The first clinical trial designed to see if two experimental Ebola vaccines actually work may begin in late January and two others are slated to start in February in West Africa, the World Health Organization said Friday.
Vaccine manufacturers and researchers are plowing ahead with plans to conduct the critical clinical trials, even if dropping case counts are creating concerns in some quarters that the studies may not arrive at clear answers about whether any of the vaccines actually works.
Dr. Marie-Paule Kieny, the senior WHO official responsible for efforts to develop and deploy Ebola vaccines and drugs, said it could take a median of six months for these studies to determine if one or several of the vaccines protects people against infection with the deadly virus.
“With a fast-growing epidemic, the speed of the trial will be very short. In an epidemic which is really faltering, the trial will be prolonged,” she admitted Friday during a press conference called to report on a day-long Ebola vaccine meeting the global health agency held on Thursday.
If one or more vaccines are shown to be effective, the results may come too late to consider mass vaccination campaigns because at this point the outbreak is not surging at a rate that would justify such a move. Targeting vaccination campaigns to areas that are still hot spots might make more sense, Kieny said.
“Even if it has limited utility because hopefully we will have broken the back of this epidemic by the time we finish these trials for this event, in future we will have this vaccine. Because we anticipate that this is not going to be the end of Ebola,” said vaccine expert Helen Rees of South Africa’s University of Witwatersrand.
Planning is most advanced for a large clinical trial to be held in Liberia, which last autumn had the fastest-growing outbreak of the three most affected countries. But today new cases in Liberia come much less frequently, making it unclear how long it would take for the trial to demonstrate whether the vaccines to be tested there work.
The most recent update from the WHO shows how dramatically the situation in Liberia had changed. In August and September, Liberia was recording 300 new confirmed cases per week. In the five working days of last week, the country recorded eight confirmed cases and 40 probable cases of Ebola.
The plan in Liberia is to test the two most advanced experimental vaccines in a three-armed trial involving 2,700 people. One third will receive a vaccine being made by GSK (formerly GlaxoSmithKline), one third will receive a vaccine being made by NewLink Genetics and Merck and the remaining portion will receive a placebo.
The NewLink-Merck vaccine was designed by researchers at Canada’s National Microbiology Laboratory in Winnipeg.
The idea behind the trial is to give the vaccine to healthy people, and then watch to see how many in each arm develops Ebola. If many people in the placebo group become infected and none or few in the vaccine groups do, it would become clear that the vaccines were protective.
But if Ebola transmission in Liberia drops to the point where few in the placebo group become infected, then more people will need to be enrolled to try to improve the likelihood that a statistically significant effect will come into view.
The more people in a trial, however, the longer it takes to run and the more the research costs.
Kieny said GSK and NewLink-Merck are still analyzing data from small Phase 1 trials of the vaccines that are taking place in a number of sites in the United States, Canada, Europe and several African countries not currently fighting Ebola.
Phase 1 trials are designed to see if a product is safe to use and to determine what the dose for a drug or vaccine should be. They are followed by larger Phase 2 and 3 trials that are designed to show if an experimental product actually works.
While there is enough data now to say that both vaccines have an acceptable safety profile, it will take the manufacturers another two to four weeks to be able to determine an appropriate dose, Kieny said.
That is a delay on previous plans. It had been hoped that the Liberia trial would begin by mid-January.
Kieny noted that at this point it seems most likely that a trial planned for Guinea might be the one that will give the earliest clue as to whether the vaccines work.
Two trials are planned for Guinea. One is an observational study, in which health-care workers will be vaccinated. They will be watched to see if new infections among health-care workers drop off after the vaccination.
Another — the one Kieny suggested might show signs of efficacy — involves a design called ring vaccination, in which people who are contacts of known cases will be vaccinated to try to prevent onward transmission.
People in some rings will be vaccinated immediately after a case is identified and others will be vaccinated after a delay. If there are fewer new cases among the contacts who were vaccinated quickly, it would suggest the vaccines are protective.
Kieny said organizers of that trial plan to vaccinate 4,500 contacts quickly and another 4,500 after a delay.
Organizers have yet to finalize the trial to be held in Sierra Leone. They will use what is known as a step-wedge design, which compares rates of new infections in people who are vaccinated early to those in people who have not yet received the vaccine. But the organizers only want to use one vaccine, and are waiting for more evidence to emerge to choose the candidate that seems the most promising, Kieny suggested.
A third manufacturer, Johnson & Johnson, indicated it is devising plans to do an efficacy trial of another Ebola vaccine later in the year, Kieny said. The company’s vaccine started Phase 1 testing this week in Britain.
Their vaccine requires two doses, a priming dose followed by a booster. In their animal studies, the booster was given two months after the first dose, though the company will try to see whether that time period could be compressed.
A two-dose delivery schedule — especially when the second dose comes weeks after the first — would not be an optimal strategy with which to try to control an outbreak. It would simply be too cumbersome and take too long to protect people. The ideal scenario would involve a one-dose vaccine that triggers rapid production of antibodies.
But Kieny said there was discussion at the meeting about potentially developing two types of Ebola vaccines, one which could be used to develop immunity quickly in an outbreak setting and another that could be given in advance of exposure to people like health-care workers who might at some point encounter Ebola.