On 3rd September, British volunteer nurse William Pooley was discharged from the Royal Free hospital in North London. What make him different to the other patients discharged that day was that Pooley had been treated in the hospital’s brand new isolation ward, having been infected with Ebola while working in Guinea. Though Pooley is just one of the many thousands that have been infected in the current outbreak of Ebola in Western Africa, now by far the worst in history, he played an important role in it – he was one of the first to be treated with the experimental drug ZMapp.
This experimental drug has quickly risen to the forefront of the battle against this outbreak, as quickly as it spread across the West of Africa. However, it began its life over a decade ago. The drug is the result of a convoluted convergence of U.S and Canadian federal agencies and industrial groups, which arose with the increasing concerns over the use of the virus in biological warfare and terrorism. This collaboration between multiple groups became a theme in the drug’s development, with Mapp Biopharmaceutical (San Diego), LeafBio (the commercial arm of Mapp Biopharmaceutical), Defyrus Inc. (Toronto), the U.S. government and the Public Health Agency of Canada all contributing to the project.
The need for an effective treatment for Ebola Virus Disease has been highlighted by the consistently high mortality rates of past outbreaks. Indeed, the mortality rate of this current outbreak stands at nearly 60%, which is actually far lower than rates previously seen. There is currently no treatment for the disease, efforts to cure it are currently limited to palliative care, such as water replacement therapy for those suffering from the diarrhoea associated with infection. Hence, the discovery of this drug created great excitement.
The drug itself is composed of three monoclonal antibodies that have been raised in mice and genetically engineered to work in humans. These antibodies act in the same way as our native ones do; that is to say they coat foreign objects that display the antigens to which they are specific and both neutralizes the function that the antigen has and attracts the cytotoxic components of the immune system to clear the foreign object. However, unlike the process that produces antibodies in a natural immune response, these antibodies will not give lasting immunity to an infection – they do not give ‘active immunity. Instead, these drugs confer ‘passive immunity’, meaning that the immunological effects provided by the drug only last as long as the antibodies are in the patient’s system. Once they have been used up, the individual is no longer immune. As such, this drug cannot be defined as a vaccine, but does give a short-term degree of immunity to treat individual cases.
The monoclonal antibodies were produced using hybridoma technology. To make Zmapp, mice are first ‘challenged’ with the antibody of interest with a series of injections. This is traditionally then followed by a process of in vitro electroporation, which is the application of an electric field to the cell, increasing the permeability of the cell membrane and hence the likelihood of antigen uptake.
Cells from the spleen of the mouse are then extracted and combined with myeloma cells. The myeloma cells confer a a growth advantage to successfully combined cells, as like all cancer cells they have become ‘immortalised’ meaning that due to mutation, they can proliferate without limit. However, to ensure that any uncombined myeloma cells do not outgrow the useful combined cells, the growth medium contains elements that ensure that only combined cells can grow. When successfully combined cells have been identified, the antibodies they produce can be harvested.
However, in order to be used therapeutically, the antibodies need to be ‘humanised’ and produced in large quantities. Once the best antibody from the hybridoma combinations has been determined, the gene encoding the antibody is extracted and certain portions are replaced with portions encoding human proteins. This process allows the antibodies to function more efficaciously in humans. Once humanisation has been completed, the antibodies must be produced in large quantities. To produce enough antibody to use it therapeutically, the plant species Nicotiana benthamania is used. The gene for the antibody is engineered into viral vectors that specifically infect plants. Like all viruses, these insert their own genome into the host organism, before creating new viruses and generating subsequent infections of other cells. This means that the plant genome in every cell will contain the gene for the humanised monoclonal antibody, allowing for greatly increased levels of production.
Zmapp is one of the few drugs in history to have been used without approval or clinical trials. Due to the severity of this outbreak and the lack of available drugs, the World Health Organisation believed it ethical to push forward the use of this drug. However, according to Peter Piot, who co-discovered the Ebola virus, it is crucial that it is not fast-tracked to approval. He has emphasised both the impressive results of a primate trial and the subsequent need for exhaustive human trials.
However, with the outbreak showing no signs of slowing down, tensions are beginning to rise over the use of this drug on Westerners, as opposed to a widespread release to the thousands of Africans currently suffering with the disease. Indeed, according to the Los Angeles Times, the sequestering of Zmapp from Africans has:
provoked outrage, feeding into African perceptions of Western insensitivity and arrogance, with a deep sense of mistrust and betrayal still lingering over the exploitation and abuses of the colonial era.
Liberia’s assistant health minister summed up the frustration of his country’s people:
The population here is asking: ‘You said there was no cure for Ebola, but the Americans are curing it?’
However, what must also be considered is the potential fallout of approving the widespread use of this completely untested drug on the ground in Africa. If this drug didn’t have the intended effect in humans, America would have serious questions to answer over the apparent use of Africans as guinea pigs. Such ethical issues rarely have to be considered for the application of drugs if they have gone through the correct trialing processes. However, the severity of this outbreak meant that these questions were always going to have to be asked in this case.
But what of the long-term future of Zmapp? Is there one? The drug’s impressive results in the few trials that have so far been conducted suggest that it certainly does have a future in terms of treatment. A study carried out at the Public Health Agency of Canada in Winnipeg found that Zmapp was efficacious in monkeys affected by the ‘Kikwit’ strain of the virus, which is not responsible for this outbreak. This gives great hope for the future, since this suggests that Zmapp can be used to treat future outbreaks, regardless of the causative strain. Human clinical trials are expected to begin soon. It must be emphasised, however that Zmapp is a treatment, not a cure. This drug does not confer the protective immunity of a vaccine, which remains the holy grail for Ebola researchers.