Come January, up to 20 000 doses of an Ebola vaccine candidate could be ready for testing in the unprecedented epidemic running through West Africa. The vaccine and another whose development is 6 weeks behind could bring hope to a desperate population panicked. Indeed, some scientists believe that the epidemic has become so great that the vaccines will be vital to stop it. But tough questions are emerging about how to design clinical trials, expected to be the first to get the shots, and when to start mass production.
Until recently, many scientists said that by the Ebola virus, it would not be ethical to use the standard procedure for testing the efficacy of a vaccine: so-called randomized controlled trials ( ECR), in which some test subjects are assigned to a control group that does not receive the current vaccine. During a consultation organized by the World Health Organization (WHO) from 29 to 30 September, however, there was unexpectedly broad support for the design of the RCT after all, but not Médecins Sans Frontières (MSF ), which plays a huge role in the current epidemic.
September 2, a vaccine manufactured by pharmaceutical giant GlaxoSmithKline (GSK) Rixensart, Belgium, in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), which entered phase trials I, in which test the 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 on October 13, with the first results expected in December.
If vaccines do not cause damage and trigger the immune response Scientists hope to see WHO recommended to jump directly into the amount on Phase III efficacy testing in Liberia, Guinea and Sierra Leone, the three affected countries. It is an unprecedented extraordinary bet to move so quickly-but that WHO consultants say is justified by the extreme Ebola threat.
In the RCTs, half of the participants are randomly assigned to receive the experimental design and the other half a dummy, or placebo; ethicists say it OK if we do not know if the vaccine will do nothing, or cause damage. If a lot more people in the placebo arm develop the disease, the vaccine works. But animal studies suggest that Ebola vaccines could well provide protection; preventing the workers also face a deadly disease Ebola is unethical, some say.
The main alternative is a trial design known as stepped corner, which takes advantage of the unavoidable reality that a large-scale study can "t give everyone the vaccine at the same exact time. Stepped-wedge trials compare infection rates among people already vaccinated with those who have yet to receive the shots. "People are more comfortable" with this configuration because everyone in such a study given the vaccine against Ebola, says Barney Graham, a virologist at NIAID in Bethesda, Maryland, who attended the meeting of the wHO.
But at the meeting, Ripley Ballou, who heads the project vaccine against Ebola for GSK pleaded for RCT-although the placebo would be replaced by an "active control" a proven vaccine (eg, against hepatitis B), at least protect participants against another virus. an RCT, Ballou argued, provides the fastest way, the most acceptable to determine if a vaccine is safe and effective, and therefore would potentially save more lives.
Ballou describes a randomized study in which 2,500 people, probably health care workers receive the vaccine and 2,500 active control. He emphasized that his GSK team were many unknowns to wrestle with, including the risk of infection of health care workers, which they estimated at 10% per year in contact with Ebola patients. Assuming this is correct, and that the vaccine works at least 80% of the time, the researchers could be "absolutely confident" the effectiveness after 30 infections, which would be likely to occur within 3 months, Ballou said. A vaccine that was 60% efficiency could still give an answer with less than 60 infections.
This is much faster than a stepped design area, he said. Such a study will enroll participants at the same point in time, but would stagger the delivery of vaccines, for example, different Ebola treatment units. But researchers have yet to observe the different communities of the same start date, introducing delays and makes it more difficult to tell if the vaccine works. Infection rates can change over time, too, which complicates the analysis.
Ballou has not won more than MSF. "The efficacy studies in affected countries and more in populations at risk should not have a placebo or an active control arm that can not be defended ethics," says Annick Antierens, a participant in the meeting which oversees experimental products Ebola MSF. Antierens said MSF will support other designs efficacy trials of the vaccine against Ebola, but would not specify which. One idea is to simply distribute the vaccine to workers health, then do a "observational" study lacks a control group, but compared vaccination status in those who became ill in those who do not.
but most meeting participants sided with Ballou says Ira Longini, a biostatistician from the University of Florida in Gainesville. Longini changed his planned speech on the corner tiered design after Ballou spoke. "I suddenly saw a true double-blind trial with another vaccine that control was the way forward, "he said. Marie-Paule Kieny, an assistant director general of WHO, said "the meeting was very tense at times" but he was finally "broad agreement" on this design. "The Rip study made sense" said Kieny.
Jeremy Farrar, a researcher from the infectious disease that leads the Wellcome Trust in London, warns that people on the front lines of Ebola may disagree. An RCT may give faster results, but if it is simply unacceptable for trial participants, a stepped wedge design is preferable. "If you were there tomorrow and you're a health care worker, would you be ready to be in a control arm when the next 3 months, you will be looking after patients with Ebola? "Farrar request." I do not want us months of discussions on how best to handle this. "
Liberian nurses pick up a dead body waiting area of a hospital in Monrovia
PHOTO :. EPA / AHMED JALLANZO
20,000 doses of the GSK vaccine that can be ready in January-double the previous-projections could be enough for several tests, which could allow different groups of participants to register in different models. "I'd do all these tests simultaneously," said Longini.
Before the tests are run, the health officials also need to decide who should participate. A WHO consultation in August recommended that efficacy trials first recruit health workers because they are at high risk and provide an essential service. But the last meeting "stopped talking about health care worker and started talking frontline helping," Ballou said, meaning that each of the doctors and nurses to janitors, people collecting the bodies, and gravediggers.
the next issue is when to intensify production. many researchers, including Longini, argue that the mass production of Ebola virus vaccines should begin positive phase I data exist to increase the likelihood of strokes will be widely available as evidence of the phase III study comes in. "I pull all stops, "says Longini. "I'll try to do 30 to 40 million doses to cover populations in West Africa risk." Farrar agrees. "We may regret that we must take these vaccines immediately if they are found not to be effective, "said Farrar," but I think that is a risk we must take. "
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