EARA Executive Director, Kirk Leech, looks at the remarkable progress in biomedical research in the search for a cure for Ebola virus which has devastated parts of central Africa in the last year.

This week, marking the first anniversary of the most recent Ebola outbreak, scientists running a clinical trial of new drugs in the Democratic Republic of the Congo (DRC) have announced a dramatic increase in survival rates.

For countries, such as the DRC, Liberia, Guinea, and Sierra Leone, Ebola is a serious health emergency. They are among the poorest countries in the world, only recently emerging from years of civil war and unrest that has left basic health infrastructures severely damaged or ruined. Living conditions are often restricted and unclean, water supplies are limited, medical treatment is scarce, and trust in officialdom, pretty much non-existent.

Massive underdevelopment and the attendant problem of political dysfunction have created a situation in which a virus like Ebola can flourish. Since 2014 a total of 28,616 cases of Ebola and 11,310 deaths were reported in Guinea, Liberia, and Sierra Leone. This is what is driving research into finding a way to halt the spread of the disease

Now, thanks in part to research involving mice and non-human primates the sponsors of the current clinical trial in DRC have announced a real breakthrough. While an experimental vaccine that was proven to be effective in monkeys had previously been shown to shield people from catching Ebola, this new development marks a first for people who have already been infected.

Presenting evidence to the World Health Organization (WHO) and the United States National Institutes of Health (NIH), the trial’s co-sponsors, said that two of the four experimental treatments had cured 90 per cent of patients who were treated with them.

These therapies were pioneered by harvesting the antibodies from humanised mouse models that were exposed to proteins from the virus, which were then pharmacologically combined and studied with non-human primate models.

“From now on, we will no longer say that Ebola is incurable. “These advances will help save thousands of lives,” said Prof Jean-Jacques Muyembe, the director general of the Institut National de Recherche Biomédicale in the DRC, which has overseen the trial.

Finding an effective treatment

Ebola, is a viral disease transmitted to people from wild animals and is thought to exist naturally in some fruit bat populations and can be transmitted to humans through bodily fluids of infected animals or the consumption of ‘bush meat.’ Once the virus is introduced to the human population it spreads through direct contact with the bodily fluids of infected people.

The DRC declared their tenth outbreak of Ebola in 40 years in August 2018. During the first eight months of the epidemic more than 1,000 cases of Ebola were reported in the affected region. However, between April and June 2019, this number has doubled, with a further 1,000 new cases reported in the last three months.

It is now by far the country’s largest-ever Ebola outbreak. It is also the second-biggest Ebola epidemic ever recorded, behind the West Africa outbreak of 2014-2016.

Starting in November 2018, patients in four treatment centres in the east of the DRC, where the outbreak rages, were randomly chosen to receive one of four investigational therapies – either an antiviral drug (Remdesivir) or one of three drugs that use monoclonal antibodies – Zmapp, mAb114 and REGN-EB3, a drug produced by Regeneron Pharmaceuticals, a US biotechnology company.

Drugs based on monoclonal antibodies are used to treat many types of cancer. The main objective of such treatments is stimulating the patient’s immune system to attack the malignant tumour cells and prevent tumour growth by blocking specific cell receptors. 

ZMapp is a cocktail of three antibodies that was first developed through research in mice and has been considered the standard of care during Ebola outbreaks. Researchers exposed mice to the Ebola virus, and the antibodies generated within the mice’s blood were then extracted.

ZMapp was tested and used during the devastating Ebola epidemic in West Africa in 2014, and the current goal was to see if the other drugs could surpass it. According to the NIH’s National Institute of Allergy and Infectious Diseases (NIAID’s) the preliminary results were significant:

• Patients receiving the monoclonal antibody cocktail REGN-EB2 had the biggest impact on lowering death rates, down to 29 percent.
• NIAID’s monoclonal antibody, mAb114, had a mortality rate of 34 percent.
• Patients receiving ZMapp in the four trial centres experienced an overall mortality rate of 49 percent.
• The results were most remarkable for patients who received treatments shortly after becoming sick, death rates dropped to 24 percent with ZMapp, 11 percent with mAb114 and just six percent with REGN-EB3, compared with 33 percent with Remdesivir.
• Mortality rates are in excess of 75 percent for infected individuals who don’t seek any form of treatment.

Future vaccine development

Compared with other viruses, Ebola has the ability to alter its shape and increase rapidly its area of infection, making it difficult for any single antibody to block its infection. That’s why a cocktail approach was chosen, like the Regeneron product – a combination of three monoclonal antibodies generated first in mice. However, this is an extremely laborious process, taking many years to produce the antibodies.

An even better solution, which may yet be in reach, would be to develop antibodies from an Ebola survivor, garnering the DNA from the white blood cells that make antibodies. This would produce antibodies already with a successful track record against the Ebola virus.

The virus can persist in a human for a very long time, for example one survivor still carried the virus in his semen 565 days after he recovered. That’s what mAb114 is – an antibody isolated from the blood of an Ebola survivor from the 1995 outbreak in the DRC. However, this persistence also suggests that is perhaps unrealistic to expect that we could ever eradicate this disease.

Nevertheless, the WHO announcement that a new trial directly comparing REGN-EB3 to mAb114 will soon begin and that all Ebola treatment units in the outbreak zone will now only administer the two most effective monoclonal antibody drugs is a significant step towards living with, and surviving the virus.

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