An experimental treatment against an Ebola-related virus can protect monkeys even when given up to 3 days after infection, the point at which they show the first signs of disease. The virus, known as Marburg, causes severe hemorrhagic fever—vomiting, diarrhea, and internal bleeding. In one outbreak, it killed 90% of people it infected. There are no proven treatments or vaccines against it.
The new results raise hopes that the treatment might be useful for human patients even if they don’t receive it until well after infection. The company that makes the compound, Tekmira, based in Burnaby, Canada, has started a human safety trial of a related drug to treat Ebola virus disease, and researchers hope that it, too, might offer protection even after a patient has started to feel ill.
Marburg and Ebola viruses are members of the filovirus family. They are made of a strand of RNA surrounded by a protein coat that allows them to infect cells. Once inside, they hijack the cell’s proteinmaking machinery to make more copies of themselves. A decade ago, filovirus expert Thomas Geisbert of the University of Texas Medical Branch in Galveston and his colleagues developed a way to jam the replication of filoviruses by giving an infected animal copies of a small interfering RNA (siRNA) molecule that binds to and blocks the viral genes. The body usually breaks down such RNA molecules, but Tekmira developed a way to enclose them in microscopic capsules called lipid nanoparticles, allowing them to enter infected cells. Working together, the Texas researchers and Tekmira staff have developed siRNA drugs against several strains of Marburg viruses as well as the Zaire ebolavirus, which is causing the current outbreak in West Africa.
Previous work in guinea pigs and monkeys has shown that the treatment can help animals survive an otherwise lethal dose of virus if it is given within a day or two of infection. However, that is before the first symptoms appear and before the virus is detectable in the blood. Patients exposed to the disease often do not seek medical attention so soon after they are infected. The new study gives the anti-Marburg virus drug “at a point that’s more realistic” for real-world use, Geisbert says. By day 3 after infection, he says, the monkeys behave as if they are starting to feel unwell. All 16 monkeys who received the treatment survived, even the four animals that received their first dose 72 hours after infection, the researchers report today in Science Translational Medicine. All five control animals died between 7 and 9 days after infection.
The new work “is a great study,” says hemorrhagic fever researcher Robert Garry of the Tulane University School of Medicine in New Orleans, Louisiana. “I definitely think this drug is going to play its role.” However, he says, the drug is more likely to be used after lab accidents or other isolated cases than in an outbreak in a developing country. The experimental animals received the drug through an IV once a day for 7 days. “Giving the drugs isn’t like popping a pill,” Garry says. “It remains to be seen what happens in the more austere environments” where Marburg fever outbreaks have so far occurred. Geisbert says he and his colleagues are testing whether shorter courses of treatment could also protect animals.
The promising results against Marburg virus raise hopes that a siRNA treatment for Ebola virus disease, called TKM-Ebola, would also work when given several days after a patient is infected. In January, Tekmira started a safety trial of the drug in healthy volunteers. The U.S. Food and Drug Administration (FDA) stopped the trial in July, asking for more information about how the drug works. Geisbert says he was told that one of the volunteers who received the highest dose of the drug experienced nausea. That was a significantly higher dose than the one he and his colleagues have used for their drug in the monkey trials, he says. On 7 August, FDA told the company that although the trial in healthy subjects should remain on hold, it would allow potential use of the drug in individuals infected with Ebola. So far, however, no patients have received it.
The World Health Organization and other organizations fighting the current Ebola outbreak in West Africa are considering whether and how to possibly use untested drugs or other therapies there as part of the efforts to get the outbreak under control.
Several patients who received another untested treatment, ZMapp, seem to be improving, according to the Liberian government and other media reports. A Liberian government representative said Tuesday that three doctors there who received the drug are showing significant improvement. Two Americans who received it are also recovering. A Spanish priest who was treated with ZMapp died. The company that makes the drug, however, has said there are no more doses available, and it will take months to manufacture more.
Geisbert says that, in theory, the siRNA drugs are not difficult to make. “Once you have the sequences, you can make the RNA pretty quickly.” The main hurdle is cost, he says. Tekmira declined to say how much the drug might cost except that it would be less than antibodies or proteins and would “approach the cost of small molecule drugs.” Geisbert says that hundreds of dollars per dose is “probably in the ballpark.”
If the drug were to be used, demand might be higher than thought, according to a paper published today in Nature. Oliver Brady, an epidemiologist at the University of Oxford in the United Kingdom, calculates that 30,000 health care workers, aid workers, patients, and their contacts would be potential candidates for a vaccine or treatment so far in the current outbreak.
The calculations are a helpful attempt to grasp the scale of the problem, Garry says, but they don’t distinguish between people who would be candidates to receive a vaccine and those who would need a treatment. A vaccine could, in theory, protect people who are not yet infected, but have a risk of exposure. That is likely to be more than 30,000 people, he says. A postexposure treatment would probably be given only to people who have tested positive for infection. That number would be much lower than 30,000, he says.
*The Ebola Files: Given the current Ebola outbreak, unprecedented in terms of number of people killed and rapid geographic spread, Science and Science Translational Medicine have made a collection of research and news articles on the viral disease freely available to researchers and the general public.