In a perspective published today in the journal Science, researchers from Fred Hutchinson Cancer Research Center and other institutions drew on lessons learned in the ongoing Ebola epidemic in West Africa to suggest guidelines for conducting vaccine clinical trials during an infectious disease emergency.
“Limited infrastructure, unpredictable variation in incidence and a public health imperative to provide vaccine as quickly as possible are common in vaccine efficacy trials even outside public health emergencies,” the researchers wrote. “Trial designs that are appropriately adapted to the most challenging settings are sorely needed, not only to improve the external validity of trial results but also to ensure that vaccine quickly reaches those most in need.”
Dr. Betz Halloran, a biostatistician and member of the Fred Hutch Public Health Sciences and Vaccine and Infectious Disease divisions; Dr. Ira Longini, a biostatistician at the University of Florida and an affiliated Fred Hutch researcher; and scientists from Harvard University; University of Iowa; Iowa Veterans Affairs Health Care System; and Epicentre in Paris, France, contributed to the editorial. Halloran and Longini are among experts who have been advising the U.S. component of the international Ebola response, using mathematical models to detect patterns of infection and monitor the effectiveness of interventions.
Countries in West Africa – primarily Sierra Leone, Guinea and Liberia – are battling the most severe outbreak of Ebola since the virus was discovered in 1976. According to the most recent World Health Organization report, more than 24,900 people have been infected and more than 10,300 have died since the epidemic was declared in March 2014.
One of the obstacles encountered by vaccine investigators was the way cases have surged in different geographic areas, thwarting efforts to design a randomized trial in which participants in each district faced the same infection risk. To counter this, the researchers suggested block randomization within small centers – that is, among small groups of people projected to have a similar risk of exposure to the virus, such as frontline workers at a single Ebola treatment center or burial workers in a single district.
Ebola is not spread through air, like a cold or flu, but through direct contact with bodily secretions. In the current outbreak, which is the first in West Africa, health workers and family members who’ve been preparing bodies for funerals appear to be responsible for the greatest spread of the virus.
Another challenge to clinical trials was that the unprecedented outbreak outpaced the speed with which experimental vaccines could be produced. Ordinarily, investigators would not start a clinical trial without enough vaccine on hand, said Halloran. But rather than waiting for production to ramp up, the researchers suggested a stepped rollout.
“If you have limited vaccine quantities, you can introduce blocks one at a time as vaccine becomes available rather than waiting until you have all the vaccine to start with,” Halloran said.
The third recommendation, called adaptive design, addresses the uncertainty in predicting future infection incidence. To test whether a vaccine protects against exposure, participants should be at high risk of infection for weeks to months after immunization, but that has proven difficult to predict. Adaptive design allows for real-time modifications, such as adding new centers or changing the sample size, based on a predetermined interim analysis of study data.
Ebola vaccine trials now underway in West Africa are threatened by the otherwise welcome news that the number of new infections is declining. According to WHO, a total of 79 new confirmed cases were reported in the week leading up to March 22, the lowest weekly total this year. Of these, 45 were from Guinea and 33 were from Sierra Leone. Liberia reported one new case after three consecutive weeks with no new cases, a drop from a peak of more than 300 new confirmed infections per week in August and September.
The suggestions offered in the Science perspective may be helpful not only in an Ebola outbreak but in evaluating vaccines for diseases such as meningococcal meningitis, cholera, Middle East Respiratory Syndrome, vector-borne viral diseases such as dengue and chikungunya, and novel flu strains, the researchers wrote.
All three proposals – block randomization, stepped rollout and adaptive design – have been tested in previous studies, Halloran said. But combining the three strategies is a novel approach to testing a vaccine candidate “under the duress of an emerging infectious disease, trying to evaluate a vaccine in the acute phase.”
“It’s really, really difficult to do something like this,” she said. “A combination of the three [proposals] can be useful for thinking outside the box.”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.
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