The era of large and deadly Ebola outbreaks may soon be over, thanks in part to vaccines and improvements in health-care delivery.
After lengthy Ebola virus disease outbreaks claimed thousands of lives in both West Africa in 2014–16 and the Democratic Republic of the Congo (DRC) in 2018–20, two outbreaks this year in those same areas have been managed quickly, leading to few infections and even fewer deaths.
These latest outbreaks, in the North Kivu Province of the DRC and in the Nzérékoré Prefecture in southern Guinea, are among the first since local and international health authorities approved two Ebola vaccines developed by Johnson & Johnson and Merck & Co.
Soon after the World Health Organization (WHO) declared the outbreaks in February, Johnson & Johnson and Merck pledged thousands of doses to the two countries, as well as to Guinea’s neighbor Sierra Leone. People in these countries had participated in the vaccines’ safety and efficacy trials during previous outbreaks.
The Ebola vaccines, coupled with improvements in infectious-disease care that included well-trained community workers and modernized hospitals, created the kind of early response that health-care experts watch closely, says John M. Dye, chief of the Viral Immunology Branch of the US Army Medical Research Institute of Infectious Diseases. After years of work to bring Ebola vaccines to fruition comes a critical test: Can rapidly deploying them quell a highly contagious virus?
The answer is a tentative yes, says Dye, who has been involved in the development of Ebola vaccines and treatments, including the antibody therapy ZMapp and Gilead Sciences’ remdesivir. The Ebola outbreak in the DRC ended in May. It lasted 3 months, and by its end, close to 1,900 people had been vaccinated. The 4-month outbreak in Guinea ended June 19; around 11,000 people were vaccinated. Eighteen people died during the two outbreaks. And these shorter, less deadly outbreaks aren’t just one-offs. A 6-month outbreak in a different part of the DRC ended in November with 55 deaths after approximately 40,000 people were vaccinated.
“The better prepared we are for these sporadic outbreaks, it will undoubtedly save lives and provide stability to the globe,” Dye says, adding that the early vaccination in the DRC and Guinea these past few months is promising. “I never say never, but with regards to this particular pathogen, I believe that lengthy outbreaks will be very unlikely.”
The death toll contrasts starkly with the humanitarian crisis brought on by the previous Ebola outbreaks: in the West Africa outbreak of 2014–16, which included Guinea, Liberia, and Sierra Leone, more than 11,000 people died, and in the DRC outbreak of 2018–20, which hit North Kivu and the surrounding provinces, more than 2,000 died.
The most recent outbreak in Guinea was likely seeded by that 2014–16 outbreak. According to an international team of scientists, a genetic analysis of virus isolates suggests that someone who was previously infected had harbored the virus for years and recently transmitted it, possibly through sex.
The apparent success of early vaccination is a preview of what may happen as viruses like the one driving the COVID-19 pandemic, SARS-CoV-2, wax and wane.
Michael Ryan, the WHO executive leading the agency’s COVID-19 activity, said at the beginning of the COVID-19 pandemic that the experience of large and deadly Ebola outbreaks has taught the public health world a great deal about how to combat COVID-19.
“I think what we’ve learned from the Ebola outbreaks is that you need to move quickly. You need to go after the virus. You need to stop the chains of transmission,” he said in the video.
This response could include early vaccination in places experiencing COVID-19 surges. But only if the vaccines can get to sometimes-remote corners and only if people will take them. In the DRC, despite the successes in rolling out Ebola vaccines, many people don’t think COVID-19 is a real disease, says Daniel Bausch, an infectious disease expert at the London School of Hygiene and Tropical Medicine. Bausch led the J&J vaccine trials in the DRC between 2018 and 2020. He tells C&EN that some people thought the Ebola vaccine trials conducted during the 2018–20 outbreak were COVID-19 trials in disguise, and that falsehood contributed to vaccine distrust.
“The DRC is one of the places where the hesitancy for COVID vaccine is amongst the highest,” Bausch says.
These are the hurdles of vaccine development, all amplified when a pathogen is already breathing down your neck: creating something that is safe and effective, finding a way to quickly mass-produce it, getting it to the right place at the right time, and convincing the people at the highest risk to take it.
Bausch says vaccines are an important part of stopping outbreaks but not the only part. Vaccinating everyone in sub-Saharan Africa—where the Zaire Ebolavirus, which tends to cause large outbreaks, is typically found—is impractical, he says. And starting large, expensive vaccination campaigns only when outbreaks happen is not the best approach.
“We’ve had great success,” he says, but in the long run, “how do we find the right marriage between outbreak response and health system strengthening so we don’t accept that it’s just forever the cycle of outbreak response?”
As the West Africa Ebola outbreak of 2014–16 gained traction, a few companies tried to take the normally yearslong process of developing and testing a vaccine and squash it into months. One of those companies was Merck.
In 2014, Merck licensed an Ebola vaccine from NewLink Genetics. The Public Health Agency of Canada had created the vaccine years earlier but had not tested it in people.
The Merck vaccine, now sold as Ervebo, is made from a live but hobbled virus called vesicular stomatitis virus (VSV) that has been genetically engineered to deliver the instructions for the glycoprotein of the Zaire Ebolavirus, the most common species of the virus to cause disease. The Ebola glycoprotein is found all over the surface of the long and lean filovirus, which uses it to get into cells, says Kartik Chandran, a virologist at the Albert Einstein College of Medicine.
The hobbled virus infects enough cells to trick the human protein-making machinery into sythesizing the Ebola glycoprotein, bits of which find their way to the surface of the human cell or into the bloodstream, where the immune system recognizes them as foreign and responds in part by making antibodies that can be deployed if a person is later infected with the real virus.
Merck licensed the vaccine a few weeks into Phase 1 trials, which began in October 2014 at several sites outside West Africa. After 3 months, the company was able to choose what it expected to be the best and safest dose of the vaccine, says Beth-Ann Coller, the company’s executive director of global clinical development.
Running any clinical trial comes with ethical challenges, but running one in the middle of an outbreak is an ethical minefield of a different sort, Bausch says. Few public health decisions were as fraught as whether to include a placebo arm in the West Africa vaccine trials in 2015 and 2016, he says. The West Africa outbreak of 2014–16 was the first time the virus pervaded urban areas. The death toll quickly mounted. Bausch says there were meetings after meetings to decide what to do. Scientists, public health officials, government officials, and community leaders spoke fiercely both on the side of placebo and against it. Some argued that without a group of people who didn’t get the vaccine, it would be hard to determine how well it worked. But others countered that in a place where skepticism of the outbreak-containing effort abounded, health-care workers were attacked, and customary funeral practices were helping the disease spread, there wasn’t political or ethical room for a placebo.
“Most countries said, ‘There’s no way we’re allowing you to do a placebo-controlled trial,’ ” Bausch says.
By March 2015, Merck had begun Phase 2 and 3 trials in Guinea. In these studies, everyone got the vaccine. Clinicians used a ring vaccination strategy, which had health-care workers vaccinate anyone who had come in contact with an infected person, as well as the contacts of that high-risk person. But the outbreak was waning; it became tough to enroll participants in Sierra Leone and Liberia. Still, in July 2015, the company had collected enough data to release early results from its trials in Guinea. The vaccine, Merck said, was 100% effective in preventing Ebola infection.
To develop a vaccine in such a short amount of time—9 months from Phase 1 to the data from Guinea on its effectiveness—was unheard of at the time, Coller says. “It was, I think, the first example, or at least the most recent one I’m aware of, of development moving that fast.”
COVID-19 vaccines were subsequently developed and tested within a year.
When the DRC outbreak started in 2018, Merck was able to administer the still-experimental vaccine under compassionate-use protocols, also using a ring vaccination strategy. Health-care workers inoculated about 225,000 people.
In a preliminary vaccine analysis released in April 2019, the WHO reported that the vaccine was 97% protective against disease. But the lack of a placebo arm caused tension in health-care circles, with some questioning the robustness of that number.
In the end, for regulatory purposes, the lack of placebo didn’t matter.
Charlie Kohler, a spokesperson for the Food and Drug Administration, tells C&EN in an email that “a key principle that emerged from the Ebola experience was the value of embedding research into the response,” which allowed companies to generate data while also providing necessary emergency access to vaccines.
Janssen, the pharmaceutical arm of Johnson & Johnson, conducted safety trials of its vaccine starting in 2015, mostly outside the nations affected by the 2014–16 outbreak in West Africa. There were few safety issues with the vaccine, and many of the trial participants who received the vaccine developed antibodies against Ebola that could prevent the virus from infecting cells (J. Infect. Dis., 2019 DOI: 10.1093/infdis/jiz071 and DOI:10.1093/infdis/jiz070).
As 2019 ended, Janssen resumed testing of its Ebola vaccine in the DRC, where it focused on inoculating people living in areas close to the center of the outbreak but where numbers of infections were still low. Janssen’s vaccine has two parts, given 8 weeks apart. The first is similar to the Merck vaccine, but instead of VSV, Janssen uses an adenovirus that carries the glycoprotein-making instructions. This is the same technology that has gone into developing the company’s COVID-19 vaccine. The second shot is an engineered vaccinia virus that carries genetic information for immune targets in Zaire ebolavirus, as well as immune targets of three other filoviruses that cause human disease.
Janssen maintains that the Merck and Janssen vaccines are complementary—the one-dose Merck vaccine is better suited for an outbreak setting, and the Janssen vaccine works well for prevention in nonoutbreak settings.
The EMA approved Janssen’s vaccine in July 2020, making it the first in the company’s vaccine pipeline to reach the market. The first shot is sold as Zabdeno, and the second, as Mvabea. The company has started the FDA approval process.
While the time it took to build the vaccines was different for both companies, their rapid progress through clinical trials was similar. Coller says that companies typically seek regulatory approvals sequentially from different agencies, but in the case of the Ebola vaccines, US, European, and African drug regulators worked together to discuss data and push through paperwork.
“It takes months and months, and even years to get all the way to the end of that,” Coller says of the approval process. “Instead, we were able to achieve licensure in at least two African countries within days and weeks of having the European Medicines Agency authorization and WHO prequalification. And I think that was a wonderful model.”
One reason the clinical timeline could be condensed was that companies threw out the old playbook of how vaccines are developed, Dye says. Instead of doing testing and manufacturing sequentially, for example, Merck and Janssen started churning out doses before all the trial results were even tabulated.
“Before, you would never start manufacturing a vaccine until you had it all the way through Phase 3,” Dye says. “You wouldn’t want to spend the money to do that.”
Public health experts stress that it takes more than vaccines to quell Ebola outbreaks—and that infections this year were quickly stamped out because other key pieces fell into place. Treatments are available now, Bausch says. Health-care workers are more experienced. Some hospitals are better equipped.
The situation during this latest outbreak in the DRC is quite different than in 2018, says Liévin Kalyongo Shamamba, a project coordinator for Doctors without Borders. That earlier outbreak was also centered in urban areas like Goma, as well as along busy transit routes. But containing the virus was harder in 2018. And Shamamba says people didn’t believe the virus existed. They had never heard of Ebola before and had never known anyone who had contracted it. The central government of the DRC was less organized to respond to the virus. Training health-care workers took time.
When this year’s outbreak began, he says, people at all levels, whether government, local workers, or people at risk, took the virus much more seriously.
The challenges of running clinical trials in the DRC were part of the larger challenges of containing a virus during a widespread outbreak, says Bausch, who was in Goma during the 2018–20 event. Riots, sometimes vaccine related and sometimes directed at the government, forced workers to shut down trial sites. COVID-19, which overlapped with the past three Ebola outbreaks in the DRC, stopped the J&J vaccine trial for several months during 2020.
But skepticism—about the efforts to quell the deadly outbreak and vaccine testing in people at the highest risk of infection—ran beyond whether people in the DRC believed the Ebola virus was real. Many people had lost children to vastly more common diseases, like malaria. They watched money roll in to treat a virus they’d never heard of, and it rankled, making some less likely to participate in trials.
“Those are the settings that we’re dealing with in these emerging diseases, often because they are new to people, and because they have lots of background stuff that’s been challenging them health-wise and politically for many years that we’re not addressing,” Bausch says.
Despite all the challenges, Bausch says, the trials gave good data. Bausch and others had a hunch, even during the worst outbreaks, that the vaccines would likely work. Vaccine hesitancy, political mistrust—these are all important and entrenched issues that need to be dealt with. But in the meantime, he says, the fact that there is even a vaccine at all, that there are treatments for Ebola, and that people don’t die as readily as they did before is remarkable.
“These are incredible advances, first of all, that we should recognize that sometimes get lost when we view all the challenges that we still have,” Bausch says.
This story was updated on June 21, 2021, to indicate the end of the Ebola outbreak in Guinea on June 19, 2021.