SHAFAQNA – As global health officials rush to begin human trials of two promising Ebola vaccines in West African medical workers, a daunting question remains unanswered: Who gets the placebo injection? If all workers get the vaccines, doctors may never know how well they work. That’s because the results might also be affected by other factors best measured with the use of a dummy shot in some participants. Yet giving some medical workers a placebo means they will face close exposure to one of the world’s deadliest diseases with no more protection than before the trial began.
The dilemma, unique in vaccine development, is generating furious debate between infectious disease experts. Either way, scientists hope that once they confirm the safety of vaccines developed by GlaxoSmithKline and NewLink Genetics, the shots can help stem an epidemic that’s killed more than 3,400 people in West Africa. A decision on the design of the trial is pending, health officials said.
“Everybody would prefer a randomized controlled trial from a scientific point of view,” said John Edmunds, a professor of epidemiology at the London School of Hygiene and Tropical Medicine. “But there are enormous ethical concerns with that, and logistical concerns.”
Safety data on the two experimental vaccines are expected next month. Assuming the shots don’t cause harm, the World Health Organization plans to start offering them in January to health workers and others at the most risk of catching Ebola in Liberia, Sierra Leone and Guinea.
A consortium involving WHO officials, Glaxo and others will make the final decision on whether the trial will have a placebo arm.
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Because no one knows for sure whether the vaccines work, the WHO will look to collect as much evidence as it can, as quickly as it can. At a meeting in Geneva last week, health experts concluded that the fastest way to generate data showing that the vaccines work would be to run a randomized controlled trial, in which roughly half of the participants get the vaccine and half get the dummy shot.
“If you want to determine whether the vaccine works or not, you still have to have people who get the disease, otherwise you don’t know,” said Marie-Paule Kieny, the WHO’s assistant director-general for health systems and innovation.
Everybody in the trials would be monitored closely for signs of infection, and treated immediately with the best standard of care if they contracted Ebola, Kieny said. Results on whether the vaccine works may be available by the end of the third quarter next year, she said.
London-based Glaxo supports placebo-controlled trials for its vaccine as the best way to get “robust safety and efficacy information in an effective and expedited way,” the company said in an email.
“I’m amazed by how the international community has responded” in expediting development of the vaccine, Donna Altenpohl, Glaxo’s vice president of public policy, said in an interview at the company’s Philadelphia offices. “This is a fight for innovation, and we’re really making progress.”
Placebo-controlled trials would be ethically permissible in a vaccine trial, where healthy volunteers are receiving the shots, but not in a trial of an Ebola treatment in which experimental drugs are given to the infected, said Peter Piot, head of the London School of Hygiene and Tropical Medicine.
“One cannot go for placebo-controlled trials, although there is a push by some to do that,” Piot said at an Oct. 7 briefing in Geneva.
Conducting a vaccine trial during an outbreak is largely uncharted territory for Glaxo and the WHO. As the manufacturer of the shot, Glaxo would be legally responsible for any unexpected side-effects, Kieny said.
In 1976 about 500 people in the United States developed Guillain- Barre Syndrome, a paralyzing nervous system disorder, and 25 died, after a nationwide vaccination campaign using hastily- developed inoculations designed at halting a feared flu pandemic that never eventuated. The Centers for Disease Control and Prevention’s director, David Sencer, was fired.
Glaxo is currently testing its Ebola vaccine in healthy volunteers in Britain and United States, and wants to have 10,000 to 15,000 doses by January to start vaccinating health-care workers on the front lines of the Ebola outbreak as part of the next stage of testing. Glaxo will need six months to figure out how to eventually produce hundreds of thousands of doses for wider use, the company has said.
Tests have started in Bethesda, Maryland, and the University of Oxford, and more are slated to begin in Gambia and Mali in the coming weeks, Altenpohl said. The company could start the second phase of clinical trials as soon as early January, she said, and the drugmaker is looking for partners to help expedite the start of the third and final phase of trials.
An alternative but slower way of showing the vaccines work would be a so-called stepped-wedge design, in which vaccination teams would go from one treatment center to another for two days at a time, offering the inoculation to anyone who wants it. In this design, there would be no placebo; those who refuse vaccination or who weren’t at the treatment center at the time of vaccination would be the “control group,” Kieny said.
That makes sense, and sidesteps the ethical issues, said Jason Schwartz, a fellow at the Princeton University Center for Human Values.
“The demands of responding to an unfolding global health emergency ought to outweigh these questions about research design,” Schwartz said in a phone interview.
One way or another, a safe and effective vaccine will be essential to help contain either the current Ebola outbreak or the next one, said the London School’s Edmunds.
“If things go well in the next few weeks and we do get on top of this virus and turn the epidemic around, which is possible, then I still think this will come back at some point,” Edmunds said. “We need to be much better prepared for the next one.”
_ With assistance from Caroline Chen in New York.
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