Researchers in Canada, Britain, the US and Mali are testing drugs they hope will stop the humanitarian disaster unfolding in west Africa – and prevent Ebola becoming as prolific as HIV
In 1959 the French microbiologist René Dubos gazed into his crystal ball and found reasons to be concerned. In his lifetime Dubos had witnessed the steady decline of diseases such as diphtheria, tuberculosis and polio, but rather than giving him confidence these medical successes filled him with foreboding. Though vaccines and therapeutic drugs had neutralised many of the threats of the past, he warned that humans could not escape the microbes that transmitted infectious diseases, because they were part of the environment and our ecology.
Complete freedom from infectious disease was a mirage, he warned. “At some unpredictable time and in some unforeseeable manner nature will strike back.”
The Ebola outbreak is arguably just such a riposte, shattering western dreams of medical utopias. While the reservoir (the long-term host) of the virus has yet to be identified (fruit bats and apes are the leading contenders) there is little doubt that Ebola is the greatest threat to the world’s health and security since HIV/Aids or that the fault lies with man and his insatiable demand for the world’s natural resources – a demand that puts an intolerable strain on ecosystems and the parasites that inhabit them.
No one knows for certain where or when the decisive “spill- over” event occurred – one theory is that “patient zero” was a two-year-old boy from Guéckédou in south-eastern Guinea who contracted Ebola from contaminated bush meat in December; another, is that Ebola is continuously emerging and that there were several simultaneous spill-overs. Whatever the case, however, the situation in west Africa is dire and getting worse by the hour – a humanitarian disaster, according to Oxfam – which is why infectious-disease experts are increasingly looking to a vaccine as our next best hope.
“A vaccine is critical because the truth is we just don’t know what is going to happen,” says Jeremy Farrar, the director of the Wellcome Trust and a veteran of several epidemic scares, including the 2003 Sars outbreak and the wave of bird flu that swept south-east Asia in 2005. “I’m very much hoping that we will be able to bring this epidemic under control using classic public health containment measures, but if those measures fail then we need an alternative strategy.”
That strategy is now the responsibility of researchers at laboratories in Britain, Canada, the US and Mali, where scientists are in a race to develop vaccines that could be shipped to west Africa as early as December, with more doses to follow next year if trials demonstrate that they are safe and effective. The frontrunner is a vaccine known as ChAd3, developed jointly by the biowarfare arm of the US National Institute of Allergy and Infectious Diseases (NIAID) and Okairos, a Swiss-Italian biotechnology company that is now part of the pharmaceutical firm GlaxoSmithKline. Trials of different versions of the ChAd3 vaccine are under way at the Jenner Institute in Oxford, the National Institutes of Health (NIH) clinical centre in Bethesda, Maryland, and the centre for vaccine development in Mali. About 140 volunteers are being enrolled across the three trial sites between now and the end of the year.
In addition, a fortnight ago the Canadian government announced that it and the Walter Reed Army Institute of Research in the US would trial yet another experimental vaccine, known as VSV-EBOV. Such is the concern about Ebola, however, that even before that trial began Canada announced that it was donating 800 vials of its vaccine to the World Health Organisation in Geneva (this is a vaccine which, so far, has only been tested on non-human primates). Last week Johnson & Johnson also announced it was investing $200m in developing a two-step Ebola vaccine together with Denmark-based biotechnology company Bavarian Nordic. Like GSK’s vaccine, the vaccine has performed well in animal trials. The difference is it involves taking two shots, the first to prime the immune system and the second to boost it. J&J is planning to begin human trials in January and says it could have 250,000 doses available by May. Separately, the WHO says it hopes to make a serum vaccine using antibodies from the blood of Ebola survivors available in Liberia within two weeks.
Meanwhile, China’s Academy of Military Medical Sciences has donated several thousand doses of an experimental drug, JK-05, for emergency use by Chinese aid workers in west Africa, while Peter Horby, a tropical disease specialist from Oxford, is in the process of testing several other promising drug candidates, including ZMapp, the drug used to successfully treat two American missionaries and the British nurse Will Pooley, at clinics in Liberia operated by Médecins Sans Frontières (MSF).
Whether these efforts will bear fruit quickly enough to halt the tide of human infections depends on two factors: how quickly the world can ramp up its response to the epidemic and what the virus decides to do next. While the first is in our hands, the second is not. Ebola, like all viruses, is constantly mutating and could theoretically become even more virulent or, conversely, evolve so as to become less virulent and more widely infective. It is this second scenario that keeps disease experts awake at night.
“This virus is now in thousands of individuals and every time that happens it gives a virus the ability to change and adapt to human beings,” says Farrar. “Then you don’t know where the virus is going to go but you run the risk that it will become a natural endemic human infection.”
In other words, Ebola could become more like HIV, a virus that, because it does not provoke obvious symptoms, at least in the early stages of infection, to date has succeeded in infecting 75 million people worldwide.
The problem is that what began as a highly containable outbreak in Guinea last December has now changed into a conflagration that is threatening to spill over from Liberia and Sierra Leone, the two worst affected countries, to Ivory Coast and Guinea-Bissau, with Mali confirming its first case last week (though, thankfully, both Senegal and Nigeria recently declared they were free of infection). Meanwhile, as the isolation of in New York last week of a MSF doctor who had recently returned from Guinea shows, there is an ongoing risk of health workers introducing Ebola to countries outside Africa.
And the longer Ebola is allowed to burn in Africa, the greater the chances that it will set off bush fires in other parts of the world. It couldn’t happen here, we are told, because our health systems are too robust. But as the World Health Organisation charts the epidemic’s relentless upward curve (10,000 cases a week by the end of October is the current prediction; cumulatively, perhaps as many as 1.4m cases by January) and stories emerge of elementary errors by hospitals and health authorities that should know better, many experts are beginning to worry that the worst could happen.
In many ways, Ebola is no different from any other infectious disease, such as influenza, that originally began life in animals. The difference is that whereas influenza is now well-established in human populations, meaning that most people will have some immunity to it, Ebola outbreaks are relatively rare.
The first documented outbreak occurred in the Yambuku district of Zaire (now the Democratic Republic of Congo) in the summer of 1976. It was there that Peter Piot, currently director of the London School of Hygiene and Tropical Medicine but then a young infectious disease expert, first encountered the virus and together with colleagues decided to name it after a river that flowed through the district. That same year at around the same time there was another outbreak in Sudan of a closely related strain, dubbed Sudan Ebolavirus. In both cases the spread of infection was amplified by contaminated needles and syringes and many medical personnel were infected.
Since then three further strains have been identified: Reston virus, Taï Forest virus (formerly known as Côte d’Ivoire Ebolavirus) and Bundibugyo virus. However, the Zaire and Sudan strains are the two commonest cause of human infections, with the Zaire strain having the highest lethality (up to 90% in some outbreaks). Curiously, Reston is the only Ebola virus not currently known to be pathogenic in humans, although it is highly lethal to non-human primates. The reasons why it has not caused disease among humans are not yet understood.
Ebola is also closely related to Marburg, another filovirus (the family of “filament” viruses) that was first identified in 1967 when it infected laboratory workers in Germany and Yugoslavia handling imported primates from Uganda. Like Ebola, Marburg is extremely virulent, causing a haemorrhagic fever that frequently proves deadly. It is for this reason that both Ebola and Marburg have attracted attention as possible biowarfare agents and that popular writers such as Richard Preston, author of the bestselling nonfiction thriller The Hot Zone, have been drawn to the subject, describing the viruses in lurid and often exaggerated terms.
One reason for the fear surrounding Ebola is that no one knows where the virus goes between outbreaks. Primates have long been known to harbour Marburg. Both it and the Ebola virus have also been found in three species of fruit bat in and around Gabon. As bats constitute a quarter of all the mammals on the planet, there is a good chance they are the main reservoir of the virus and that the consumption of bats, or chimps infected by bats, could be the main route towards human infections, but to date no one has been able to prove it.
The good news is that humans seem to represent an end point for the virus, with evidence of only “stuttering” chains of transmission during outbreaks and no evidence that humans can reintroduce the virus back into another animal (however, there is evidence that fruit bats may have introduced the Reston strain of the virus into Asian pig farms). The bad news is that Ebola has multiple strategies for evading our immune system.
Dr Erica Ollmann Saphire understands Ebola as well as any scientist alive. A structural biologist at the Scripps Research Institute in La Jolla, California, Saphire has been working with laboratories around the world to map the structure of the Ebola virus in an effort to pinpoint its weak spots and identify antibody targets for drugs and vaccines.
In popular discourses Ebola, which can provoke internal haemorrhaging and, in some cases, bloody effusions, has been dubbed the “Hammer horror virus” and compared to the creature in Alien, but according to Saphire the metaphor that best describes Ebola at a molecular level is that of a “Transformer”.
Like the children’s toy that can be unfolded and refolded to turn it from a truck to a robot and back again, Ebola is able to change shape seemingly at will. According to Saphire, this facility, which is controlled by a single protein known as VP40, defies a central dogma of molecular biology: namely, that gene sequence dictates function. Although Ebola has seven genes, by rearranging its protein structure the virus is able to carry out far more than seven functions.
“We don’t typically expect molecules in biology to do that,” says Saphire. “We expect proteins to have one particular form – just the robot. But Ebola can unfold from a robot to a truck. It can walk and talk and shoot, and other times it can carry a lot of cargo and drive at high speeds along the highway.”
This has important implications for drug design because it means that you may need to devise therapies that are effective against both the robot and truck forms of Ebola in order to be sure of neutralising the virus.
That is not the end of Ebola’s tricks, however. Ebola is also a master at evading our immune system. It does this by employing two other proteins, known as VP35 and VP24. The first enables the long filament-like strands of virus to form a spiral shape that Saphire likens to an invisibility cloak. Meanwhile, VP24 blocks the release of interferon, the protein that signals the presence of a foreign pathogen and tells the body to ramp up its immune response.
Another factor in Ebola’s favour is that half its mass is carbohydrate, the compound that provides energy for human cells, so again our immune system doesn’t register the virus as foreign. In addition, the glycoproteins the virus uses to bind to receptor sites on host cells are arranged along the main trunk of the virus, where they lie concealed beneath leafy side branches. It is only when the virus is sucked into the interior of the cell that it severs these branches by hijacking enzymes within the cell and reveals its true nature. But by then it is too late. Now the virus can use the cell’s machinery to produce millions of copies of itself.
From then on it’s a race between the virus and our immune system. Unlike HIV, which only infects two types of immune cells, Ebola first infects the leucocytes, the white cells that patrol the blood and lymph system. Then it attacks nearly every other type of cell. This process typically takes between two and 21 days, with death occurring, on average, six to 16 days after the onset of the illness.
The first symptoms are fever, headache and fatigue. But as the virus begins to overwhelm more cells, the cells burst, prompting a chemical release that leads to inflammation and toxic shock. As the viral load increases, patients suffer stomach pains, bloody diarrhoea, severe sore throats, jaundice and vomiting. Eventually the viral load becomes too great, prompting the immune system to go into overdrive and launch an all-out attack known as a cytokine storm, which causes even more damage. The final stage comes when cells infected with the virus attach themselves to the inside of vessels and arteries, weakening them to the point where they begin to leak fluids, leading to a dramatic fall in blood pressure and multiple organ shutdown. In half of cases, the result is uncontrollable haemorrhaging. In the most extreme cases of all these fluids may seep from the nose and mouth and it may appear as if victims are weeping “tears of blood”.
For those who have witnessed someone in the death throes of Ebola at close quarters it is an unforgettable sight. One moment, victims are dazed and expressionless. The next they are doubled up in pain and bringing up haemorrhagic discharges from their stomachs – a substance known as “black vomit”. The nearest historical equivalent are the 18th-century outbreaks of yellow fever, a disease that also produces a dark viscous vomit, or the cholera epidemics of the 19th century. Then, as in Freetown and Monrovia today, people collapsed on the streets of London, Liverpool and New York, expiring in pools of fetid fluids as they were shunned by passers-by.
It is in the hope of saving Africans from further pain that volunteers are now being enrolled in trials. The most advanced is the trial at the Jenner Institute, which uses ChAd3 (chimp adenovirus type 3, a chimpanzee “cold” virus) as a vector (or agent) to deliver a small segment of genetic material from the Zaire strain of the virus. This is the strain behind the current outbreak in Guinea, Liberia and Sierra Leone, but unlike the circulating strain the genetic material in the vaccine has been neutralised and the virus does not replicate, so the vaccinated individual cannot become infected with Ebola. Instead, the idea is that the Ebola gene will prompt the cells of the vaccine recipient to manufacture a single protein on the surface of the Ebola virus and that this will induce an immune response.
Using the same principle, scientists at the NIH facilities in Bethesda and Mali are trialling a vaccine using genetic material from both the Zaire and Sudan strains of Ebola, while the Canadians are using another animal virus called vesicular stomatitis virus (VSV) to deliver genetic material from Ebola to recipients’ cells.
The GlaxoSmithKline vaccine has already performed well in animal trials, providing macaque monkeys with 100% protection against Ebola for up to 10 months. But our immune system is very different from that of macaques and, to date, no vector-based vaccine has been licensed for any disease in humans. That is why scientists are proceeding with caution and testing the vaccine in different concentrations in order to ascertain the lowest dose that will elicit an immune response.
“The big question is, will the immune responses that we generate with the vaccine be strong enough?” says Professor Adrian Hill, the director of the Jenner Institute. “That’s always a question with new vaccines.”
It is a question to which Nick Owen, who works as an editorial and social media co-ordinator at MSF’s London office, is keen to know the answer. Earlier this month he became one of the first volunteers to receive the vaccine. He felt a bit “flu-ey” the day after the injection, but otherwise the only discomfort is giving blood once a month so that his antibody levels can be measured.
“It is odd to think I have a small bit of one of the world’s deadliest viruses coursing through my veins but sitting here in the office, hearing what my colleagues in west Africa were going through, I thought it was the least I could do,” says Owen. “To date 13 of my colleagues have died from the virus after contracting it in their communities. All I’m doing is giving a pint of blood over six months.”
Ruth Atkins, an NHS communications manager and former nurse from Oxford, is similarly phlegmatic about her contribution. “I’ve had people say to me I’m a heroine for volunteering to be a guinea pig, but I don’t feel that way at all. I’m just playing my part. The nurses and doctors in Sierra Leone are the real heroes. That’s where the attention should be.”
In theory, if the phase one safety trial goes well, then GSK could be in a position to launch the final stage of the tests early next year. What the world can’t afford, says the Wellcome Trust’s Farrar, is to be in a position where the vaccine is shown to be safe and effective but where we have to wait another three to six months to produce it. It is for this reason that the trust has put up £2.8m to fund the production of additional doses of GSK’s vaccine and that Farrar is asking for the usual ethical considerations to be waived.To persuade drug firms to make Ebola vaccines a priority the European Commission is also talking about setting up a €200m fund to offset manufacturers’ research costs. In theory GSK and firms like Johnson & Johnson, could make substantial profits by selling their vaccines to national governments to be stockpiled ahead of an outbreak, as occurred in the run-up to the 2009 swine flu pandemic. In the case of less developed countries the purchase of Eblola vaccines would most likely be subsidised by the UN. However, there is a chance that the next outbreak of Ebola will be caused by a completely different strain of the virus, against which current vaccines could be ineffective.
In theory GSK could make as many as 10,000 doses of its vaccine available as early as December – double that if it proves effective in lower doses. Health workers would be the first to receive it, followed in theory by patients in the early stages of Ebola infection who would otherwise face a high risk of death. Farrar points out that when a virologist conducting mouse experiments with the Ebola virus at a lab in Hamburg in 2007 accidentally pricked her finger, she was immediately offered an experimental vaccine and asks: “Why should people in west Africa be treated any differently?”
Even if the vaccine cannot be produced in sufficient quantities in time – and last week GSK said it feared its product would be “too late for this epidemic” – Farrar argues that by funding critical research now the world will be in a much better position to respond to Ebola if and when it strikes again.
That is a distinct possibility. While in the past Ebola outbreaks have been self-limiting, this outbreak may be different, argues Peter Piot. “From the perspective of a virus, it isn’t desirable for its host, within which the pathogen hopes to multiply, to die so quickly,” he told the Observer. “It would be much better for the virus to allow us to stay alive longer… a mutation that would allow Ebola patients to live a couple of weeks longer is certainly possible.”
We must hope that will not happen. Writing half a century ago, Dubos, foreseeing the dangers of rapid technological change and increasing ecological imbalances, urged politicians to “think globally, and act locally”. Although he despaired that his message was going unheeded, Dubos remained an optimist to the end. The trick, he argued, was for scientists to cultivate “an alertness to the unexpected and to be aware that many surprising effects are likely to result from even trivial disturbances of ecological equilibrium”.
Mark Honigsbaum is a Wellcome Trust Research Fellow at Queen Mary University of London