Earlier this week, Medécins Sans Frontières (Doctors Without Borders) reported something that might have seemed unimaginable at the zenith of the Ebola epidemic, when the aid agency had to turn dying patients away from its teeming treatment facilities.
Only 50 or so of the 650 isolation beds at MSF's eight Ebola treatment centres in West Africa are now occupied.
The empty beds are a tangible sign of the steep decline in new cases in Guinea, Sierra Leone and Liberia, a development that is being greeted with cautious optimism – and warnings against complacency – in the international public health community.
Beneath the optimism is a growing acknowledgment that, what is undoubtedly good for the people of West Africa, is very likely bad for the quest to bring Ebola vaccines and treatments to market.
Case counts are plummeting just as the first large-scale trial of experimental Ebola vaccines is about to get under way in Liberia, where only 29 new cases have been confirmed so far in January, down from a high of 359 in a single week in September.
The phase III trial of two vaccine candidates, including one made in Canada, needs to have enough Liberians at risk of Ebola exposure to determine if either shot shields people from the virus.
Already, the U.S. National Institutes of Health, which is sponsoring the trial in partnership with the Liberian government, is pondering enrolling more than the planned 27,000 volunteers and expanding into Sierra Leone to make up for the dearth of new patients in Liberia.
The sponsors of two other major trials slated to begin at the end of February in Sierra Leone and Guinea are looking at tweaking their designs for the same reason. And the senior World Health Organization official in charge of developing experimental Ebola vaccines and therapies conceded in an interview this week that if cases continue to decline, the trials could be inconclusive.
"There might even be, hypothetically, a [situation] where you don't have enough cases to definitely conclude on whether the vaccine is efficacious or not," said Marie-Paule Kieny, the WHO's assistant director-general for health systems and innovation. "We are not there at this moment. But it is not completely out of the question."
Ross Upshur, a professor in the Dalla Lana School of Public Health at the University of Toronto who chairs the WHO's ethics working group on Ebola interventions, said the reduction in cases could imperil hopes of having a vaccine ready to tackle future Ebola outbreaks, which he called inevitable.
"It is a concern," he said, "but it's a good concern to have. One thing that everybody should be clear about is that the goal of responding to the Ebola outbreak was to bring it to an end. The goal was not to have an opportunity to test new vaccines and therapeutics."
Still, at its height, the massive West African outbreak offered a chance to test Ebola vaccines in the real world, something the small community of scientists studying the disease thought might never happen.
Two vaccine candidates, which had performed well in tests on non-human primates, quickly moved to the front of the pack.
One, based on a chimpanzee cold virus, is being developed by the pharmaceutical giant GlaxoSmithKline and the U.S. National Institute for Allergy and Infectious Diseases, part of the National Institutes of Health.
The other, which uses a genetically engineered version of the vesicular stomatitis virus to provoke an immune response against Ebola, was discovered largely at Canada's National Microbiology Laboratory in Winnipeg and is being developed by NewLink Genetics and another large pharmaceutical player, Merck.
Both shots are to be in the Liberia trial.
The Canadian-made vaccine has already undergone phase I human safety trials at seven sites in total: two sites in the United States and five more in Halifax, Germany, Kenya, Gabon and Switzerland.
The trial in Geneva, which was testing two high doses of the Canadian vaccine when the efforts began in November, was suspended for three weeks in late December and early January after a total of 11 patients reported mild to moderate pain in the joints of their fingers and toes, a side effect the investigators had not expected.
Those effects subsided, and the trial resumed on Jan. 5 at lower doses. The last of 115 volunteers received the vaccination this week, said Angela Huttner, an infectious disease specialist at the University Hospitals of Geneva and a co-investigator on the trial. None of the other sites, which were testing lower doses of the vaccine, have reported similar side effects.
Manuel Schibler was one of the first volunteers to receive the Canadian vaccine. An infectious disease specialist at the University Hospitals of Geneva, he rolled up his sleeve in November to receive the shot before he set off for Sierra Leone, where he is treating Ebola patients at an MSF centre in the capital, Freetown.
"I thought [the vaccine] showed some promising results in non-human primates. I found it very logical to test it as soon as possible in humans in this epidemic. For me, that was quite a natural thing to do," Dr. Schibler said in an interview from Freetown.
Despite being vaccinated, Dr. Schibler is not letting his guard down when he dons his spacesuit-like protective equipment and heads into the isolation unit to help patients.
"Personally, I believe in the efficacy of the vaccine, but the truth is nobody knows for now," he said. "Because of that, I, of course, apply the same safety measures as anyone in the field."
Knowing for sure is the goal of the vaccine trials. But if the case counts continue to decline – the 100-bed unit where Dr. Schibler is working had only 17 patients as of Tuesday, MSF said – drug companies may have to pursue another path to regulatory approval for Ebola vaccines and therapies.
Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases, told reporters last week that one option would be to use the U.S. Food and Drug Administration's animal efficacy rule, which allows drug makers to lean more heavily on the results of animal studies when developing life-saving drugs that cannot practically or ethically be tested on humans.
Trial data on how safe the Ebola vaccines are and what kind of immune response they provoke would help that process, even if efforts to prove efficacy do not pan out.
"Nobody should be lamenting the fact that we may miss an opportunity to actually get good data because getting good data would be in a context where there was evolving and ongoing transmission," Dr. Upshur said. "Our overarching goal from the beginning has been to end this outbreak as fast as possible."
Small trials of some experimental Ebola treatments are already under way or about to start in West Africa
An antiviral drug made by the Japanese company Toyama Chemical Co. Ltd., part of the FujiFilm Group, Favipiravir has been approved in Japan for the treatment of novel or re-emerging strains of influenza. It has also been shown to be effective at treating Ebola in mice. On Dec. 17, a clinical trial of favipiravir began at the Médecins Sans Frontières (Doctors Without Borders) treatment centre in Guéckédou, Guinea, led by the French National Institute of Health and Medical Research. Any Ebola patient at the centre who wants the drug will receive it; their outcomes will be compared with patients treated at the centre before the trial began. The first conclusive results are not expected until a few months into this year, MSF says.
An antiviral developed by North Carolina-based Chimerix Inc., Brincidofovir was reportedly given to Thomas Eric Duncan, the Liberian man who died of Ebola in a Dallas hospital last fall, and Craig Spencer, the New York doctor who contracted the virus in Guinea and later recovered. The University of Oxford, on behalf of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), is leading a trial of the drug at MSF's Elwa3 treatment centre in Monrovia. The trial, funded by the Wellcome Trust, a London-based medical charity, began Jan. 1.
Plasma from Ebola survivors, who develop antibodies against the virus, has shown signs of aiding in some patients' recovery. A clinical trial of this method is expected to start in the coming weeks at MSF's Donka Ebola centre in Guinea's capital, Conakry.
An experimental therapy developed in large part at the National Microbiology Laboratory in Winnipeg, ZMapp was given to several patients early in the Ebola outbreak before supplies ran out. The U.S. Biomedical Advanced Research and Development Authority has been working with San Diego-based Mapp Biopharmaceutical to speed up production of the therapy, which is grown in tobacco plants. The director of BARDA told reporters at a telephone briefing last week that there are now somewhere between 50 and 150 three-dose treatment courses of ZMapp available for clinical trials. Anthony Fauci, the director of the U.S. National Institute of Allergy and Infectious Diseases, said during the same news conference that it could take as few as 12 patients or as many as 40 to determine if ZMapp works.
Another experimental treatment with a Canadian connection, TKM-Ebola was developed by the British Columbia-based drug company Tekmira Pharmaceuticals. Tekmira recently produced a modified version of its TKM-Ebola therapy tailored to the variant of the Zaire strain of the virus that caused the outbreak in West Africa. Human trials of the new version of the drug, called TKM-Ebola-Guinea, are expected to start in West Africa early this year, according to the company. Like the Brincidofovir trial, the TKM-Ebola-Guinea trial will be run by the University of Oxford on behalf of ISARIC and funded by the Wellcome Trust.