In August 2014, the World Health Organization (WHO) declared the Ebola outbreak then raging in West Africa a “public health emergency of international concern,” a formal designation by the WHO’s Emergency Committee that reflects the fact that the disease was spreading internationally and posed a risk to other countries yet unaffected. By the time the public health emergency was terminated in March 2016, the outbreak had turned into an epidemic — it lasted over two years, nearly 26,700 people had been infected, and over 11,300 had died. This is the first Ebola outbreak to occur in West Africa and to reach epidemic proportions, but the story of the disease starts 40 years ago, in 1976, when the first known outbreaks were described.
Ebola, a viral hemorrhagic fever, is a highly infectious disease, spread by direct or indirect contact with bodily fluids of an infected person. Early signs include fever, sore throat, and muscular pain, followed by vomiting, diarrhea, a rash, and decreased liver and kidney function. In later stages, Ebola can cause internal and external bleeding. The death rate for Ebola is between 25 and 90 percent of those infected, depending on the outbreak, but the average is approximately 50 percent, usually within sixteen days after symptoms first appear.
The death rate for Ebola is between 25 and 90 percent of those infected, depending on the outbreak, but the average is approximately 50 percent, usually within sixteen days after symptoms first appear.
The symptoms of Ebola can be treated and attempts can be made to stop the disease from spreading, but there is no specific treatment or vaccine. When the extent of this recent outbreak became apparent, the search for treatment and vaccines ramped up quickly. Luckily, scientists had already been working for years to find a vaccine for Ebola.
“Some people have the view that if there isn’t a market for something, research can’t proceed,” said Nancy Sullivan, PhD, Chief of the Biodefense Research Section, Vaccine Research Center at the National Institutes of Health (NIH). “The prevailing narrative is that Ebola vaccine research had been abandoned or not funded until the outbreak in 2013, but my work and other work on vaccines for hemorrhagic fevers have been continuously funded for many years. Because of the way vaccine development research works, you can’t wait until you need a vaccine to do research. It’s critical to invest in basic research because you don’t know when the vaccine will be important.”
While it might seem that the vaccines tested in the recent outbreak appeared suddenly, they were based on many years of research. Notably, the first Ebola vaccine breakthrough article was published by Sullivan and her colleagues in 2000, and, at the time, according to Sullivan, no one outside the scientific community was interested. The former chief of vaccines for Merck was reported as saying “there’s no market for this,” while the Wall Street Journal noted that “Ebola kills its victims so swiftly that outbreaks burn themselves out, never causing more than a few hundred deaths at a time.” Even a spokesman for the Bill and Melinda Gates Foundation said that an Ebola vaccine fell low on their priority list because it strikes only a small number of people.
“While people outside our research community often think that Ebola vaccine work hasn’t been funded, those who do know that we have continuously received funding for our work don’t necessarily understand why,” says Sullivan. “Scientists are sometimes ridiculed because the work is esoteric and doesn’t make sense to people. But our studies from a decade ago helped lead to the vaccines that are being tested now. Our goal is to develop treatments and vaccines that can be transferred to biopharma for more advanced development work and for them to handle issues beyond the scientific, such as potential political issues involved in testing a vaccine in another country.”
That paper, published in 2000, focused on the first successful monkey vaccine for Ebola, which came after developing a vaccine that worked in mice.
While people outside our research community often think that Ebola vaccine work hasn’t been funded, those who do know that we have continuously received funding for our work don’t necessarily understand why.
“Many of our vaccines for monkeys failed,” said Sullivan. “We think of vaccines as being the tool we have for viral infections, but they were failing. Our major question, which we answered in the paper, was what was needed to get protection against Ebola, given the way the virus replicates, which allows it to attack all organs at once.”
From there, it was still not a straight line to a vaccine that worked for humans. In 2003, Sullivan’s team developed a vaccine that worked well in humans but did not work in everyone. Tweaks were necessary to address these issues and create a vaccine that worked for all people. Finally, in 2014, human clinical trials of this Ebola vaccine began, led by GlaxoSmithKline (GSK).
Along with the GSK vaccine—which is known as cAd3-EBO and is being tested in Guinea— two other Ebola vaccines are in human trials. One, from Johnson & Johnson and Bavarian Nordic and developed with help from the NIH, is a two-dose vaccine known as Ad26.ZEBOV/ MVA-BN that was shown to be safe in Phase 1 trials conducted on healthy volunteers in the United Kingdom. The other, known as rVSV-ZEBOV, is from Merck and was developed by the Public Health Agency of Canada. This vaccine is currently in Phase 3 testing in Guinea.
While the basic process for developing a vaccine happens over decades, processes around testing for Ebola vaccines have been sped up during the outbreak. Because of the urgent need for vaccines to help stem the outbreak, the U.S. Food and Drug Administration (FDA) worked to align their activities across divisions so that reviews could happen in days, rather than months. For example, in the case of Ebola, they accelerated the launch of Phase 1 trials, then helped align international groups to generate safety data more rapidly than pharmaceutical companies could do themselves. This also led to more samples to help choose the dose for efficacy trials.
However, now that the outbreak has been stemmed (although there are still new cases of Ebola), it has become too difficult to do efficacy trials in the affected population. GSK, for example, planned to enroll over 27,000 volunteers for their Phase 3 trial, but had to stop enrolling at 1,500 volunteers for lack of available patients. Merck, however, has continued to hold efficacy trials by using ring vaccination, a method in which they vaccinate the contacts of new cases. While this study lacks a control group, interim results suggest that the vaccine is 100 percent effective; Merck is planning to submit it for regulatory approval in 2017.
These differing methods, according to Sullivan, are part of a central debate in vaccine development. On one side are those who say that if adequate efficacy data or safety data are lacking, then a control group must be included in the study no matter what. This will help ensure that the vaccine does what it is supposed to do safely. However, there is also the view that if there’s a large outbreak, such as in the case of Ebola, there is a moral obligation to give a promising vaccine to everyone.
In light of these considerations, a WHO committee in 2014 “concluded unanimously that it would be acceptable on both ethical and evidential grounds to use as potential treatments or for prevention unregistered interventions that have shown promising results in the laboratory and in animal models but have not yet been evaluated for safety and efficacy in humans, provided that certain conditions are met.” These conditions include transparency, fair distribution, informed consent, freedom of choice, respect for the person and preservation of dignity, and basing the use of interventions on the best possible assessment of risk and benefit. The interventions must be evaluated using the best possible clinical studies the circumstances allow for and researchers have an obligation to collect and share all scientifically relevant data generated. However, despite the unanimous decision and these requirements, the WHO ruling is controversial among both scientists and bioethicists.
According to Sullivan, the lessons learned from the development of an Ebola vaccine are now being applied to the development of a Zika vaccine. These valuable lessons about the mechanics of the vaccine development itself, along with the development of the protocols and processes necessary to test potential vaccines and get them to those affected in an epidemic, mean that research into the Zika vaccine is happening much more quickly than it might have had the world not recently seen a recent epidemic.
The lessons learned from the development of an Ebola vaccine are now being applied to the development of a Zika vaccine.
Researchers at Harvard Medical School, Inovio, and the NIH have all recently announced the development of DNA vaccines, a new type of vaccine that contains only a small piece of a virus’s genetic code, for Zika. A small human safety trial for Inovio’s vaccine will start in summer 2016. While the method of vaccination and the disease may be different, the sense of urgency with which research is being conducted and the speed with which vaccines are being tested shows the lessons of Ebola in action.
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