The current outbreak of Ebola in West Africa is taking a massive toll in several countries, including Guinea (where the outbreak originated), Sierra Leone, Liberia and Nigeria. The most recent estimates indicate over 2000 confirmed cases of the disease, with almost 1200 deaths reported. Several African countries have imposed a temporary ban on flights coming in from the above countries, which will undoubtedly have a major social and economic impact. Meanwhile, the World Health Organization (WHO) has said the scale of the outbreak had been ‘vastly underestimated’. The charity Medicins Sans Frontiers has also predicted that the outbreak will take about 6 months to bring under control.
However, the question remains as to why the outbreak could not have been detected and controlled sooner. What did scientists already know about the Ebola Virus? why were no vaccines already developed? what will be the impact of this outbreak on research into the Ebola Virus? Answers to these questions will be central to our ability to respond to any future outbreaks and improve the prospects of patients who contract this deadly virus.
What Is Ebola?
Firstly, it is important to realise that there is no single Ebola Virus. Five strains of Ebola have been identified to date. Each of these have different rates of lethality and not all have the ability to infect humans. The current outbreak in Africa is caused by the Zaire strain, first identified as the cause of the 1976 outbreak in the Ebola river valley in Zaire in 1976. Zaire Ebolavirus is associated with the highest rates of Ebola-related mortality, with some estimates suggesting that up to 90% of infected individuals will die. At first, infected persons may develop flu-like symptoms such as fever, muscle weakness, vomiting, diarrhoea and fatigue. After a few days patients may show abnormalities in blood clotting, which often lead to widespread internal bleeding. Death in the majority of cases is due to a massive reduction in blood pressure, which eventually leads to multi-organ failure. The time from initial infection to death can be as little as two weeks. As you probably know by now, transmission of Ebola is only possible via bodily fluids, such as blood and saliva, which explains the particularly high risk for healthcare workers. There is an excellent video on the main features Ebola in 4 minutes, shown below:
The biological basis of disease caused by Ebola is ascribed to a single component of the virus known as a glycoprotein, which is essentially a protein coated with many carbohydrate molecules. This glycoprotein is made by the virus in two forms; a secreted glycoprotein which detaches from the virus, and a transmembrane glycoprotein form which stays attached to the outer coat of the virus. Current evidence suggests that the transmembrane glycoprotein allows the virus to attach to cells lining blood vessels, before the virus enters these cells and hijacks internal components to allow itself to replicate. Infection of these cells initially causes the production of small molecules known as cytokines, which lead to a state of local inflammation and are responsible for the flu-like symptoms seen in the early stages of disease. After a while, infection of blood vessel cells leads to disruption of contact between adjacent cells, leading to leakage of blood. Eventually, the massive production of cytokines coupled with loss of blood leads to multi-organ failure and death
You may at this stage ask: does our immune system not protect us against Ebola? This is where secreted glycoproteins come into it. The evidence to date suggests that secreted glycoproteins can attach themselves to various types of immune cells to prevent them from attacking the virus, thereby enabling the virus to replicate without interference. Recent studies also suggest another component of the virus, VP24, suppresses an effective immune response.
It seems almost incredible that such simple biological mechanisms are responsible for such chaos, doesn’t it? There has also been much concern within the scientific community that the Ebola virus could be harnessed for bio-terrorism and lead to international catastrophe. So why could vaccines not be developed against Ebola in the same way that they have for other micro-organisms?
Are any vaccines being developed for Ebola?
Several types of vaccines against Ebola have already been developed and tested in animals harbouring Ebola infection. Due to the low prevalence of Ebola infection in humans and high risk of transmission to scientists, ideal vaccine candidates should have proven effectiveness under laboratory conditions in non-human primates , such as chimps and apes which are very closely related to humans.
The most promising vaccines for Ebola currently in development involves inactive viruses (not capable of causing disease) engineered to display a synthetic form of the Ebola glycoprotein. The idea is to introduce a component of the virus into the body to ‘prime’ the immune system, so if the virus is encountered again various types of immune cells are ready to attack and destroy it before it can cause disease. This strategy has been shown to be effective in non-human primates and to be safe in a small number of healthy human patients. Further studies evaluating this vaccine in a larger number of healthy and Ebola-infected patients is necessary before it can be approved for widespread use.
While engineered viruses are among the most promising vaccine candidates, a number of issues have slowed research into this area, including existing immune protection against the viruses in great apes and the ability of supposedly inactivated viruses to cause disease in animal models of Ebola.
In addition, the appropriate choice of vaccine will depend on the scenario in which it is to be used. For example, a slow-acting vaccine may be appropriate in the case of healthcare workers who require long-term protection against the virus. However, a more rapidly acting vaccine would be necessary in the event of an Ebola outbreak resulting from unforeseen bio-terrorism. Vaccines administered to people in high-risk areas would probably be more effective if they were able to produce immunity against more than one Ebola strain. Therefore, much research is needed to develop situation-specific vaccines.
What are the experimental drugs approved by the WHO to deal with Ebola?
At the forefront of the media coverage of Ebola in recent days has been the decision by the WHO to approve the use of experimental drugs for Ebola, which have never been tested in humans before. Chief among these is Zmapp, a serum developed by combining two different antibody cocktails from two biopharmaceutical companies: Mapp Biopharmaceuticals and Defyrus inc.
Antibodies are the bodies first method of defence against foreign invaders (pathogens). After an infection is detected, antibodies containing regions specific against part of a pathogen are rapidly produced. Antibodies produced against Ebola may prevent the virus from attaching itself to its target cells, a process known as neutralisation. Antibodies against Ebola may also lead to targeting of the virus to immune cells specialised for destruction of the pathogen. As disruption of antibody production is central to Ebola establishing disease, administration of externally-derived antibodies may help fend off infection. Indeed, ZMapp may have helped save the lives of two doctors who contracted Ebola. It is too early to tell whether ZMapp is effective in humans after Ebola exposure, but its increasing use in infected individuals will certainly be instructive.
Another potential drug effective against Ebola may be Favipiravir, developed by Fujifilm, which has already been shown to be safe in clinical trials in humans with influenza. A study published earlier this year showed Favipiravir to effectively block replication of Ebola viruses in mice, although evidence in primates is lacking. The exact mechanism by which Favipiravir works is not known, but it is believed to interfere with the ability of the virus to replicate its genetic material.
There is no report to date of Ebola patients being treated with Favipiravir but depending on the success of ZMapp, it may prove to be a second-line alternative.
What are the implications of the current outbreak on the future of Ebola research/treatment?
Current research on Ebola treatments is mainly conducted by small bioscience companies in North America, who derive the majority of their funding from the US Department of Defense (DoD). In fact one company, Tekmira Pharmaceuticals, recently secured a $140 million contract from DoD for research on Ebola. It just goes to show how importantly the US take the threat of bio-terrorism. There is little financial incentive for the pharmaceutical giants (e.g. Pfizer, AstraZeneca, GSK) to step into this area owing to the scarcity of demand for Ebola vaccines in the short to medium-term.
You would think that following this outbreak there would be more funding pushed into basic science research for Ebola. Yes and No. While BioCryst Pharmaceuticals, manufacturers of the experimental drug BCX4430, has received $4.1 million from the National Institute of Allergy and Infectious Diseases, the US government has chosen not to renew a lucrative $15 million contract for research on Lassa fever, with knock-on implications for Ebola research in Africa. Some funding has also been withdrawn from the labs that helped develop ZMapp.
Although the World Bank recently announced $200 million of funding to assist the primary care of affected patients and communities, greater investment in basic science to accelerate vaccine development is likely to be more cost-effective over the long-term.
The use of experimental drugs in Ebola patients will undoubtedly help researchers understand which drugs work in humans. Tragic as their situation is, these Ebola patients are playing an important role in refining knowledge in this area. The social and economic impact of Ebola in West Africa should not be underestimated. Loss of healthcare workers will make treatment more difficult the longer the outbreak continues. Reduced flow of tourists to West Africa is having a major impact, as is reduced trade between countries that have closed their borders. Forecasts for the growth in Liberia’s GDP have already been revised down one percentage point by the International Monetary Fund.
The longer the current outbreak continues the more pressing the demand on science and healthcare. We should use this outbreak to learn vital lessons that will stand us in good stead for dealing with similar outbreaks in future.
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