In DepthInfectious Diseases

Ebola vaccine trials raise ethical issues

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Science  17 Oct 2014:
Vol. 346, Issue 6207, pp. 289-290
DOI: 10.1126/science.346.6207.289

Come January, as many as 20,000 doses of an Ebola vaccine candidate may be ready for testing in the unprecedented epidemic racing through West Africa. The vaccine—and another one whose development is 6 weeks behind—could bring hope to a desperate, panicked population. Indeed, some scientists believe that the epidemic has grown so large that vaccines will be essential to stopping it. But difficult questions are now emerging about how to design clinical trials, who should be the first to get the shots, and when to begin mass production.

Until recently, many scientists said that with Ebola, it wouldn't be ethical to use the standard procedure for testing a vaccine's efficacy: so-called randomized controlled trials (RCTs), in which some trial subjects are assigned to a control group that doesn't receive the actual vaccine. At a consultation held by the World Health Organization (WHO) on 29 to 30 September, however, there was unexpectedly broad support for the RCT design after all—but not from Doctors Without Borders (MSF), which is playing a huge role in the current outbreak.

On 2 September, one of the vaccines, made by pharmaceutical giant GlaxoSmithKline (GSK) of Rixensart, Belgium, in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), entered phase I trials, which test safety and immune responses in a small number of healthy volunteers. Preliminary results could be available as early as November. Similar studies for the other vaccine, developed by the Public Health Agency of Canada and produced by NewLink Genetics in Ames, Iowa, were launched 13 October, with early results expected in December.

If the vaccines do not cause harm and trigger the immune response scientists hope to see, WHO has recommended jumping straight into what amount to phase III efficacy tests in Liberia, Guinea, and Sierra Leone, the three hard-hit countries. It's an extraordinary, unprecedented gamble to move so quickly—but one that WHO consultants say is warranted by Ebola's extreme threat.

In RCTs, half of the participants are randomly assigned to receive the experimental shot and the other half a dummy, or placebo; ethicists say that's OK if it's unclear whether the vaccine will help, do nothing, or cause harm. If significantly more people in the placebo arm develop disease, the vaccine works. But animal experiments suggest the Ebola vaccines could well offer protection; keeping them from workers facing a disease as deadly as Ebola is unethical, some say.

The leading alternative is a trial design known as stepped-wedge, which takes advantage of the inescapable reality that a large-scale study can't give everyone the vaccine on the exact same date. Stepped-wedge trials compare the rates of infection in people already vaccinated with those who have yet to receive the shots. “People are more comfortable” with this setup because everyone in such a study gets the Ebola vaccine, says Barney Graham, a virologist at NIAID in Bethesda, Maryland, who attended the WHO meeting.

But at the meeting, Ripley Ballou, who heads the Ebola vaccine project for GSK, argued for an RCT—although the placebo would be replaced with an “active control,” a proven vaccine (for instance, against hepatitis B) that would at least protect participants against another virus. An RCT, Ballou argued, offers the fastest, most acceptable route to determining whether a vaccine is safe and effective, and thus would potentially save the most lives.

Ballou described a randomized study in which 2500 people, probably health care workers, 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 this is correct, and that the vaccine works at least 80% of the time, researchers could be “absolutely confident” about efficacy after 30 infections, which would likely occur within 3 months, Ballou says. A vaccine that had 60% efficacy could still yield an answer with fewer than 60 infections.

That's much faster than a stepped-wedge design, he contends. Such a study would enroll participants at the same point in time, but would stagger distribution of vaccine, say, to different Ebola treatment units. But researchers would still have to observe the different communities from the same start date, introducing delays and making it harder to tell whether the vaccine works. Infection rates might change over time, too, complicating the analysis.

Ballou didn't win over MSF. “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 trial designs, but would not specify which ones. One idea is to just distribute vaccine to health care workers and then do an “observational” study that does not have a control group but compares vaccination status in those who became ill to those who did not.

But most meeting participants sided with Ballou, says Ira Longini, a biostatistician from the University of Florida in Gainesville. Longini changed his planned talk on the stepped-wedge design after Ballou spoke. “I suddenly saw a real double-blinded trial with another vaccine as the control was the way to go,” he says. Marie-Paule Kieny, a WHO assistant director-general, says “the meeting was quite tense at moments,” but that there ultimately was “broad agreement” on this design. “Rip's study made sense,” Kieny says.

Jeremy Farrar, an infectious disease researcher who heads the Wellcome Trust in London, cautions that people on the front lines of Ebola may disagree. An RCT may yield results faster, but if it's simply unacceptable for trial participants, a stepped-wedge design is preferable. “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?” Farrar asks. “I don't want us to have months of discussions about the best way of handling this.”

Liberian nurses pick up a dead body from the waiting area of a hospital in Monrovia.

PHOTO: EPA/AHMED JALLANZO

The 20,000 doses of the GSK vaccine that may be ready by January—double earlier projections—could be enough for several trials, which might allow different groups of participants to enroll in different designs. “I would do all these trials simultaneously,” Longini says.

Before the trials are launched, health officials also need to decide who should participate. An August WHO consultation recommended that efficacy trials first recruit health care workers, as they are at high risk and provide a critical service. But the latest meeting “stopped talking about health care worker and started talking about front-line caregiver,” Ballou says, which means everyone from doctors and nurses to janitors, people who collect the bodies, and gravediggers.

The next issue is when to scale up production. Many researchers, including Longini, argue that massive production of Ebola vaccines should begin as soon as positive phase I data exist, to increase the likelihood that shots will be widely available when the evidence from the phase III study comes in. “I'd pull out all the stops,” Longini says. “I'd try to make 30 to 40 million doses to cover at-risk West African populations.” Farrar agrees. “We may come to regret that we have to throw those vaccines away if they prove not to be effective,” Farrar says, “but I think that is a risk we have to take.”

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