.
"So 10,000 people, three years, $100 million," he said.
An alternative may be MIMIC, a DARPA technology developed by Florida-based biotechnology company VaxDesign Corp.
Each of MIMIC's 128--by-85-millimeter plastic plates contains 96 tiny wells filled with mixtures of human immune cells and biological molecules. Each well represents a human immune system.
The system can predict the effectiveness of vaccine additives called adjuvants and molecules that the immune system recognizes called antigens, VaxDesign officials said, adding that it can predict dosing, dose timing and cross-protection against other viral strains; determine the potency of stockpiled vaccines; and compare the effects of different manufacturing methods on vaccine potency.
"It's a very clever technology," Magill said. "I can look at the immune responses in the MIMIC system and tell you that this is going to work, this is going to protect patients, they're not going to get sick and it's going to be really safe."
In September, Sanofi Pasteur, the vaccine division of the Lyon, France-based Sanofi-Aventis Group, signed a binding agreement to buy VaxDesign for $60 million.
The full potential of MIMIC -- to take the place of clinical trials -- could take years to realize. But Magill said he has confidence in the technology.
"Where this will be useful is in what we call the downselect -- when you're in the business and you've got five vaccine candidates and you're not sure which one is going to work," he said. Today, to downselect the best candidate a company would have to do a year-long Phase 1 study for each candidate that would cost $5 million to $78 million per trial. "But what if I can just replace all that by going into MIMIC up front?" Magill said.
"Let's say I spend $1 million in MIMIC, but I get the answer in two months and that predicts the vaccine that I need to take into humans," he said. "That's huge. And I think the likelihood of that occurring is pretty high."
MIMIC will work in parallel with AMP to test candidate H1N1 vaccines, Magill said, and both will complement other projects that also are part of Blue Angel.
Technologies developed for Blue Angel eventually will apply to a range of flu viruses and other diseases, Magill added.
"Blue Angel's vaccine portfolio alone has generated four facilities, four [technical] approaches, two clinical trials, two [FDA investigational new drug applications], the MIMIC and a variety of other spinoff technologies," he said, adding that it could take a decade to commercialize the technology.
Such an outcome for plant-based vaccines would be amazing, he said.
"We don't see very often that a response like this essentially creates a new industry. But we'll see," Magill said. "You still have to go through clinical trials ... and work through all the issues. But I would say initially things are quite pleasing and somewhat promising."
DARPA H1N1 Acceleration (Blue Angel)
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 | A highly magnified digitally colorized transmission electron micrograph of virus particles from a pandemic H1N1 patient sample. Centers for Disease Control and Prevention photo by Cynthia Goldsmith Download screen-resolution Download high-resolution |
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