Researchers racing to develop a vaccine that could help halt the Ebola epidemic are getting good news: Early human clinical trials of one leading candidate, involving small groups of volunteers in the United States and Europe, suggest that the vaccine is safe.
But the most fraught part of the unprecedented effort lies ahead: Testing the effectiveness of potential vaccines on tens of thousands of people in Ebola-stricken areas of West Africa.
That task, which the World Health Organization expects will begin in January, is raising hard questions for scientists and governments: With the epidemic raging, is it acceptable to conduct a randomized controlled trial, considered the “gold standard” of research? That would produce the best and quickest data but would mean some participants would not be given a potentially live-saving vaccine.
There are logistical challenges as well: How can vaccines be safely transported and kept at the cold temperatures required in areas without reliable electricity? And how do you recruit and track volunteers during the middle of an epidemic, in countries with shattered health-care systems?
Experts are rushing to answer these difficult questions on a timetable unheard of in the world of drug development.
“Six months ago, this was not on anybody’s radar,” said Ripley Ballou, a former U.S. Army researcher who is a vice president at GlaxoSmithKline, which is developing one of the potential Ebola vaccines with the National Institutes of Health. “Something that normally takes five to seven years to do, we’re compressing into a matter of months. . . . We’re going to be pushing the system awfully hard to make this happen.”
Now, with the epidemic deepening by the day in West Africa and traditional public health methods for containing the virus so far unable to keep up with its rapid spread, some officials have speculated that a vaccine might be the only way left to suppress the outbreak, which has resulted in nearly 10,000 reported cases and almost 5,000 deaths in the affected countries.
Jeremy Farrar, director of the London-based medical charity the Wellcome Trust, which has helped fund the GSK vaccine and other Ebola research, says it’s possible the epidemic has “gone beyond the capacity” of tactics such as quarantining and contact tracing to stop its spread. “We have to have a Plan B,” he said.
Anthony Fauci, head of NIH’s National Institute of Allergy and Infectious Diseases, agrees that the global effort to stop the outbreak might not be sufficient or arrive quickly enough to halt the spread of Ebola in West Africa. “It is conceivable that you will actually need a vaccine to stop the epidemic,” Fauci said. “It won’t just be a commodity for health-care workers. It will be an essential tool to try to turn the epidemic around.”
But first, scientists must prove that a vaccine works.
The vaccine being developed by England-based GSK is one of two that health-care leaders hope could be ready to begin distributing on a broader scale later next year in the hard-hit countries of Liberia, Sierra Leone and Guinea.
Based on a chimpanzee cold virus called chimp adenovirus type 3, the vaccine is designed to deliver pieces of genetic material from two Ebola species: Sudan and Zaire, the type responsible for the epidemic in West Africa. The vaccine, which cannot actually infect those who receive it and is designed to trigger an immune response in the patient, has shown promising results in animal trials.
Initial results from small human safety trials at the NIH and Oxford — another trial began recently in Mali — have shown no signs of harm. Researchers expect more robust safety data later this year, including on what doses prompt the appropriate immune response. Already, GSK is taking steps to ramp up production of the vaccine and to begin much larger trials, which could involve as many as 20,000 to 30,000 people, in the Ebola-affected countries in West Africa.
But researchers are still figuring out exactly how to design and carry out those trials. At a recent WHO gathering, Ballou made a forceful argument for conducting a randomized control trial, in which half of the patients, possibly health workers, would receive doses of the vaccine, while the other half would receive a different vaccine, perhaps for hepatitis B. Researchers would monitor both groups to see if fewer infections occur in the group that gets the vaccine. If data suggest the vaccine works, the trial could end and mass vaccination could begin.
“It could happen very fast,” Ballou said. “The intent would be collecting and analyzing the data in as close to real time as possible. . . . As soon as we’re convinced the vaccine works, or doesn’t work, we stop the trial. If it works, everybody gets the vaccine. If it doesn’t work, we stop the trial and stop giving out the vaccine.”
There was widespread agreement at the recent WHO meeting that such a trial would provide the best data in the shortest amount of time. But some experts have wondered whether it would be ethical to have a control group in settings such as Ebola clinics in West Africa, where workers are at heightened risk of contracting the deadly disease. Still others said it could be preferable to do a “step wedge” trial, in which certain groups of volunteers are vaccinated sequentially. That approach ensures all patients in a trial eventually do receive the drug — the later groups act as a control for the first recipients — but the data tends to be less reliable and slower in coming.
Ballou and other researchers said they have no ethical dilemma in having a control group in West Africa, assuming the individual governments sign off on the plan. They note there are limited supplies of the vaccine, and there is no guarantee those receiving it will be better off than those who do not.
“You really don’t know; the vaccine could be harmful,” said Ira Longini, a biostatistician at the University of Florida who has long studied infectious disease outbreaks. “Without doing a randomized controlled trial, we will not know what the efficacy is of the vaccine. We shouldn’t be mass vaccinating with a vaccine where we don’t have a clear estimate that it’s at least not harmful.”
Fauci added it is important to acknowledge cultural sensitivities as well. “The last thing in the world you want to do is to widely distribute . . . a vaccine to black West Africa, made by the white Western world, and it turns out to not only not be effective, but it turns out to actually have a paradoxical negative effect,” Fauci said.
In addition, Ballou said GSK needs the most solid information it can get to persuade regulators to ultimately approve a vaccine, and to make sure it reliably works so that it could be deployed in future outbreaks. “If you don’t start with sound data, all of this is angels dancing on the head of a pin,” he said.
Farrar said that whatever trial design scientists ultimately choose, the key is not to debate it for months. “We just need to make those decisions and move on,” he said.
Even when researchers settle on the structure for human trials in West Africa, carrying them out will be difficult. The GSK vaccine must be kept at a constant minus-80 degrees Celsius (minus-112 Fahrenheit). Researchers must recruit willing volunteers for the trials, then keep track of both vaccinated and unvaccinated people.
“It’s a large, complicated operation, and it’s not easy to do in a developing country,” Longini said. “Not to mention the fact this would be done on an emergency basis, in a chaotic situation, in a place with very poor public health infrastructure.”
Marie-Paule Kieny, a WHO assistant director-general, alluded to those challenges on Tuesday in announcing the push to get vaccine trials underway by January in West Africa. “It’s a very fragile situation in these countries,” she said. “Politically not terribly stable; there are safety issues; there are concerns about logistics.”
Those potential hurdles are what keep Ballou up at night.
“My biggest fear is we’ll have a good vaccine, a great plan, and we just won’t be able to do it because it’s not feasible,” he said.
Meanwhile, trials are underway on another leading vaccine candidate, developed by the Public Health Agency of Canada and licensed to a small Iowa-based company called NewLink Genetics. Initial safety trials began recently at Walter Reed Army Institute of Research in Silver Spring, Md., and will soon begin in Germany, Switzerland, Gabon and Kenya. Early results are expected in December, and broader trials in West Africa also could start the beginning of 2015, said the WHO’s Kieny.
“It’s very important that both of these vaccines are developed in parallel,” Farrar said. “It’s absolutely critical that we don’t put all our eggs in one basket, that we don’t just have a single option here.”
Other potential vaccines also lie on the horizon.
Johnson & Johnson announced this week that, in collaboration with the NIH, it is committing up to $200 million to accelerate its own Ebola vaccine, with a goal of beginning human trials early next year and producing 250,000 doses by May. Researchers at Thomas Jefferson University in Philadelphia are working on yet another potential vaccine, and the WHO’s Kieny said the group is trying to get more details about other vaccines under development in Russia.
Meanwhile, Ballou said, GSK is preparing to move its Ebola vaccine production from Rome to Belgium, where it has a much larger facility.
“We’re producing as much of it as we can, as fast as we can,” he said, adding that the company will need to make stockpiles of the vaccine not only for this epidemic, but for future ones.
And if it turns out that after producing all that vaccine, it doesn’t actually work?
“This is such a human tragedy, and there are so many people losing their lives and so much potential for it to get even worse,” Longini said. “Throwing away a few million doses of vaccine pales in comparison to how much good a vaccine could do.”