A clinical trial of one or perhaps two experimental vaccines designed to protect against the Ebola Sudan virus could soon begin in Uganda, as long as the country agrees to allow the research to take place, an official of the World Health Organization said Wednesday.
The trial could get underway within a couple of weeks and definitely before the end of October, said Ana Maria Henao-Restrepo, who heads WHO’s R&D Blueprint effort to develop drugs, diagnostics, and vaccines to respond to outbreaks of rare and dangerous pathogens.
Henao-Restrepo and her team in WHO’s Health Emergencies Program have been meeting since last week to try to determine if any of the vaccines in development are far enough along to warrant testing in the fast-growing Ebola Sudan outbreak, which was first recognized early last week.
This is the first Ebola Sudan outbreak in a decade, presenting a rare opportunity to test a vaccine for this species of Ebola virus. Although Uganda announced the first confirmed case on Sept. 20, the first case may date back to early August. There have already been at least 36 cases and 23 deaths.
“We are doing everything that you are supposed to do when you want to get a trial started in a week or two maximum,” Henao-Restrepo said during a small briefing. Discussions have included the Ugandan government, which has nominated a principal investigator for the trial.
Henao-Restrepo said the government appears willing to allow the trial to proceed, but must still clear some internal hurdles, such as getting regulatory approval and agreement from an ethics review committee. “So we cannot say now that the trial will happen until we get the approvals,” she said.
There are two licensed vaccines that protect against the Ebola Zaire species, but the Zaire and Sudan versions of these viruses are different enough from one another that those two vaccines — made by Merck and Janssen, a division of Johnson & Johnson — will not work against this virus.
Gary Kobinger, an Ebola expert who was involved in the early development of the Merck vaccine, applauded the efforts to use this opportunity to try to add an Ebola Sudan vaccine to the world’s armamentarium against Ebola viruses.
“It is great to see WHO leading efforts to have a clinical study evaluating a … vaccine to protect against this deadly pathogen,” Kobinger, who directs the Galveston National Laboratory at the University of Texas Medical Branch, said in an email.
“Many vaccine candidates have shown full protection in pre-clinical studies and fortunately this one candidate is available (tens of thousands of doses) in clinical grade quality. The rapid response from WHO to have this readiness is remarkable and [is] what I think is a positive result of what was learned from the 2014-16 Ebola outbreak in West Africa.”
The vaccine Kobinger was referring to was the first that will be tested. It is being developed in a partnership between the Washington, D.C.-based Sabin Vaccine Institute and the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. At present there are only 100 doses of the vaccine in ready-to-use format and they belong to the VRC.
“We are working with Uganda and WHO to determine the best way to use these doses in the current outbreak,” Richard Koup, acting director of the VCR, told STAT in an email. “The Sabin Vaccine Institute has bulk drug substance for thousands of vaccine doses that must be vialed; they are currently working through the timeline for those activities.”
There are six candidate vaccines, as experimental vaccines are called, that target Ebola Sudan. But only three have advanced to the stage where human clinical trials have begun.
In all three cases, the human trials have been the small initial trials that determine how much vaccine should be given in a dose. Those trials also generate enough safety and immunogenicity data to show that a candidate vaccine appears to be safe enough to proceed with testing, and provide enough evidence of potential benefit to pursue larger trials aimed at determining whether the vaccine actually works.
The vaccine that is furthest along is the Sabin Institute vaccine, Henao-Restrepo said. This vaccine, which uses an adenovirus that infects chimpanzees to deliver the Ebola Sudan glycoprotein to the immune system, was developed at the VRC and for a time was licensed by vaccine behemoth GSK. Prior to the massive West African Ebola outbreak of 2014-2016, GSK was developing a number of vaccines for several Ebola species and for Marburg, a related virus. During that outbreak, a WHO-led clinical trial in Guinea showed that Merck’s Ebola Zaire vaccine was effective, generating data that led to its licensure by the Food and Drug Administration and the European Medicines Agency.
A trial testing the GSK vaccine ended without conclusive results, however, because other control measures finally brought the outbreak to an end. GSK abandoned these vaccines after that outbreak and in 2019 the company donated the license for the vaccine candidates to the Sabin Institute.
A second vaccine, being developed by scientists at the University of Oxford’s Jenner Institute, may also be tested, if the outbreak continues long enough to get it into the field. That vaccine — which was developed by the research group that designed AstraZeneca’s Covid-19 vaccine — uses a different adenovirus, one that infects humans, to carry both the Ebola Sudan and Ebola Zaire glycoproteins into the body.
Both vaccines are designed as single-dose vaccines.
The trial design used in Guinea to test the Merck Ebola Zaire vaccine will be used in Uganda, Henao-Restrepo said. Rather than a standard randomized controlled trial, where volunteers are assigned to receive a vaccine or a placebo, this trial will employ a ring vaccination design. People who are contacts of known cases will be offered vaccine and will be monitored to see if they develop disease. The rings of contacts of some cases will be offered vaccine immediately, while others will be offered vaccine after a delay. If fewer infections arise among the contacts who are vaccinated quickly, the vaccine will be deemed to have worked.
In recent Ebola Zaire outbreaks in the Democratic Republic of the Congo, the DRC government, the WHO, and other response partners have used a method where they vaccinated contacts of cases and then the contacts of contacts. But this time only the first ring of contacts will be offered vaccine, Henao-Restropo said.
“Our experience from DRC shows that this is where the transmission is,” she said, noting that roughly 90% of the secondary transmission occurred among contacts of cases.
Given existing supplies of these vaccines, that is just as well.
The WHO has been told the Sabin Institute has 40,000 doses of its vaccine in bulk form. Plans are underway to have the bulk vaccine processed into a ready-to-use format, a process known as fill and finish. Henao-Restrepo said the goal is to have that work done in October and November.
There are 71 doses of the Oxford vaccine at present, she said, with the Serum Institute of India working to produce 20,000 more over the same time frame.
“Governments on both sides of the Atlantic and their partners are working to try to accelerate this calendar. But it takes a few weeks to put bulk vaccine into vials,” she said.
The trial can begin with the 100 doses of the Sabin Institute’s vaccine, Henao-Restrepo said, noting that is enough vaccine for 10 rings of contacts.
There is a third vaccine that could be tested, a two-dose vaccine developed by Janssen. There are 3,500 vials of that vaccine, but the company put the development project on hold. Henao-Restrepo said the company said it would review the situation and consider whether it wants the candidate to be added to the mix of those being tested.
It seems likely some or all of these vaccines will work; testing done in non-human primates, the best model for human Ebola infection, showed nearly all the animals were protected.
But all three use adenoviruses as a means of introducing the virus to be protected against — Ebola Sudan — to the immune system. And experience with Covid vaccines suggests there may be problems with adenovirus vaccine platforms. Both the AstraZeneca and the Janssen vaccines were associated with a rare but serious side effect, which involved dangerous clotting and bleeding. A number of recipients of these vaccines died.
Henao-Restrepo said that issue is in the mix in discussions about testing these vaccines, but she noted that the risk-benefit ratio here is different. Ebola Zaire has a high fatality rate — 64% so far in this outbreak. Also, the clotting problems associated with the AstraZeneca and Janssen vaccines were even rarer in Africa than elsewhere, she said, noting if the trials proceed there will be a strong surveillance effort to monitor for adverse events.
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