Erica Ollmann Saphire at Scripps event showing a model of the Ebola surface protein (white) with three ZMapp antibodies attached.

Melissa Jacobs/The Scripps Research Institute

Erica Ollmann Saphire at Scripps event showing a model of the Ebola surface protein (white) with three ZMapp antibodies attached.

Experimental Ebola drug saves monkeys, but will this translate to humans?

Jon is a staff writer for Science.

SAN DIEGO, CALIFORNIA—This past Wednesday, at a discussion titled “Stopping the Deadly Ebola Outbreak” held at the Scripps Research Institute here, a local TV reporter repeatedly prodded one of the star panelists, Kevin Whaley, the CEO of Mapp Biopharmaceutical of San Diego.

After Whaley explained that he had no idea whether ZMapp, his company’s now famous experimental antibody cocktail used to treat Ebola victims, really worked, the journalist continued to press. “From what you’ve seen in your research—and what your heart says—what do you say?”

The audience of 100 people or so broke into nervous giggles.

“I’m not willing to speculate on that,” Whaley replied.

The dogged reporter gave it one more try, referring to two American health workers who were infected with Ebola in Liberia, returned to the United States and received ZMapp, and lived to tell about it. “How happy were you to see the two missionaries walk out of the hospital?”

“That was certainly very satisfying, and hopefully ZMapp played some role in that,” Whaley said. “But that remains to be seen.”

The exchange highlights the growing hope that some biomedical intervention—such as a treatment like ZMapp—will allow more people to survive Ebola infections. Time and time again, however, hope and hype have become knotted together.

Today, that knot is sure to grow tighter with the publication online in Nature of an encouraging monkey experiment with ZMapp, in which 100% of the infected monkeys survived. It is sure to further raise expectations of a cure—and further confuse the public about just how near a cure might be. Even the authors of the new study caution that extending the monkey results to humans could be a long and difficult task.

The experiments, led by Gary Kobinger of the Public Health Agency of Canada in Winnipeg, first tested combinations of Ebola antibodies made by his lab and Mapp Bio to find a cocktail that worked best in guinea pigs and then monkeys. They selected the concoction now called ZMapp and gave it to three groups of six monkeys; all received intramuscular injections of high doses of Ebola virus. A control group of three monkeys were given dummy drugs.

The treated monkeys each received a total of three doses of ZMapp, one every 3 days. Treatment began at 3 days postinfection for one group, at 4 days for another, and at 5 for a third. All 18 of the monkeys had evidence of infection, many became ill, and two nearly died.

In the end, 100% of the treated monkeys survived, and 100% of the control animals quickly died. Although the experiment used an older Ebola virus that differs from the strain now in West Africa, the researchers showed in a test-tube study that ZMapp also worked against the more recently isolated virus.

The results are “a monumental achievement,” wrote virologist Thomas Geisbert, who studies Ebola virus at the University of Texas Medical Branch at Galveston, in a Nature editorial accompanying the study.

“It’s a great study,” Geisbert tells ScienceInsider. “I’ve got shelves and shelves and shelves of things that inhibit Ebola in cell culture and a small percent inhibit it in guinea pigs or mice. And I’ve got shelves and shelves of things that work in guinea pigs and mice but not in monkeys. If you save 100% of monkeys up to 5 days after infecting them, that’s a huge bar to clear.”

In a teleconference held by Nature today, Kobinger said it was “quite remarkable” that they could rescue infected animals that had advanced disease, which he called “a very important step forward in the fight against Ebola virus.” But Kobinger also stressed that many unknowns remain about the differences between this monkey model and human infection.

To begin with, most humans are infected by exposure to bodily fluids from people with Ebola, not by syringes that hold a huge bolus of virus injected into their muscles. This kills monkeys on average in 8 days, while it typically takes 3 to 21 days for humans to develop symptoms. “It’s very hard to translate” the disease progression in this monkey model to humans, Kobinger said. But a monkey infected by this route and left untreated for 5 days is 3 days away from death he said, which indicates that ZMapp worked well into the disease.

The monkeys received three doses of ZMapp, and it sometimes required a second one before the level of Ebola virus in their blood—the viral load—dropped. With the seven treated humans, one person who died received only a single dose, and no one has yet reported how many doses the others received. Kobinger said he “would not expect” a single dose to work. “What the antibody is really doing is buying time,” said Kobinger, stressing the importance of proper medical care on survival.

Kobinger said he had no idea whether the antibodies had any effect on viral load in these patients, as they were given the experimental ZMapp on a “compassionate use” basis. “When each of the clinicians or clinical teams that have been using ZMapp release their data, we’ll get a better sense of maybe the efficacy, but even then, it’s hard because it’s not really a designed study,” Kobinger said. “Unfortunately, it may be limited what we’re really going to learn from those seven patients.”

In preliminary experiments not reported in the Nature paper, Korbinger said he has in vivo evidence that ZMapp works against the strain now circulating in West Africa. He said future experiments will analyze the impact of providing infected monkeys with effective intensive care. His group also wants to see how low of a dose of ZMapp they can give infected monkeys and still rescue them. “One of the things that is very urgent for us to do is a dose de-escalation study so that we can see what the minimum amount of antibody is so maybe with the same amount of material we could do more,” he said.

The availability of ZMapp is a critical issue for the growing number of people who want access to it on a compassionate use basis. Mapp Bio says it now has no more ZMapp on hand. Kentucky BioProcessing in Owensboro grows the ZMapp antibodies in tobacco plants. In a 2012 press release, that company’s chief operating officer, Barry Bratcher, said it had a fully automated production system “that operates in accordance with good manufacturing practices” and could “generate a new antibody lot in two weeks to rapidly address new threats and new outbreaks.” Bratcher did not reply to an e-mail from ScienceInsider to discuss that prediction.

At the Scripps panel talk, Whaley told ScienceInsider that they were still trying to sort out production issues. “Clearly we misstated [the production time needed],” Whaley said. “That clearly was not our intention.”

Questions also have been raised about how it was decided to give ZMapp to the seven people who have received ZMapp so far, two of whom were from Europe and two from the United States. Whaley said the company responds to requests that come through the U.S. Food and Drug Administration and has no say in who ultimately had received the product.

Two of the seven ZMapp patients have died. Their outcomes ultimately say nothing about the treatment: The people received the drug at different stages of disease, and four were evacuated to wealthy countries for top-notch care—likely the most important determinant of survival. No information has become public about the effect the antibodies had on their levels of virus. What’s more, it’s an experiment without a control. “These people did not have an identical twin who was infected the same day and didn’t get treated,” said Scripps structural biologist Erica Ollmann Saphire, who was a panelist at the event there and helped Mapp Bio select antibodies. “That’s why we need to do the human clinical trial.”

Human studies of ZMapp are scheduled to begin in early 2015.

Meanwhile, Ebola cases continue to rise. The World Health Organization as of yesterday reported 3069 cases and 1552 deaths, a case fatality rate of 52%. Senegal today reported its first case.

*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.

Posted in Biology, Health Ebola