DARPA Effort Speeds Biothreat Response

WASHINGTON, Nov. 2, 2010 — Spurred by the 21st century’s first flu pan­dem­ic, the Defense Depart­ment has devel­oped new, faster ways to make vac­cines that could save lives around the world.

New vac­cine tech­nolo­gies not only will speed the U.S. gov­ern­ment response to infec­tious dis­eases, but also will give offi­cials bet­ter options for fight­ing bioter­ror attacks, a DOD sci­en­tist said.

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, told Amer­i­can 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.”

U.S. Depart­ment of Defense
Office of the Assis­tant Sec­re­tary of Defense (Pub­lic Affairs)

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