Pharma & drug development

Ebola: a timeline

The medical community has been accused of not engaging in enough drug development and research to counter the deadly Ebola virus. We chart the story of Ebola, from its first isolation in 1976 to the latest outbreak and new efforts to rush a vaccine into mass production.

1976 – Ebola first isolated 

The Ebola virus was first isolated in 1976, during outbreaks in South Sudan and the Democratic Republic of the Congo (formerly Zaire). Named after the nearby Ebola river, the virus caused 318 cases and 280 deaths in the DRC, and 284 cases and 151 deaths in Sudan. While these outbreaks were caused by different strains, they were recognised as a new type of virus, belonging to a virus family called Filoviridae. Its origins were unknown.

Because of the mystery surrounding its natural habitat, efforts were focused not on treating the condition but on containing its spread. With the help of the World Health Organization, quarantines were imposed, medical equipment was sterilised and protective clothing was provided. But with the Zaire variant killing 88% of sufferers, it was clear the new virus posed a major threat to human health.

1977 – First cure attempted

Despite placing the emphasis on prevention, some researchers did try their hand at developing a cure. David Heymann, part of the team investigating the outbreak, stayed behind in Zaire for ten weeks, collecting a unit of blood every week from a small group of survivors. Because their blood serum contains a high level of antibodies, transferring it to sufferers could theoretically help them fight the virus.

This convalescent serum was not trialed in Africa, as the outbreak had already ended by the time it could be used. In 1977, however, a researcher in England contracted Ebola when dealing with an infected guinea pig. The serum was administered, and he survived.

1989 – Third strain identified

A third strain of the virus, Reston ebolavirus, was identified in 1989, when infected monkeys were imported from the Philippines into Virginia. These crab-eating macaque monkeys were initially misdiagnosed with simian hemorrhagic fever virus, but it later became apparent that the dead animals had Ebola antibodies in their blood.

Blood samples were taken from 178 animal handlers, six of whom had seroconverted (i.e., been infected with the virus). Luckily, none of these people became ill, suggesting that this strain of Ebola posed little danger to humans.

This discovery took place during a long period of Ebola inactivity, with no outbreaks recorded in the years between 1980 and 1993. A fourth strain (Tai Forest ebolavirus) was identified in 1994, when a scientist became ill after conducting an autopsy on a wild chimpanzee.

1995 – Serum treatment successful

The second major outbreak took place in 1995, again in the DRC. In April that year, a hospital laboratory technician underwent surgery for what was thought to be a perforated bowel. Soon the medical personnel who were treating him began to show symptoms, and their caregivers in turn became infected. In total, 315 people were affected, of whom 254 died.

As per the initial outbreaks, efforts were focused on educational and quarantine measures along with active surveillance in clinics. In this case, however, a serum treatment showed some success. Five survivors donated their blood, which was transferred to eight sick patients. Seven of them survived, far higher than would be expected in a disease with a mortality rate of 80%.

While that result is certainly encouraging, a later re-analysis concluded that the patients in question would probably have recovered even without the serum. As well as the obvious difficulties associated with finding donors, the jury is still out as to whether this treatment really works.

Currently, the WHO says that blood serum from survivors may be used if methods are developed to collect and administer it safely.

2000 – Containment efforts 

A further epidemic hit Uganda in October 2000, when the Sudan strain of the virus infected 425 and killed 224 (53%). Again, the WHO encouraged healthcare workers to focus on reducing transmission, through imposing infection control practices, educating the community and isolating identified patients. The three most serious risks were cited as attending patients’ funerals, having contact with infecting family members, and providing medical care without taking appropriate precautions.

A new and deadly strain of the virus, Bundibugyo ebolavirus, was identified in 2007, emerging once again in 2012. To date, there are five known types of ebolavirus, four of which pose a threat to humans and three of which have proven lethal.

2009 – Experimental vaccine shows success

In March 2009, a lab worker in Hamburg accidentally pricked her finger with a needle carrying the Ebola virus. She was given an experimental vaccine, which was being developed by scientists in Canada and the US. It consisted of a live vesicular stomatitis virus carrying an Ebola protein, and had been tested only on monkeys.

While the woman survived, and showed no symptoms, it was unclear whether this was because the vaccine worked or whether because she hadn’t received enough viral load to cause an infection. In macaque monkeys, the vaccine is nearly 100% effective in preventing infection, and has also been useful as a treatment when administered soon after an exposure. 

2010 – TKM-Ebola trial

Because of the limited size of the outbreaks, pharmaceutical companies have not historically treated Ebola as a priority. However, in recent years this has begun to change. With the threat of bioterrorism mounting, various experimental treatments have been trialed.

In May 2010, Tekmira Pharmaceuticals in Canada published some encouraging findings in the Lancet. They had created a drug that could protect primates from Ebola, by targeting strands of the viral RNA and blocking it from creating certain proteins. That year, the company signed a $140 million contract with the US Department of Defense to advance the drug’s development.

A phase I trial was instigated in January 2014, testing out the safety of TKM-Ebola on healthy adult subjects. By March, the company had been granted an FDA Fast Track designation to expedite the development and review process. Unfortunately, the trial was put on hold in July when regulators requested further safety data.

2012 – Zmapp trial

Mapp Biopharmaceutical has been developing its own drug, Zmapp, a cocktail of genetically-engineered antibodies which is based on the same principle as blood serum cures.

A study published in 2012 found that Ebola-infected rhesus monkeys survived when they received monoclonal antibodies one hour after infection. These findings were borne out in 2013, when a different combination of antibodies was administered to great success. Since then, the two serums have been combined to create Zmapp. The drug was due to start human trials when the latest outbreak began.

December 2013 – Start of Ebola epidemic

In December 2013, a two-year-old child died in Guinea, suffering from haemmorhagic fever. The infection spread, and in March 2014 the World Health Organization reported a major Ebola outbreak in the region. Unusually for such outbreaks, the epidemic was not confined to a single country, but instead had spread from Guinea to Liberia, Nigeria and Sierra Leone.

March 2014 – Vaccines fast-tracked

This latest outbreak has expedited attempts to find a cure. In March 2014, a group at the University of Texas Medical Branch was awarded a five-year grant to work on three promising Ebola therapies. One is a small-molecule inhibitor called a SIRNA; one is based on monoclonal antibodies and one is the experimental vaccine that may have saved the lab-worker in 2009.

Meanwhile, several other vaccine candidates are being supported by the National Institutes of Health (NIH). Two of these are being developed by commercial companies – Crucell biopharmaceutical company and Profectus Biosciences – while a further offering, by the National Institute of Allergy and Infectious Diseases, has been fast tracked. This will be tested in phase 1 clinical trials this autumn.

If such efforts come to fruition, the first Ebola vaccines may be available as early as 2016. Investment may be needed from international agencies if the appropriate levels of funding are to be secured.

July 2014 – Zmapp treatment

The standard hospital treatment for Ebola is based upon intravenous rehydration, along with antibiotics. However, with a state of emergency ongoing, various pharma companies have been able to bypass normal protocols and supply their experimental drugs in limited quantities.

Zmapp has been credited with helping several patients recover, including two American doctors. Although it has never been tested on humans, and is several years removed from FDA approval, the WHO has deemed it ‘ethical’ for use for use in this context.

While Zmapp has been widely hyped, it should be stressed that this is not a silver bullet – two people have died despite taking the treatment, and in the absence of any human trials it is impossible to determine its efficacy. Very few courses of the treatment have been manufactured.
August 2014 –Quarantine and a Japanese drug

By mid August, 2,127 suspected cases and 1,145 deaths had been reported. The WHO has declared a state of international public health emergency, and has claimed that the number of sufferers may be vastly underestimated. There is a particular state of crisis in Liberia’s capital, Monrovia, where much of the city’s healthcare system has come to a standstill.

On 16 August, following an attack on a quarantine centre, 17 suspected patients went missing. For the first time in nearly a hundred years, authorities have imposed a cordon sanitaire – a massive quarantine zone containing around a million people. With thousands of quarantined people lacking access to food, the success of such containment efforts is hanging in the balance.

Japanese firm Fujifilm Holdings has said it will ship Avigan (also known as Favipiravir) into the affected countries if requested. This experimental anti-viral drug has been used against new strains of influenza, but has never been trialed against Ebola, either on humans or monkeys. Clinical tests are currently underway in the United States.

Japan has said it has sufficient supplies to treat 20,000 people, along with a system for continuous production. These have been offered to the World Health Organization, with the promise that Japan could supply the drug at short notice.

 

This timeline appears in the October edition of Pharma Technology Focus

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