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New Vaccine and Treatment Excite Ebola Researchers

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Science  14 Nov 2003:
Vol. 302, Issue 5648, pp. 1141-1142
DOI: 10.1126/science.302.5648.1141

Recent advances—including a second vaccine candidate and the first treatment shown to work in monkeys—offer hope for controlling a gruesome disease

The thrill is gone. Ebola, long the most frightening disease in the public's mind, has begun to lose its sex appeal. In 1995, the world was mesmerized when the virus erupted in Kikwit, Zaire, now the Democratic Republic of the Congo. But an outbreak in the neighboring Republic of the Congo earlier this year barely made headlines. Smallpox has become the world's favorite nightmare.

But the researchers who study Ebola and its close relative, Marburg, remain fascinated by the things that titillated readers and moviegoers a decade ago: the 50% to 90% mortality rate, the horror of widespread hemorrhage in some patients, and the ongoing hunt for the natural reservoir. And bit by bit, they're unraveling the mechanisms that make Ebola so devastating. At a meeting* last month at the National Institutes of Health's Vaccine Research Center in Bethesda, Maryland, researchers also unveiled data about a second promising vaccine candidate and presented a potential treatment for Ebola, an advance that virologist C. J. Peters of the University of Texas Medical Branch in Galveston called “extremely impressive,” especially given the obstacles in the field.

Although Ebola incidence seems to be on the rise, it remains rare—according to the World Health Organization (WHO), it has claimed just over 1000 human lives in 30 years—so only a handful of labs study it. Progress is also hampered by the lack of so-called biosafety level 4 labs with space or permission to house monkeys. (Many new ones are on the drawing boards or under construction, but most will take years to complete.)

It's unclear why epidemics occur almost yearly now, whereas almost 20 years elapsed between the first known outbreaks, in Zaire and Sudan in 1976, and the next, in Kikwit. Nor do researchers understand why Ebola is currently pushing some ape populations in central Africa to the brink of extinction (Science, 11 April, p. 232).

Finding a treatment for Ebola is still one of the top priorities. Although researchers have found several antivirals that worked in mice and guinea pigs, none was effective in monkeys. Other approaches have failed as well. For instance, a monoclonal antibody called KZ52 that was derived from the bone marrow of an Ebola survivor in Kikwit looked promising in guinea pigs. In a recent study, however, it failed to protect rhesus macaques, Dennis Burton of the Scripps Research Institute in La Jolla, California, reported at the meeting.

Monkey wrench.

New work sheds light on how the Ebola virus—seen here budding from an infected human cell—disrupts the blood-clotting system.


Another way to treat Ebola would be to try to block the physiological cascade that the virus triggers rather than target the virus itself. Many researchers are now focusing on this complex, and poorly understood, process. Researchers know that the bleeding in Ebola is caused by coagulopathy, a dysfunction of the blood-clotting system, but it's not quite clear where this starts or how it can be stopped. At the meeting, a team led by Tom Geisbert of the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland, presented evidence that macrophages, which are a type of white blood cell, play an important role. When infected by the virus, they start expressing a clotting protein called tissue factor (TF) on their surfaces. These molecules attract other clotting molecules from the blood, resulting in localized, harmful blood clots that leave the body vulnerable to bleeding elsewhere.

The USAMRIID group decided to treat rhesus monkeys with an anticoagulant called rNAPc2, which counteracts the effects of TF. (A company called Dendreon is also testing the anticoagulant as a treatment for acute coronary syndromes.) Given immediately after Ebola infection or within 24 hours and continuing for 8 days, the drug saved the lives of three out of nine monkeys and slowed death by several days in the remaining six. All three controls died.

Because infection in rhesus monkeys is almost universally lethal, a 30% reduction in mortality is “incredible,” says Pierre Formenty, a virologist at WHO in Geneva, Switzerland. Virologist Mike Bray of the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says, “Tom has really done quite a remarkable thing: to show where the coagulopathy is arising, and that interfering with it actually has some benefit.” Peters notes that in humans, who have a fighting chance of their own, mortality rates might be reduced even more. But Vincent Deubel of the Pasteur Institute in Lyon, France, was less impressed. “I think we need to do better,” he says.

Meanwhile, several vaccine strategies appear to be paying off. Three years ago, Nancy Sullivan and colleagues at the Vaccine Research Center reported success in monkeys using a two-pronged approach: three shots of “naked DNA,” expressing Ebola's glycoprotein, followed by one shot with an adenovirus engineered to express glycoprotein as well (Science, 3 November 2000, p. 923). But that regimen takes 6 months to produce immunity; in September of this year, the same team, together with Geisbert's group, reported in Nature that even a single shot of the adenovirus alone was protective, in as little as 28 days. Such a fast-acting vaccine would be a major advantage during outbreaks, Sullivan says, when villagers would need to be protected on short order. The center is now doing safety trials for the DNA component of the vaccine in humans, and it plans to start doing the same for the adenovirus soon.

In Winnipeg, Canada, Heinz Feldmann, Steven Jones, and their colleagues at the National Microbiology Laboratory have developed a competing vaccine, based on an animal pathogen called vesicular stomatitis virus (VSV), which causes a disease whose symptoms resemble those of foot and mouth—although it's in a different virus family and not nearly as virulent—in cattle, horses, and pigs. Using techniques developed by Yale University's John Rose, who's pioneering the use of VSV as a vector for an HIV vaccine, the team replaced VSV's glycoprotein with that of Ebola. After experiments in mice and guinea pigs proved successful, the Canadian team had Geisbert test the vaccine at USAMRIID. To their surprise, they discovered that the VSV vaccine, too, could protect after a single shot and within a month. “It looks very promising,” Deubel says. “Three weeks ago, we had one promising vaccine,” says Bray. “Now we have two.”

But the new vaccine has potential downsides: VSV can occasionally cause illness in humans; what's more, animal health experts worry about using a livestock disease agent as a human vaccine. If the researchers can show that the engineered VSV is not pathogenic and vaccinees don't shed much of the virus, the vaccine might have a future, said Feldmann. Still, Deubel predicts that it will face an uphill regulatory battle.

With safety trials for the prime-boost vaccine under way, the next phase—a field test in Africa to demonstrate efficacy—is beginning to give researchers headaches. Clashes over issues such as how to bury deceased patients have often strained relations between local populations and the international teams trying to quash outbreaks. During last year's outbreak in Gabon, health care workers felt so threatened that they withdrew from an affected town. Conducting a trial under such circumstances “is going to be extremely difficult,” says Deubel.

The Vaccine Research Center is already discussing these issues with WHO and plans to talk to African governments about a trial with the adenovirus-alone variant of the vaccine, says Sullivan. Among the many thorny questions: Should there be a placebo group? Many think that with Ebola, it would be unethical and impossible to explain why some don't get a real vaccine; but dropping the placebo arm would make it harder to demonstrate efficacy.

WHO's Formenty thinks that a drug might have a better chance than a vaccine of being accepted by the community—and could help reduce Ebola's spread as well. Currently, patients often avoid hospitals because doctors don't have much to offer them; as a result, caregivers are more likely to become infected. If Geisbert's or another therapy could give patients a better shot at survival, they might come to the clinic, Formenty says, where they could be isolated: “That would be a great step forward.”

  • *Symposium on Viral Hemorrhagic Fevers, 14 to 17 October.

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