In DepthThe Ebola Epidemic

High hopes for Guinean vaccine trial

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Science  16 Jan 2015:
Vol. 347, Issue 6219, pp. 219-220
DOI: 10.1126/science.347.6219.219

A health worker at the Ebola treatment center run by the French Red Cross society in Macenta, Guinea.


When Western researchers began laying the groundwork for real-world tests of Ebola vaccines late last summer, Guinea was last on their list of likely locations. It had fewer weekly cases than neighboring Sierra Leone and Liberia, and patients were scattered over a country the size of the United Kingdom with a very weak infrastructure. At an expert meeting in Geneva, Switzerland, on 23 October, the U.S. National Institutes of Health (NIH) presented a trial plan for Liberia, while the U.S. Centers for Disease Control and Prevention (CDC) offered proposals for Sierra Leone—but there was nothing for Guinea. “What about us?” the Guinean delegates asked, says biostatistician Ira Longini from the University of Florida in Gainesville, who attended the gathering. “You've left us out.”

Now, in an ironic twist, many scientists say that an unusual Ebola vaccine trial set to begin next month in Guinea may produce the earliest—and perhaps the only—answers about vaccine efficacy. New cases of Ebola have dropped precipitously in Liberia, and begun to ebb in Sierra Leone, making it much harder to demonstrate whether a vaccine works—perhaps even impossible. In Guinea, however, a less intense epidemic has not relented, possibly making it “the only country where the trial will have enough power to give an answer,” says Adrian Hill, a vaccine researcher at the University of Oxford in the United Kingdom.

The push to test Ebola vaccines is accelerating. Last fall, an international ethical panel convened by the World Health Organization (WHO) judged that the unprecedented threat made it acceptable to take Ebola vaccines straight from small, phase I safety studies to large phase III efficacy studies, while simultaneously conducting phase II studies. Two vaccines are now almost ready to make the leap. One, made by GlaxoSmith-Kline (GSK), contains a chimp adenovirus equipped with a gene that codes for the Ebola surface protein. The other, developed by NewLink Genetics but now manufactured by Merck, uses a livestock virus called VSV to carry an Ebola gene.

How to design the studies has been the subject of intense ethical and methodological debates. In the end, researchers settled on very different designs for each country. In Liberia, the study will use a classic randomized controlled trial with three arms, one for each of the two vaccines and a third in which people receive neither. It will target the general population in the capital, Monrovia. CDC's plan for Sierra Leone is to recruit workers at Ebola treatment units; everyone will receive the vaccine, but some earlier than others. The trial has yet to select the vaccine it will test.

The welcome decline in cases in those two nations means that the trials need to include large numbers of people to determine efficacy. Although NIH now plans to enroll nearly 10,000 people in each arm of the Liberian trial, current infection rates mean it will take about 6 months to reach a statistically significant answer if the vaccine protects 50% of those who get it, says Ripley Ballou, who heads GSK's Ebola vaccine project. (An answer would come faster if protection rates are better.)

But Liberia's epidemic could end by mid-2015, suggests a model published this week in PLOS Biology. “There is a real risk that we won't have an answer at all at the end of the day,” Ballou says. That's why, in addition to counting cases and deaths, researchers should carefully study immune responses in vaccine recipients to learn as much as possible from each trial, says vaccinologist Claire-Anne Siegrist of the University of Geneva.

The Guinea study will feature an old vaccine strategy, never used before in a clinical trial, which may yield results more quickly. Inspired by the global campaign that eradicated smallpox in the 1960s, it rests on a concept called ring vaccination. Researchers will search for people newly infected with Ebola, then attempt to vaccinate a “ring” of people living around them—most likely their village or neighborhood. In half of the rings, researchers will administer the vaccine immediately to an average of 50 people; they will compare their outcomes to other rings where researchers wait between 4 and 8 weeks to administer the vaccine, says John-Arne Røttingen of the Norwegian Institute of Public Health in Oslo, who leads the study's steering group. (It was designed by a coalition including WHO, Doctors Without Borders, Longini, and several other academic partners.) Front-line health workers will also receive the vaccine, without a control group.

The vaccine for the Guinea trial has yet to be chosen, but “we will start in February, even if it is the 28th of February at 11:30 p.m.,” WHO's Ana Maria Henao-Restrepo told an Ebola vaccine meeting at the Mérieux Foundation in Veyrier-du-Lac, France, this week. The study could have answers after 3 months, Røttingen says.

If one of the vaccines works and case numbers keep dwindling, a targeted ring vaccination strategy to mop up remaining virus pockets may become the best way to battle the epidemic, Røttingen says.

“It's a very interesting design from a group of very smart people,” says Ballou, who adds that the logistical challenges in Guinea remain daunting. The study will have to chase cases over a vast area, and it doesn't have the operational and financial support of major players like NIH or CDC.

Meanwhile, a third vaccine candidate has entered the fray: a pair of new vaccines used in tandem. Last week, Johnson & Johnson announced that it had launched a phase I test; it is also looking for phase III study sites. Whether one of the three countries can support a second big study—and whether there will be enough new infections once the vaccines are ready for their big leap—remains to be seen.

Correction (23 January 2015): An Ebola vaccine trial in Liberia is not led by NIH, as this story said, but by a partnership between the Liberian and U.S. governments.

  • * With reporting by Kai Kupferschmidt and Jon Cohen.


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