Amid unrelenting chaos and violence, scientists and doctors in the Democratic Republic of Congo have been running a clinical trial of new drugs to try to combat a year-long Ebola outbreak. On Monday, the trial’s cosponsors at the World Health Organization and the National Institutes of Health announced that two of the experimental treatments appear to dramatically boost survival rates.
While an experimental vaccine previously had been shown to shield people from catching Ebola, the news marks a first for people who already have been infected. “From now on, we will no longer say that Ebola is incurable,” said Jean-Jacques Muyembe, director-general of the Institut National de Recherche Biomedicale in the DRC, which has overseen the trial’s operations on the ground.
Starting last November, patients in four treatment centres in the country’s east, where the outbreak is at its worst, were randomly assigned to receive one of four investigational therapies—either an antiviral drug called remdesivir or one of three drugs that use monoclonal antibodies. Scientists concocted these big, Y-shaped proteins to recognize the specific shapes of invading bacteria and viruses and then recruit immune cells to attack those pathogens. One of these, a drug called ZMapp, is currently considered the standard of care during Ebola outbreaks. It had been tested and used during the devastating Ebola epidemic in West Africa in 2014, and the goal was to see if those other drugs could outperform it. But preliminary data from the first 681 patients (out of a planned 725) showed such strong results that the trial has now been stopped.
Patients receiving Zmapp in the four trial centres experienced an overall mortality rate of 49 percent, according to Anthony Fauci, director of the NIH’s National Institute of Allergy and Infectious Diseases. (Mortality rates are in excess of 75 percent for infected individuals who don’t seek any form of treatment.) The monoclonal antibody cocktail produced by a company called Regeneron Pharmaceuticals had the biggest impact on lowering death rates, down to 29 percent, while NIAID’s monoclonal antibody, called mAb114, had a mortality rate of 34 percent. The results were most striking for patients who received treatments soon after becoming sick when their viral loads were still low—death rates dropped to 11 percent with mAb114 and just 6 percent with Regeneron’s drug, compared with 24 percent with ZMapp and 33 percent with Remdesivir.
Drugs based on monoclonal antibodies have become a mainstay of modern medicine—fending off a variety of diseases from cancer to lupus. But it takes many years of painstaking reverse-engineering to make them. Zmapp, for instance, was developed by infecting mice with Ebola and then collecting the antibodies the mice produced against the virus. Those antibodies then had to be further engineered to look more like a human antibody, so as not to provoke an immune reaction. Ebola infiltrates its victims’ cells using spiky proteins on the virus’s outer shell, so researchers screened the antibodies for the ones that did the best job of binding to those proteins. Block access, and the virus can’t replicate and spread. But compared with other viruses, Ebola is large and has the ability to change shape, making it difficult for anyone antibody to block its infection. That’s why a cocktail approach has become favoured, like the Regeneron product—a combination of three monoclonal antibodies generated first in mice.
An even better solution, some have posited, would be to mine the serum of Ebola survivors and harvest the DNA from the white blood cells that make antibodies. That would yield a set of genetic instructions for making antibodies with a proven track record against the Ebola virus. That’s what the NIH’s mAb114 is—an antibody isolated from the blood of a survivor of a 1995 outbreak in Kikwit, DRC. Scientists discovered it a few years ago—they had been circulating in his body for more than a decade.
With the WHO’s announcement, a new trial will now kick-off, directly comparing Regeneron to mAb114, which is being produced by a Florida-based company called Ridgeback Biotherapeutics. And all Ebola treatment units in the outbreak zone will now only administer the two most effective monoclonal antibody drugs, according to the WHO’s director of health emergencies, Mike Ryan.
“Today’s news puts us one more step to saving more lives,” said Ryan. “The success is clear. But there’s also a tragedy linked to the success. The tragedy is that not enough people are being treated. We are still seeing too many people staying away from treatment centres, people not being found in time to benefit from these therapies.”
Since the ongoing outbreak began last August in DRC’s North Kivu province, more than 2,800 people have become infected, with 1,794 confirmed deaths. It is the second-largest Ebola outbreak ever recorded. On July 17, the WHO declared it a “public health emergency of international concern,” after a case showed up in Goma, a large city bordering Rwanda. The risk of transmission across international borders remains high.