When Ebola Returns, Will the World be Ready?
A year ago there were dire predictions as the worst Ebola outbreak in history spread through west Africa. There was no Ebola vaccine or approved treatments available. Should another outbreak occur, of Ebola or any other deadly pathogen, hopefully the story will unfold differently.
By Michael Dumiak
The world’s worst outbreak of Ebola seems to have abated.
Sierra Leone was declared free of Ebola on Nov. 7, and as of Nov. 23, Guinea had no more Ebola patients and had started a six-week evaluation at the end of which it could also be deemed Ebola-free. Even so, despite being declared Ebola-free twice before (once in May and then again in September), three new cases of the disease were reported last month in Liberia.
After killing more than 11,000 people, the focus is shifting from how to extinguish the Ebola outbreak to learning from it. Close attention is still being paid to the virus in labs around the world and in the offices of the World Health Organization (WHO). Much of this attention is focused either on improving the response to the next epidemic or developing ways to prevent another outbreak of this scale from ever occurring in the first place.
There are now at least six Ebola vaccine candidates in clinical trials (see table, below). While data collected so far look promising, the environment in which these candidates are being studied and developed has changed quite a bit from a year ago when the epidemic in west Africa was raging. Vaccine developers, public agencies, and governments formed partnerships to rapidly accelerate the clinical development of these candidates. The entire searing experience of this outbreak is providing landmark and long-term lessons in how to respond to emerging pathogens and public health crises, how to quicken vaccine research and development, and even how vaccine vectors and formulations can inform efforts against endemic diseases like HIV, malaria, and tuberculosis.
Stopping a frightening bug
The Ebola virus, part of the Filoviridae family, is a single-stranded RNA virus that was first identified near the Ebola River valley in the Democratic Republic of Congo, then Zaire, in 1976. It causes a highly lethal hemorrhagic fever syndrome in humans and nonhuman primates, with mortality rates ranging from 50 percent to 90 percent in the half-dozen outbreaks that have occurred in central and west Africa over the last three decades. The virus infects many different kinds of cells, including dendritic cells, endothelial cells, hepatocytes, epithelial cells, monocytes, and macrophages. It then moves through the lymph system into the liver, spleen, and adrenal glands, eventually leading to organ failure. All this occurs in just two to three weeks. After this time, complications of Ebola infection will either kill you, or because of an effective immune response, intensive medical treatment, or both, it won’t.
Ebola is highly infectious: a single drop of blood can contain millions of viral copies. The virus gets into humans through mucous membranes, such as tear ducts or nasal passages, or breaks in the skin. The number of hazmat-suited healthcare workers who contracted the virus during the last outbreak shows it takes very little for it to make effective contact. But the virus is not airborne—it needs direct, fluid-to-fluid contact to spread. And because the virus runs its course in humans so quickly, symptomatic Ebola sufferers are less likely to spread the virus to large numbers of people.
What makes Ebola so scary is its high case fatality rate, says Vincent Racaniello, a Columbia University microbiologist, blogger, and host of the This Week in Virology podcast. Proper clinical care can have a real impact on reducing mortality. Building clinics, employing epidemiological tracing of Ebola patients in viral hotspots, vigilant hygiene, stringent burial practices, effective quarantine, and heroic medical treatment are the factors which brought this latest outbreak from the nightmarish forecasts of a year ago to where it is now. In the future, though, a preventive vaccine, coupled with effective treatments, may also be available.
Of the at least a half-dozen preventive vaccine candidates in different stages of clinical trials, the two candidates furthest along in development are the products of recently formed partnerships among public research institutions and large private pharmaceutical manufacturers.
GlaxoSmithKline (GSK), the UK-headquartered pharmaceutical firm, is pursuing a candidate in collaboration with the US National Institute of Allergy and Infectious Diseases (NIAID) called ChAd3-ZEBOV. ChAd3-ZEBOV is a one-dose vaccine that uses a non-replicating, live-attenuated chimpanzee adenovirus serotype 3 (ChAd3) vector to express part of the Ebola glycoprotein, the major surface protein on the virus. This protein induces antibody and cellular immune responses, both of which are thought to be important for protection. Phase I safety trials showed no safety concerns and indicated that Ebola glycoprotein-specific antibodies were induced in all the volunteers.GSK is currently conducting a Phase II trial involving 3,000 adults and 600 children in western Africa, but not in the three countries most affected by the epidemic. ChAd3-ZEBOV was set to be part of a big Phase III trial in Liberia, potentially enrolling 27,000 volunteers, but plans were halted earlier this year as the outbreak ebbed.
Merck, meanwhile, has progressed rapidly with another candidate, rVSV-EBOV-GP, first developed by the Public Health Agency of Canada. The agency then licensed the vaccine for US$205,000 to NewLink Genetics, an oncology and immunology biotech company in Iowa. As the wave of Ebola cases crested in November 2014, Merck bought the license from NewLink for $30 million, with an additional $20 million and potential royalties to come if the candidate passed efficacy trials and went into production (no royalties would come from purchases by low-income nations, but stockpiles for militaries and civilian populations of wealthier countries would appear to be included). The US Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response contributed $30 million to a wholly-owned subsidiary of NewLink, BioProtection Systems Corp., to underwrite initial clinical trials. The contract has options to extend the agreement 10 months beyond the original 14 months with another $41 million in funding. The rVSV-EBOV-GP candidate utilizes an attenuated, replication-competent Vesicular Stomatitis Virus vector that, like ChAd3, is genetically engineered to express a bit of the Ebola glycoprotein in order to provoke an immune response. This vaccine is currently in Phase II and III clinical trials in Liberia, Guinea, and Sierra Leone.
The way the Ebola crisis unfolded pressed vaccine development efforts to breakneck speeds, making it seem like these new vaccines appeared almost overnight. In fact, most of them had years of research behind them. Both ChAd3-ZEBOV and rVSV-EBOV-GP have their origins in turn-of-the-century biodefense research. Before the unprecedented 2014 Ebola outbreak gained traction, the National Institutes of Health (NIH) was already planning safety studies of the ChAd3 candidate to begin in March 2015.
Within a year the world has gone from having no volunteers in any clinical trial of an Ebola vaccine to more than 20 clinical trials on five continents ranging from Phase I through to efficacy, says Vasee Moorthy, team leader for vaccine development at the WHO. “It’s all very novel.”
The scale of the 2014 outbreak created an unprecedented sense of urgency. “There was a global focus on moving development very quickly,” says Rip Ballou, GSK’s vice president of clinical research and translational science. Vaccine manufacturers performed feats under extraordinary time pressure. GSK compressed the process of determining dosage from what normally would be a three-to-five-year timeframe into a matter of months.
This was possible because they did many studies simultaneously instead of sequentially. GSK started its original Phase I study, then two weeks later started another study in the UK that expanded the dose range, and then two weeks after that started a study in Mali with a parallel study in Lausanne, Switzerland, to collect additional safety data.
Ethics committees, which would normally take a week or two to evaluate a trial structure, were asked for responses in days if not overnight. Protocols for drug and vaccine testing are incredibly rigorous, detailed, and complex. Negotiating how to adapt them in order to respond to a crisis situation required flexibility on the part of vaccine manufacturers and regulators, Ballou says. It took a lot of good will between all parties. “That allows things to happen that normally do not at that pace.”
But even with this incredible speed, some researchers were left about three-quarters of the way to the finish line before the number of Ebola cases dwindled, affecting their ability to conduct efficacy trials. For ChAd3-ZEBOV, dosage, safety, and tolerance data are in, but actual efficacy data are not. Ballou says GSK will supplement the data it has collected already with studies in nonhuman primates. The company is still about six or seven months away from submitting data to regulators in a bid to license its vaccine and is in ongoing discussions with US and European regulators about how best to do this. “We don’t think they’ve taken a firm position on what data will be required. We would hope there is not a complete rethink about this,” he says. Ballou is cheered in part because the GSK candidate has a similar method of action to Merck’s, and for that candidate, efficacy data is available.
Merck’s experimental rVSV-EBOV-GP vaccine candidate was tested in a trial involving 7,651 individuals in Guinea that was conducted earlier this year. This trial, known as the ‘ring trial,’ used the same kind of trial design used in the fight against smallpox. In this instance, ‘rings’ of close contacts to Ebola-infected individuals are vaccinated. Half the contacts in the rings are vaccinated immediately after a case is diagnosed; as a control, the other half is vaccinated three weeks later. The study was organized by the WHO. Both GSK and Merck got invitations to test their candidates, but GSK couldn’t provide enough doses of its vaccine by the trial’s start date.
An interim analysis of the trial was published in July (Lancet 386, 857, 2015). Swati Gupta, Merck’s executive director for Public Health and Scientific Affairs, says the vaccine appears safe and vaccinated volunteers showed immune responses to Ebola at three months and six months. Researchers are continuing to follow the volunteers. The study shows that in villages where Ebola outbreaks occurred, the vaccinated volunteers remained Ebola-free from a week to 10 days after injection. This translates to 100 percent protection in the interim results. “We’re pretty excited,” Gupta says. “We’re pursuing licensure as aggressively as we possibly can.”
|Learning from Ebola|
The World Health Organization engaged the Harvard Global Health Institute and the London School of Hygiene & Tropical Medicine to report on and recommend public health reforms in the wake of the 2014 Ebola epidemic. Their report, Will Ebola Change the Game? (Lancet 386, 857, 2015) concludes that the latest outbreak exposed systemic weaknesses in the international institutions responsible for protecting the public. The report outlines 10 recommendations it considers are “warranted and feasible.”
Partnering for progress
The rapid and dramatic progress in research and development of Ebola vaccine candidates was a direct result of public-private partnerships, some of which predate the Ebola outbreak, and some that were forged during the crisis. This did not happen in a particularly systematic way. GSK, for example, has its Ebola candidate now because in 2013 it bought Okairos, a Swiss vaccines firm that had developed interesting (and exclusive) technologies for stimulating CD8+ T cells. Okairos also had been collaborating with NIAID on the Ebola work; GSK inherited it.
Intense focus, pressure, and funding put wind in the sails of these partnerships. During late summer 2014 the WHO convened the scientific and regulatory community, manufacturers, and governments. Funding followed. For the ZEBOV Phase I trials, for example, the Wellcome Trust underwrote one of the arms and the NIH managed it. The fact that Ebola eventually landed in London and the US might also have played a factor in putting a charge into the response. “It’s in the domestic interest of countries to invest as an insurance policy for their own populations,” says Moorthy. “Because if there’s a problem ‘over there,’ there’s probably going to be a problem ‘over here’ soon,” he says.
One reason there is no vaccine currently on the market for Ebola or many other emerging pathogens is because they are not commercially viable. Racaniello suggests one future option would be developing vaccines and antivirals for emerging pathogens to the point of preclinical development or perhaps Phase I safety testing. “And then they’ll be stored until an outbreak happens,” he says, which would position them for fast-track studies.
But some researchers would like to go much further than this, calling for new ways to stimulate investment in vaccines that do not have a commercial incentive. Stanley Plotkin, an executive advisor to Sanofi Pasteur and researcher who helped discover the rubella vaccine, joined Princeton University molecular biology and infectious disease expert Adel Mahmoud and Jeremy Farrar, director of the UK’s Wellcome Trust, in calling for a $2 billion global vaccine development fund to fill the gaps from market inefficiency and public-sector inability or unwillingness to fund vaccine development for infectious diseases (NEJM 373, 297, 2015).
Encouraging and formalizing long-term public-private partnerships could also be a model for speeding up drug and vaccine development. “The Ebola effort had a lot of really positive features,” says Mark Feinberg, Merck Vaccines’ former Chief Public Health and Science Officer and the newly appointed chief executive of the International AIDS Vaccine Initiative. Feinberg helped to guide the public-private partnership developing rVSV-EBOV-GP while he was with Merck. “It also highlights how we need to be more proactive and more strategic.”
For specific diseases it would make sense to establish foundational data and stand ready to evaluate efficacy should an outbreak occur. But there are known pathogens for which we don’t have vaccines or therapeutics that need to be addressed before a pandemic occurs, Feinberg says. “Deciding our priorities here will be important. Developing platform technologies which allow us to be nimble and expeditious in bringing forward vaccines against newly-emerging pathogens is a way in which we could make progress,” he says. Another step that’s necessary is figuring out how to realistically engage the private sector in a way that makes most use of their expertise, enabling technologies, and intellectual resources. “It should do so in a way that works for them, in a way that doesn’t show itself to be a major opportunity cost, or in a way that can’t be accommodated amidst their work to develop other kinds of therapies.”
The public sector also needs to get more engaged. “It’s all going to depend on public-sector investment and the understanding that it’s in the interest of those with resources to invest ahead of time,” Moorthy says. “The bottom line is that it will have to be public-sector funds mobilized in order to incentivize researchers and developers and manufacturers.”
Ballou says however future scenarios unfold, there must be a better way than what’s just happened. “Our experience with this pandemic is that this is no way to respond. The idea that we drop everything we’re doing, shifting resources from critical internal ongoing programs to respond to a global need—we do that because it is the right thing to do. But it is a very disruptive activity that puts the whole business at risk in the long run,” he says. “We think there needs to be a fundamentally different way of doing this. I think governments need to recognize that investment is required to protect their populations, and that this cannot be done strictly and solely with multinational vaccine developers of which there are only a handful that can actually address this kind of work.”
Feinberg takes a number of lessons from the Ebola vaccine development experience. “It demonstrated pretty vividly the benefits of current models of collaboration and how people can work together in new ways,” he says. “But it’s just the beginning in thinking of how we can do far better in that regard. Generalizing those models to meet established threats—such as HIV—will be all to the good.”
|Tracking Ebola Funding|
The first-ever estimate of global investment in Ebola research and development indicates a total of US$165 mil-lion was made available in 2014 by a combination of public, private, and philanthropic funders, according to the new G-FINDER report published by the Sydney-based think tank Policy Cures. Almost 90% of this funding ($146 million) went toward product development, either for vaccines aimed at preventing infection with the deadly virus or treatments, with the rest going toward basic research and diagnostics. Investment in Ebola vac-cine research and development ($69 million total) was split equally between industry investors and North American and European public sector agencies.
At the launch of the latest G-FINDER report in Washington DC on 3 December, lead author Nick Chapman of Policy Cures noted that these investments took place largely in the latter half of 2014 as mobilization of the Ebola response accelerated. Chapman also cited a rough estimate of $10 million for Ebola funding in 2013.
Ebola is the newest addition to the annual G-FINDER report, which summarizes funding data for 35 diseases that primarily impact low- and middle-income countries. — Tom Harmon, senior policy analyst at IAVI
Certainly one of the fringe benefits of Ebola vaccine development is that it is helping to advance the development of viral vector platforms. For the first time the VSV and ChAd vectors are getting widespread testing in humans. VSV is a vector of interest to HIV researchers. It’s also potentially interesting for malaria, TB, and several other pathogens. As Moorthy points out, only one recombinant viral vector vaccine that he knows of is already licensed, that being Sanofi’s yellow fever platform used for its vaccine against Japanese Encephalitis. “The increasing maturity of viral vectors in vaccine development is manifest in Ebola vaccines.”
Ebola will also have a lasting impact on vaccine development and distribution practices. The latest outbreak led to the introduction of tools such as Intellectual Ventures’ ArcTec chamber, which can keep vaccine at minus 80 degrees centigrade for up to five days. New diagnostics, essential for distinguishing Ebola from other causes of hemorrhagic fever, also made it into the field.
Moorthy says the WHO is already drafting plans for vaccination scenarios. They want two classes of vaccine: one for use in ring vaccinations in the context of an ongoing outbreak, another that would confer durable protection for specific target groups, such as frontline health workers, or even as long-term prophylaxis for the general population.
The US Centers for Disease Control and Prevention’s (CDC) deputy director, Anne Schuchat, thinks there’s a path to licensure for the Ebola vaccines given all the trial data gathered during the outbreak as well as data from animal studies. The CDC set up permanent offices in the three outbreak countries. “We need to develop public health capacity with countries and global partners,” she says. “Detecting, responding to, and preventing emerging infections is vital to protecting the rest of the world.”
Michael Dumiak reports on global science, technology, and public health and is based in Berlin.