The slowdown in the West African Ebola epidemic is welcome news and reason to be hopeful—but it’s also creating a new problem. With fewer new cases occurring, it is becoming more and more difficult to test vaccines and drugs. As a result, conflicts are looming over who can test Ebola drugs and vaccines in Guinea and Sierra Leone.

In Guinea, a large consortium that includes Doctors Without Borders (MSF) and the World Health Organization (WHO) vaccinated the first volunteers at risk of Ebola on Monday in a big trial of a vaccine produced by Merck and NewLink Genetics. But the team feels threatened because researchers at the U.S. National Institutes of Health (NIH) are looking to move another vaccine study from Liberia, where the epidemic has come to a virtual standstill, to Guinea.

The U.S. move could jeopardize the Guinean trial, says John-Arne Røttingen of the Norwegian Institute of Public Health in Oslo, who chairs the study’s steering committee. "Can the two trials be going on in the same place? I don’t think so," says Marie-Paule Kieny, an assistant director-general at WHO. "There is a risk, if this is not done in an orderly way, that neither trial is conclusive in the end."

But Clifford Lane, head of clinical research at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, which is part of NIH, says that Guinea, which reported 45 new patients last week, can accommodate both studies. "Guinea is basically as large as Sierra Leone and Liberia together," he says. "It would seem reasonable to at least explore the possibility."

Meanwhile, an international team testing an Ebola drug called TKM-Ebola in Sierra Leone is worried that NIH is seeking to expand its trial of ZMapp, another Ebola therapy, from Liberia to Sierra Leone. That move could prevent the researchers from expanding their TKM-Ebola trial as planned, or even create direct competition at an Ebola treatment unit in the Sierra Leonean town of Port Loko where it is already under way.

Before the current outbreak, scientists never had a real chance to test Ebola drugs or vaccines for efficacy. The products hadn’t moved through phase I safety studies, and the outbreaks were much smaller and always ended within a few months. The current epidemic, which has caused almost 25,000 cases and more than 10,000 deaths, offers a unique opportunity to test candidate vaccines and drugs that could save lives in the future, scientists say.

Ironically, Guinea was initially passed over when vaccine trials were planned. Last October, when some models suggested more than a million people might get Ebola, scientists, politicians, and regulators met in Geneva, Switzerland, to discuss how to push ahead with candidate vaccines. At the end of that meeting, plans had been agreed to study vaccines in Sierra Leone and Liberia; Guinea, where the outbreak had started but which had fewer patients, was seen as a particularly difficult environment for testing a vaccine. Feeling that was unfair, some meeting participants formed a working group to design a trial for Guinea and make sure that at least some Guineans would have early access to the experimental vaccines.

The group came up with an unusual design called a "ring vaccination trial," in which a ring of people around a newly discovered Ebola patient is vaccinated. Entire rings are randomized to be vaccinated either immediately or after 21 days. If significantly more people contract Ebola in the latter rings, the vaccine is deemed effective.

The NIH study, on the other hand, is designed as a classic randomized controlled trial (RCT), with one group receiving the Merck–NewLink Genetics vaccine candidate, another group a different vaccine developed by GlaxoSmithKline, and a third group receiving a placebo. The researchers started vaccinating healthy adults in Liberia in early February, initially to study how safe the vaccines are and how much of an immune response they generate. "We think we will have a very good safety and immunogenicity database," Lane says.

After several hundred vaccinations, the scientists are ready to start phase III, in which efficacy is tested. But that won’t be possible in Liberia, where only one patient has been confirmed in the past 3 weeks, Lane says. "We are committed to trying to complete the study. To do that we are probably going to have to work in Guinea and/or Sierra Leone," he says. The team has reached out to the Guinean ministry of health and to French researchers working on a drug trial in Guinea, "to see if something can be put together," Lane adds. "I would hope that a country like Guinea is big enough to do at least two studies."

No, it's not, says Peter Smith, an epidemiologist at the London School of Hygiene & Tropical Medicine who was asked by WHO to study the issue. (Smith is not directly involved with the ring vaccination trial, but he chairs the board of the Norwegian Global Health and Vaccination Research program, which is co-funding it.) "My conclusion is that it would not be feasible to successfully run both trials in Guinea at the same time (unless there is a radical change in the epidemiology of the disease in Guinea and disease incidence rates increase to levels very much higher than they are now)," he writes in an e-mail to ScienceInsider.

Allocating one part of the country for the NIH study and excluding cases in that area from the ring vaccination trial would not work, Smith says, because the likelihood of catching Ebola is only big enough in the area around Conakry, the capital, where the WHO-MSF study has already started. "It would not only jeopardize the chances of the ring vaccination trial having sufficient power to show efficacy but also, unless NIH was prepared to increase the size of their trial very substantially, the NIH trial would have little or no power to detect efficacy."

Whether Guinea will agree to host the NIH trial as well is unclear, but there is clearly a need for the two groups to talk, Røttingen says. "I hope we can sit down and have a good discussion with them; we haven’t been able to do that at this stage." A compromise could be to run the two trials one after the other, Kieny says. The ring vaccination trial is scheduled to enroll 190 rings by late May; the last vaccinations would take place 3 weeks after that. Add a few months of follow-up, Kieny says, and then NIH could start its own study. "Frankly, they are not ready to start now anyway."

Lane says it would likely take 6 to 8 weeks to start the new trial in Guinea. The study should not be delayed further, he argues, partly because the design of the WHO-MSF study may not be the best for assessing how effective a vaccine is. For instance, he says, most of the prevented cases in the ring vaccination trial would occur shortly after exposure, leaving it open to how well the vaccine protects in the longer term. "If my goal is to get the most effective vaccine as quickly as possible to the largest number of people possible, I do think an RCT is the most direct way," he says.

In Sierra Leone, researchers from the University of Oxford recently started a trial of TKM-Ebola, an experimental Ebola therapeutic made of synthetic, small, interfering RNAs. Now, the NIH-led effort to test the antibody cocktail ZMapp is expanding from Liberia to Sierra Leone as well. "We hear rumors that NIH have reached an agreement with the Sierra Leone government to conduct the ZMapp trial in any Ebola treatment unit—even those that have trials already running," says Peter Horby, the lead investigator of the TKM-Ebola study. "If this is correct, it will jeopardize ongoing trials and lead to conflict."

Lane says that the government of Sierra Leone decides what treatment units will participate, and that Port Loko, where the TKM-Ebola study is running, is currently not included in the list. "We defer to our local partners," Lane says.

However, Lane argues that patients should have access to the most promising experimental drugs available, and that the animal data for ZMapp look better than those for TKM-Ebola. Horby agrees with that assessment, but says it is not clear how that translates into humans. (He says his team offered to test ZMapp in Sierra Leone but did not get access to the product because the U.S. Food and Drug Administration did not approve the study design, in which patients who receive TKM-Ebola are compared with Ebola patients at other treatment units who did not get the drug.) "It would not be sensible or ethical to stop a well-running trial of a promising product for an alternative promising product," Horby says.

The start of the ring vaccination study in Guinea on Monday came exactly 1 year after the first case of the deadly disease was diagnosed in the country, alerting the world to what has become the worst Ebola outbreak ever seen. Setting up the trial has been a huge challenge, given the bad infrastructure in Guinea and the widespread distrust of the health system among the population, Kieny says. "This is a great success," she says. "There has been great community engagement and no problems with violence."

*The Ebola Files: Science and Science Translational Medicine have made a collection of research and news articles on the Ebola virus and the current outbreak freely available to researchers and the general public.