workers of ELWA3 hospital in Monrovia, where many patients are treated Ebola
PHOTO :. DOMINIQUE FAGET / IMAGES AFP / GETTY
On October 2, Ashoka Mukpo left his father a voice message from Monrovia, saying he had " unwelcome but not unexpected news. "Mukpo, an independent US cameraman for NBC News, had tested positive for Ebola. Mukpo's father, Mitchell Levy, a pulmonologist who directs intensive care at Rhode Island hospital in Providence, immediately helped organize the transfer of his son to the Nebraska Medical Center in Omaha, one of four specialized centers of Ebola in the United States.
the big question then was how to treat the patient .
medical team, which included Levy, designed to intensively monitor Mukpo and give him the replacement of intravenous fluids and electrolytes, antibiotics to fight secondary infections, and medications to slow diarrhea and vomiting. But there were also three non-available treatments. TKM-Ebola, which inhibits the viral RNA, worked beautifully in monkeys, the best animal model. Kent Brantly, a medical missionary in Liberia who developed the Ebola virus and recovered, offered to donate plasma removed from the blood, which contained antibodies that might help. And there was brincidofovir, a drug being developed for other viral infections has been shown to stop the Ebola virus in test tubes. (The most famous drug candidate, zmapp, was not available at the time.)
After careful consideration, Mukpo and his doctors have chosen to use the serum with a proven response to and other virus-brincidofovir, which has significant safety record. But they decided to give up TKM-Ebola, despite its promise, due to concerns that it could trigger an overproduction of cytokines, a dangerous inflammatory response also caused by the Ebola virus, and limited data from human trials. "I'm not quite on my deathbed and does not need to take risks enormous," said Mukpo. Her doctor father had reached a similar conclusion. "I do not have a high degree of confidence that brincidofovir would work, but I was reluctant to try an experimental agent without data," says Levy.
Mukpo survived, but nobody has any idea whether experimental treatments have helped, did nothing, or even slowed his recovery. The same is true for Brantly and 17 other Ebola patients who received experimental interventions in the US and Europe. (Another Ebola patient was treated in Germany without experimental intervention.) Many like Mukpo, received multiple treatments at the same time, making it difficult to disentangle the impact of one of them. The fact that they were supported in modern hospitals, well-staffed can also help explain why 75% survived (see box, p. 911). "Probably the best we can say is that experimental treatments are not killing anyone," said Michael Kurilla, who heads the Office of Biodefense Research Resources and translational research at the National Institute of Allergies and infectious diseases (NIAID) in Rockville, Maryland.
now it's about to change. from next month, researchers will begin testing in West Africa to find an answer solid to the key question: are treatments work Carried out in makeshift emergency hospitals by researchers wearing full protective equipment in the middle of a deadly epidemic, it will be some of the drug trials most unusual ever done. and they also raise important ethical and practical questions, some of which were intensely debated at a meeting of the World health Organization (WHO) in Geneva, Switzerland, on 11 and 12 November .
Recovered patients Ebola Ashoka Mukpo with his father Mitchell Levy, a pulmonologist who helped guide treatment of Mukpo.
PHOTO: TAYLOR WILSON / Nebraska Medical Center
Perhaps most importantly, is it right to do randomized controlled trials (ECR), in which some people do not get the novel procedure? Médecins Sans Frontières (MSF), which led the medical response to the epidemic, not not say with such a deadly disease Ebola. Instead, on November 13th MSF said it will take part in three tests that will use another design in which all those who registered receives untested treatment. But others argue that these configurations can not give clear answers and wasting valuable scientific opportunity.
There is a debate uncomfortable and complex held under the pressure of extreme weather. "Everybody stepped outside their comfort zone in a big way," said Peter Horby of the University of Oxford in the UK, who heads one of upcoming trials and attended the meeting WHO
tO cURRENT ePIDEMIC dE started, Ebola treatment development was painfully slow. Since the first recognized outbreak in 1976, the virus has resurfaced two dozen times, but until 2014, it was less sickened 2,500 people in total. This was not done for an attractive market for private companies, leaving most of the research to be funded by the Government of the United States, which worries that hostile nations or bioterrorist can launch horrific attacks with the virus. and because traditional containment efforts have ceased epidemic to date in a few months, researchers have had little opportunity to test new treatments.
Among the candidates, the two leaders are TKM-Ebola, an inhibitor of RNA virus packaged in a lipid nanoparticle and zmapp, a cocktail of three antibodies that Ebola rose to fame in August, when it was given to laboratory Brantly did. (A CNN report breathlessly called a "secret serum which probably saved his life.") These drugs worked better than any other in monkey studies, which puts the "light years" other treatment, said Thomas Geisbert of the University of Texas Medical Branch at Galveston, who led many key experiences. "If I were exposed to the virus that I would take zmapp Tekmira or drugs and I do not worry," dit- he.
"Everyone keeps talking zmapp," said Annick Antierens, who heads the experimental on work Ebola drug to MSF in Geneva. But both zmapp and TKM-Ebola are relatively difficult to make, and despite vigorous efforts to accelerate their production less than a thousand of each of doses may be ready by the end of the year. both are difficult to test in affected countries because they require intravenous infusions.
other candidates are more easily manufactured and administered, but data supporting their use are lower. brincidofovir was designed to interfere with the replication of viral DNA, and it is now Phase III in progress against cytomegalovirus and adenovirus; about 1,000 people received this spring Chimerix, the manufacturer, had two laboratories outside test the drug against Ebola virus. they found that the drug effectively inhibited the virus in TestTube studies. Brincidofovir can not be tested in monkeys, because an enzyme in animals rapidly inactivate the drug, but Chimerix says studies in guinea pigs and mice are in progress.
Another option is favipiravir, a flu drug approved in Japan that has protected mice from Ebola when administered 6 days after exposure to the virus. But unlike monkeys, mice do develop a mild disease from Ebola strains, so that the experiment using a mouse genetically modified to lack the immune system against viruses. This makes the results difficult to interpret.
whole blood or plasma component-containing antibodies could theoretically be harvested from thousands of recovered Ebola patients, but "convalescent serum" has not worked well in monkey experiments. A published report shows that seven out of eight who received whole blood of survivors during a 1995 epidemic Ebola in the Democratic Republic of Congo have survived, but they were treated late in the course of the disease, and some researchers believe they might have recovered without serum. A horse serum that contains antibodies Ebola is being developed, too.
The drugs that target only the symptoms of Ebola, rather than the virus itself, could also help. Doctors in Germany, for example, two patients treated with an experimental treatment called FX06 which aims to stop the leakage of fluid from blood vessels, a major problem in patients with advanced infections Ebola virus. One patient recovered, the other died.
Many other ideas were. Kurilla sets up a WHO database publish negative results to discourage researchers from pursuing compounds that do not pass muster in screening assays or animal experiments. "We are flooded with people who suggest the same thing again and again," he said. A doctor in Liberia in particular, has received considerable attention for touting HIV drugs lamivudine, but there is zero evidence from laboratory tests that it has an anti-Ebola activity.
The researchers now unprecedented chance to test candidate therapies systematically. At the WHO meeting in Geneva last week, researchers who wish to conduct clinical trials for treatment of Ebola met with regulators, pharmacologists and representatives of the three most affected countries to work on how to spend anecdotes on the disks of evidence and test drugs. More than 0 products have been put forward as possible treatments, but far too few clinics are qualified to participate in trials, participants were informed. And given the lack of supply, and zmapp TKM-Ebola are not on the table yet. Instead, the least promising treatments go forward first.
An international consortium led by Johan van Griensven the Institute of tropical Medicine in Antwerp, Belgium, plans to test the convalescent serum in Conakry, the Guinean capital. The biomedical research INSERM French agency will conduct a trial to favipiravir Gueckedou, Guinea. Brincidofovir and will be tested in a study by Oxford or in Sierra Leone or Liberia. The three clinical trials will share a simple form to collect more data base; anything recording is extremely heavy when healthcare workers wear bulky protective gear.
patients in the processing unit Ebola spare in Kenema, Sierra Leone, in August
PHOTO :. WHO Ebola INTERVENTION TEAM
the ethical issues surrounding the tests have troubled the scientific community and humanitarian community and have been "vigorously debated" at the meeting, according to WHO. MSF said that for now it will not participate in trials that randomly decide who would receive treatment. "If an epidemic like this with such a high mortality rate would occur in Europe, I do not think that would be acceptable randomization patients," said MSF Antierens. "I certainly would not get the level of care if there is a promising drug available. "an editorial discussed many published online October 10 in the Lancet , signed by prominent ethicists and scientists from 11 countries, made the same point. Some fear RCTs can even trigger protests and violent reactions of the families of patients and their communities.
But others say that testing without an untreated control group raise ethical problems of their own. " I do not know if these agents could be harmful, and given a disease with a mortality rate as high as this one, you might not be able to detect this injury "without a control arm, said Clifford Lane, clinical director NIAID in Bethesda, Maryland. ECR also reduce the confusion introduced by variables such as how sick people are at the beginning of treatment and whether patients in a trial also receive better care. Randomization, Lane said, is the only effective way to "make sense of anything."
The three studies that will begin first, all MSF centers, will not have a design randomized instead, all patients will receive the treatment. survival rate 14 days later will be compared to survival in previous patients who did not receive treatment (the convalescent serum trial will also have an arm. " competitor "of control that escapes the ethical problems. Some patients will not be treated because there is no donor with a matching blood type)
Antierens agrees that these tests may not detect small effects of a drug, but says the goal is to determine whether an intervention is worthless or working well. "We are not interested in whether certain liver enzymes are a little higher," she said . "We are looking for a significant change in survival." Brincidofovir for testing, for example, researchers have agreed to define the survival less than 50% as "failure" and above 80% "success." If the data is ambiguous, an RCT could be considered, she said.
the horrific nature of the epidemic led to others rarely observed in clinical studies arrangements. The researchers responsible for the study favipiravir initially wanted to target adults in the first 2 days of illness. MSF called for the design to be changed so that no one can be denied to the people of drugs, including who were sick longer and children. "People on the ground said:" What we will do when a family arrives? We treat the parents and not the child? "Xavier said Lamballerie of Aix-Marseille University in France, who is leading the study. The study brincidofovir recruit up to 140 people, and at the request of MSF will continue to provide the drug while the test data are being analyzed to ensure that no patient misses a potentially effective treatment.
PROMOTERS dE RCTS are aggressively pushing ahead with test plans, too. Luciana Borio of the US Food and Drug Administration in Silver Spring, Maryland, who attended the WHO meeting; NIAID Lane; and others have developed a protocol that would test multiple interventions, including zmapp and TKM-Ebola in one large RCT, using sophisticated Bayesian statistics to get an answer as quickly as possible. Lane is currently negotiating with the Liberian government about the implementation of many of these studies. Liberia is not opposed to ECR, said Stephen Kennedy, a researcher at the University of Liberia Pacific Institute for Research and Evaluation African Centre in Monrovia, which advises the Ministry of Health of the countries on its control of research Ebola clinic. "We must use the gold standard," said Kennedy. "We understand the problems and we know what is appropriate for Liberia."
Borio understands the concerns about randomization, but said that do not get a clear answer would be worse. non-randomized trials were announced last week a "significant risk of not generating interpretable data," said Borio. "It is so important to get this right. It is important for patients who become affected in this outbreak, and for generations to come, given that future outbreaks will surely occur. "
The US phased out the use of leaded gasoline for automobiles in 1996 but many small aircraft continue to run on it. It is disturbing to some experts on public health, because lead is a potent neurotoxin, and lead to the aviation gas is now the largest contributor to the nation of lead pollution in the air. And studies suggest that people who live near or work in airports may have high levels of lead in their blood. Consequently, advocates for years have pushed the aviation industry to get the lead aviation gasoline, or avgas.
Last week brought a milestone in this effort. The Center for Environmental Health (CEH), an advocacy group based in Oakland, California, announced a legal settlement with 30 companies that sell or distribute avgas lead in California, bringing closure to a long trial that been closely watched in the small -Construction community. Under the regulation, companies must sell the lowest leaded petrol which is commercially available in sufficient quantities, warn the public about exposure to lead hazards by signs displayed in airports and notices sent to nearby residences, and pay a total of $ 550,000 in penalties and legal costs.
"We are very optimistic that he will make a transition [away from leaded avgas] happen," said Caroline Cox, research director of CEH. It is a change, she said, that "should have happened back when they passed cars away from leaded gasoline."
Lead is added to avgas to prevent engine knock, which can cause safety problems during the flight. Avgas is the last remaining lead in transport fuel in the United States, where about 167,000 mainly small aircraft piston engine use, according to the Federal Aviation Administration (FAA). (commercial Aircraft and many business jets use unleaded jet lead.) Approximately 480 tonnes of lead avgas were released to the air of the country in 2011, more than half of the total amount released lead this year, according to the environmental protection Agency. in 2013, the agency found that two of the 17 airports where lead emissions were monitored exceeds its quality standards the air to lead, both in California.
Phasing lead auto gas, and its ban in household paint and other measures, is credited with a dramatic drop in the mean levels of lead in the blood of American children since the 1970s emissions of lead in avgas air are much lower than past emissions of lead from automobile gas. Yet a 2011 study found that children living a kilometer of airports in North Carolina where planes avgas use had higher levels of lead in their blood than children living farther. A 2013 study showed that the aircraft maintenance workers at airports that sold lead avgas had higher levels of lead in the blood that workers in airports that do not.
CEH initiated legal proceedings in May 2011 under Safe Drinking Toxic Enforcement Act of Water and California, also known as Proposition 65. The state is home to more than 0 airports serving small aircraft, but CEH targeted companies operating at 23 of the busiest those located near population centers, said Cox. Some in the industry worried costume mean the end of AVGAS sale and grounding of 37,000 avgas-using aircraft in California, where the settlement avoids.
Ray Richmond, CEO of Crownair Aviation in San Diego, said the long legal battle hurt its business, costing tens of thousands of dollars, including legal fees and more than $ 7,000 in penalties imposed by Regulation. Richmond said that the main beneficiaries appear to be lawyers rather than the environment through reductions in fuel and lead content that companies like his reality have little control over what fuel they can offer. "I'm glad it is over," he said. "The impact for us is that there is a lot of money to spend on something that we do not think that solves the real problem."
Alternatives to lead avgas exist for many aircraft, but they are not widely available in airports. About three-quarters of US planes that run on avgas could use regular gasoline automotive unleaded, provided it is free of ethanol. But only about 100 US airports offer it-a small fraction of the approximately 20,000 in the country. The regulation requires distributors to offer this fuel AVGAS mogas-called at any avgas in California seller based at the airport making the request, subject to several conditions.
Another alternative is a kind of avgas known as 100VLL name, for "very low lead," which has a maximum lead content of 19% lower than standard avgas and is usable by entire fleet burn avgas. She, too, is rarely sold and is unavailable in California. Cox said she is optimistic the settlement will help bring fuel not only in California but also at the national level by creating demand. "Our hope is that we have all these airports in California that have committed to buy as it becomes available this creates a market demand and company will start providing," she said.
the aviation industry has long been that the best solution is one unleaded alternative fuel that will work for all aircraft now burning leaded avgas. avgas the market is so small, industry officials say it will never make economic sense to sell more than one fuel at airports serving the AVGAS. FAA customers with broad industry support, is working to identify a replacement unleaded avgas. in 2011, the agency has announced a target make available a 2018, but a recent press release said that tests candidates fuels would be completed by then.
Although he expressed his satisfaction with the terms of the agreement, Mark Willey, CEO of Napa Jet Center, a defendant in the lawsuit, said he and other stakeholders to reduce aviation fuel lead content will probably wait for replacement, the resolution of the FAA or regulation.
in the end, a federal regulation requiring a transition nationally for unleaded gasoline is what is needed, said Marcie Keever, legal director of Friends of the Earth in Berkeley, California , an advocacy group that was not involved in the trial of CEH. Nevertheless, Keever said the regulation is a step in the right direction. "It helps us to get on the road to make lead free and make people aware that there is a possibility to go lead-free," she said.
A health worker Ebola treatment center run by the company of the French Red Cross in Macenta, Guinea
PHOTO :. KENZO TRIBOUILLARD / AFP / GETTY IMAGES
When Western scholars began to lay the real world test bases to end Ebola virus vaccines of last summer, Guinea has been on their list of potential locations. There were fewer cases per week that neighboring Sierra Leone and Liberia, and the patients were scattered over a country the size of the UK with very little infrastructure. At a meeting of experts in Geneva, Switzerland, on October 23, the National Institutes of Health (NIH) presented a test plan for Liberia, while the US Centers for Disease Control and Prevention (CDC) offered proposals for Sierra Leone, but there was nothing for Guinea. "What about us?" Guinean delegates asked, said biostatistician Ira Longini of the University of Florida in Gainesville, who attended the meeting. "You let us out."
Now, in an ironic twist, many scientists say an unusual Ebola vaccine trial is expected to begin next month in Guinea may produce the first and perhaps the only answers on vaccine efficacy . New cases of Ebola in Liberia fell sharply, and began to drop in Sierra Leone, which makes it much more difficult to prove whether a vaccine works maybe even impossible. In Guinea, however, a less intense epidemic has not assigned, perhaps making it "the only country where the trial will be enough power to give an answer," says Adrian Hill, a vaccine researcher at the Oxford University in the UK.
the push to test for Ebola vaccines is accelerating. last fall, an international ethics committee convened by the World health Organisation ( WHO) found that the unprecedented threat acceptable to take the Ebola virus vaccines directly from small phase I safety studies in large phase III efficacy studies, while simultaneously conducting phase II studies. two vaccines are now almost ready to jump in. one by GlaxoSmith-Kline (GSK), contains a chimpanzee adenovirus with a gene that codes for the Ebola virus surface protein. the other, developed by NewLink Genetics but now manufactured by Merck, uses a virus called livestock VSV Ebola for transporting a gene.
How to design studies was the subject of intense ethical and methodological debates. In the end, the researchers settled on very different models for each country. In Liberia, the study will use a conventional randomized controlled trial with three arms, one for each of the two vaccines and a third in which people do not receive. It will target the general population in the capital, Monrovia. The CDC plan for Sierra Leone is to recruit workers in Ebola treatment units; everyone will get the vaccine, but some sooner than others. The trial has yet to choose the vaccine, it will test.
The welcome decline in the cases of these two nations means that testing should include a lot of people to determine their effectiveness. Although NIH now plans to enroll nearly 10,000 people in each arm of the trial of Liberia, the current infection rates mean that about 6 months will take to reach a statistically significant response if the vaccine protects 50% of those who get it, said Ripley Ballou, who heads the project vaccine against Ebola GSK. (One answer would come faster if protection rates are better.)
But the epidemic of Liberia could end in mid-2015, suggesting a model published this week in PLOS Biology . "There is a real risk that we will not have an answer at all to the end of the day," said Ballou. Therefore, in addition to counting the cases and deaths, researchers should investigate the immune responses carefully in vaccine recipients to learn as much as possible of each test, said Claire-Anne Siegrist vaccinologist of the University of Geneva.
Guinea study will present an old vaccine strategy, never before used in a clinical trial, it which can yield results more quickly. Inspired by the worldwide campaign that smallpox eradicated in the 1960s, it is based on a concept called ring vaccination. the researchers will look for people newly infected with Ebola, then try . vaccinating a "ring" of people living around them, most likely their village or neighborhood in half rings, the researchers administered the vaccine immediately to an average of 50 people; they will compare their results with other rings where researchers expect 4 to 8 weeks for the vaccine, says John-Arne Röttingen of the Public Health Institute in Oslo, Norway, who heads the study steering group . (It was designed by a coalition including WHO, Médecins Sans Frontières, Longini and several other academic partners.) Frontline health workers will also receive the vaccine, with no control group.
The vaccine for Guinea trial has not yet been chosen, but "we will start in February, even though it is February 28th at 23:30," WHO is Ana Maria Henao-Restrepo said a vaccine against Ebola meeting at the Fondation Mérieux in Veyrier-du-Lac, France, this week. The study could have answers after 3 months, said Röttingen.
If any of the vaccine works and the number of cases keep falling, targeted ring vaccination strategy to mop up remaining pockets of virus can become the best way to fight against the epidemic, said Röttingen .
"It is a very interesting design of a group of very smart people," says Ballou, who adds that the logistical challenges remain daunting in Guinea. The study will chase the case over a wide area, and it does not have the operational and financial support of major players such as NIH or CDC
Meanwhile, a third vaccine candidate has entered the fray :. a pair of new vaccines used in tandem. the week last, Johnson & Johnson announced that it had initiated a Phase I testing and is also looking to phase III study sites Whether any of the three countries can bear a second large study and that. there will be enough new infections once the vaccines are ready for their big jump-remains to be seen.
Correction (23 January 2015) :. a vaccine trial against Ebola virus in Liberia has not conducted by the NIH, as the story says, but by a partnership between the Liberian government and the United States
↵ * with reporting by Kai Kupferschmidt and Jon Cohen.
A health worker Ebola treatment center run by the company of the French Red Cross in Macenta, Guinea
PHOTO :. KENZO TRIBOUILLARD / AFP / GETTY IMAGES
When Western scholars began to lay the real world test bases to end Ebola virus vaccines of last summer, Guinea has been on their list of potential locations. There were fewer cases per week that neighboring Sierra Leone and Liberia, and the patients were scattered over a country the size of the UK with very little infrastructure. At a meeting of experts in Geneva, Switzerland, on October 23, the National Institutes of Health (NIH) presented a test plan for Liberia, while the US Centers for Disease Control and Prevention (CDC) offered proposals for Sierra Leone, but there was nothing for Guinea. "What about us?" Guinean delegates asked, said biostatistician Ira Longini of the University of Florida in Gainesville, who attended the meeting. "You let us out."
Now, in an ironic twist, many scientists say an unusual Ebola vaccine trial is expected to begin next month in Guinea may produce the first and perhaps the only answers on vaccine efficacy . New cases of Ebola in Liberia fell sharply, and began to drop in Sierra Leone, which makes it much more difficult to prove whether a vaccine works maybe even impossible. In Guinea, however, a less intense epidemic has not assigned, perhaps making it "the only country where the trial will be enough power to give an answer," says Adrian Hill, a vaccine researcher at the Oxford University in the UK.
the push to test for Ebola vaccines is accelerating. last fall, an international ethics committee convened by the World health Organisation ( WHO) found that the unprecedented threat acceptable to take the Ebola virus vaccines directly from small phase I safety studies in large phase III efficacy studies, while simultaneously conducting phase II studies. two vaccines are now almost ready to jump in. one by GlaxoSmith-Kline (GSK), contains a chimpanzee adenovirus with a gene that codes for the Ebola virus surface protein. the other, developed by NewLink Genetics but now manufactured by Merck, uses a virus called livestock VSV Ebola for transporting a gene.
How to design studies was the subject of intense ethical and methodological debates. In the end, the researchers settled on very different models for each country. In Liberia, the study will use a conventional randomized controlled trial with three arms, one for each of the two vaccines and a third in which people do not receive. It will target the general population in the capital, Monrovia. The CDC plan for Sierra Leone is to recruit workers in Ebola treatment units; everyone will get the vaccine, but some sooner than others. The trial has yet to choose the vaccine, it will test.
The welcome decline in the cases of these two nations means that testing should include a lot of people to determine their effectiveness. Although NIH now plans to enroll nearly 10,000 people in each arm of the trial of Liberia, the current infection rates mean that about 6 months will take to reach a statistically significant response if the vaccine protects 50% of those who get it, said Ripley Ballou, who heads the project vaccine against Ebola GSK. (One answer would come faster if protection rates are better.)
But the epidemic of Liberia could end in mid-2015, suggesting a model published this week in PLOS Biology . "There is a real risk that we will not have an answer at all to the end of the day," said Ballou. Therefore, in addition to counting the cases and deaths, researchers should investigate the immune responses carefully in vaccine recipients to learn as much as possible of each test, said Claire-Anne Siegrist vaccinologist of the University of Geneva.
Guinea study will present an old vaccine strategy, never before used in a clinical trial, it which can yield results more quickly. Inspired by the worldwide campaign that smallpox eradicated in the 1960s, it is based on a concept called ring vaccination. the researchers will look for people newly infected with Ebola, then try . vaccinating a "ring" of people living around them, most likely their village or neighborhood in half rings, the researchers administered the vaccine immediately to an average of 50 people; they will compare their results with other rings where researchers expect 4 to 8 weeks for the vaccine, says John-Arne Röttingen of the Public Health Institute in Oslo, Norway, who heads the study steering group . (It was designed by a coalition including WHO, Médecins Sans Frontières, Longini and several other academic partners.) Frontline health workers will also receive the vaccine, with no control group.
The vaccine for Guinea trial has not yet been chosen, but "we will start in February, even though it is February 28th at 23:30," WHO is Ana Maria Henao-Restrepo said a vaccine against Ebola meeting at the Fondation Mérieux in Veyrier-du-Lac, France, this week. The study could have answers after 3 months, said Röttingen.
If any of the vaccine works and the number of cases keep falling, targeted ring vaccination strategy to mop up remaining pockets of virus can become the best way to fight against the epidemic, said Röttingen .
"It is a very interesting design of a group of very smart people," says Ballou, who adds that the logistical challenges remain daunting in Guinea. The study will chase the case over a wide area, and it does not have the operational and financial support of major players such as NIH or CDC
Meanwhile, a third vaccine candidate has entered the fray :. a pair of new vaccines used in tandem. the week last, Johnson & Johnson announced that it had initiated a Phase I testing and is also looking to phase III study sites Whether any of the three countries can bear a second large study and that. there will be enough new infections once the vaccines are ready for their big jump-remains to be seen.
Correction (23 January 2015) :. a vaccine trial against Ebola virus in Liberia has not conducted by the NIH, as the story says, but by a partnership between the Liberian government and the United States
↵ * with reporting by Kai Kupferschmidt and Jon Cohen.
In anticipation of the 2016 budget proposal, the White House has tipped his hand on a big priority: fight against antibiotic resistance. A fact sheet released today describes how President Barack Obama plans to double government investment in the fight against the mounting crisis resistant infections Public health medicines disseminating approximately $ 1.2 billion in funding for several federal agencies.
This amount includes $ 650 million for the National Institutes of Health (NIH) and the Authority for Advanced Biomedical Research and development (BARDA) to study the bacterial resistance mechanisms and promote the development of new antibiotics and diagnostics. NIH funding would also support a clinical trial network that would allow developers to collect drug data more easily between multiple clinics, according to the information sheet.
The US Centers for Disease Control and Prevention would receive $ 280 million for monitoring and research, including the addition of 10 sites to its Emerging Infections Program. The fact sheet also shows two new programs :. A detection network to identify new outbreaks and a comprehensive approach "isolate bank" to collect known resistant bacteria
Meanwhile, the Food and Drug Administration will receive 47 million $ to evaluate new drugs and diagnostics and to continue its efforts to eliminate the use of certain antibiotics in animal feed, a major threat to the value of these drugs as human medicines. The Ministry of Agriculture also see a quadrupling of its funding to explore alternatives to the use of antibiotics in livestock.
The overall approach follows closely the recommendations of a recent report by the Council Chairman of Advisors on Science and Technology, says Amanda Jezek, vice president of public policy at the Infectious Diseases Society of America in Washington, DC "this appears to be what we expected in terms of next steps," she said.
proposal is the latest international effort to revitalize research and development drug-industry historically inhospitable antibiotics for major pharmaceutical companies. the short-term treatment with antibiotics and doctors' desire to retain the most effective drugs for future emergencies make it difficult for companies to make profits. and in scientific research to identify new targets for antibacterial drugs, "the low-hanging fruit has been picked," says Gail Cassell, an executive pharmaceutical company and a visiting scholar at Harvard Medical School who chairs a working group on antimicrobial resistance to the American Society for Microbiology.
But the new funding is likely to stimulate development, said Cassell, who praises in particular the emphasis placed by the White House on new diagnostics. Doctors are desperate means for detecting resistant microbes and choose the right treatment quickly, without waiting days for lab results. Earlier this year, the White House announced that the NIH and BARDA would co-sponsor a price of $ 20 million for a quicker test to recognize highly resistant infections. But Cassell stresses that developing societies, these technologies face other obstacles including the health-care reimbursement complexities for their products that can not be treated with a financial boost from the government alone.
jãzëk expects that part of the budget proposal met with sympathetic ears in Congress, both the House of Representatives and the Senate have the priority to the issue and proposed legislation to create a route 'accelerated approval for new antibiotics, she said. "The image of the federal budget will be difficult," she said, but the jockey for new funds, the proposal "represents a better chance than most."
The initiative of antibiotics will be part of the request of Obama budget to be fully unveiled on February 2, 2016 for the fiscal year that begins in October.
Click here to see all of our coverage of the 2016 budget
President Barack Obama this morning unveiled the Precision Medicine Initiative, it will include in its budget request for 2016 a hearing White House East Room packed with federal leaders of science, university researchers, patient advocacy groups and research, the guests of the Congress, and executives from the pharmaceutical industry. Basically, they seemed to rejoice in his plan to find ways to use genomics and other molecular information to tailor patient care.
After mocking his own knowledge of science a model of chromosomes made from pink swim noodles "was helpful for me," he said, Obama explained that accuracy of medicine ". deliver the right treatments at the right time, every time to the right person "such an approach" gives us one of the greatest opportunities for medical new breakthroughs we have ever seen, "he added. He then described the $ 215 million initiative, which includes new support for cancer genomics and molecular targeted drug testing at the National cancer Institute (NCI), and plan to study the links between genes, health and the environment as 1 million Americans pooling of existing participants in cohort studies.
"so, if we have a large data set, a large pool of people is varied, and that allows us to really draw not only the genome of a single person, but now we can begin to see connections and patterns and correlations that helps us refine exactly what we try to do regarding treatment , "the president said in his 20-minute speech, flanked by a red and blue model of the DNA double helix
in the room were different patients, Elana Simon, a young survivor of a rare liver cancer who helped sequence the type of cancer, who introduced the president. the former dominant basketball great Kareem Abdul-Jabbar, who apparently takes a targeted treatment for his leukemia; and cystic fibrosis patient William Elder, a medical student 27 years and invited to the State of the Union address that takes a new drug for the genetic flaw underlying form of the disease.
Representative Diana DeGette (D-CO), who worked on the 21st century Cures, a plan to accelerate the development of drugs and Senator Lamar Alexander (R-TN), which has similar goals were also present.
Sitting in the ranking were the two lieutenants who will carry the bulk of precision medicine plan: National Institutes of Health (NIH) Director Francis Collins and NCI Director Harold Varmus. Another participant was Craig Venter, who led the private effort to sequence the human genome in the 190s who were involved with public effort led by Collins. (There are fifteen, Venter was sitting in the same room with Collins when President Bill Clinton announced the first draft of the human genome.) Venter is now CEO of a company called Human Longevity Inc. that aims to sequence genomes of 1 million participants by 2020 a new competitor to private Collins federal cohort study, perhaps.
many other medical biobank genome projects in the centers and university health companies claim to be part of the cohort study of 1 million people. NIH will begin to explore which studies to include a meeting of 11 to 12 February (agenda here) which will also examine issues ranging from the protection of data using electronic medical records.
Amidst all the hoopla, a leading human geneticist in the audience offered a cautionary note. David Altshuler, who recently left the Vertex Pharmaceuticals Broad Institute in Boston, which makes drugs for cystic fibrosis brother, warns that even if the new American cohort study 1 million can discover new potential drug targets, will be 10 to 15 years before these discoveries lead to a successful drug.
"This is the first step," said Altshuler. "No amount of genome sequencing could never lead to a new drug directly."
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Fixed, February 2 10:30 :. An earlier version of this story badly told that the treatment Elana Simon involved sequencing the tumor
A committee convened by the Institute of Medicine (IOM) proposed a new name for a condition known variously as chronic fatigue syndrome or myalgic encephalomyelitis. The new name unwieldy: systemic disease effort intolerance, or Minion. In a report published today, the committee also suggests a new set of diagnostic criteria for Minion.
Having reviewed more than 9,000 scientific studies, hear expert testimony, and solicit public comments, the Committee concluded that "the name " Chronic fatigue syndrome has done a disservice to many patients, "calling it" stigmatizing and trivializing. " myalgic encephalomyelitis (ME), they noted, "does not accurately describes the main features of the disease."
There are at least 20 sets of diagnostic criteria, the Committee noted that confused patients, clinicians and their families and researchers studying the disease. The proposed diagnostic criteria are more focused on "core symptoms" as a reduced capacity or with disabilities to work and study, malaise after exercise, and sleep "unrefreshing". The report, "Fatigue Syndrome Beyond Myalgic Encephalitis / chronic: Redefining disease," runs 235 pages
Peter Rowe, who heads the chronic fatigue clinic the. S Johns Hopkins Children Center in Baltimore, Maryland, and was one of 15 members, had praise for the process and product. "This report is phenomenal," said Rowe, noting that it had unanimous support. "It has the best summary of the evidence that I have ever read." The US Department of Health and Human Services and the 'social security administration sponsored the study and the IOM report.
systemic intolerance disease effort does not exactly roll on the tongue. Committee member of the IOM Ronald Davis, a biochemist who heads the genome center at Stanford University in Palo Alto, California, said the group considered some 100 options. "Boy, did we struggle with that," he said. "it is difficult to find a good name, and I do not think it's a perfect name. "
But Davis believes that its essential to eliminate chronic fatigue syndrome. "My son is sick, and when I tell people, they say, 'I had that once, because they were tired once," he said. "ME is a better name, but n 'there is no real data that match the name. "
Davis hopes the report will convince all clinicians they can diagnose the disease and it is real." I will hope get rid of those who can not believe, "said Davis. "They're going to keep it for themselves. It is the incompetence and it is malpractice."
The new diagnostic criteria are based on the so-called consensus criteria in Canada to first put forward in 03. But the report offers a simple separate definition that focuses on "the central element of this disorder," said President Ellen Wright Clayton of the committee to "public dissemination event" held at IOM this morning. "The essence of this disorder is that if patients with this disorder are involved in the effort - cognitive, emotional, physical, whatever - that their symptoms are made much worse and often for an extended period of time, "said Clayton, professor of law at Vanderbilt University in Nashville. the name, she said, is a reflection." We want to name what it is, " she says. "This is what the patient experience."
The committee was "struck by the relative scarcity of research" that disappeared in Minion. "Remarkably little research funding has been made available to study the etiology, pathophysiology and effective treatment of this disease, especially given the number of people affected, "the report said. (He cited estimates say between 836,000 and 2.5 million Americans chronic or ME fatigue syndrome, but Davis points out that some popular diagnostic criteria have definitions too liberal for the condition.)
the report recommends a multidisciplinary committee reviews the diagnostic criteria Minion within 5 years. Rowe said they may want to review the name, too. "We do not think it's going to be the name forever, but it is a step forward," he said.
SEATTLE, WASHINGTON When French scientists presented the results of a drug test at a conference Ebola release Monday, they did it with a lot of warnings, but their message was hopeful: the drug favipiravir seemed to reduce mortality in people with low and medium-high levels of virus in the blood the researchers told reporters at the Conference on retroviruses and opportunistic infections (CROI) here.
But when the head of Denis Malvy study from the University of Bordeaux in France has presented more details on the results CROI, many colleagues have cooled. Many scientists have criticized the evidence and the design of the trial, which is underway at four clinics in Guinea. "It tells us nothing," said epidemiologist Scott Hammer of Columbia University, who chaired the meeting.
In her presentation, Malvy focused on a group of 40 patients who started the trial with viral loads lower than 29 others who obviously do not enjoy favipiravir. As he said on Monday, only six of the 40 patients died than half what was expected on the basis of similar patients treated in the same clinics during the last 3 months. In addition, after 4 days of starting treatment on favipiravir, a drug against influenza, 51% of these patients had low levels of virus in their blood than the standard test could not detect it. "There was a signal that monotherapy favipiravir can reduce the viral load," said Malvy.
Malvy was careful to note the limitations of what he called a "non-comparative proofing" concept study. "the purpose of this test is to provide evidence that will better designed trials," said Malvy. "This type of test does not provide a high level of proof and does not definitively answer a question." Studies are underway in France with blood samples from the same patients will analyze more closely the evolution of Ebola virus levels every day they received treatment. The researchers will also for the first time to determine if the drug has an effect in monkeys, an animal model widely used for Ebola. And the current study may provide more data.
But Hammer said the trial was "a lot of flaws in it, from study design to data interpretation." The immune system naturally drives down viral levels, making it difficult to separate the effects of the drug, he noted. Because the study did not compare treated with untreated people who sought care at the same time he used what is called a "historical" control-Hammer said he could not determine whether these drops in viral levels or providing putative survival are related to favipiravir.
Since the beginning exploded in August, researchers have vigorously debated how to set up studies of drugs and vaccines for Ebola, some randomized controlled studies advocating, in which a group of patients do not receive the drug as the fastest way to get results. Clifford Lane, deputy director at the National Institute of Allergy and Infectious Diseases of the United States, made this point in his presentation at the meeting, but did not single favipiravir the critical study. "As uncontrolled, supposedly compassionate studies fail to clear conclusions, they blur the water to the point that it becomes increasingly difficult to carry out appropriate studies," warned Lane.
Together with Liberian officials, Lane is about to launch a randomized study of an antibody cocktail called ;. zmapp this study does not include a control group in which patients will receive standard care, but not the drug Lane says Guinea and Sierra Leone have so far refused to participate in the study because of ethical concerns not giving the treatment to all participants. (Sierra Leone has shown some support for the design, however, and discussions are continuing.)
Jean-François Delfraissy, which coordinates the response of France Ebola and also heads the HIV / AIDS research program of the country, said he disagreed with Lane and contrasts the argument zmapp tests as planned. "I'm a principal investigator for a long time with randomized controlled trials, and early combination therapy for HIV, they are not required to show the drugs are useful," said Delfraissy, who co-signed an editorial the Lancet which opposed this design for Ebola treatments. "It's hard to have a randomized trial when mortality is 50% or 60%."
Delfraissy does not rule out supporting the official with zmapp modification. "It is an open question," he said, noting that he had discussions with Lane here. Specifically, Delfraissy said if the studies on monkeys and finer analysis of patient samples were positive, perhaps the standard of care should include favipiravir in the control arm in the studies and zmapp other experimental treatments.
Hammer said he understands the perspective of Delfraissy but said, randomized controlled trials have played an important role in the history of the development of drugs against HIV. It highlights a controversial study in 1997, a year after the so-called "triple therapy" has proven itself found that three antiretroviral drugs were better than two. "We proved," said Hammer. "And there was no BS about it later."
A new report on the ethics of Ebola, released today by the US presidential Commission for the study of bioethical issues, takes a nuanced view of questions about the design of the study, the committee does not comment on placebo-controlled studies, but leaves room for other models too well. "test designs should be methodologically rigorous and capable of generating results that are clearly interpretable acceptable to host communities and, wherever possible, to minimize delays to the completion of the research" the report said. "The well-designed controlled trials placebo can meet these conditions, and innovative designs, such as adaptive randomization, should be considered as a way to answer these research objectives."
* Ebola files: science and Science Translational Medicine made a collection of research articles and news about the Ebola virus and the current epidemic available for researchers and the general public.
Researchers hope to recruit 100,000 Pakistanis and Bangladeshis living in East London in one of the first large studies in the long term to explore the links between genetics and health in a poor ethnic community. The study, launched today, is also one of the largest effort yet to find rare individuals who are healthy, despite the absence of a specific gene.
East London is home to many poor immigrants from Pakistan and Bangladesh, and communities suffering from high rates of diseases such as heart disease and diabetes. The study East London Genes & Health will focus on two groups that are left out of most genetic studies, which rely heavily those of Northern European descent. "It is a great opportunity to improve health and the health of the population in East London," said co-leader of the study David van Heel from Queen Mary University of London, who announced study today. the funding of £ 4 million comes from the Wellcome Trust and the Medical Research Council in the United Kingdom.
researchers also hope to gather information on healthy people who have mutations in both copies of a gene that make it non-functional. These rare individuals could shed light on "what happens when parts of the genetic material are not working," says co-study leader Richard Trembath. If the missing gene protects somewhat against the disease, a drug that targets this gene could treat the disease without causing side effects. An example is PCSK9 , a gene found to be missing in a woman "perfect health" in Texas that led to a new class of cholesterol-lowering drugs, notes van Heel.
These "human knockouts" are extremely rare in the general population. But the chances that someone will inherit two knocked-out copies of the same gene were higher in the groups in which relatives often marry, such as the Pakistani and Bangladeshi communities. (This explains why the rare monogenic diseases are more common in these groups, although the study of these diseases are not the purpose of the study is London, it is the subject of another large British study, Genomes project 100,000.) "It's an opportunity for us to better understand the appearance" of knocked-out genes, van Heel said.
investigators plan to spend 4 years to recruit volunteers 16 and older, healthy or ill, from Bangladesh or Pakistan. Participants will give a saliva sample and allow scientists to access their health records. Sanger Institute Wellcome Trust has agreed exomes sequence (DNA encoding the protein) to the first 25,000 participants, hopefully by the end of 2017, van Heel said. The Broad Institute in Cambridge, Massachusetts, will contribute to genomic analysis.
Some participants may be invited in the next two decades to participate in the study of diseases, gene knockout, and how certain genes influence how people respond to medicines. Volunteers will not receive any direct benefit from the study, Trembath admits, but they will have the opportunity "to make a difference to the health of future generations."
Researchers have found a way to deliver genes to activating molecules called transcription factors in specific tissues of a live animal for the first time. The approach that many have written off as too difficult technically prevented form of liver damage in mice, although it has many more technical hurdles before it can be used in other tissues, or in people.
"This is a very exciting job," said Hsiang-Rong Tseng, a chemist at the University of California (UC), Los Angeles. ". It will bring the area of provision of transcription factor in a different place "
Our cells produce over a thousand unique transcription factors, each of which binds to a specific region of DNA to ask the transcription of a gene. created from DNA from an RNA template for a new protein Modification of the activity of these factors could, for example, an amplifier for the production of proteins that suppress tumors or reduce inflammation, and even reprogramming of adult cells in immature cells or types of cells. and unlike other gene therapy approaches that introduce permanently DNA to stimulate the production of proteins, factors transcription decompose and leave no lasting effect on the genome.
But cells have ways to close on or destroy relatively large proteins such as transcription factors when they are delivered to the outside rather than to be realized within the cell, said Niren Murthy, a Bioengineering at UC Berkeley. If a transcription factor enters a cell at all, he will eventually digested in a waste disposal organelle called the lysosome, and never will where it can turn on a core gene. "This remains a major unsolved problem," he said. And from proteins, transcription factors are particularly sensitive to chemical modification, he adds. Linking to useful molecules that might interact with cell receptors or penetrating membranes often means changing their chemical structures so they are no longer their work.
in 2011, the group Tseng has found a new way to deliver bulky transcription factors in cells without substantially altering their structure chemical. by setting a transcription factor to a DNA loop that contains the same sequence, it is intended to recognize in the cell, and then wrapping it in a positively charged nanoparticle that can penetrate the cell membrane, they were able to provide the protein in human cells in a dish.
in the new study, Murthy and his colleagues built on this basic concept connection to attach a transcription factor to a part of the DNA, but they used DNA as scaffolding to hold several other molecules that come in handy on the trip of the transcription factor. This new complex, which they called an assembled DNA recombinant transcription factor (DART) has two chemical chains that can disrupt the membrane of a cell lysosome. They are capped with sugar molecules that prevent them from working until the DART is trapped in the highly acidic contents of the organelle. These sugars also originally intended DART specifically the liver cells by interacting with receptors on their surfaces.
For the first prototype DART, the group chose a well-studied transcription factor called Nrf2, which regulates a number of inflammatory and antioxidant genes. "In animal models, it has literally been able to protect against all known inflammatory diseases, from Alzheimer's disease to liver disease to atherosclerosis," says Murthy. To test the ability of the DART send this protein in the liver, the researchers first injected mice with a high dose of the painkiller acetaminophen pain which is likely to cause liver damage. an hour later, they injected DARTs of Nrf2 bearing.
They found that the DARTs were taken up primarily in the liver and increase the expression of three genes known to protect against oxidative stress. liver samples of treated mice closely resembled DART those of healthy mice, while livers of untreated mice showed significant damage, the group announced online today Nature Materials .
These results are "quite dramatic "said José Manautou, a toxicologist at the University of Connecticut, Storrs, and treatment may be helpful for patients with acetaminophen overdose. But these patients usually arrive at the hospital a day after ingestion, not an hour, he said. Murthy's team is currently working on studies to see if the treatment can actually reverse existing damage, including the effects of chronic liver disease.
Others are much more interested in seeing DARTs work on other tissues. "It is relatively easy to get things made by liver cells," says David Frank, an oncologist at the Dana-Farber Cancer Institute in Boston. "It's always a bit the first step in a new technology delivery. "But he sees significant potential in cancer, for example, if a DART could incorporate a mutated version of a transcription factor that stops the genes that promote tumor growth.
groupMurthy has no immediate plans to work on targeting other tissues. the sugar they used in this study has a double objective at hand disrupt membranes and liver targeting. "in theory, you could do the same with peptides and antibodies and things like that, "he said," but the chemistry is going to get much more complicated. "
Tseng, who continued to work on its own transcription factor delivery method to reprogram adult cells into stem cells, is enthusiastic about the DART strategy. "We struggled trying to find a good way to apply this transcription factor Delivery of history," he said. "I could not think of anything better at this point." But he warned that the proteins they -Same are very expensive, which puts extra pressure on the use of transcription factor therapies. "If they work well, then I think the cost may not be the issue," he said, "but you need to find the key applications beyond the liver damage. "
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See the full textAs the heat built before the monsoon rains in the Indian state of Bihar to the north, hundreds of young children come down with a disease that kills many victims and leaves others brain damage. Now scientists believe they have unmasked the mystery culprit: a toxin in the fruit lychee. After an investigation of 2 years, the researchers suggest in the January 30 issue Morbidity and Mortality Weekly Report as the results of the disease crashing sugar levels in the blood probably due to a lychee toxin known to cause hypoglycemia in rats. Two other groups fingered toxin Current Science and in the May issue of Emerging Infectious Diseases . The mechanism emphasizes the threat of similar toxins in fruits related to West Africa and the Caribbean, as well as a mushroom in China.
↵ * Bangalore, India
The world is facing an epidemic of multidrug-resistant typhoid. This is the conclusion of the largest study to date of the genomes of the bacteria that causes the disease, Salmonella enterica Typhi. According to researchers, a clone of the bacterium that is often multiresistant, called H58, rolls across Asia and Africa. Its spread is likely to increase the cost of treatment and lead to more complications, they warn.
"There is a sense of urgency now," said Gordon Dougan, a geneticist at the Wellcome Trust Sanger Institute in Hinxton, UK, and an author of the paper.
typhoid spread by contaminated water or food, causing fever, headaches and other symptoms. If untreated, the disease can lead to complications such as gastrointestinal perforation and kill up to 20% of patients. estimates range from 10 million to 30 million cases per year. About 0,000 people die. S. enterica Typhi that are resistant to multiple antibiotics appeared in the 1970s but H58 was of particular concern to scientists because it is cropping up in more and more countries.
for an overview of its spread, the scientists analyzed the genomes of 1,832 samples from 21 countries Asia, Africa and Oceania. The clone probably emerged in South Asia around 1985 and then picked up the resistance genes in subsequent years, before spreading to Southeast Asia and Africa, Dougan said.
In Africa, the clone was probably introduced repeatedly in Kenya and was broadcast from there to the south, the authors report online today in Nature Genetics . In an article last month in PLOS Neglected Tropical Diseases , Dougan and other scientists followed the emergence of H58 in one hospital in Malawi. From 1998 to 2010, there were an average of 14 typhoid fever diagnoses a year in hospital. Approximately 7% of isolates were resistant to multiple drugs. In 2014, there were 782 diagnoses, 97% with multidrug resistance. "As soon as it arrives in your country, you have to turn to more expensive antimicrobial," said Dougan.
It is not known why H58 is so successful. One possible explanation: The clone may have mutated to survive better in the fabric carriers that spread the disease without becoming ill themselves. There are some genetic changes in H58 that can point to that says Dougan. "But that's speculation," he warns. Why some bacterial clones become dominant is still a mystery, says Mark Achtman, a microbiologist at the University of Warwick in the UK. "It is a phenomenon that we see again and even in different bacteria and it has never been heard. "
The document is one of the largest samples of bacterial genome that whoever published Achtman said. Much was already known about H58 spread, he said. "But this is the first time we had such a comprehensive list of Salmonella typhi and the H58 group in typhi." Said Dougan he and his colleagues have sequenced more typhoid isolates to identify the origins of H58.
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See the full textin the 1950s, researchers found that when the flow of a young mouse is connected to an old mouse, the older pet seems to be rejuvenated. Since 05, a handful of laboratories have been strongly pursue the molecules responsible, hoping to use them to slow or reverse aging in people. One in particular stood out: a protein found in the blood known as young GDF11. In several high-level documents, two of them published last year in Science , a Harvard University team said the GDF11 levels decline in older animals, and replacing rebuilds muscles, brain and heart. But the work described this week Cell Metabolism by Novartis team contests GDF11 rejuvenation powers. Their paper casts doubt on the tests used in previous research and suggests that GDF11 actually inhibits muscle regeneration.
Some people enrolled in clinical trials with the US National Institutes of Health (NIH) continue the use of experimental drugs despite the possibility compounds have fungal contamination.
NIH suspended operations yesterday at a plant that makes experimental drugs for clinical center of the body following an investigation by the Food and Drug Administration (FDA) that revealed multiple problems that could expose sterile drugs to contamination. Forty-six trials currently underway receive the materials of the installation, and the NIH is looking for other sources of products for about 250 patients involved in the studies. In some cases, however, find other sources will not be possible, and some tests will be delayed, says Lawrence Tabak, principal deputy director of NIH.
In addition, some test subjects, after being informed of the risks, asked to continue their experimental treatments made by the now closed facility. The Director Francis Collins NIH has granted exceptions to those whose conditions could be severely compromised if they receive their next scheduled dose. They will be monitored for signs of infection. "Many of them have taken products for some time, without adverse effects. The risk of infection is low, but we still want to be careful," said Tabak.
"This is a painful and unacceptable situation," Collins said in a statement. "the fact that patients may have been put at risk due to non-compliance with standard operating procedures in the Development section pharmaceutical NIH clinical Center is deeply troubling. I will personally supervise the measures necessary to protect patient safety and to remedy the position as soon as possible. "
In April, an employee of Clinical Center had noticed what appeared to be a fungal infection in a vial of albumin used in the administration of interleukin drugs in experimental-after studies was unable to get the liquid out of the bottle. visual inspection of about 650 bottles of the same batch has revealed additional contaminated vial. Six patients from three studies were given bottles of the same lot, although it is unclear if these bottles or others were infected. At this point, none of the six have developed signs of infection or disease.
After the episode in April, an internal review was conducted, says Tabak, who noted several problems with the physical installation. Although the exact date is unknown, at some point the FDA received an anonymous complaint and conducted an unannounced inspection of the facility located on the NIH Bethesda, Maryland, campus between May 19 and May 29. Their 14-page assessment identifies a number of shortcomings, both physical and operational. An exhaust duct leading from one of the "clean rooms" of the installation on the roof was missing a filter or screen, for example, and flaws in the air handling system could expose the sterile products microbial contamination during processing. The report noted deficiencies in the processes of cleaning and disinfection (insects were found in two of the five cleanroom ceiling light berries), and examples of the formation of apparently insufficient staff (laboratory workers with clothes that have left part of their face, neck and arms exposed).
to date, all the facility's products were visually inspected, and no obvious additional contamination was observed. NIH is attempting to send products to a contracting laboratory outside of further testing, which could take several weeks. They are also in the process of contacting and monitoring of patients in the 43 remaining studies. Treatment studies for autoimmune diseases and rare genetic as well as various forms of cancer are among those likely to be affected.
A full review with external experts in engineering, microbial practices, and sterility practices is expected, and the NIH is intended to provide a temporary corrective action plan to the FDA on 19 June.
In the fall of 2013, the emails arrived in scientists from dozens of inboxes informing that their work had been selected for the examination of a project to replicate 50 high-impact papers cancer biology. The project Reproducibility: cancer biology, an open ambitious scientific effort to check whether the key results in the best journals can be replicated by independent laboratories, has raised concerns in the community. Almost all scientists targeted by the project who spoke with Science agrees that cancer biology studies, as in many other areas, too often turn be irreproducible. But few feel comfortable with this particular effort, which plans to announce its conclusions in the coming months. The leaders of the project say it will ultimately benefit the field by measuring the magnitude of the problem of reproducibility in cancer biology.
To read the full article, see the June issue 26 Science .
Vaccines save millions of lives each year by teaching the immune system how to fight against certain viruses or bacteria. But a new study suggests that, paradoxically, they could sometimes teach the pathogens become more dangerous too.
The study is controversial. It was made in chickens, and some scientists say there is little interest for human vaccination; they fear it will strengthen doubts about the appropriateness or safety of vaccines. It should not, says lead author Andrew Read, a biologist at Pennsylvania State University, University Park: The study provides no support for the anti-vaccine movement. But it suggests that some vaccines may be monitored more closely, he argues, or supported with additional measures to prevent unintended consequences.
evolutionary science suggests that many pathogens are not life threatening or even not very virulent, because if they kill their host too quickly that they can not spread to other victims. Now enter the vaccination. Some vaccines do not prevent infection, but they do reduce how sick patients become. As supported Read the first time in a document Nature 14 years ago, keeping alive their guests as "imperfect" or "leaks" could give vaccines deadly pathogens from one side, it allowing them to spread when they would normally burn quickly.
now, Read has published a paper showing that what seems to have happened with Marek's disease, a viral infection in chickens. Marek's disease is spread when infected birds shed virus from their feather follicles, which is then inhaled dust by other chickens. Poultry farmers to vaccinate against the disease, maintaining their healthy flocks but keeps chickens from becoming infected and spreading the virus regularly. In recent decades, Marek's disease has become much more virulent that some scholars believe is the result of vaccination.
Read chickens and researchers from Pirbright Institute in Compton, UK, infected with Marek's disease virus of different strains known to cover the spectrum of low to high virulence. When birds are not vaccinated, infection by highly virulent strains killed them so fast that they lose very little virus-orders of magnitude less than when they were infected with less virulent strains. But in vaccinated birds, the opposite was true: People infected with the more virulent strains of virus shed more than birds infected with less virulent strain
In one experiment unvaccinated birds infected the most virulent strains were housed together. with healthy birds. Again, the infected chickens had died in a short time, leaving no chance of spreading the disease to their healthy cage mates. But when the vaccinated birds were infected with the highly virulent strain, they lived longer and all healthy birds housed with them became infected and died. So "immunization allowed the onward transmission of the virus otherwise too deadly for transmitting, unvaccinated people at risk of severe disease and death," the authors write online today in PLOS Biology .
study is compelling, said Michael Lässig, a physicist at the University of Cologne in Germany, who studies the evolution of flu. "But it is a very special set of circumstances" he warns. "I would be careful to draw general conclusions."
Adrian Hill, a vaccine researcher at the University of Oxford in the UK, said the experiments support the idea that vaccines have made of Marek's disease deadly, but do not prove many other things have changed in the poultry industry in the last decades. flocks became much larger, for example, which could also encourage more virulent strains. But Read said these "hot strains" would disappear very quickly if vaccines were taken
Hill did not doubt that some vaccines may lead to increased virulence. the real issue is the probability to occur. His response: It is very unlikely, and not something we should be worried. "They took 15 years to do an experiment on the only example of what happens."
Read counters that there may be other examples. Feline Calicivirus, which causes a respiratory infection in cats, is a strong candidate, he said, "there have been outbreaks of" superhot Watch is particularly concerned about the bird flu in Europe and the United States, whole poultry flocks are generally slaughtered to stop an epidemic "strains in vaccinated populations." ;. Asian farmers often use birds vaccine against influenza. "You might have the emergence of strains superhot," as a result, they say it. Ab Osterhaus, a virologist at Erasmus MC in Rotterdam, the Netherlands, said it is "very unlikely, but a scenario can not be excluded."
But what about human diseases? Most human vaccines used today are not "leaky"; they are very good at stopping the transmission of the disease. But researchers are turning to diseases that are more difficult to protect against, such as malaria or HIV, they set their sights lower, to vaccines that prevent severe disease, but not infection. "We are entering the era of vaccines fleeing humans," says Read. Candidate vaccines against Ebola and malaria which recently received an important stamp of approval in Europe should certainly be used if they are safe and effective, he said, but could lead to more virulent pathogens. "We need to have a responsible discussion about it."
but for Hill, the comments themselves are irresponsible. Read "no more evidence that this will happen with an Ebola vaccine that will happen with another vaccine in humans," he said. "He should stop scaremongering." The whole distinction between vaccines and fleeing nonleaky is flawed, Hill argues: ". Each vaccine is pierced, in that some people are not protected by it, some people are partially protected, some people have the disease prevention, and other infection prevention not " millions worldwide receive shots of each month and there is no evidence that this has never led to a deadly disease become, said Hill.
moreover, the natural immunity should have the same effect, he adds :. After we recover from illness, we usually end up with a limited "leaky" protection against a pathogen that is not very different from what vaccines reach, said Hill "for malaria, regardless of the fact today vaccine is a drop in the ocean of any immunity which is in Africa of all infections to all people."
hill worried that the reading task will play into the hands of antivaxxers. Read but said that even if a human vaccine is never shown to cause dangerous changes in the pathogen, it would not be a reason not to vaccinate. The most important thing would be to support immunization with other vacuum transmission measurements, such as bed nets against malaria.
Ironically, the increase in virulence, it would be even more important to vaccinate everyone, he said, because that universal vaccination would prevent the most dangerous strains of harming anyone. This is in fact what happened in Marek's disease, Read said. "I think because of these vaccines, the industry has created strains superhot, but the vaccine still works beautifully because it can be delivered to any single vulnerable bird."
* Correction, July 28, 4:07 p.m. :. a quote by Adrian Hill, this story has been corrected
