The hunt for Ebola medicines is being accelerated
Sep 18th 2014
THE lucky ones are admitted to a health centre. They arrive bleeding, in taxis, on foot, in wheelbarrows and sometimes in ambulances. Mostly there is little help available and patients are dying alone, lying on the ground and lucky to receive even palliative care. Médecins Sans Frontières, a medical charity that has treated more than two-thirds of the known patients, says its centres are overwhelmed.
The death toll from the Ebola virus is continuing to grow alarmingly. On September 9th the World Health Organisation (WHO) said it had recorded 4,293 cases in five west African countries, of which at least 2,296 people had died (see map below). But even the WHO’s experts believe that is an underestimate as many people are suspected to be dying at home. By some estimates 12,000 people have been infected with Ebola so far.
In Liberia the disease is spreading quickly. The country’s existence is now “seriously threatened” as the functions of state are disrupted, Brownie Samukai, Liberia’s minister of national defence, said this week. The health system, already weak, is breaking down. At least 160 Liberian health-care workers have contracted the disease and half of them have died. Ebola is also spreading in Guinea, Sierra Leone and Nigeria, and a case has been reported in Senegal. This is the worst-ever outbreak. Yet even though the disease was discovered almost 40 years ago, there are no licensed treatments or vaccines.
That is largely because Ebola has been an intermittent disease in some of the world’s least-developed places. Previous outbreaks flared up but then died back. The virus is transmitted to people from wild animals (fruit bats are a natural host) and then spread by contact with body fluids. As Ebola was confined to poor countries and largely containable with strict infection controls, there was little commercial reason for drug companies to embark on years of costly clinical trials to bring Ebola medicine
Stepping up the pace
The scale of the present outbreak, together with the fear and suffering it is causing, has resulted in a burst of scientific activity to find new treatments and vaccines. Some of these medicines look promising. But to contain the spread of Ebola, scientists and health officials will have to bypass many of the existing rules that govern the delivery of new drugs, and develop potential remedies with unprecedented speed.
This strategy is being endorsed widely. In August experts from the WHO concluded that, provided certain conditions are met, it would be ethical to offer unproven, experimental treatments or methods to prevent infection. Ebola experts gathered by the WHO in Geneva on September 4th-5th repeated this, and said the delivery of new medicines was now essential.
A number of groups are pushing ahead with human trials of vaccines that have shown promise in animal tests. Last week the first phase 1 clinical trials started in America for a vaccine developed by the US National Institutes of Health (NIH) and GlaxoSmithKline (GSK). In parallel, a British group is planning tests using volunteers in the UK, the Gambia and Mali.
Phase 1 trials are used to test whether a drug is safe in healthy individuals, after which a series of further trials establish whether it works. But in this case, vaccines are expected to be offered directly to health-care workers in infected areas once the initial tests are complete. The effects of the vaccine would then be monitored in the field.
The NIH/GSK vaccine is based on a benign virus which causes a cold in chimpanzees (an adenovirus). It is able to infect cells and deliver fragments of genetic material from two variations of Ebola (one of which is the Zaire strain responsible for the current outbreak). When Ebola proteins are expressed by infected cells, an immune response is triggered. A version using a single strain of Ebola is also being tested.
On September 7th, Nature Medicine reported that immediate and lasting immunity to Ebola could be stimulated in monkeys if a dual jab is used. The first jab primes the immune system with an adenovirus-based vaccine; the second boosts it with a modified vacciniavirus (the active component of the vaccine that eradicated smallpox). Johnson & Johnson, a big American health-care company, has accelerated laboratory testing of a combined vaccine, which could begin clinical trials next year.
Another candidate vaccine was developed many years ago by the Public Health Agency of Canada. It was recently licensed by NewLink Genetics of Ames, Iowa, which has approval to start phase 1 trials. This jab is based on a vesicular stomatitis virus (VSV), a livestock infection that resembles foot-and-mouth disease. VSV has been used previously to develop vaccines. The new vaccine, VSV-EBOV, is a live, replicating virus that infects cells and carries Ebola viral proteins into the host. Again, this stimulates an immune response.
Importantly, VSV-EBOV also works in monkeys after they have been infected. The reason Ebola is so deadly is that the virus is good at tamping down the innate immune response to viral infection, says Jonathan Ball, a professor of molecular virology at the University of Nottingham in Britain. Thus Ebola replicates unchecked before the immune system can adapt and mount a tailored response. Some people recover naturally. They are able to summon defences more speedily, and before their bodies are overcome with symptoms such as organ failure and haemorrhaging.
Production under way
The results of the safety trials will start to arrive in November, and vaccines may be provided immediately to health-care workers who agree to be injected—some vaccine production is already under way. Experts hope they will be safe, as the viral “platforms” on which they are based have already been tested in humans. But these vaccines will not be available to restrain the epidemic over the next few months—a time that many think will be critical in containing the disease.
The experts at the WHO’s Geneva meeting were most optimistic about two related methods of treatment: whole blood transfusion and purified blood plasma, known as convalescent serum. The idea is to take blood containing Ebola antibodies from survivors and give this to existing patients where, according to theory, the antibodies will then fight the virus. There are no data yet on the efficacy of this treatment on a large scale, but transfusions were used in previous Ebola outbreaks, and have been used for over 100 years on a small scale to combat other infectious diseases. Jeremy Farrar, director of the Wellcome Trust, a large British health charity, agrees with this approach. He adds that such blood products can be safely provided, and are accepted widely in the affected countries.
There are other possibilities, too. Mapp Biopharmaceutical, a San Diego drug company, is developing a cocktail of monoclonal antibodies, made by genetic engineering. These appear to protect against the Ebola virus. In tests, all 18 monkeys given ZMapp, as the treatment is called, were protected even five days after infection. Four infected people have received it, and two have recovered. But doctors do not know if ZMapp helped. Because the drug is difficult to make, supplies are exhausted for now.
Another approach to fighting Ebola is to constrain viral replication. Tekmira Pharmaceuticals, a Canadian firm, is working on TKM-EBOLA, a drug that silences the cellular messages that allow viral proteins to be made. Human trials were halted earlier this year because the drug caused flu-like symptoms—but America’s Food and Drug Administration has recently agreed that it can now be tried on Ebola patients. Other antivirals, such as Favipiravir, an influenza treatment, might also help. But more data from animal tests are needed.
Some researchers propose going “off-label” with the unapproved use of existing drugs for other purposes. Interferon drugs have an antiviral effect and statins might help treat the complications of Ebola, such as organ failure. Experts at the WHO worry about the potential for harm with statins. But it is possible that some doctors, lacking alternatives, might try them.
The arrival of new medicines will encourage health-care workers who have given up their posts to return to attend the sick. It would also help address the fear and panic that is proving so disastrous in the infected countries. But there are other difficulties. One is highlighted in a forthcoming working paper for the National Bureau of Economic Research, which finds that some Indian drugmakers are taking advantage of the lack of regulatory oversight to send their lowest-quality antibiotics to Africa.
The biggest problem remains containment, especially in the months before new medicines arrive. Virologists, such as Dr Ball at Nottingham, worry that increasing human-to-human transmission is giving Ebola the opportunity to become more transmissible. Each time the virus replicates, new mutations appear. It has accumulated and hung on to some mutations, like “cherries on a one-armed bandit”, he says. Nobody knows what would happen if Ebola hit the jackpot with a strain that is even better-adapted to humans. But the outcome could be grim, for Africa and the rest of the world.
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