When Ripley Ballou came to a Geneva, Switzerland, meeting about Ebola vaccines last week, he had a tough message to sell. In the efficacy tests for such vaccines that may start in West Africa in a few months, half of the volunteers should randomly be assigned into a control arm, Ballou argued—a group of people at risk of becoming infected who would not receive an experimental Ebola vaccine. Instead, they would serve as so-called active controls and be injected with other, approved vaccines, for instance against hepatitis B or pneumococcal disease. That would be the fastest way to know whether the Ebola vaccines work and can be deployed widely, Ballou said—and thus potentially save the most lives.

It was a controversial opinion. Health care workers at the front lines of Ebola, who will serve as the target group in the first efficacy tests, are so vulnerable that giving them anything other than the experimental vaccine seems inhumane and could create tensions, some contended. “Going into this meeting, we were told the idea of a controlled trial … was not going to be acceptable,” says Ballou, who heads the crash program to develop an Ebola vaccine at GlaxoSmithKline (GSK) in Rixensart, Belgium.

Indeed, Ballou didn't win everyone over in his talk at the meeting, which took place on 29 and 30 September at the headquarters of the World Health Organization (WHO). Representatives of Doctors Without Borders (MSF) were strongly opposed to giving trial participants anything other than an actual Ebola vaccine candidate—and they didn't change their minds. "The meeting was quite tense at moments,” says Marie-Paule Kieny, a WHO assistant director-general and vaccine expert.

But many scientists did leave the meeting convinced that the randomized, controlled design proposed by Ballou should be used, as hard as it may be to explain, because it will be the fastest way to know if the vaccine works. "The attendees had a strong sense that there was no time to waste,” especially after they were given an update on the situation in West Africa, Kieny says. “I was expecting more controversy.” Looking back, “we basically said what people thought needed to be said but were afraid to say,” Ballou says.

The GSK vaccine only went into a human for the first time on 2 September, in a phase I trial that will involve a few hundred volunteers not at risk of infection. If the vaccine proves safe and triggers the kind of immune responses that monkey studies suggest confer protection, some 10,000 or so doses will ship to the three most affected countries in West Africa by January.

The compound, which GSK has developed in collaboration with the U.S. National Institute of Allergy and Infectious Diseases (NIAID), is one of two vaccine candidates that may soon enter real-world efficacy trials; the other was developed by the Public Health Agency of Canada and is produced by NewLink Genetics in Ames, Iowa.

It’s an extraordinary, unprecedented gamble to move so quickly. Normally, vaccines take many years to advance from small phase I studies, which look at safety and immune responses; to phase II studies, which do the same in larger groups; to phase III, in which efficacy is tested in large populations at risk of the disease. An earlier WHO consultation made the startling announcement on 5 September that this crisis required compressing the timeline, which effectively does away with traditional phase III studies.

At last week's meeting, vaccinemakers, researchers, ethicists, clinicians, epidemiologists, statisticians, and representatives of the affected countries met to sort through thorny ethical and statistical issues about how to design the efficacy trials in Liberia, Sierra Leone, and Guinea—the three countries ravaged by Ebola.

The meeting participants roundly agreed that it did not make sense to just give the experimental vaccines to health care workers on a so-called compassionate use basis and without an efficacy trial, as has happened with experimental Ebola treatments such as ZMapp and TKM-Ebola; that strategy is simply too dangerous with a vaccine, which goes into healthy people. “The last thing you want to do is roll out a vaccine that does nothing to protect people or even harms them,” says Marylyn Addo, an expert on emerging infections at the University Medical Center Hamburg-Eppendorf in Germany who attended the meeting. An actual trial is needed, the meeting concluded; it's the setup that's subject to debate.

The tried-and-true design of vaccine efficacy trials randomly assigns half of the participants to receive the experimental shot and the other half a dummy, or placebo. No one knows what they receive, and the vaccine works if more people in the control arm develop disease than those who got the actual vaccine. Before the meeting, many researchers felt that this design would be unethical, knowing that health care workers are at considerable risk and Ebola is so often fatal. The same was true for a variation on this scheme, which replaced the placebo with an active control that would at least protect participants against another virus, if not Ebola.

The leading alternative is a design known as step-wedge, which essentially uses time to create a control group. In this design, researchers take advantage of the inescapable reality that large-scale trials can't give everyone the vaccine on the exact same date; they compare the rates of infection in people already vaccinated with those who have yet to receive the shots. Barney Graham, a virologist at NIAID in Bethesda, Maryland, who attended the meeting, says “people are more comfortable” with the step-wedge design, because everyone in such a study would get the Ebola vaccine.

But statistically speaking, this design makes it more difficult to determine the vaccine’s worth, and it takes longer, Ballou explained in Geneva. The most practical way to do a step-wedge study is to randomize the sequence of vaccine distribution to, for instance, different Ebola treatment units. But researchers still have to observe the different communities for the same amount of time. A step-wedge trial also makes it more difficult to control for biases like differences in rates of new infection, behavior, and availability of protection suits.

Most meeting participants found themselves in agreement, says Ira Longini, a biostatistician from the University of Florida in Gainesville, who came to the meeting expressly to present a talk on the step-wedge design. “I worked a lot of that up, but my talk was after [Ballou’s], and I had to modify it quite a bit because I suddenly saw a real double-blinded trial with another vaccine as the control was the way to go,” Longini says. “I think the first day of the meeting things evolved quite differently than many people expected.”

Ballou described a randomized study in which 2500 people would receive the vaccine and 2500 an active control. He stressed that his team at GSK had many unknowns to wrestle with, including health care workers' infection risk—which they estimated at 10% per year spent in contact with Ebola patients. Assuming that's correct and that the vaccine works at least 80% of the time, researchers could be "absolutely confident" about efficacy after 30 infections and within 3 months, Ballou says. A vaccine that had 60% efficacy could still yield an answer with fewer than 60 infections.

“Rip’s study made sense,” WHO's Kieny says. “There was a broad agreement that [such a trial] would get a definitive result much sooner.” Discussions will now start with affected countries to see where the trial might be feasible, she says.

But MSF representatives remain unconvinced. “Studies on efficacy in affected countries and more so in at-risk populations should not have a placebo or active control arm as this cannot be defended ethically,” says Annick Antierens, a meeting attendee who oversees experimental Ebola products for MSF. Antierens says MSF would support other Ebola vaccine efficacy trials designs, but would not specify which ones. “It is not up to MSF to decide exactly what design should be used, as this will depend on the setting and the situation at the time of the trial,” she says.

Jeremy Farrar, an infectious disease researcher who heads the Wellcome Trust research charity in London, thinks a randomized, controlled trial is ethical for the simple reason that no one really knows whether the vaccine will offer protection. But he questions whether it will be acceptable to participants at high risk of contracting Ebola. “If you were there tomorrow and you were a health care worker, would you be willing to be in a control arm, when the next 3 months you will be looking after patients with Ebola?” he asks. A step-wedge trial would avoid that problem, Farrar says. “I don’t want us to have months of discussions about the best way of handling this.”

There may be a way around the debate. GSK has predicted that by January it will have at least 10,000 doses of its vaccine—an Ebola surface protein gene stitched inside a harmless chimpanzee adenovirus—which means that even if the randomized, controlled studies are done, there may be enough for less rigorous designs such as the step-wedge trial. “I would do all these trials simultaneously,” Longini says. The meeting also discussed doing randomized, controlled trials in African countries that are not affected, and in special populations, such as children and HIV-infected people, to gather more data about safety and immune responses.

If everything goes according to plan, Kieny says, a phase III trial could reveal as soon as April whether the GSK vaccine works. The other candidate vaccine, produced by NewLink Genetics, is lagging behind. It has faced several delays, and some have accused the company of dragging its feet, but human studies will likely start by the end of the month. NewLink is looking for a major corporate partner to move the vaccine forward. “I think that would be a big help,” Kieny says.

An earlier WHO consultation recommended that if vaccine supplies are limited, efficacy trials should first recruit volunteers from health care workers, as they both are at high risk and provide a critical service to society to help combat the epidemic. That doesn't just mean doctors and nurses. “An interesting outcome of the meeting is we stopped talking about health care worker and started talking about front-line care giver,” Ballou says. “It’s from the doctor to the person cleaning the ward to the gravedigger.”

The trials will work best if they enroll volunteers who are affiliated with a specialized Ebola treatment facility rather than general clinics or private practices. “You have to be able to recruit them and follow them, and the farther you get away from a treatment facility, the harder that’s going to be,” Ballou says. (The safety trial for the vesicular stomatitis virus vaccine in Geneva will also recruit health care workers who eventually are going to the affected region.)

Conditions for the trials will be far more difficult than those vaccine researchers usually deal with. The health care systems in Liberia, Sierra Leone, and Guinea are crippled; potential participants may be wary of an experimental product made by foreigners; ethical reviews may be hard to perform locally; and security could become be a problem, Ballou says. “The thing I’m really worried about," he says, "is we have a great plan and we may have a great vaccine and, at end of day, we may not be able to do the trial.”

*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.