In DepthInfectious Diseases

Ebola drugs still stuck in lab

Science  25 Jul 2014:
Vol. 345, Issue 6195, pp. 364-365
DOI: 10.1126/science.345.6195.364

Health workers carry the body of an Ebola virus victim in Kenema, Sierra Leone, on 25 June 2014.

PHOTO: STRINGER/REUTERS/CORBIS

There's little doubt what Erica Ollmann Saphire would do if she had Ebola or knew she had been exposed. The x-ray crystallographer at the Scripps Research Institute in San Diego, California, is leading an international effort to develop a potent mix of monoclonal antibodies against the virus, some of which have already shown promise in animals. Knowing the staggering case fatality rate of this hemorrhagic fever, Ollmann Saphire says she would take the antibodies—never mind that they haven't been tested for safety. “Believe me, I'd run for the freezer and ask for forgiveness instead of permission,” she says.

Many Ebola researchers say they, too, would eagerly try the antibodies—or one of the promising candidate drugs, or an experimental Ebola vaccine. And they would love for people in Sierra Leone, Guinea, and Liberia to have access to experimental therapies as well, as the death toll from the largest Ebola outbreak on record climbs past 600. But it's not going to happen.

As the outbreak in West Africa worsened, debates intensified among scientists, government officials, and company executives about bringing some of these unapproved products to Africa on a so-called compassionate use basis—after all, “something is better than nothing,” Ollman Saphire says. “I have been on at least half a dozen conference calls about this,” says Lisa Hensley, an expert in hemorrhagic fever viruses at the National Institute of Allergy and Infectious Diseases (NIAID) in Frederick, Maryland.

But the organizations fighting Ebola on the ground say they simply can't bring an untested, unlicensed drug to a population that's already distrustful of the teams trying to stamp out the outbreak. “Some people are throwing stones at us,” says Armand Sprecher, a public health specialist at the Brussels office of Doctors Without Borders. “There are rumors that we are spreading disease, harvesting organs, and other horrible things. Bringing in unlicensed things to experiment on people could be very counterproductive.” A representative for the World Health Organization (WHO) adds that using vaccines now “would not be ethical, feasible, or wise.”

Longtime Ebola researchers say they accept that decision, but they're frustrated. “It's very, very disappointing,” says Heinz Feldmann of NIAID's Rocky Mountain Laboratories in Hamilton, Montana, who has helped develop a promising vaccine candidate. But Feldmann hopes the tragedy will at least help unclog the product pipeline.

With 1048 reported cases and 632 deaths since March—a 60% fatality rate—the West African outbreak shows no signs of tapering off. People in the affected countries are more mobile than in the central African regions struck by Ebola in the past, Sprecher says, giving the virus more options to spread. What's familiar are the cultural problems in battling Ebola. The measures that will contain the virus—strictly isolating patients, tracing and monitoring their contacts, and burying the dead quickly and safely—are often difficult for the local population to accept.

Despite the media's fascination with Ebola, the disease is exceedingly rare, which has slowed the development of countermeasures. Before the current one, all known outbreaks had caused fewer than 2400 cases, across a dozen African countries over 3 decades. Add the poverty of those countries, and the market for drugs and vaccines looks unpromising. (Complicating matters, Ebola-Zaire, now raging in West Africa, is just the most common of five Ebola species; each needs its own countermeasures.) Most research has been funded by the U.S. government in response to worries about biowarfare and bioterrorism.

But that support hasn't been enough to bring a single product to the market. Feldmann's vaccine, for instance, consists of a livestock pathogen called vesicular stomatitis virus (VSV) in which one gene has been replaced with that for Ebola's surface glycoprotein. It gives rhesus macaques full protection against Ebola-Zaire and saved four out of eight animals when given 30 minutes after an otherwise lethal dose of the virus. But the Public Health Agency of Canada (PHAC) in Winnipeg, Feldmann's previous employer, has yet to take it to phase I safety trials in human volunteers. Profectus BioSciences in Tarrytown, New York, which is developing a similar vaccine, needs some $2 million to produce it under good manufacturing practice standards, a prerequisite for any human study.

A leading drug candidate has more funding and is further advanced, but it also faces obstacles. The compound, identified by U.S. Army researchers and based on RNA interference, is in development at Tekmira Pharmaceuticals Corp., a Burnaby, Canada–based company that has a Pentagon contract worth up to $140 million to produce it. But on 3 July, the company announced that the Food and Drug Administration had put a phase I trial on hold because it wants more data and a change in the protocol to protect participants' safety. Tekmira says it expects to resolve the issue by the end of the year.

Monoclonal antibodies are similarly stymied. In the $28 million NIAID-funded project that Ollmann Saphire is leading, 25 labs from seven countries are pooling their antibodies to see which cocktail best blocks the virus. But again, none of these has entered a phase I trial. The same is true for a powerful nucleoside analog—a small molecule that's cheap to make—developed by the U.S. Army Medical Research Institute of Infectious Diseases. A promising antisense-based compound by Sarepta Therapeutics in Cambridge, Massachusetts, was put on ice after the Pentagon ended its funding in 2012.

Still, an exception was once made for compassionate use of an Ebola therapy. In 2009, when a German researcher pricked her finger with a syringe containing Ebola, the VSV vaccine was rushed from Winnipeg to Hamburg, where she received it 48 hours after the accident and remained healthy. Whether the vaccine helped can't be determined.

But that was a single case in an intensive care unit in a Western hospital where the patient could be monitored closely for side effects and treated if needed, says PHAC virologist Gary Kobinger. Doing the same for hundreds of people in Africa is virtually impossible, he says. Getting informed consent would be a huge challenge. And no drug or vaccine is going to work once patients are very ill, says Ebola researcher Thomas Geisbert of the University of Texas Medical Branch in Galveston; if patients seek care too late, that could create the mistaken impression that the interventions are useless. “If something goes wrong this could be a disaster,” Feldmann says. “So we have to work hard and come up with a really good plan for the next outbreak.”

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