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Ebola: Zmapp effective in macaques (rhesus monkeys)

Featured post via Medpage Today (29:08:2014)
By Michael Smith
A controversial cocktail of Ebola antibodies was safe and highly effective in saving the lives of rhesus macaques, even as the animals neared death from the virus, researchers reported.

The medication, dubbed ZMapp, saved all 18 animals in a study, even when they were given the first of three doses 5 days after infection, when the clinical signs of disease were apparent, according to Gary Kobinger, PhD, of the Public Health Agency of Canada.

The antibody cocktail has been used several times, on a compassionate basis, to treat people during the current West African outbreak. That use has been controversial because, among other issues, the medication has had no formal tests in humans.

Also, because the supply was limited, questions arose as to which patients were allowed to receive the compassionate treatment. Two were American healthcare workers who were already receiving top-level care.

Kobinger said the compassionate use was not designed as a study and it's difficult to know what effect the medication had. Nevertheless, "it's going to be very important to see what comes out of that compassionate use in humans," he told reporters in a media briefing.

What is clear, he and colleagues reported in Nature, is that the ZMapp cocktail can completely reverse the effects of Ebola infection in macaques, even when animals are very sick and would ordinarily die within 3 days.

On average, Kobinger said, macaques given a lethal dose of Ebola die within 8 days of infection. He and colleagues treated animals with the ZMapp product starting 3, 4, and 5 days after infection and saved all of them.

In such experiments, he told MedPage Today, the animals usually have virus in the blood and clinical signs of disease, such as fever, by day three "and definitely by day five."

The 5-day delay before successful treatment is the longest that has ever been observed, Kobinger said.

Kobinger added the antibody cocktail had no apparent adverse effects, either in healthy animals or in those who recovered and were given a fourth dose later.

"We have never seen any (adverse effects) in nonhuman primates," he said.

But he cautioned that the study was conducted in animals, so that effects in humans could well be different. Among other things, Kobinger said, human exposure is inadvertent, with different doses in different patients, so that responses vary.

For that reason, it's important to study safety and effectiveness in people, although "testing the latter is clearly difficult," commented Thomas Geisbert, PhD, of the University of Texas Medical Branch at Galveston.

Geisbert and colleagues have been studying small interfering RNA molecules as treatments for hemorrhagic fevers and last week reported data on a product aimed at Marburg virus.

In a Nature article accompanying the Kobinger report, Geisbert argued that a range of interventions is needed to control Ebola in the future, including antibodies, small molecules, and vaccines, many of which are under development.

An important factor might be money: "In the long run, the manufacture of ZMapp could require investment in infrastructure for making monoclonal antibodies at an industrial scale -- assuming that funding is available to pay the production costs," Geisbert concluded.

A clinical trial of the ZMapp product could be under way in early 2015, Kobinger said, although he noted that's up to the U.S. company that has licensed the medication, Mapp Biopharmaceuticals of San Diego.

However, an experimental Ebola vaccine will enter phase I clinical trials next week, the National Institute of Allergy and Infectious Diseases said Thursday. It's the first of several early stage trials of vaccine candidates, the agency said, that will evaluate safety and immunogenicity in healthy volunteers.

But even if those trials show the drugs are safe and immunogenic, it would still be some time before they could be used, even on an emergency basis, institute Director Anthony Fauci, MD, earlier told MedPage Today.

Meanwhile, the outbreak in West Africa continues to rage, with the World Health Organization reporting 3,052 probable, confirmed and suspect cases, with 1,546 deaths.

The outbreak is the largest in history, both in numbers and geographical extent, and shows no signs of flagging, the WHO reported. The agency noted that more than 40% of cases have occurred within the past 21 days, although most are concentrated in a few places in the four affected countries -- Guinea, Liberia, Sierra Leone, and Nigeria. (A case in neighboring Senegal, the country's first if confirmed, was reported Friday.)

The WHO has said that reported cases are very likely an underestimate, since some people do not seek medical attention. The agency also said the toll could go as high as 20,000 cases before the outbreak comes under control.

A separate outbreak appears to be under way in the Democratic Republic of Congo, a country in Central Africa formerly known as Zaire where Ebola virus was first identified.

Between July 28 and Aug. 18, the WHO reported, 24 suspected cases of hemorrhagic fever, including 13 deaths, have been reported, but neither the index case nor her contacts have a history of travel to West Africa.

Samples are being tested to confirm that the disease was caused by Ebola and, if so, to identify the strain.

There are five species of Ebola virus, including the Zaire species that caused the first known outbreak in the 1970s and which is responsible for the current West Africa outbreak.

Kobinger and colleagues said they tested their cocktail against the Kikwit strain of the Zaire species, which was isolated after a 1995 outbreak in the Democratic Republic of Congo and is used as a reference strain in research.

But lab tests of ZMapp against the Guinea variant involved in the current outbreak showed the medication had comparable or even slightly better binding kinetics than it does against the Kikwit strain, Kobinger said.

As well, he said the investigators have preliminary data in animals using the current circulating strain "and it performed at least as well if not better in vivo."

A next step in the research is to see how much of the drug is actually needed. The animals in the Nature study were given 50 milligrams per kilogram of body weight in three doses 3 days apart.

But Kobinger said the investigators are now trying to see if response correlates with the viral load of Ebola and if lower doses could rescue animals with a smaller amount of circulating virus.

Complicating the issue is that available supplies of ZMapp, which is grown in genetically modified tobacco plants, have been used up, he said.

Meanwhile, investigators working on the ground in the affected region suggest that Ebola mortality -- now at about 51% in the outbreak -- can be cut sharply with proper care.

"With more personnel, basic monitoring, and supportive treatment, many of the sickest patients with Ebola virus disease do not need to die," according to researchers led by Robert Fowler, MD, of the University of Toronto in Canada.

But, in an analysis in the American Journal of Respiratory and Critical Care Medicine, Fowler and colleagues paint a picture of health systems initially lacking the ability to provide that care.

For weeks, they reported, they and other health care workers in Guinea had an isolation unit and lab support for diagnosis but "no beds and no monitoring mechanism to check blood pressure, fluid balance, basic potentially life-threatening biochemical abnormalities or oxygenation."

"Thankfully we had the most important aspects of supportive care -- oral rehydration and intravenous fluids when patients could not maintain oral intake," Fowler and colleagues added.

As critical care specialists know, they said, the key to successful supportive care is "aggressive prevention of intravascular volume depletion, correcting profound electrolyte abnormalities, and preventing the complications of shock."

It "can and should be applied in both resource-constrained and resource-rich settings," Fowler and colleagues argued, and could cut the mortality of Ebola sharply.

Source: MedPage Today

Michael Smith
North American Correspondent

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