Researchers once again scramble to launch trials during a crisis
| THE INDEPENDENT | A multipronged international effort has begun to pull out all the stops to launch trials of experimental Ebola vaccines in Uganda, which declared an outbreak of the deadly disease on 20 September. According to the most recent World Health Organization (WHO) update, Uganda had by Sept.29 had 35 confirmed cumulative cases, and 7 cumulative Ebola deaths, and 427 contacts listed for follow up. A trial of a vaccine candidate that’s farthest along in development could launch before the end of next month.
Proven vaccines exist for Zaire ebolavirus, which has led to a dozen outbreaks in the neighboring Democratic Republic of the Congo (DRC) and was responsible for the massive Ebola epidemic in West Africa in 2014.
But those vaccines cannot control this outbreak because it’s being driven by a distant viral relative known as Sudan ebolavirus, which last caused an outbreak, also in Uganda, in 2012.
The Zaire and Sudan ebolaviruses “are not variants and they’re not strains—they’re different viruses,” says Nancy Sullivan, who heads biodefense research at the National Institute of Allergy and Infectious Diseases (NIAID) and has collaborated on Ebola vaccine studies.
Researchers have long recognised that the world badly needs a Sudan ebolavirus vaccine: In 2016, Science published a survey of 50 leading vaccine researchers who ranked the Sudan ebolavirus vaccine as the number one R&D priority based on feasibility and need. But vaccinemakers have had little financial incentive to produce one. Even if the current trial succeeds, producing enough doses fast enough will be a challenge.
Three experimental Sudan ebolavirus vaccines have been tested in human studies, but because outbreaks are so rare, they have not had a real-world test.
“We are moving really fast this time and people are really willing to work to get these vaccines on the ground,” says Ana Maria Henao-Restrepo, a WHO vaccine specialist who is coordinating discussions between the Ugandan government and stakeholders elsewhere in the world, including vaccine manufacturers, funders, and nongovernmental organisations.
The farthest ahead is a candidate that the pharmaceutical giant GlaxoSmithKline began to develop during the West African outbreak; GSK donated the license for it to the nonprofit Sabin Vaccine Institute in 2019. The single-dose vaccine contains the gene for the surface protein of the virus stitched into a harmless chimpanzee adenovirus (ChAd), which serves as a shuttle to deliver the payload into cells.
The U.S. government’s Biomedical Advanced Research and Development Authority in 2019 awarded Sabin a $128 million contract to develop the product, and the candidate has worked well in monkey studies and small-scale clinical trials conducted by NIAID’s Vaccine Research Center.
Henao-Restrepo says WHO organised two rounds of consultations this week with vaccine developers and others, which led to a unanimous agreement that the Sabin candidate should be first in line for a Ugandan trial. Ugandan health officials are now evaluating a draft proposal for this trial. If all goes well, Henao-Restrepo says a study could begin before the end of October.
NIAID’s Richard Koup, acting director of the vaccine research center, says it has 100 doses of the vaccine and has made them available to Uganda. Another 40,000 doses exist in bulk form that need to be put in vials. The Coalition for Epidemic Preparedness Innovations (CEPI), a nonprofit that supports R&D for vaccines, is working with Sabin to find a manufacturer who can do what’s called “fill and finish.”
Nicole Lurie, CEPI’s U.S. director, says the current outbreak once again shows how difficult it is to manufacture and deploy experimental vaccines that might help stop an outbreak.
“This is a great case example of all of the gaps that need to be plugged,” Lurie says. “It demonstrates that the world is not yet set up to be clear about who has responsibility for what when it comes to responding to a deadly outbreak. If the virus spreads beyond Uganda and a vaccine is shown to work, Lurie says, countries may once again find themselves waiting in line for it, as they did for COVID-19 shots.
“This outbreak could get really bad and it’s not clear whose responsibility it is to manufacture additional doses,” she says, “The fact that we find ourselves in this situation now is nuts.”
Ideally, she says, when outbreaks surface, governments and philanthropies would fund the manufacture of the most promising candidates to prepare for the worst.
A second candidate is not far behind. The University of Oxford has 71 doses of its experimental single-shot vaccine, which aims to protect against both the Sudan and Zaire viruses and is made with a different ChAd. The candidate, a variation of the widely used COVID-19 vaccine that Oxford brought to market with AstraZeneca, has yet to prove itself in a monkey study. Oxford has contracted with the Serum Institute of India to produce 20,000 more doses in the next few months, Henao-Restrepo says.
The European Commission in July 2020 approved a vaccine made by Johnson & Johnson that might protect against both Ebola viruses, but it requires two doses spaced over 56 days, a drawback when a virus is spreading fast. The company has 3500 doses of the vaccine. Monkey studies showed it was protective, and human trials demonstrated its safety and ability to stimulate relevant immune responses. Three other Sudan ebolavirus vaccine candidates are at earlier stages of development.
WHO’s proposed trial in Uganda, which only CEPI so far has offered to help fund, will adopt the same unusual strategy as a 2015 study in Guinea that first proved the worth of a Zaire ebolavirus vaccine. Instead of testing the vaccine in the general population, the researchers, led by Henao-Restrepo, gave it to contacts of known cases in what’s known as a ring vaccination strategy. To sidestep ethical dilemmas of withholding a potential lifesaving medicine in a dire situation, the researchers did not compare the vaccine with a placebo shot, but instead gave some participants the vaccine immediately, whereas others were in a “delayed” group.
Ebola outbreaks historically have come to an end without vaccines: Surveillance, isolating infected people, strict hygiene efforts, and personal protective equipment for health care teams can all limit spread. But the DRC has used Zaire ebolavirus vaccines half a dozen times over the past 4 years to speed the end of outbreaks.
Henao-Restrepo says vaccines also make it easier to find contacts of cases “because you’re offering something to the community,” she says. (For reasons that still aren’t clear, contacts have been unusually difficult to identify in the Uganda outbreak.) In addition, mortality tends to drop for people who receive the vaccine soon after infection, and these people are also less likely to infect others.
But Sullivan, who soon will leave NIAID to become director of the National Emerging Infectious Diseases Laboratories at Boston University, frets that the world is once again finding itself underprepared to combat an outbreak of a long recognized viral threat. “All of the pandemic preparedness we’re doing isn’t enough,” she says.