When Ripley Ballou came to Geneva, Switzerland, meeting on the Ebola virus vaccines last week, he was a hard sell message. In tests of effectiveness of these vaccines that can start in West Africa in a few months, half of the volunteers should be randomly assigned to a control arm, Ballou argued-a group of people at risk of infection who would not benefit from an experimental Ebola vaccine. Instead, they serve as witnesses said assets to be injected with other vaccines approved, for example against hepatitis B and pneumococcal disease. This would be the best way to know if Ebola vaccines work and can be deployed widely, Ballou said and potentially save more lives.
He was a controversial opinion. health workers to Ebola front line, which will serve as the target group in the first tests of effectiveness, are so vulnerable by giving them other than the experimental vaccine everything seems inhumane and could create tensions, some argued . "Going into this meeting, we were told that the idea of a controlled trial ... was not going to be acceptable," says Ballou, who heads the emergency program to develop a vaccine against Ebola GlaxoSmithKline (GSK) in Rixensart, Belgium.
Indeed, Ballou has not won everyone during his speech at the meeting, which took place on 29 and 30 September at the headquarters the World health Organization (WHO). Médecins Sans Frontières representatives (MSF) were strongly opposed to giving participants a real test other vaccine Ebola anything candidate and they do not change their spirits. "the meeting was very tense at times," said Marie-Paule Kieny, a Deputy Director General of WHO and specialist vaccines.
But many scientists leave the meeting convinced that the randomized controlled design proposed by Ballou should be used, as hard as it may be to explain, because it will be the best way to know if the vaccine works. "Participants had a strong feeling that there was no time to lose," especially after they received an update on the situation in West Africa, Kieny said. "I m ' are expecting more controversy. " Looking back, "we basically said what people thought he had to say, but afraid to say," Ballou said.
The GSK vaccine only went into a human for the first time on September 2, in a Phase I trial will involve hundreds of volunteers do not risk of infection. If the vaccine proves safe and triggers the kind of immune response that monkey studies suggest confer protection, some 10,000 or more doses will be delivered to the three most affected countries in West Africa in January.
The compound that GSK has developed in collaboration with the US National Institute of Allergy and Infectious Diseases (NIAID), is one of two candidate vaccines that may soon enter efficacy trials in the real world; the other was developed by the Canadian Public Health Agency and is produced by NewLink Genetics in Ames, Iowa.
This is an unprecedented extraordinary bet to move so fast. Normally, vaccines take many years to advance small Phase I studies, which explore the safety and immune responses; Phase II studies, which are the same in large groups; Phase III, where effectiveness is tested in populations at risk for the disease. A previous WHO consultation made the surprising announcement, September 5 that this crisis requires compressing the timeline, making it effectively disappear traditional phase III studies.
At the meeting last week, vaccinemakers, researchers, ethicists, clinicians, epidemiologists, statisticians and representatives of countries met to sort out the ethical and thorny statistical issues on how to design efficacy trials in Liberia, Sierra Leone and Guinea three countries hit by the Ebola virus.
participants in the meeting agreed that smoothly makes no sense to give just experimental vaccines for health care workers on a base supposedly compassionate and without an efficacy trial, as happened with experimental treatments such as Ebola and zmapp TKM-Ebola; this strategy is simply too dangerous with a vaccine, which is in healthy people. "The last thing you want to do is deploy a vaccine that does nothing to protect people or even their night," says Marylyn Addo, an expert on emerging infections at the University Medical Center Hamburg-Eppendorf in Germany who . attended the meeting A real test is necessary, the meeting concluded,. it is the configuration that is the subject of debate
the proven design and true vaccine efficacy trials randomly assign the half of the participants to receive the experimental firing and the other half a dummy, or placebo. Nobody knows what they receive, and the vaccine works if more people in the control arm of developing the disease than those who got the current vaccine. Before the meeting, many researchers have found that this design would be unethical, given that health care workers are at considerable risk and the Ebola virus is so often fatal. the same was true for a variation on this scheme, which replaced the placebo with active control which would at least protect participants against another virus, otherwise Ebola.
The main alternative is a design known as step-wedge, which essentially uses the time to create a control group. In this design, researchers are taking advantage of the unavoidable reality that large trials can not give everyone the vaccine at the same exact date; they compare those with infection rates previously vaccinated with those who have yet to receive the shots. Barney Graham, a virologist at NIAID in Bethesda, Maryland, who attended the meeting, said "people are more comfortable" with the corner of stage design, because everyone in such a study would get the vaccine against Ebola.
But statistically speaking, this design, it is more difficult to determine the value of the vaccine, and it takes more time, Ballou said in Geneva. The most practical way to make a step-area study is to randomize the vaccine distribution sequence, for example, Ebola treatment units. But researchers have yet to observe the various communities for the same amount of time. A step wedge test also makes it harder to control bias such as differences in rates of new infections, behavior, and availability of protective clothing.
Most meeting participants found themselves in agreement, said Ira Longini, a biostatistician from the University of Florida in Gainesville, who came expressly to the meeting to make a presentation on the design stage corner. "I work a lot of that, but my speech was after [Ballou’s], and I had to change a little because I suddenly saw a true double-blind trial with another vaccine that control was the way to go," Longini says . "I think the first day of the meeting things have evolved very differently than many people expected."
Ballou describes a randomized study in which 2,500 people receive the vaccine and 2,500 active control. He stressed his team GSK were many unknowns to wrestle with, including the risk that the infection of health care workers they estimated at 10% per year in contact with Ebola patients. assuming that is correct and that the vaccine works at least 80% of the time, the researchers could be "absolutely confident" the effectiveness after 30 infections and 3 months, said Ballou. a vaccine that was 60% efficiency could still give a response with less than 60 infections.
"study direction Rip," Kieny said WHO. "There was broad agreement [such a trial] get a final result much sooner." Discussions will now start with the affected countries to see where the test could be possible, she said.
But MSF representatives remain skeptical. "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. MSF said Antierens support other Ebola vaccine effectiveness against the designs of trials, but would not specify which ones. "It is not for MSF to decide exactly what design should be used, as this will depend on the context and the situation at the trial, "she said.
Jeremy Farrar, a researcher on infectious diseases who heads the Wellcome Trust research organization in London, thinks, a randomized controlled trial is ethical for the simple reason that no one really knows if the vaccine will offer protection. But he wonders if it will be acceptable to participants at high risk of contracting Ebola. "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? "He asks. A test area step would avoid this problem, Farrar said. "I do not mean that we have months of discussions on how best to handle this."
There may be a way around the debate. GSK has predicted that by January there will be at least 10,000 doses of the Ebola-a gene vaccine stitched surface protein in a harmless adenovirus chimpanzee which means that although randomized, controlled studies are done, there may be enough for the less rigorous designs such as test corner stage. "I'd do all these tests simultaneously," said Longini. The meeting also discussed how, randomized controlled trials in African countries that are not affected, and in special populations such as children and people infected with HIV, to gather more data on safety and immune responses.
If all goes according to plan, Kieny said a Phase III trial could reveal from April if the GSK vaccine works. The other candidate vaccine, produced by NewLink Genetics, is lagging behind. He faced several delays, and some have accused the company of dragging its feet, but human studies will probably start at the end of the month. NewLink is looking for a major corporate partner to move the vaccine forward. "I think it would be a great help," said Kieny.
A previous WHO consultation recommended that if vaccine supplies are limited, efficacy trials should first recruit volunteer health workers, because both are high-risk and provide an essential service to society to help combat the epidemic. This means not only doctors and nurses. "An interesting result of the meeting we stopped to talk health care workers and started talking first care line," said Ballou. "It is the doctor to the person cleaning the room gravedigger."
The tests will work best if they enroll volunteers who are affiliated with a specialized Ebola treatment facility rather than general clinics or private practices. "You must be able to recruit them and follow them, and you move away from a treatment plant, the more difficult it will be," said Ballou. (The safety trial for the vaccine against vesicular stomatitis virus in Geneva will also recruit health care workers that ultimately go into the affected area.)
Conditions for the tests will be much more difficult than vaccine researchers typically deal with. Health care systems in Liberia, Sierra Leone and Guinea are paralyzed; potential participants may be wary of an experimental product made by foreigners; ethical reviews may be difficult to perform locally and security could become a problem, said Ballou. "The thing I'm really worried," he said, "is that we have a great plan and we can have a great vaccine and, late in the day, we may not be able to do the test."
* Ebola files: Given the current Ebola epidemic, unprecedented in terms of the number of people killed and the rapid geographic spread, science and science Translational Medicine made a collection of research and articles on viral disease available for researchers and the general public.
0 Komentar