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PostPosted: Fri Aug 29, 2014 2:43 pm 
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References

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Acknowledgements
Abstract• Introduction• Selecting for the best mAb combinations• ZMapp1 or ZMapp2-treated NHPs• ZMapp-treated NHPs• ZMapp cross-reacts with Guinea EBOV• Discussion• Methods• References• Acknowledgements• Author information• Extended data figures and tables
The authors thank K. Tierney, A. Grolla, S. Jones, J. Dong and D. Kobasa for their excellent technical assistance, V. Klimyuk and Y. Gleba for access to the magnICON expression system, and H. Steinkellner for access to transgenic N. benthamiana. This work was supported by the Defense Threat Reduction Agency (DTRA contract HDTRA1-13-C-0018), the National Institutes of Health (U19AI109762), the Public Health Agency of Canada (PHAC), and a Canadian Safety and Security Program (CSSP) grant to G.P.K. and X.Q. G.W. is the recipient of a Doctoral Research Award from the Canadian Institute for Health Research (CIHR).

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PostPosted: Fri Aug 29, 2014 2:46 pm 
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Extended data figures and tables

Extended Data Figures
Extended Data Figure 1: Clinical scores for each ZMapp-treated group. (432 KB)
Arrows indicate treatment days. Dashed line represents humane endpoint threshold. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, Clinical score of Group D (blue); b, clinical score of Group E (orange); c, clinical score of Group F (green).

Extended Data Figure 2: Viraemia for each ZMapp-treated group. (374 KB)
Arrows indicate treatment days. Faded symbols/lines are the other two treatment groups, for comparison. Control group (Group G) is shown in black on all three panels. a, TCID50 of Group D (blue); b, TCID50 of Group E (orange); c, TCID50 of Group F (green). d, Viraemia by RT–qPCR of Group D (blue); e, Viraemia by RT–qPCR of Group E (orange); f, Viraemia by RT–qPCR of Group F (green).

Extended Data Tables
Extended Data Table 1: Blood viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (63 KB)
Extended Data Table 2: Oral swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (46 KB)
Extended Data Table 3: Nasal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (48 KB)
Extended Data Table 4: Rectal swab viraemia measured by RT–qPCR for the ZMapp1- and ZMapp2-treated NHPs (48 KB)
Extended Data Table 5: Blood viraemia measured by RT–qPCR for the ZMapp-treated NHPs (81 KB)

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PostPosted: Fri Aug 29, 2014 2:50 pm 
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Erica Ollman of the Scripps Research Institute holds a model of the ZMapp antibody cocktail.

Experimental Ebola drug saves monkeys, but will this translate to humans?

By Jon Cohen 29 August 2014 1:30 pm
LA JOLLA, CALIFORNIA – This past Wednesday, at a discussion titled “Stopping the Deadly Ebola Outbreak” held at the Scripps Research Institute here, a local TV reporter repeatedly prodded one of the star panelists, Kevin Whaley, the CEO of Mapp Biopharmaceutical of San Diego.

After Whaley explained that he had no idea whether ZMapp, his company’s now famous experimental antibody cocktail used to treat Ebola victims, really worked, the journalist continued to press. “From what you’ve seen in your research--and what your heart says--what do you say?”

The audience of 100 people or so broke into nervous giggles.

“I’m not willing to speculate on that,” Whaley replied.

The dogged reporter gave it one more try, referring to two American health workers who were infected with Ebola in Liberia, returned to the U.S. and received ZMapp, and lived to tell about it. “How happy were you to see the two missionaries walk out of the hospital?”

“That was certainly very satisfying, and hopefully ZMapp played some roll in that,” said Whaley. “But that remains to be seen.”

The exchange highlights the growing hope that some biomedical intervention – such as a treatment like ZMapp -- will allow more people to survive Ebola infections. Time and time again, however, hope and hype have become knotted together.

Today, that knot is sure to grow tighter with the publication online in Nature of an encouraging monkey experiment with ZMapp, in which 100% of the infected monkeys survived. It is sure to further raise expectations of a cure -- and further confuse the public about just how near a cure might be. Even the authors of the new study caution that extending the monkey results to humans could be a long and difficult task.

The experiments, led by Gary Kobinger of the Public Health Agency of Canada in Winnipeg, first tested combinations of Ebola antibodies made by his lab and Mapp Bio to find a cocktail that worked best in guinea pigs and then monkeys. They selected the concoction now called ZMapp and gave it to three groups of six monkeys; all received intramuscular injections of high doses of Ebola virus. A control group of three monkeys were given dummy drugs.

The treated monkeys each received three doses of ZMapp, once every three days. Treatment began at three days post infection for one group, at four days for another, and at five for a third. All 18 of the monkeys had evidence of infection, many became ill, and two nearly died.

In the end, 100% of the treated monkeys survived and 100% of the control animals quickly died. Although the experiment used an older Ebola virus that differs from the strain now in West Africa, the researchers showed in a test tube study that ZMapp also worked against the more recently isolated virus.

The results are “a monumental achievement,” virologist Thomas Geisbert, who studies Ebola virus at the University of Texas Medical Branch at Galveston, wrote in a Nature editorial accompanying the study. ”

“It’s a great study,” Geisbert tells ScienceInsider. “I’ve got shelves and shelves and shelves of things that inhibit Ebola in cell culture and small percent inhibit it in guinea pigs or mice. And I’ve got shelves and shelves of things that work in guinea pigs and mice but not in monkeys. If you save 100% of monkeys up to five days after infecting them, that’s a huge bar to clear.”

In a teleconference held by Nature today, Kobinger said it was “quite remarkable” that they could rescue infected animals that had advanced disease, which he called “a very important step forward in the fight against Ebola virus.” But Kobinger also stressed that many unknowns remain about the differences between this monkey model and human infection.

To begin with, most humans are infected by exposure to bodily fluids from people with Ebola, not by syringes that hold a huge bolus of virus injected into their muscles. This kills monkeys on average in 8 days, while it typically takes 3 to 21 days for humans to develop symptoms. “It’s very hard to translate” the disease progression in this monkey model to humans, said Kobinger. But a monkey infected by this route and left untreated for 5 days is 3 days away from death he said, which indicates that ZMapp worked well into the disease.

The monkeys received three doses of ZMapp, and it sometimes required a second one before the level of Ebola virus in their blood—the viral load--dropped. With the seven treated humans, one person who died only received a single dose, and no one has yet reported how many doses the others received. Kobinger said he “would not expect” a single dose to work. “What the antibody is really doing is buying time,” said Kobinger, stressing the importance of proper medical care on survival.

Kobinger said he had no idea whether the antibodies had any effect on viral load in these patients, as they were given the experimental ZMapp on a “compassionate use” basis. “When each of the clinicians or clinical teams that have been using ZMapp release their data, we’ll get a better sense of maybe the efficacy, but even then, it’s hard because it’s not really a designed study,” said Kobinger. “Unfortunately, it may be limited what we’re really going to learn from those seven patients.”

In preliminary experiments not reported in the Nature paper, Korbinger said he has in vivo evidence that ZMapp works against the strain currently circulating in West Africa. He said future experiments will analyze the impact of providing infected monkeys with effective intensive care. His group also wants to see how low of a dose of ZMapp they can give infected monkeys and still rescue them. “One of the things that is very urgent for us to do is a dose de-escalation study so that we can see what the minimum amount of antibody so maybe with the same amount of material we could do more,” he said.

The availability of ZMapp is a critical issue for the growing number of people who want access to it on a compassionate use basis. Mapp Bio says it currently has no more ZMapp on hand. Kentucky BioProcessing in Owensboro grows the ZMapp antibodies in tobacco plants. In a 2012 press release, that company’s chief operating officer, Barry Bratcher, said it had a fully automated production system “that operates in accordance with good manufacturing practices” and could “generate a new antibody lot in two weeks to rapidly address new threats and new outbreaks.” Bratcher did not reply to an e-mail from ScienceInsider to discuss that prediction.

At the Scripps panel talk, Whaley told ScienceInsider that they were still trying to sort out production issues. “Clearly we misstated [the production time needed],” said Whaley. “That clearly was not our intention.”

Questions also have been raised about how it was decided to give ZMapp to the seven people who have received ZMapp so far, two of whom were from Europe and two from the United States. Whaley said the company responds to requests that come through the U.S. Food and Drug Administration and has no say in who ultimately had received the product.

Two of the seven ZMapp patients have died. Their outcomes ultimately say nothing about the treatment: the people received the drug at different stages of disease, and four were evacuated to wealthy countries for topnotch care—likely the most important determinant of survival. No information has become public about the effect the antibodies had on their levels of virus. What’s more, it’s an experiment without a control. “These people did not have an identical twin who was infected the same day and didn’t get treated,” said Scripps structural biologist Erica Ollmann Saphire, who was a panelist at the event there and helped Mapp Bio select antibodies. “That’s why we need to do the human clinical trial.”

Human studies of ZMapp are scheduled to begin in early 2015.

Meanwhile, Ebola cases continue to rise. The World Health Organization as of yesterday reported 3,069 cases and 1,552 deaths, a case fatality rate of 52%. Senegal today reported its first case.

Posted in Biology

http://news.sciencemag.org/biology/2014 ... ate-humans

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PostPosted: Fri Aug 29, 2014 2:56 pm 
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New Treatment Provides Hope for Human Ebola Cases
ZMapp Cocktail Saved Monkeys When Administered Up to Five Days After Infection

By GAUTAM NAIK CONNECT
Updated Aug. 29, 2014 2:03 p.m. ET
In an important breakthrough in the fight against Ebola, scientists have used an experimental drug to completely cure 18 monkeys infected with the deadly virus. WSJ's Gautam Naik reports.
An experimental drug cocktail has cured monkeys inoculated with a lethal dose of the Ebola virus, setting the stage for scientists to test the treatment in people.

While other drugs have shown some success in protecting monkeys against Ebola, they had to be dispensed within two days of exposure to the virus. By contrast, the latest treatment, known as ZMapp, saved the animals when it was administered up to five days after infection, when the monkeys were days or even hours from death.

"These results are very encouraging," said Peter Piot, co-discoverer of the Ebola virus and director of the London School of Hygiene & Tropical Medicine, who didn't participate in the study. Four decades after Ebola was first identified, "we may be on our way to an effective treatment."

There are currently no approved treatments or vaccines against Ebola. The latest study was published Friday in the journal Nature.

The scale of the current Ebola outbreak sweeping west Africa has highlighted the need for a powerful post-infection Ebola drug. At least 1,552 people have died after contracting the virus, and the World Health Organization has warned that the number of people infected could jump to 20,000 in the next nine months.

There also are worrying signs that Ebola is spreading beyond Guinea, Liberia, Sierra Leone and Nigeria. The Democratic Republic of the Congo, which stretches eastward to the center of the continent, recorded its first cases this week. On Friday, Senegal announced that a 21-year-old Guinean man believed to have contracted the virus was in quarantine in a hospital in Dakar, the state-run news agency reported.

In the study published in Nature, researchers described how they conducted tests on guinea pigs until they arrived at a particularly potent cocktail of three so-called monoclonal antibodies, which are designed to bind to the Ebola virus and neutralize it.

The cocktail, ZMapp, was tested on rhesus monkeys who were injected with a lethal dose of Ebola. Three groups of infected animals, consisting of six monkeys each, then received doses of the drug cocktail in varying intervals.

To the researchers' surprise, all 18 animals survived, with none having detectable levels of the virus three weeks after exposure. Severe symptoms of the disease—heavy bleeding, rashes and a large increase in liver enzymes—disappeared.

By comparison, three monkeys that didn't receive the drug died by day eight.

"The level of improvement was beyond my expectations," said Gary Kobinger of the Public Health Agency of Canada and a lead author of the Nature study.

It remains to be seen whether the drug will be effective in people. So far, seven people infected with Ebola have received the drug on a "compassionate use" basis. Some pulled through, but it is unclear whether, or to what extent, the drug was a factor in their survival.

Image

It could be some two years before early-stage clinical trials determine whether Zmapp is safe for people, which makes it out of reach for those imperiled in the current epidemic. At that juncture, if the drug is shown to be safe, some countries may amass a small stockpile of the experimental medicine that can be administered in an emergency.

One complication is that there are different strains of Ebola, which may require different drug cocktails. The Ebola strain used in the Nature experiment is different to the new Zaire strain rampaging through west Africa. But Dr. Kobinger and his colleagues reported that ZMapp also worked against the new Zaire strain when tested in a lab dish.

ZMapp is made by Mapp Biopharmaceutical Inc. of San Diego. The drug is manufactured in tobacco plants that have been engineered so they mass-produce the antibodies that make up ZMapp.

A unit of tobacco-products maker Reynolds American Inc. RAI +0.26% manufactures the drug using tobacco plants in Kentucky.

Drew Hinshaw in Monrovia, Liberia, contributed to this article.

Write to Gautam Naik at gautam.naik@wsj.com

http://online.wsj.com/articles/new-trea ... 1409331697

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PostPosted: Fri Aug 29, 2014 3:01 pm 
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Experimental Ebola drug cured 100% of monkeys tested
Liz Szabo, USA TODAY 1:09 p.m. EDT August 29, 2014

In what scientists are calling a "monumental achievement," an experimental medication called ZMapp — given on a compassionate basis to a handful of Ebola victims in the current outbreak — cured 100% of monkeys treated in a Canadian study, researchers announced Friday.

ZMapp, made by Mapp Biopharmaceuticals of San Diego, is in the early stage of development and has never been formally tested in humans. In a study published Friday in the journal Nature, however, the drug allowed all 18 rhesus macaques infected with a lethal dose of Ebola to recover. The drug worked even when given five days after infection. The monkeys received three doses of ZMapp, administered three days apart, according to the study, which was conducted by the Public Health Agency of Canada.

The three monkeys that did not receive ZMapp died within eight days of infection.

In monkeys given ZMapp, however, the drug reversed severe symptoms, including severe bleeding, rashes and elevated liver enzymes, a sign of liver failure. Three weeks after infection, tests showed the surviving animals had no detectable Ebola virus in their blood.

"It's fantastic news," says study co-author Gary Kobinger of the Public Health Agency of Canada. "This strongly supports" the hope that ZMapp will work in humans, he says.

The results are "a monumental achievement," says Ebola researcher Thomas Geisbert of the University of Texas Medical Branch at Galveston, who was not involved in the current study but who wrote an accompanying editorial.

Doctors used a different strain of Ebola virus in their study than the one that's currently circulating in West Africa. However, they tested ZMapp in test tubes against the current strain and found that it blocked infection.

Although ZMapp hasn't been tested for safety in humans, its manufacturer shared a handful of doses with Ebola victims as a last-ditch effort to save their lives. Four of those patients — including two Americans and two Liberian health workers — survived after taking the drug. A fifth aid worker, who is now being treated in London, also has begun treatment with ZMapp. A Spanish priest and Liberian doctor given ZMapp died.

Mapp Biopharmaceuticals has said that there are no more doses of ZMapp left. The drug, which includes three man-made antibodies to Ebola, takes months to manufacture. The antibodies are intended to allow the patients' immune system to respond to Ebola and fight off the infection.

Given the limited experience with ZMapp in humans, it's not yet possible to know how ZMapp works in humans, Geisbert says.

That's because ZMapp has been given to only a handful of patients, with no control group for comparison, he says.

The Americans' cases are also unique. One of the American doctors who received ZMapp, Kent Brantly, also received a blood transfusion from a teenager who survived Ebola. So it's possible that the transfusion, not ZMapp, should get credit for saving him, Geisbert says. Receiving intensive care at Emory University Hospital in Atlanta — one of the best hospitals in the world — also could have helped the Americans survive.

Geisbert notes that about half of Ebola patients survive without taking ZMapp.
Image
Dr. Frank Thieme, Manager of Development at Icon Genetics, holds a nicotiana benthamiana plant, which is a close relative of tobacco, in a greenhouse at the company's facilities on August 14 in Halle, Germany. Icon Genetics has developed a process to produce proteins and enzymes from this plant that will be used in the production of ZMapp, which is able to stop infections in monkeys but hasn't been formally tested on humans.

Dr. Frank Thieme, manager of development at Icon Genetics, holds a nicotiana benthamiana plant, a close relative of tobacco, in a greenhouse at the company's facilities in Halle, Germany. Icon Genetics has developed a process to produce proteins and enzymes from this plant that will be used in the production of ZMapp, which is able to stop infections in monkeys but hasn't been formally tested on humans.(Photo: Sean Gallup, Getty Images)
It's possible that the two Ebola patients who died after taking ZMapp got the drug too late, Geisbert says. There is a "point of no return," he says, after which time nothing can save someone with Ebola, which causes tiny leaks in blood vessels, leading to massive internal and external bleeding, as well as organ failure. The immune system also can overreact in the late stages of Ebola, causing more harm than good.

Three of the five species of Ebola virus are lethal to humans, Geisbert notes. A treatment that works against one species — or different strains of the same species — may not necessarily work against others.

Ebola has infected more than 3,000 people in Guinea, Sierra Leone, Liberia, Nigeria and Senegal, killing half of them, according to the World Health Organization. Senegal reported its first case of Ebola on Friday.

In a worrying development, researchers reported Thursday in Science that the Zaire strain of Ebola virus — the type now circulating in West Africa — appears to have mutated from its original form. The virus appears to be changing as it moves across Africa. Kobinger says he doesn't know how those mutations will affect the efficacy of ZMapp.

Doctors at the National Institutes of Health plan to launch the first human trial of an Ebola vaccine next week at the institute's campus in Bethesda, Md., using healthy volunteers. The early study, using just 20 volunteers, will assess the experimental vaccine's safety and ability to activate the immune system to recognize the Ebola virus.

Additional vaccine studies will be conducted in Bethesda, the United Kingdom and West Africa throughout the fall, NIH officials said Thursday. Early results from the first NIH trial are expected before the end of the year.

Five experimental vaccines under development have been shown to completely protect monkeys against Ebola, Geisbert says. But only one of those vaccines is effective in a single injection — as opposed to multiple shots — an important practical advantage when trying to vaccinate hundreds or thousands of people in developing nations.

Getting a usable treatment or vaccine could take many more months, however, officials caution. The best way to control the current outbreak is with traditional measures: diagnosing patients, isolating them, tracing their contacts and testing them, and extending the process out in circles, until all exposed patients have been isolated.

http://www.usatoday.com/story/news/nati ... topstories

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PostPosted: Fri Aug 29, 2014 3:06 pm 
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Experimental Ebola drug ZMapp cures 100 percent of lab monkeys
BY SHARON BEGLEY
NEW YORK Fri Aug 29, 2014 1:00pm EDT

Aug 29 (Reuters) - The experimental Ebola drug ZMapp cured all 18 of the lab monkeys infected with the deadly virus, including those suffering the fever and hemorrhaging characteristic of the disease and just hours from death, scientists reported on Friday.

Even monkeys not treated until five days after infection survived. No other experimental Ebola therapy has ever shown success in primates when given that long after infection; the five days is analogous to nine to 11 days after infection in people.

Although two American aid workers who contracted Ebola in Liberia were cured after receiving ZMapp, their physicians do not know if the drug helped. A Liberian doctor with the disease died this week despite being given the drug, as did a Spanish priest.

ZMapp, produced by San Diego-based Mapp Biopharmaceutical, has never been scientifically tested in people, and the current study was the first in primates. The success is therefore a "monumental achievement," virologist Thomas Geisbert of the University of Texas Medical Branch wrote in a commentary on the paper, published online in Nature.

There are no approved Ebola vaccines or treatments, but human safety trials will begin next week on a vaccine from GlaxoSmithKline Plc and this autumn on one from NewLink Genetics Corp.

The Ebola outbreak in West Africa has killed 1,552 people out of 3,069 confirmed cases, the World Health Organization said, and is on pace to infect 20,000. Neither governments nor private medical groups have been able to contain the outbreak, which WHO said will almost certainly continue into 2015.

ZMapp is a mix of three antibodies that bind to proteins on Ebola viruses and trigger the immune system to destroy them. Mapp had previously developed two different cocktails of antibodies, but they protected only 43 percent of monkeys when given as late as five days after infection.

For the current study, scientists led by Gary Kobinger of the Public Health Agency of Canada set out to identify the optimal mix of antibodies from the earlier cocktails. His team tested the antibodies in guinea pigs one at a time and in various combinations, identifying the two best performers last December.

The two graduated to tests in 12 rhesus monkeys. This spring the winner of that face-off, ZMapp, was given to another 18 infected monkeys - three doses at three-day intervals starting three, four or five days after infection.

All three untreated monkeys, in contrast, died of Ebola by day eight. With ZMapp, even advanced symptoms such as rashes, liver dysfunction and hemorrhaging disappeared, a result Kobinger called "beyond my own expectations."

"This is an extremely encouraging result," said David Evans, professor of virology at England's University of Warwick, who was not involved in the study.

The success suggests that ZMapp "offers the best option" for treating Ebola, Kobinger's team wrote, and should be tested for safety in people to enable its compassionate use "as soon as possible."

The Ebola strain in the study is the Kikwit variant, not the Guinea strain responsible for the current outbreak. ZMapp inhibited replication of the Guinea strain in lab dishes, however, suggesting it might be broadly effective.

Mapp has no more doses of ZMapp, which is produced in the leaves of tobacco plants at Kentucky BioProcessing, a unit of Reynolds American Inc. Greenhouses there began making more ZMapp "a couple of weeks ago, but the process takes time," said Reynolds spokeswoman Maura Payne.

It aims to produce enough for tests necessary to seek regulatory approval of ZMapp, she said, "and we plan to begin that testing protocol by year-end." (Editing by Matthew Lewis)

http://www.reuters.com/article/2014/08/ ... XJ20140829

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CBS/AP August 29, 2014, 3:06 PM
ZMapp cures monkeys of Ebola virus

The experimental Ebola drug known as ZMapp has healed all 18 monkeys infected with the deadly virus in a new study. If subsequent studies prove as promising, the treatment may help fight the outbreak raging through West Africa -- once more of the drug can be made.

For the study, published online Friday by the journal Nature, researchers gave the monkeys ZMapp three to five days after they were infected with the virus and when most were already showing symptoms. That is several days later than any other experimental Ebola treatment tested so far.

"For animal data, it's extremely impressive," said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which had a role in the work.

In another study, the drug also completely protected six other monkeys given a slightly different version of it three days after infection in a pilot test. These two studies are the first monkey tests ever done on ZMapp, which is a compound of three antibodies that attach to cells infected with Ebola, helping the immune system kill them.

It's not known how well the drug would work in people, who can take up to 21 days to show symptoms and are not infected the way these monkeys were in a lab. Several experts said it's not possible to estimate a window of opportunity for treating people, but that it was encouraging that the animals recovered when treated even after advanced disease developed.

Primates have been good stand-ins for people for many viral diseases, but how well they predict human responses to Ebola, "we just don't know," said Dr. Cameron Wolfe, a Duke University infectious disease specialist. The study also "tells us nothing about side effects" people might have, he added.

ZMapp had never been tested in humans before two Americans aid workers, Nancy Writebol and Dr. Kent Brantly, who got Ebola while working in Africa were allowed to try it. Both of them recovered. The rest of the limited supply was given to five others. In recent weeks, the use of the untested drug on a limited number of patients has incited an ethical dilemma over who should get it.

Of the seven people known to have been treated with ZMapp, two have died -- a Liberian doctor and a Spanish priest. The priest received only one of three planned doses. Two Africans who received ZMapp in Liberia -- a Congolese doctor and a Liberian physician's assistant who were expected to be released from a treatment center on Friday. A British nurse also got the drug, reportedly the two unused doses left over from treating the Spanish priest.

There is no more ZMapp now, and once a new batch is ready, it still needs some basic tests before it can be tried again during the African outbreak, Fauci said. "We do need to know what the proper dose is" in people and that it's safe, he said.

ZMapp's maker, Mapp Biopharmaceutical Inc., of San Diego, has said that it will take several months to make more. The drug is grown in tobacco plants and was developed with U.S. government support.

Gary Kobinger, a professor at Public Health Agency of Canada in Winnipeg and lead author of the ZMapp study, said it takes about a month to make 20 to 40 doses at a Kentucky plant where the drug is being produced. Officials have said they are looking at other facilities and other ways to ramp up production, and Kobinger said there were plans for a clinical trial to test ZMapp in people early next year.

"The treatment window in humans needs to be established in a well-controlled trial" that also would explore the correct dose of ZMapp in people," Erica Ollmann Saphire, a Scripps Research Institute professor who has worked with some of the study leaders on antibodies to Ebola, wrote in an email. "Given its tremendous efficacy in the nonhuman primates, I don't see how it couldn't be helpful in people."

Ebola has killed more than 1,500 people this year and the World Health Organization says there could be as many as 20,000 cases before the outbreak is brought under control. On Friday, it spread to a fifth African country -- Senegal, where a university student who traveled there from Guinea was being treated.

There is no approved vaccine or specific treatment for Ebola, just supportive care to keep them hydrated and nourished. Efforts have focused on finding cases and tracking their contacts to limit the disease, which spreads through contact with blood and other fluids. However, on Thursday, U.S. federal health officials announced they plan next week to start a human trial on an Ebola vaccine that's proved to be promising when tested on animals.

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http://www.cbsnews.com/news/zmapp-cures ... ola-virus/

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PostPosted: Fri Aug 29, 2014 3:55 pm 
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Study Says ZMapp Works Against Ebola
By ANDREW POLLACKAUG. 29, 2014

A new study provides strong evidence that the experimental drug given to two American aid workers stricken with Ebola in Africa really works and could make a difference in the current outbreak — if more of it could be produced.

In the study, all 18 monkeys exposed to a lethal dose of Ebola virus survived when given the drug, known as ZMapp, even when the treatment was started five days after infection, when the animals were already sick.

Moreover, the monkeys’ symptoms, such as excessive bleeding, rashes and signs of liver toxicity, eventually disappeared. By contrast, all three monkeys in the control group died.

Experts said these were the best monkey results reported to date for any Ebola drug, raising hopes that the drug will work in people.

“I think it strongly supports that concept,” Gary P. Kobinger, the senior author of the study, said in a telephone news conference Friday, shortly before the paper was published by the journal Nature. Still, Dr. Kobinger, a researcher for the Public Health Agency of Canada, cautioned that effectiveness in monkeys was not “proof” that a drug would work in people.

Kartik Chandran, an expert on Ebola who was not involved in the study, said the results were impressive.

“To actually be able to reverse all those symptoms and signs and bring them back to baseline, I think that is pretty astounding,” said Dr. Chandran, an associate professor of microbiology and immunology at the Albert Einstein College of Medicine. “If you are going to give somebody something during this outbreak, this would be it.”

The problem is that the supply of ZMapp is exhausted, according to Mapp Biopharmaceutical, the nine-person San Diego company that is developing the drug. And it is expected to take months to make more of the drug, which is produced in genetically engineered tobacco plants.

ZMapp came to the world’s attention early this month when it appeared to help two American aid workers stricken in Liberia and later flown to Emory University Hospital in Atlanta. The workers, Dr. Kent Brantly and Nancy Writebol, recovered and were discharged from the hospital last week.

Doctors say it is impossible to say what role ZMapp played in their recovery. Nonetheless, there has been a clamor for the drug and an ethical debate about who was entitled to the handful of treatment courses available.

The remaining supplies went to a Spanish priest, three doctors in Liberia and, just this week, a British nurse recovering in London. The priest, Miguel Pajares, and one of the Liberians, Dr. Abraham Borbor, died.

Father Pajares received one of the recommended three doses before he died, and the remainder has gone to the British nurse, William Pooley, according to a person involved in the discussions about drug allocation.

Some other experimental drugs have shown the ability to protect monkeys from Ebola if given shortly after infection, up to about two days. That might make such a drug useful for what is called postexposure prophylaxis — for example, after a person is stuck by an infected needle.

But in an outbreak like the one in Africa, most people do not know they are infected until symptoms develop. Most if not all of the people who have received ZMapp, for instance, were already sick. Hence it would be important that a drug could work even if treatment starts after symptoms appear, as was the case in this study.

Dr. Kobinger, who works at the National Microbiology Laboratory in Winnipeg, Manitoba, said it was difficult to know how that aspect of the monkey results would translate in humans..

People can take up to 21 days to develop symptoms. In the study, the monkeys not given ZMapp died by eight days after infection. He said the next step would be to see if the drug can work even if started six or seven days after exposure, though at some point, the organs would be too damaged to allow for recovery.

ZMapp is a cocktail of three monoclonal antibodies, which are immune system proteins that can isolate and neutralize an invading pathogen. The antibodies were initially harvested from mice exposed to a protein from Ebola, then genetically engineered to make them more like human antibodies.

The resulting antibodies are then manufactured in genetically engineered tobacco plants. A spokesman for Reynolds American, the tobacco company that owns the Kentucky manufacturing facility, said production began again about two weeks ago, but he declined to say how much could be produced how quickly.

Based on information from Dr. Kobinger and others, it can take a couple of months for the facility to come up to full speed, after which it can produce 20 to 40 treatment courses a month. But it is possible that yields can be improved and that doses can be lowered so a given amount of drug would treat more people.

Robin Robinson, director of the federal agency that procures drugs and vaccines for public health emergencies, said through a spokeswoman that enough of the drug was expected to be available by the end of the year to conduct a Phase 1 clinical trial to test the safety of ZMapp.

Other companies that can produce drugs in tobacco will be enlisted, said Dr. Robinson, whose agency, the Biomedical Advanced Research and Development Authority, is part of the Department of Health and Human Services.

He said that there was debate about how quickly to deploy the drug in Africa but that officials thought it was important to test the safety in healthy volunteers first.

Mapp, which was working with the Defense Department, and Dr. Kobinger’s laboratory initially developed their own three-antibody cocktails. When the two groups learned of each other, they joined forces.

They tested individual antibodies and various combinations in guinea pigs, and the two best combinations were then tested in monkeys. The winner of that face-off — consisting of two antibodies from Canada and one from the United States — became ZMapp.

The results reported Friday, particularly the protection when treatment was started five days after infection, were significantly better than those of the original Canadian and American cocktails.

“We of course expected an improvement — I mean, we were at least hoping for it,” Dr. Kobinger said. “But the level of improvement was at least beyond my own expectation.”

In the study, the monkeys were injected with a high dose of the virus. They then received three doses of ZMapp spaced three days apart, with the first dose coming three, four or five days after exposure.

The virus used in the experiment was from an outbreak in 1995. But some laboratory tests showed that ZMapp also inhibited the strain involved in the current outbreak.

http://www.nytimes.com/2014/08/30/world ... .html?_r=0

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PostPosted: Fri Aug 29, 2014 4:32 pm 
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ZMapp drug fully protects monkeys against Ebola virus
Experimental treatment to fight infection finds success in animal test
BY NATHAN SEPPA 2:38PM, AUGUST 29, 2014

ZMapp, the experimental drug recently given to six people infected with Ebola, has rescued 18 Rhesus macaque monkeys injected with the live virus.

A U.S.-Canadian research team exposed 21 monkeys to Ebola. Eighteen received a three-shot regimen of ZMapp — starting three, four or five days after infection — and survived, even though 11 had developed fever and two were starting to hemorrhage. The other three infected monkeys weren’t given ZMapp and died, the scientists report August 29 in Nature.

Results from treating human patients with the experimental drug, which uses antibodies against the virus, have been more mixed; at least two have died.

ZMapp and other drugs or vaccines now in development could eventually be used in efforts to stop the current Ebola outbreak. The outbreak could last another six to nine months, according to a “response roadmap” released by the World Health Organization on August 28. More than 3,000 people have been infected with Ebola and more than 1,500 have died. By the time this outbreak ends, however, the number of cases could exceed 20,000, the WHO report warns.

https://www.sciencenews.org/article/zma ... bola-virus

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PostPosted: Fri Aug 29, 2014 4:37 pm 
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Ebola drug Zmapp is 100% effective at treating monkeys with the deadly disease, scientists declare
All 18 rhesus macaques treated with the drug made 'complete recovery'
Animals were cured even when given the drug five days after infection
Monkeys not given the experimental drug quickly fell seriously ill and died
ZMapp is blend of three lab-made antibodies designed to neutralise the virus
Two U.S. doctors given the drug after contracting Ebola later recovered
Experts warned today the disease is mutating rapidly
By ANNA HODGEKISS FOR MAILONLINE
PUBLISHED: 12:11 EST, 29 August 2014 | UPDATED: 15:10 EST, 29 August 2014

Hopes of a breakthrough in the fight against Ebola have been raised by the 100 per cent successful treatment of monkeys with the deadly disease.
The experimental drug ZMapp cured the animals even when administered five days after infection, while they were displaying severe symptoms.
All 18 rhesus macaques made a complete recovery, in contrast to three other untreated monkeys that quickly fell seriously ill and died.
Nicotiana benthamiana, the plant from which ZMapp is derived. New research shows the experimental drug ZMapp cured the monkeys even when administered five days after infection
+4
Nicotiana benthamiana, the plant from which ZMapp is derived. New research shows the experimental drug ZMapp cured the monkeys even when administered five days after infection
ZMapp is a blend of three laboratory-made antibodies designed to neutralise the virus.
Two U.S. doctors given the drug after they were infected with Ebola while working in Liberia subsequently recovered.
But it is not known whether they were saved by the drug or just lucky. About 45 per cent of those infected in the current outbreak have survived without treatment.
At least two other patients treated with ZMapp have died, possibly because help got to them too late.
The new research, published in a special report on Nature journal's website, provides hard evidence that the drug works and can be highly effective.

A team of scientists led by Dr Gary Kobinger, from the Public Health Agency of Canada, wrote: 'ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use ...
'We hope that initial safety testing in humans will be undertaken soon, preferably within the next few months, to enable the compassionate use of ZMapp as soon as possible.'
The news follows a warning from the World Health Organisation (WHO) that the Ebola outbreak in West Africa could eventually claim more than 20,000 victims.
Latest figures show 1,552 deaths from the 3,069 cases reported so far.

ZMapp is being used to treat William Pooley, the first Briton to contract the virus while working as a nurse at a remote health centre in Sierra Leone

Dr Abraham Borbor, was being treated with ZMapp but lost his battle with Ebola this week. He was the deputy chief medical doctor at the country's largest hospital

ZMapp is being used to treat William Pooley (left) the first Briton to contract the virus while working as a nurse at a remote health centre in Sierra Leone and (right) Dr Abraham Borbor, was being treated with ZMapp but lost his battle with Ebola this week. He was the deputy chief medical doctor at the country's largest hospital
Ebola, belonging to the family of 'filoviruses', ranks alongside Marburg virus as one of the world's deadliest infections. Fatality rates in previous outbreaks have been as high as 90 per cent.
It kills by overwhelming the immune system and sending the body into shock as blood pressure drops to dangerous levels.
Currently there are is no approved vaccine or post-exposure treatment. Management of the Ebola outbreak in Africa has been confined to palliative care and physical attempts to prevent transmission.
The development of ZMapp and its success in treating advanced stages of Ebola infection was described as a 'monumental achievement' by Professor Thomas Geisbert, from the University of Texas, writing in Nature.
He added: 'The next crucial step will be to formally assess its safety and effectiveness. Testing the latter is clearly difficult, because intentional infection of human subjects in clinical trials is not possible.'
EBOLA VIRUS IS 'MUTATING RAPIDLY,' EXPERTS WARN
Researchers claim the Ebola virus disease (EVD) is rapidly and continually mutating, making it harder to diagnose and treat.
A study of the initial patients diagnosed with the virus in Sierra Leone revealed almost 400 genetic modifications.
And it could be detrimental not only to current treatments, but also to future vaccines that are in the works.
The team of researchers, led by the Broad Institute in Massachusetts and Harvard University, analysed more than 99 Ebola virus genomes.
These were collected from 78 patients diagnosed with Ebola in Sierra Leona in the first 24 days of the outbreak.
Their findings, reported in the journal Science, could have important implications for rapid field diagnostic tests.
The team found more than 300 genetic changes that make the 2014 Ebola virus genomes distinct from the viral genomes tied to previous Ebola outbreaks.
They also found variations in the genome sequence indicating that, from the samples analysed, the outbreak started from a single introduction into humans, subsequently spreading from person to person over many months.
The treated monkeys were exposed to a lethal level of Ebola virus before receiving three doses of ZMapp starting three, four and five days after infection.
The treatment reversed Ebola symptoms including excessive bleeding, rashes, and liver damage.
Three weeks after they were infected, no trace of the virus could be detected in the animals' blood.
Untreated monkeys all succumbed to the virus by day eight after infection.
One drawback of the research was that it used a version of the virus different from the Guinea strain responsible for the current outbreak, which was not available at the time.
But the scientists went on to show that ZMapp blocks replication of the Guinea strain in laboratory tests.
Dr Alain Kohl, from the Medical Research Council/University of Glasgow Centre for Virus Research, said: 'What needs to be done next is assess against how many strains and species of the virus it can act.
Clinical trials in humans are not possible so some questions will go unanswered. At present too few people have received the drug to allow conclusions about efficacy and treatment timings, though in emergency situations it is at least one potentially useful option.'
David Evans, Professor of Virology at the University of Warwick, said: 'All animals survived and had undetectable viral loads 21 days post-infection. This is an extremely encouraging result for a virus which has an incubation period of two to 21 days in humans and for which no vaccine exists.
'These results do not prove that the healthcare workers who received ZMapp and recovered did so due to the therapy. Others who also received ZMapp succumbed to the virus.
'Distinguishing between correlation and causation will require analysis of the clinical data on viral loads before and after therapy was administered. Nevertheless, the results are encouraging.'
Professor Martin Hibberd, from the London School of Hygiene & Tropical Medicine, said: 'This looks to be a very well designed study with better than expected results, which give great hope for future clinical trials.
'I hope the team can receive sufficient funding to undertake these clinical trials straight away as this is by far the most advanced potential treatment option available to my knowledge.'
ARE YOU AT RISK OF CATCHING THE INCURABLE, DEADLY DISEASE?

What is Ebola virus disease?
Ebola is a severe, often fatal illness, with a death rate of up to 90 per cent.The illness affects humans as well as primates, including monkeys, gorillas and chimpanzees.
How do people become infected with the virus?
Ebola is transmitted through close contact with the blood, secretions, organs or other bodily fluids of infected animals.
In Africa infection in humans has happened as a result of contact with chimpanzees, gorillas, fruit bats, monkeys, forest antelope and porcupines found ill or dead in the rainforest.
Once a person becomes infected, the virus can spread through contact with a sufferer's blood, urine, saliva, stools and semen. A person can also become infected if broken skin comes into contact with a victim's soiled clothing, bed linen or used needles.
Men who have recovered from the disease, can still spread the virus to their partner through their semen for seven weeks after recovery.
Who is most at risk?
Those at risk during an outbreak include:
health workers
family members or others in close contact with infected people
mourners with direct contact with the bodies of deceased victims
hunters in contact with dead animals
What are the typical signs and symptoms?
Sudden onset of fever, intense weakness, muscle pain, headache and sore throat. That is followed by vomiting, diarrhoea, rash, impaired kidney and liver function and internal and external bleeding.
The incubation period is between two and 21 days. A person will become contagious once they start to show symptoms.
When should you seek medical care?
If a person is in an area affected by the outbreak, or has been in contact with a person known or suspected to have Ebola, they should seek medical help immediately.


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