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Ebola vaccine trials to begin in Baltimore next month

Human trials of experimental Ebola vaccines have begun – more than one of them in Maryland.

An unusual request recently appeared in classifieds and on campus bulletin boards — Wanted: Baltimore-area volunteers to test a vaccine for the Ebola virus.

The response was overwhelming, said Kirsten Lyke, an associate professor at the University of Maryland School of Medicine who is working on the study. The slots for the study were filled within days by people eager to help stop an epidemic that is paralyzing western Africa and panicking Americans.

By this time next month, researchers expect that nearly two dozen Baltimoreans will be building immunity to Ebola, to help prove a vaccine could safely and effectively stem the virus' unabated spread in Guinea, Liberia and Sierra Leone.

The testing in Baltimore represents another front in an expanding battle being fought by the medical school's Center for Vaccine Development and others.

This month, the center began human trials of the same vaccine in Mali, testing it in the population that the World Health Organization is seeking to inoculate as soon as possible.

Another vaccine developed in Canada began trials this month at the Walter Reed Army Institute of Research in Silver Spring. And the Baltimore biotech company Profectus BioSciences could begin human testing of a different vaccine within a year after landing U.S. government investment last week.

A host of experimental vaccines and treatments for Ebola are speeding through regulatory processes that would usually take months or years as the number of cases grows exponentially in Africa and the outbreak threatens to spill into the United States and other developed nations. The uncomfortable truth, scientists said, is that investors had little motivation to support Ebola research when outbreaks were confined to African villages. But this outbreak has changed that.

"These are extraordinary times," Lyke said.

A vaccine is seen as key in slowing the spread of the virus, which has killed 4,500 of the 9,000 people it has infected in West Africa and proved difficult to contain even in a Dallas hospital that admitted the United States' first Ebola patient last month. A Liberian man with the virus infected at least two nurses before he died Oct. 8.

Dr. Thomas Frieden, director of the federal Centers for Disease Control and Prevention, said that if the outbreak is not contained in Africa and eventually quashed, it could have lasting repercussions for world health. President Barack Obama appointed Ron Klain as "Ebola czar" on Friday.

In battling the outbreak, public health officials were faced with a challenge: Usually, the process of developing a vaccine and testing it for safety and efficacy takes years. Given the urgency of the outbreak, that sort of timeline wasn't possible.

In early August, World Health Organization officials met to consider troubling ethical questions. Could they conduct human trials of unlicensed vaccine candidates amid the epidemic? They decided it would be worth the risk and pledged that while the process would be sped up, no corners would be cut.

Within days, planning for studies, including the Mali trials, began, said Dr. Myron Levine, director of the Center for Vaccine Development. A process that would normally take nearly a year, involving many layers of ethical reviews, was conducted in two months, he said.

"This was warp speed," Levine said.

The center was tapped to work with a sister organization in Mali, a partnership with the country's Ministry of Health, to conduct trials. Mali shares a border with Guinea in West Africa.

Scientists have found vehicles for inciting an immune response that guards against Ebola in animals — mainly viruses that have been modified so the body recognizes them as Ebola but that don't cause sickness in humans. Several projects had shown safety and efficacy in animals, but were slow to advance into human trials.

University of Maryland medical researchers are testing a vaccine developed at the National Institute of Allergy and Infectious Diseases, which is part of the National Institutes of Health. It uses a chimpanzee cold virus that carries an Ebola protein. The viruses are genetically altered so they cannot reproduce, but the immune system nonetheless produces antibodies to counteract them.

As it became clear that the Ebola outbreak was accelerating, the NIH conducted a pilot study last month to preliminarily test the vaccine's safety in humans. After that review, Lyke and her colleagues got the green light to proceed with a Phase 1 trial on 20 healthy adults in Baltimore.

Separately, the World Health Organization is driving a study that includes the Mali trials.

Both could produce results within months — and, if successful, could be quickly used to stem the outbreak. There are various strains of Ebola, as well as similar diseases that cause hemorrhagic fever, for which officials hope to develop vaccines, but the NIH-developed vaccine is tailored to the strain that has triggered the current outbreak.

The protocol for the trials requires a measured approach. In the World Health Organization study, the vaccine was first injected gradually into healthy adults at Oxford University. A week after the first five subjects were shown to have handled the vaccine without adverse results, Levine and colleagues in Mali were allowed to inject the first of 40 health workers who will receive the vaccine.

The next day, two more health workers received the injection. The rest were scheduled to follow over the next few weeks. The "stepped" protocol seeks to minimize risks, so injections can be stopped if adverse reactions appear. So far, that hasn't been the case.

"The fact is, if there were something, some safety signal, that appeared that suggested there's a problem, the studies would be stopped," Levine said. "That hasn't happened."

Lyke said researchers aim to begin trials in Baltimore, at the Center for Vaccine Development on West Baltimore Street, by early November. Before then, they must collect data on research subjects to establish a baseline for health indicators such as kidney and liver function, and ensure that the subjects do not have some other illness that might compromise their immune systems.

Once the subjects receive the injection, more tests are conducted to make sure that those health indicators haven't changed and to measure immune response. Those tests will continue for nearly a year.

While the vaccine's safety can be gauged within the first several weeks after injection, Lyke said, evaluating efficacy is the more challenging part.

Researchers have only been able to feasibly develop vaccines and therapies for pathogens like Ebola since drug reforms made in the wake of the Sept. 11 attacks. Widespread fears about biological and chemical weapons pushed the change in policy.

Normally, clinical trials for a drug would culminate in a blind study that compared the treatment to a placebo. But in the case of Ebola, that would require exposing subjects to the virus and denying some of them the experimental vaccine — neither of which is ethical.

Instead, a new U.S. Food and Drug Administration rule allows such vaccines or treatments to bypass the normal later-stage human testing and instead rely largely on studies that show effectiveness in animal subjects. Human testing is performed largely to evaluate safety, though data is also collected to gauge effectiveness.

Since then, the FDA has applied the rule in approving only a handful of licenses, including treatments for plague and anthrax.

The Ebola vaccines are testing the rule as well. Because researchers cannot ethically expose human subjects to the Ebola virus, they instead have to compare the immune response to that of animal subjects, and, as much as possible, to the immune response of Ebola survivors.

"To some degree, we're going to have to do some guessing," Lyke said.

Researchers expect different types of vaccines to have different effects on the immune system. Because the vaccine being tested in Mali and Baltimore uses a weakened virus, it might be tolerated better but not last as long as vaccines that use live viruses, said Dr. Thomas Geisbert, a professor of microbiology and immunology at the University of Texas Medical Branch at Galveston who has studied Ebola for decades and helped develop the Profectus vaccine. The trials are also testing the performance of varying dosage levels, ranging from 25 billion to 50 billion modified virus particles.

It is unclear whether some vaccine candidates could require rounds of booster shots to prolong immunity, or whether others might provide longer immunity but at greater risk of side effects.

Profectus' vaccine uses a live virus that has been genetically altered. It can still reproduce, but its ability to do so is limited, so it doesn't overgrow in the body, Geisbert said.

The Canadian vaccine, licensed to the Iowa company NewLink Genetics Corp., uses the same live virus as Profectus' candidate, a pathogen found in livestock called vesicular stomatitis virus.

The researchers welcome the competition, though they don't call it that.

"The more Ebola vaccines we can have, and the more we have data to see their advantages and disadvantages, the better," Levine said. "I hope we have multiple options to choose from."

Still, some question whether enough is being done to ensure that a vaccine will be mass-produced quickly. At an Ebola symposium hosted by the Johns Hopkins University Bloomberg School of Public Health last week, University of Minnesota epidemiologist Michael Osterholm suggested that the outbreak could explode if it reaches slums in more African cities or other continents. He called a widely distributed vaccine the best tool to stop it.

While expedited regulatory review and new investments in the vaccine candidates have prompted swift progress, it might not be fast enough, Osterholm said.

Even under the best conditions, if the experimental vaccines prove to be safe and effective, a significant number of doses would not be available until late in the first quarter of 2015, the World Health Organization said.

"There's a big disconnect between the time it takes to get us there and getting it into somebody in Africa," Osterholm said. "When we're talking about a $57 million investment from the U.S., that's a drop in the bucket if we're really interested in moving vaccine."

Reuters contributed to this article.

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