Special report: Ebola's thin harvest

Special report: Ebola's thin harvest -

Since November 29, not a single new case of Ebola was reported in Guinea, Sierra Leone or Liberia. If no new cases pop up, the world will be able to declare January 14 as 2 years Ebola epidemic has ended at the end, after more than 28,0 cases and 11,300 deaths.

The victory also mean the end of an unprecedented era in the search for Ebola. The tragedy provided a unique opportunity: Never had the disease affected enough people to allow researchers to test drugs and Ebola vaccines in a real context. As the number of cases exploded in mid-2014, they initiated a broad research program that runs at breakneck speed.

But the harvest of this massive effort is thin.

The greatest success to date is a vaccine produced by Merck. A July 31 report to The Lancet documented remarkable effectiveness in a real-world test in Guinea. But all other results have yet to appear in the scientific literature. And careful consideration of the data so far supported by dozens of interviews with leaders of the study and other experts Ebola clearly shows that almost every other trial seems destined to end questionable results or total failure . The results of those who have completed are proving difficult to publish in high-level journals.

The reasons are varied and complex. Even under the best circumstances, clinical trials may not provide satisfactory results. In this case, many studies have begun too late, when the epidemic was already down, and ran out of patients. Others had ideas which from the beginning were unlikely to provide a clear answer. A pharmaceutical company abandoned a trial for reasons he never specified, and the fate of another trial remains obscure, even to the World Health Organization.

(Click image to enlarge.)

"thin harvest", explains where the Ebola clinical trials in Guinea, Sierra Leone and Liberia stand today and what they are most likely to yield

brincidofovir :. A test purposes without explanation
TKM-Ebola: Negative results prove difficult to publish
favipiravir: A large study fails to give solid answers
Interferon: A test that few believed in
zmapp: the front-runner is fading
the blood of survivors A trial whose fate is not known
plasma Cloudy results filtered blood
vaccines: The only real success story so far

for more science news and research coverage of the Ebola epidemic to visit our collection "files Ebola." For more coverage, see the January 1 issue of Science.

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brincidofovir

a trial ends without an explanation

On January 30, Chimerix Durham, North Carolina, has pulled the plug on a clinical trial of its experimental drug brincidofovir patients Ebola. The drug, which mimics a DNA building block is active against many viruses in test tube experiments and in human studies to treat cytomegalovirus and adenovirus. But the Ebola test began on 1 January by researchers working with Médecins Sans Frontières (MSF) in a clinic Ebola in Monrovia, was canceled after only four registered patients.

The announcement surprised even the scientists running the trial. "The press knew before me," says Stephen Kennedy, a Liberian investigator on the study's principal investigator Peter Horby of Oxford University in the UK said the reasons Chimerix not be told;. In a statement press the company has simply noted that the number of new cases in Liberia had "decreased significantly."

Horby said he doubts the decision was related to how the drug made in the first four patients. Instead, he believes Chimerix decided he did not want to continue bringing to market brincidofovir Ebola after discussions with the US Food and Drug Administration (FDA) has raised questions about the interpretation of studies animals. As chief scientist of the FDA, Luciana Borio in Silver Spring, Maryland, says she can not comment. "We have asked the company to disclose the facts surrounding the case and we could not." (FDA does not oversee the trial of Liberia itself.)

"Someone should call Chimerix and ask them," said Marie-Paule Kieny of the World Health Organization in Geneva Switzerland, who coordinated the international research effort on the Ebola virus. Science did this, but a spokesman for the company declined to comment.

Whatever motivation, "it was frustrating," said Horby. "We have invested a huge amount of resources, time, effort, in very difficult circumstances, such as MSF. it must not have been arrested at least it was for a very good reason. "With so few patients enrolled, the study results are" uninterpretable "said Horby, which nevertheless still hopes to publish a paper on the subject

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TKM-Ebola

negative results prove difficult to publish

at the peak of the Ebola outbreak in September 2014, the World health Organization (WHO) gathered experts in Geneva, Switzerland, to discuss the myriad potential treatments and help identify the most promising. The group has given priority to interventions that have proven successful in monkeys experimentally infected with Ebola and a drug called TKM-Ebola ended at the front of the pack. Made by Tekmira Pharmaceuticals Corporation of Vancouver, Canada, TKM-Ebola interferes with RNA of the Ebola virus.

But the company has had precious few doses, and a formal clinical trial was slow to start. Some researchers also frowned upon because the study was launched March 11 in Sierra Leone, has not had a randomized controlled design. But Peter Horby, a respected researcher from the University of Oxford in the UK, led the study, and the Wellcome Trust funded. Hopes ran high that it would at least give an indication of whether the encouraging results monkey would be supported in humans.

On June 19, however, Tekmira ended suddenly the study, without fully explaining why. Horby said after testing the drug on 14 patients, the study had reached a predefined "border futility." This means entering other patients was "unlikely to show that the drug was significantly beneficial," he said.

The absence of a clear advantage was "disappointing," Horby said, but he noted that it is not unusual for drugs to work in monkeys and humans fail. A problem may have been that animals were treated early in their illness; most Ebola patients seek care very late, he said.

next disappointment came when Horby The New England Journal of Medicine ( NEJM ) rejected a paper describing the results. He speculates that scientific publications are losing interest in Ebola, and the fact that this study lacked a randomized design and clear results have worked against her as well.

"Newspapers have published large amounts of anecdotal evidence on one or two cases and hundreds and hundreds of opinion and comment pieces, but we struggled to publish final data information but no trial, "said Horby. Although he understands that negative studies are less exciting," you have to balance this against the enormous difficulty of these tests and the almost complete absence of any data on the effects of treatment. "

WHO Assistant Director-General Marie Paule Kieny shares her frustration." it is problematic because it is very important that these results are in the open, "she said. A spokesman NEJM says she can not comment because the journal publication process is confidential. Horby said the document is currently being studied in another paper

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favipiravir

A large study fails to give solid answers

The largest study on the treatment done in the favipiravir tested Ebola epidemic, drug against influenza. The trial ended after the listing of more than 0 people, and its results could soon appear in a scientific journal. But the study may not give a clear answer to the key question: he works

favipiravir that inhibits viral enzyme called RNA polymerase critical and is developed by Fujifilm in Japan, has shown activity Ebola virus in test tubes and in mice. At the beginning of the epidemic, there was a big advantage over other drug candidates: He was generous and had proven safe when administered to healthy volunteers in Phase trials. Researchers at the National Institute of France for Health and Medical Research (INSERM) began a collaboration with researchers in Guinea, French-speaking countries, to test favipiravir four Ebola treatment units.

In February, the INSERM researchers presented what they said were encouraging preliminary results based on the first 69 patients. The drug appeared to save the lives of people who came to clinics with low levels of Ebola, they said. French President Francois Hollande welcomed the results in a press release and invited leading research Ebola at the Elysee Palace in Paris. Since then, all patients Ebola in Guinea were offered favipiravir.

Many researchers were less impressed. INSERM team has not used a randomized controlled trial (RCT) design, but gave all eligible patients of the drug; their results were compared to a group of Ebola patients who fell ill before the start of the trial. The problem is that the mortality greatly depends on the quality of care Ebola, which varies considerably over time and from one to another treatment facility. This makes such comparisons difficult. The drug also worked only in people without treatment have a much better chance of surviving Ebola because when they first sought care, they had relatively low levels of virus in their blood.

An RCT would have been impossible, says researcher INSERM Denis Malvy; it was unacceptable for the local population, already distrustful of the government and foreign workers Ebola. He said building research collaborations was hard enough without the added stress of asking local employees to refuse treatment to a control group. "It is easy to criticize a study," he said. "We decided to look for a signal, not a formal proof of efficacy."

But now, nobody is sure favipiravir should be used in the next Ebola outbreak. That's the bottom line, says Luciana Borio of the US Food and Drug Administration, and it shows that uncontrolled studies can cause more harm than good. "The result was that the nebula data area we were so scared about," said Borio. "We left not knowing if the product help, hurt, or does nothing."

The study design was also one of the reasons why the New England Journal of Medicine (NEJM) rejected an article on the results, said Malvy; instead of the newspaper offered him a letter of 300 words to the publisher, he said was laughable. (A NEJM spokesman declined to comment.) The study is now under review at PLOS Medicine Malvy said

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Interferon

A trial that few believed in

When Ebola spiral out of control in the summer of 2014, immunologist Eleanor Fish, University of Toronto in Canada thought it had some thing that could save lives. Since no treatment was available, Fish said it was logical to try interferon, a group of biochemicals with antiviral activity she had long studied.

Many scientists Ebola disagreed.

Fish sent the World Health Organization (WHO) study showing that interferon-α, delivered by an adenovirus and combined with a cocktail of antibodies, has an efficacy in monkeys infected with Ebola virus. But other researchers noted that has not been shown only interferons do anything. A panel requested by WHO to prioritize drugs for testing interferons considered "problematic". Side effects such as fever and muscle aches, which are similar to Ebola symptoms-could create problems in the Ebola treatment centers, the group said. "Basically, all interferons do not work," Peter Jahrling, a researcher Ebola veteran at the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, told a WHO meeting, summarizing the evidence animal therapies for Ebola. "I do not know why you want to do a clinical trial with them."

given the lack of alternatives at the time, Fish pushed forward with a test of the interferon-β, including in vitro studies suggested was the most effective way to counteract the replication of the Ebola virus, she said. she teamed with Guinean epidemiologist Mandy Kader Konde set up a clinical trial in the Ebola treatment center in Coyah, about 2 hours northeast of the capital, Conakry. But it was not until March 2015 to write the protocol and get the study approved by Guinean regulators. D by then, the number of Ebola cases had fallen sharply. Because interferons may make things worse if taken at the end of the infection, the trial enrolled patients within 6 days after onset of symptoms, which still has limited enrollment.

Ultimately, only nine patients participated in the study. All received interferon-β; having a placebo arm was unacceptable in Guinea, Fish said, that patient outcomes were compared with those of 21 untreated patients, matched for age, who were seen in the same center in the same period. Given the study design and small size, "I do not think there will be something out of this," said Marie-Paule Kieny WHO.

But fish disagrees. "Statistical analyzes indicate that [interferon] offered a therapeutic advantage," she wrote in an email to Science . "We have a number of measures that we evaluated that support this." Fish declined to elaborate, but said the data will soon be submitted for publication

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zmapp

A front- fane runner

zmapp, cocktail three artificial Ebola antibodies, has been the darling of the world of research and the media since missionary Kent Brantly and Nancy Writebol received treatment in the summer of 2014. CNN has described as a "secret serum that probably saved" their lives . CNN reporter Sanjay Gupta, a medical doctor said one source describes how Brantly had a "sudden deterioration" in Liberia and "thought he was going to die," but after receiving zmapp, "within 20 minutes to an hour" it was "a nearly complete reversal of symptoms. "However, from individual cases for statistical data that the drug really works in people was difficult.

zmapp worked brilliantly in monkey experiments, even save the animals in advanced stages of infection. When the antibody cocktail was administered to animals up to 5 days after infection with Ebola virus, each of them survived, scientists reported in Nature in August 2014. veteran Ebola researcher Thomas Geisbert of the University of Texas Medical Branch in Galveston called the result a "monumental achievement." But zmapp made by Mapp biopharmaceutical in San Diego, California, was so rare that by the mid-February 2015, only nine people had received and some were dead, adding that whatever its potential, there were limits.

it took until 27 February for a formal trial randomized controlled zmapp to start in Liberia, conducted by the US National Institute of allergy and infectious diseases (NIAID). But by then, the epidemic in Liberia was practically over. the team expanded the study Sierra Leone and hit a collaboration with french researchers working in Guinea to recruit patients there. (One patient in the US has also been included in the trial.)

But time was not on the side of the study. To date, the trial has enrolled about 70 patients, said lead researcher Clifford Lane NIAID in Bethesda, Maryland. Complicating the study is that patients also receive favipiravir Guinea, based on a French study inconclusive in this country that suggested he was an anti-Ebola effect. The team will zmapp a subset of country analysis to see if the effects of the two drugs can be untangled.

What the forerunner of the past will be shown to work remains the big question. The study safety data independently and the Supervisory Board (DSMB) that looks at the results once a month or more. "They have not yet stopped the trial, so we know he must at least do something," said Marie-Paule Kieny of the World Health Organization, which is still hopeful that zmapp become second story clinical success of the Ebola outbreak, after Merck

vaccine. But Lane's safer. "it is very difficult to read between the lines of a DSMB recommendation," he said. However, "I am hopeful that, although the data do not reach statistical significance, there could be at least a tendency to effectiveness of humans who support animal data."

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the blood of survivors

A trial whose fate is not known

whole blood of Ebola survivors has been given to people with the disease as an experimental treatment. This tarpaulin hung outside of Liberia treatment center when closing

The people who survive an infection like Ebola have a powerful weapon in their blood. Antibodies that conquered the invading microbe. In principle, a surviving blood infusion could be a lifeline for people newly infected. But an initial study in Sierra Leone test this concept remained unpublished and nobody seems to know what happened with the data.

The World Health Organization (WHO) has pushed for therapies studies based on blood early in the Ebola epidemic as the most promising drug candidates were rare, while the number of survivors was growing. These studies can be performed with either whole blood or its plasma, which has removed the cells; it is much more difficult technically because it requires so-called plasmapheresis machine to separate the plasma and cells.

Gevao Sahr, a hematologist at the University of Sierra Leone in Freetown and consultant to the Ministry of Health of the country and sanitation, decided to try the simplest option from the start. A study of whole blood transfusion began in the fall of 2014 in the hospital 34 military in Freetown. But at the same time, an international consensus has emerged that the use of plasma was the way forward, and collaborations have been set up to ship plasmapheresis machines and West Africa to test this strategy in Ebola three affected countries.

The whole blood study in Sierra Leone seems to have ended at the end of 2014; Gevao became the principal investigator for the plasma study of the country, in collaboration with the University of Liverpool in the UK and other partners.

But data from the whole blood study were published. Some press reports have suggested that he was successful, and Wiltshire Johnson Pharmacy Board of Sierra Leone to oversee clinical trials in the country, said Science 33 patients out of 44 who received transfusion survived. These are much higher survival rates than were reported at the time to untreated Ebola. But scientists warn that it is unclear how patients were selected for the trial, or if their care differed in other ways that made them more likely to survive.

Gevao did not respond to emails from Science . Scientists working on plasma studies say they do not know what happened with the whole study of blood. Neither is WHO. "I have not yet seen the results," said WHO Assistant Director-General Marie-Paule Kieny. "We have to chase it, we need to know what happened"

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Plasma

Cloudy results filtered blood

the blood of Ebola survivors contains antibodies that could help sick people with the disease, but blood is a precious commodity: donors can not be bled frequently, and the product must be used within a few months. .

Health Meaning

Special report: Ebola's thin harvest

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