The World Health Organisation (WHO) has estimated that since the outbreak of the latest Ebola epidemic in 2013, there have been 23,217 suspected cases and 9,353 deaths. Scientists from Oxford University have played an integral part in leading the effort to fight it. This has mainly consisted of setting up clinical trials to test the efficacy and safety of both possible vaccines and possible cures. The investigation this week takes a deeper look at this contribution, and interviews some of the researchers behind it. The articles featured below introduce the investigation. They give an explanation of the key things to know about Ebola, as well as a first hand account of the practical considerations researchers face when working in the field.

Other articles in this investigation:

Fever, headache, muscle pain, diarrhoea: an introduction to Ebola

Chanatjit Cheawsamoot

In October 2014, the World Health Organisation (WHO) concluded that the current Ebola epidemic is larger than all past Ebola outbreaks combined. While most people will have begun to be aware of the Ebola epidemic in the autumn of 2014, the start of the outbreak was actually much earlier – in late 2013. The epidemic began in Guinea during December 2013 and the WHO was officially notified of the rapidly evolving Ebola disease outbreak in March 2014. The three most affected countries in West Africa – Guinea, Liberia, and Sierra Leone – face an immense challenge as they try to control the spread of the Ebola virus and to provide treatment for all those infected. 

Although the current outbreak is exceptionally large, there have been previous outbreaks of Ebola before in West Africa, albeit on smaller geographic scales. The WHO speculates that the larger scale of this epidemic is due to certain characteristics of the affected populations and insufficient control efforts. For example, the populations of Guinea, Liberia, and Sierra Leone are highly interconnected, with relatively easy connections by road between rural towns and villages and between densely populated national capitals, providing a golden opportunity for the Ebola virus to spread among populations. Symptoms of Ebola include fever, severe headache, muscle pain, diarrhoea, and unexplained haemorrhage.

The natural reservoir host (the long term host of a pathogen for an infectious disease) of the Ebola virus remains unknown. However, current evidence suggests that reservoir hosts for the Ebola virus are likely to be bats, suggesting a possibility that humans became infected directly from bats in caves, as well as when they come into contact with tissue from infected apes and other species.

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Transmission of the Ebola virus is through blood and body fluids – including but not limited to urine, saliva, sweat, faeces, vomit, breast milk,and semen of a person who is sick with Ebola. It is not spread by air, water, or food. As Ebola doesnot spread through casual contact, the risk of an outbreak outside of Africa is very low if effective hygiene control measures are implemented.

As for all diseases, epidemiologists strive to calculate the basic reproduction number (R0), which is the key to figuring out how infectious a disease is. It expresses how many people one infected person can pass the disease onto. This value for Ebola varies from population to population but they are all close to two, indicating that each infected person has the potential to pass on the disease to two other people. Compared to other epidemics in the past, the basic reproduction number of Ebola is much smaller. For example, measles had an R0 value of 18 before a vaccine was procured. This shows that even though the fatality rate is high (around 60 per cent), the Ebola virus is not very good at transmitting itself at all.

Thus, one strategy in controlling the epidemic is reducing the basic reproductive value to below one, which means that an infected person will no longer pass the disease on to anybody, effectively preventing the spread of Ebola. This can be done via the isolation of infected patients to prevent the transmission of the virus to uninfected people.

With the prospects for a novel and successful Ebola vaccine, immunising just over half of the affected populations can halt the spread of the Ebola virus. Of course, ensuring that everyone who is at risk is immunised would be desirable but this level is the minimum that is needed to contain the Ebola virus disease.

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Because the Ebola virus is spread mainly through contact with the bodily fluids of symptomatic patients, transmission can also be prevented by a combination of early diagnosis, contact tracing, patient isolation, and care and safe burial. Contact tracing involves finding everyone who has come into contact with an Ebola patient, after which they are tracked for 21 days for signs of illness. If a contact develops Ebola symptoms, they are immediately isolated and provided with treatment. This process is crucial in stopping the spread of the disease.

As vaccines against the Ebola virus are being tested for safety and effectiveness, other treatments are used to maintain the health of patients, such as providing intravenous fluids, maintaining blood pressure, and treating other infections if they occur. Until then, successful recovery from Ebola depends on the patient’s immune response and the quality of supportive care. As vaccine trials for Ebola are being carried out at The Jenner Institute in Oxford, there is yet hope that a cure will be found.

Pierro Olliaro, a professor of Tropical Medicine working on Ebola, discusses the practical elements of his work

Ebola is a deadly disease, but fortunately it cannot be transmitted as easily as can, for instance, flu: it needs direct contact with body fluids, and only a person with symptoms can pass the virus onto another person. The virus circulates in nature, and humans can occasionally catch it from infected wild animals, like bats and monkeys. Then, when the person starts developing symptoms – and only then – they will start infecting other people around them. Particularly dangerous are traditional burials, which can generate many more cases from one single instance.

In the past, epidemics have generally been confined to remote areas and were curbed before they reached highly-populated areas. Unfortunately, this is not what happened this time. In the countries in West Africa where Ebola has spread havoc during this last epidemic, people, governments, and international aid generally underestimated the magnitude of the problem, probably thinking that the epidemic would simply die down on its own. Ignoring the looming disaster, life carried on as usual, unsafe practices continued allowing the number of cases to pile up and the disease to spread further afield – to amount to an appalling 23,000 cases as of today.

When I first visited West Africa in October 2014, several months into the epidemic, it had become only too obvious how real the problem was, and a number of measures had been set in place to hold off the spread of the disease.

Simple measures are very effective: do not touch anyone, touch as few things as possible, possibly avoid public transportation, and wash your hands as often as possible. Tanks of chlorinated water stand outside shops, offices, hotels with which you are required to wash your hands before entering; hand antiseptics are in high demand.

Things change completely when it comes to getting close to a suspected or confirmed case in a screening or treatment centre. Here, the risk of exposure increases with medical acts like visiting a patient or taking a blood sample.

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Doctors and nurses wear personal protective equipment (PPE) clothing that covers them from head to toe. Donning the PPE, including mask, visor or goggles, hood, apron, etc. takes about ten minutes, and doffing it takes even longer – it is the most critical part of all, to prevent infected material possibly present on the outside from getting in touch with the body. In between, one would have spent one hour inside; at this point the scrub that you are wearing underneath would be completely soaked, wellies and surgical gloves (two pairs) filled with sweat that had trickled down. Scrupulous adherence to very strict procedures has proved very effective: of the hundreds of healthcare workers who have been treating thousands of Ebola patients in this epidemic, very few have become infected, mostly because of needle injuries or a breach in protocol.

If being in an Ebola-stricken country is a poignant experience, returning can be quite a journey. Your temperature is checked and you are questioned several times as to what you have been doing at the airports of embarkation, transit, and arrival.

On landing in the UK, Border Control will know where you have been, even if you’d stopped over for a few days elsewhere on your way back. You will be asked kindly to wait for a Public Health England (PHE) official to come and assess you. If you’ve been deployed to work on Ebola (one would hardly think of visiting those countries as a tourist, these days), PHE would be fully aware of your movements and whereabouts, and would provide you with instructions and have a box delivered at your home with various materials, including a tympanic thermometer.

This latter piece of equipment will become your closest pal for the next three weeks. You will have to measure your temperature twice a day and will have to report any fever or symptoms. A form of paranoia kicks in, as in winter, you could catch flu or any other seasonal bug from your kids at home or Joe Bloggs in the street.

But that’s not all. Dealing with people and perceptions back home will be a challenge. Despite scientific evidence that one can only transmit the infection if symptomatic, not all, including some close friends, would be prepared to entertain the same relationship with you as they would have done otherwise, “out of an abundance of caution”, they claim. Such should not be the case, at the level of individuals or a country. Let’s de-mystify beliefs.

Part of C+’s investigation into Oxford’s role in the fight against Ebola

Imagine that one day, on your walk to the library, you notice a child has fallen into a shallow pond and appears to be drowning. To wade in and save the child would be easy, but it will mean that your brand new pair of shoes will get muddy. Do you have any obligation to save the child?

Initial thoughts: depends on the shoes. But when the moral philosopher Peter Singer posed this dilemma to his students, they exclaimed that they would save the child, for of course the importance of saving a child far outweighs the cost of getting one’s clothes muddy. It wouldn’t make any difference where the child was from, or whether or not others made an attempt to save her.

Passivity in this situation would be blatantly immoral, tantamount to murder. Singer raises the question: if I choose to spend money on a pair of shoes, a night out, or several cups of coffee without giving money to charity, am I effectively choosing these luxury items over the lives of others?

Put simply, yes. The analogy is crude but accurate. Since the first recorded death of a two year old on 28th December 2013, the current outbreak of Ebola has caused more than 9,353 fatalities in Guinea, Liberia, and Sierra Leone. I am not advocating that we give up all luxuries (Heaven knows I love my shoes and lattes) but the case for giving to charity, especially in the case of Ebola, is undeniable.

Of course there are problems with charity. It was disheartening to learn this week that one third of the money that Sierra Leone received from donations could not be accounted for, according to national auditors. There is a risk that aid can fall into the wrong hands, be it corrupt government officials or terrorist organisations. But even if only two thirds of the money given goes to the right place, that is better than no aid at all.

It is perfectly reasonable to want to know where your money is going, and if it is being used ethically and effectively. But we risk throwing the baby out with the bath water by concentrating on what goes wrong, rather than the great deal that goes right. The Ebola outbreak is a textbook example of when aid works. Thanks to the courage of health workers and volunteers in Sierra Leone, Ghana, and New Guinea, Ebola infection rates are falling as the disease is brought under control.

Thousands of children were able to return to school this week in Liberia, and a vaccine should be available for use in West Africa from next year. It is also worth, perhaps cynically, noting that many of the donors who gave money to fight Ebola were hardly disinterested parties. Fears of a more global epidemic might prompt some to self-interested action.

Ebola has been a problem in West Africa since the first outbreak in 1976, but it was only when the disease risked becoming an epidemic that would cross continents that the international community started to take serious action. We are a global community, and in an increasingly interconnected world, a problem for one country becomes a problem for all. Helping to contain the infection abroad helps to protect the UK. The same self-interested reasoning applies to many long term aid projects. Projects that promote education for those who would otherwise go without are hardly ever ineffective, as education stimulates long term economic growth, creating wealth for both donor and receiver.

Ultimately, the issue of whether or not it is Britain’s moral duty to help affected countries comes down to the question of whether you think that someone else’s suffering is as important as your own. We are often told that charity begins at home. But too often it ends there as well.

Other articles in this investigation:

Part of C+’s investigation into Oxford’s role in the fight against Ebola

Dr Tommy Rampling is the lead medical doctor on the first human Ebola vaccine trial at the Jenner Institute in Oxford. The trial examines the safety of two separate vaccines, as well as their ability to generate an immune response against Ebola.

Rampling has a strong sense of purpose in the importance of this mission, telling me, “Before the latter part of 2014, these vaccines had never been given to humans. Our aim, therefore, is firstly to demonstrate that these
vaccines are safe. The next real question is whether or not this vaccine schedule will work.

“There is no safe way of definitively answering that question in the UK, but after the vaccines have been given we can look at some specific parts of the immune system, such as antibodies and T-cells, to look for activation against parts of the Ebola virus. This will give some indication as to which strategies are worth pursuing further in the countries worst affected by the current outbreak.”

The issue that seems to dominate the fight against Ebola is the problem of adapting normal clinical trial practice to the extraordinary situation of an epidemic. A key aspect is the length of time it takes to get the trial running – 18 months in normal practice. However, where there is a will, there is a way, and Rampling has been surprised by the speed of progress, “What has been exceptional for this particular trial has been the speed and flexibility of the relevant authorities in expediting our applications in the face of a global health crisis.”

Once the trial gets regulatory and ethical approval, the next step is to recruit volunteers. As this trial is for a vaccine, it can take place in Oxford, unlike Peter Horby’s trial of potential cures, which, for obvious reasons, can only test those already infected with Ebola and therefore must be based in West Africa.

The selection of volunteers is a rigorous process. As Rampling describes, “Volunteers are identified by response to ethically approved adverts, and if suitable for the trial, they are invited to attend a face-to-face screening. This involves a thorough explanation of the trial, including the risks, with one of the trial doctors.

“If they are happy to proceed, and sign the consent form, we assess their medical health through a history examination and blood and urine tests. If, after all of this, the volunteers meet all of the requirements, they are offered an appointment for vaccination.”

The initial results of these trials have been promising, and using some of the information gained from them, the Jenner Institute is now working in collaboration with the University of Maryland to run a similar trial in Mali.

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The planned West African trials pose a very different set of challenges for Rampling and his colleagues, differences he is keen to stress in full. “A major difference will be the size of the studies. The African studies will need to be much larger than the early studies in order optimise the ‘power’ of the study to quantify the effect of the vaccine. Several trial designs have been proposed, each requiring several thousand subjects to be vaccinated to generate meaningful results.

“Furthermore, in order to detect a vaccine effect, the vaccinated group will need to be compared to an unvaccinated ‘control’ group who are at a similar risk of disease. This raises difficult ethical questions as to how best to fairly conduct these trials, and has been the subject of much discussion in the international scientific community.

“Finally, there are cultural differences, such as the scarcity of staff and resources, the difficulty of procedures (e.g. blood taking), all of which may put trial staff at risk of infection, and require that many adaptations to the trial design must be made to be suitable for the environment.”

Added to all of this is a new challenge, one that gets a conflicted response from Rampling, namely the recent fall in the number of new Ebola cases. For Rampling, “The decline in case incidence in the affected countries is extremely encouraging from a humanitarian and a global health perspective but it does pose novel challenges for analysing the effectiveness of drug therapies and vaccines. It is critical, therefore, to adapt scientific strategies to tackle this issue.

“Although there has been a sharp decrease in new cases in some regions of the worst affected countries, it is likely that there will continue to be sporadic outbreaks of disease in towns and villages for some time to come. New trial designs have been proposed that are suited to answering the key questions in this evolving disease burden.

“The global scientific community is in agreement that we must continue to act quickly and effectively, and glean as much information as we can from this tragic outbreak, so we can prevent similar occurrences in the future.”

Other articles in this investigation:

Part of C+’s investigation into Oxford’s role in the fight against Ebola

The key statistic is 9,353. That is the number of people who the World Health Organisation (WHO) has estimated have died of Ebola since the beginning of the current outbreak until February 16th of this year.

In the fight against Ebola, there are two parallel efforts: the attempt to find a vaccine, and the attempt to find a cure for those already infected. Peter Horby, as the Group Leader of Oxford’s Epidemic Diseases Research Group, is leading Oxford’s contribution to finding a cure. His role involves running the clinical trials needed to establish which drugs work and are safe to use. However, with the current circumstances far from ideal for a clinical trial, these trials bring up all sorts of ethical concerns.

The first issue was about whether there should be any trials at all. For, as Horby says, “None of the Ebola specific therapies had completed safety evaluations in healthy adults, so there were some questions about whether it would be okay to go straight to Ebola patients with these drugs.” Eventually, in August last year, WHO concluded that it would be ethical to go ahead, and it was at this stage that Horby’s group first received funding from the Wellcome Trust to set up a platform to evaluate “some of the most promising experimental therapeutics”. In choosing which drugs to test, the group had to consider not only which ones were most likely to work and were safest to use, but also which ones were most readily available. ZMapp, for instance, had shown great potential in animal studies, and the two people who took it recovered fully. However, there were only enough stocks in the entire world to treat seven people and little hope of mass production anytime soon. Horby had to turn his attention elsewhere. The drug they eventually chose was brincidofovir: it ticked all the boxes, was readily available, and administered as a daily pill, thus being easy to take.

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The next step was to set up the trial. This process normally takes 18 months, but Ebola does not work to the time frame that scientists are used to. Horby’s team got the time down to three and half months, and, according to him, even that was “still too slow by the standards of an Ebola epidemic”. It was at this stage that other ethical questions arose. For instance, Horby asks, “Should we give these experimental drugs to children and pregnant women?” The drugs had never been tested on children before and there was a worry that the drug would cause foetal abnormalities if given to pregnant women. However, at the same time, both groups have high case fatalities and are therefore in need of the drugs the most. Indeed, Horby points out that the argument against giving it to pregnant women is fairly theoretical as “to date, none of the foetuses of pregnant women that have had Ebola have survived”.

The other big ethical debate focused on whether to “randomise” the trial, which means randomly giving some patients a placebo so that they can act as a control for the trial. Whilst this is fairly standard practice in normal clinical trials, the question had to be asked as to whether it would be appropriate in this one. After all, those who get the placebo would then only receive the regular standard of care for Ebola that they would have received had they not taken the trial. However, given that this standard of care, consisting of intravenous fluids and symptom relief, has a roughly 60 per cent death rate, Horby wonders if this practice is truly ethical. It is a controversial debate, and according to Horby, “In the USA, the Food and Drug Administration [FDA] have been strongly in favour of randomised trials. We have not done that because we felt it was doubtful that we would be able to implement that sort of trial design.”

He went on to point out that the trials presented practical as well as ethical problems. “You are working in an environment where you can only see the patients whilst wearing protective equipment, and you can only stay inside for about a hour because it is too hot otherwise. You have limited access to medical equipment: for instance, how do you measure blood pressure or monitor heart sounds when you cannot put a stethoscope in your ears with protective equipment on?” The team has been forced to be ‘creative’. For instance, “We have been putting scanners in the treatment centres. You take the patient records and you scan them before destroying them.”

Unfortunately, after all the work that went into the brincidofovir clinical trial, the drug company pulled out earlier this month, citing concerns about the low number of patients involved. The trial had to end. Whilst this was “very disappointing”, the research group is already setting up a different trial for a different drug, TKM-Ebola, in Sierra Leone.

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We then moved onto the question of what it is like to work with such a dangerous disease. Horby is upfront with his answer, telling me, “It is a very harrowing disease. There are a lot of children affected, a lot of families affected because of the way it is transmitted by close contact. You often get multiple family members affected, so you will get mothers, fathers, their children, and their siblings all being admitted and then dying. So, you see some very tragic situations where there will be children who will have lost most of their family members.”

However, we ended the interview on a note of hope, with Horby giving his predictions for the future. “The epidemic seems to be coming under control in Liberia, Sierra Leone and Guinea. My feeling is that it will grumble on for several more months but will likely be contained towards the second half of this year completely.”

Other articles in this investigation: