US and Gates Foundation look to push new Ebola vaccine

Federal officials are planning to sharply increase production of ZMapp, which is viewed by many experts as the most promising experimental drug for treating people infected with Ebola in West Africa. http://www.nytimes.com/2014/10/02/world/us-to-increase-production-of-experimental-drug-but-may-not-meet-demand.html?hp&action=click&pgtype=Homepage&version=HpSum&module=first-column-region&region=top-news&WT.nav=top-news&_r=0
The Department of Health and Human Services is in advanced discussions to enlist Caliber Biotherapeutics, a Texas company that can produce the drug in millions of tobacco plants, according to federal officials and pharmaceutical industry executives.
Federal officials, along with two of the world’s biggest charities — the Bill & Melinda Gates Foundation and the Wellcome Trust — are also looking at arranging for production of ZMapp in animal cells, the more conventional method used by the biotechnology industry. Although that would take longer, it would allow for greater output by tapping into the biotechnology industry’s huge production capacity.
“We’re going with multiple manufacturers,” a federal official said, speaking on condition of anonymity because contracts have not yet been signed. “Caliber is certainly one we’re considering.”
Despite the new efforts, supplies of the drug are expected to be limited to hundreds or thousands of treatment courses by early next year, which would not be nearly enough if the epidemic continues to spiral out of control.
“The biology just doesn’t allow you to do it tomorrow,” said Alan Magill, who heads the malaria program at the Gates Foundation and is trying to arrange for more ZMapp production.
ZMapp was able to protect monkeys from Ebola even when administered five days after infection. And it may have helped a few people infected during the current outbreak, including two American aid workers who got Ebola in Liberia and recovered at Emory University Hospital in Atlanta.
Still, there was only enough ZMapp for seven patients, two of whom subsequently died.
Experts say it is impossible to tell from such limited experience how well ZMapp works. And there are other experimental drugs that have shown promise in animal testing, and production of those might also be increased.
But for now, ZMapp may offer the best shot because it consists of proteins called monoclonal antibodies, widely used as drugs in the biotechnology industry, which latch onto the virus and neutralize it. “It’s extremely rational that an antibody against Ebola would be effective,” said Dr. Susan Desmond-Hellmann, chief executive of the Gates Foundation and a former biotechnology industry executive. “It is extremely rational that it would be safe.”
ZMapp, which is actually a cocktail of three different antibodies, is being developed by Mapp Biopharmaceutical, a tiny San Diego company, with funding from the United States and Canadian governments.
The doses used to treat the American aid workers were produced in tobacco leaves at a facility in Owensboro, Ky., that is owned by Reynolds American, the tobacco company.
That facility has now resumed production, but the federal official said it was expected to produce only about 10 to 20 treatment courses by the end of the year, and the same amount every month going forward.
So the Biomedical Advanced Research and Development Authority, a branch of the Department of Health and Human Services, is considering additional production from Caliber, which is based in Bryan, Tex., and co-operates on projects with Texas A&M University.
Caliber also produces proteins, including antibodies, in hydroponically grown tobacco plants but has a larger production capacity than the Kentucky facility.
No official contract has been signed, so plans could still change. But federal officials have visited Caliber regularly.
“They are actively engaged, pretty much on a daily basis, working with Caliber and A&M,” Dr. Brett P. Giroir, the chief executive of the Texas A&M Health Science Center, said Wednesday. Executives at Caliber and Mapp declined to comment for this article. Both Caliber and the Kentucky facility sprang from a project sponsored by the
Defense Advanced Research Projects Agency, which was looking for a way to quickly produce vaccines or therapeutic proteins in the event of an emergency like a flu pandemic.
Now these facilities are likely to get their first big test. “It’s not been tested, live-fire,” the federal official said. “And now we’re doing
it.”
The system involves infecting tobacco with a genetically engineered virus that contains the instructions to make the antibody.
“Every time the virus tries to replicate, it spins out a copy of a monoclonal antibody,” said Charles J. Arntzen, a professor at Arizona State University who has long worked on such systems. The leaves are ground up to extract the antibody.
The federal official said that Caliber and other facilities that will be brought on line could produce 40 to 100 treatment courses per month.
But Dr. Giroir of Texas A&M and a biotechnology industry executive familiar with Caliber said Caliber could potentially produce hundreds of treatment courses a month.
Researchers say the dose used in the monkey experiments, which was also used to treat the patients in Africa, is probably more than needed. If monkey testing can confirm that a lower dose is sufficient, then many more human treatment courses can be made.
There are also efforts underway to increase the amount of protein produced by each plant. Mapp is said to be working with another small company, Novici Biotech, which has a method of tweaking the genetic instructions for the antibodies in a way that could boost production.
Monoclonal antibodies used for drugs — like Herceptin and Avastin for cancer, and Humira and Remicade for rheumatoid arthritis — are typically produced in genetically engineered Chinese hamster ovary cells, or CHO cells, which are grown in giant stainless steel vats.
While production in tobacco is said to be faster and cheaper to get started, there is only limited tobacco capacity, while there is a huge capacity in the biotechnology industry to produce antibodies in CHO cells.
The Gates Foundation and the Wellcome Trust, as well as federal officials, are helping to scout some of this capacity for ZMapp production. However, it would take months to genetically engineer CHO cells to produce the antibodies and to scale up production. Meaningful production would not come until next year.
And officials say new monkey testing might be needed to show the antibodies produced in CHO cells are as effective as those produced in tobacco. At least one earlier study suggested this was not the case.
Federal officials said some of the early doses of ZMapp will be tested for safety in healthy volunteers. That is controversial because it means the scarce drug would be diverted from patients in Africa.
Dr. Jeremy Farrar, director of the Wellcome Trust, said it was necessary to establish basic safety, particularly in light of mistrust of Western medicine by some people in the outbreak area. “The reality is,” he added, that such safety testing “will happen quicker in the U.S. or the U.K.” But the Wellcome Trust has given a grant of about $5.2 million to a consortium that will move quickly to test ZMapp and other drugs in sick patients in Africa.

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