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Doctors work to prevent avian flu

In the intellectual race against a possible avian flu pandemic, scientists such as Dr. Robert Edelman are beginning to talk publicly about a new idea.

Why not, the University of Maryland vaccine expert suggested recently to a group of Israeli doctors at Ben Gurion University Hospital, combine the avian influenza vaccine with the one for the regular flu?

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"I presented the idea, and everyone jumped on it," said Edelman, one of several scientists pondering the notion to help ward off the bird flu in people.

But would it be a perfect solution? Hardly, as even Edelman attests. Instead, the idea shows the complexity of the riddle confronting public health authorities and the physicians and scientists who advise them.

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The challenges include whether to vaccinate against avian flu when it has yet to spread from person to person, given all vaccines' risk of side effects. And there are manufacturing and scientific challenges, including how to engineer the vaccine so it packs more punch.

As bird flu spreads sporadically from flocks to people in a growing number of countries -- most recently, Turkey -- scientists look for flu-fighting solutions in hopes of preventing a pandemic. The World Health Organization says the disease has killed 80 of the 149 people confirmed to have contracted it, mostly in Asia.

Scientists are working hard to stay ahead of it. They are sequencing the genomes of dozens of strains of influenza to deduce how to disable them. They are testing different ways to make bird flu vaccine, including using eggs, using animal cells in big, brewerylike vats, and using cells from insects.

They're also exploring various ways to administer it, including injecting it into muscle or in the skin and spraying it up the nose. Another option might be to use a skin patch similar to the one people wear to quit smoking.

At the University of Maryland School of Medicine in Baltimore, clinical trials in about 150 healthy adults found no serious side effects. Trials will test whether adding a chemical to one version of the vaccine -- which now requires at least two shots to produce effects -- will make a smaller dose work better.

A combined vaccine is yet another idea designed to help ward off the spread of a virus that -- while now passed only from birds to people -- might change into one that could spread swiftly from person to person.

Dr. Bruce Gellin called the idea of priming the human immune system to develop a memory for potential pandemic viruses "an attractive immunological theory." But the director of the National Vaccine Program Office, part of the Department of Health and Human Services, cautioned that "we need to develop a sound scientific database before it can be considered as a public health policy."

The combination might help people fight off avian flu, if it ever began spreading among humans, scientists speculate. And the prospect of added protection might encourage people to get the annual shot, boosting the limited demand and relatively puny profits that have driven many companies out of the vaccine business, the thinking goes.

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"All these considerations being expressed are worthy of careful analysis and investigation," said Dr. Roland Levandowski, chief of a National Institutes of Health section that studies respiratory diseases, including flu. "I think we need to make all the preparations we can."

To understand the proposed solutions, it's helpful to understand what public health authorities see as the major challenges of fighting avian flu.

First, influenza generally spreads quickly, potentially thwarting the effectiveness of quarantines.

A second challenge is that there aren't many manufacturers who want to make vaccines, and the ones that do are busy. Companies can make far more money with heart disease or cancer drugs, which are given repeatedly and sell for more than a once-a-year flu shot.

The seasonal flu vaccine must also be made fresh yearly, because the strains of the flu circulating change from one year to the next. Demand for the shots also fluctuates, subject to a fickle public, and what flu vaccine isn't sold each year must be thrown out.

As a result, there are only four companies licensed to sell seasonal flu vaccine in the United States. Production takes months, and manufacturing plants are few, meaning companies wouldn't be able to react quickly once avian flu began spreading.

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Third, the avian flu virus spread among birds may be changing, and the exact strain scientists must target to protect people is not yet known. The virus has passed from birds to people who directly handle them but not from one person to another. Other changes in the virus may cause that to happen.

Viral changes mean any stockpiled avian flu vaccine might not be exactly the right one. And besides, the frozen vaccine has a shelf life of only about 18 months, said Dr. Phillip Russell, former director of the Walter Reed Army Institute of Research.

Lastly, medicines such as Tamiflu and Relenza -- antivirals taken after exposure -- don't prevent the flu; they only shorten its course, Russell said.

Therefore, he said at a recent University of Maryland School of Law seminar on avian flu, "I have a high degree of skepticism that any other measures [besides a vaccine] are going to have an impact on morbidity or mortality."

It isn't clear where the idea for combining avian flu vaccine and the regular seasonal variety originated, but one of its chief proponents is Russell. A retired Army major general, he now consults for clients such as the Bill and Melinda Gates Foundation and other companies.

He thinks combining the vaccine for the avian strain with the seasonal ones could boost demand, giving companies more incentive to make it.

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What's more, while the virus may continue to change, the strain now in trials could be similar enough to the next generation of virus that it might help, Russell and others said. Primer shots, and booster shots in succeeding years, could help protect the human immune system.

The vaccine likely would have to be tested by itself in larger trials and then in combination with a seasonal flu vaccine.

Still, even an advocate like Russell believes there are drawbacks -- including ethical and economic concerns over giving a vaccine to millions for a virus that isn't widely spreading among them.

"This is a public policy decision, so the community that would have to be convinced would be the public health community," Russell said.

Annually, experts from the World Health Organization and the Centers for Disease Control and Prevention monitor circulating strains of influenza. The WHO then advises various governments which strains should be targeted in that year's vaccine.

The idea of priming people for avian flu has its roots in how medicine fights the regular flu in children, using a primer-booster regimen. Their immune systems have never been exposed to many strains of it, said Dr. James D. Campbell, a University of Maryland assistant professor of pediatrics who oversees avian flu trials there.

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The H5N1 virus -- the avian strain that has killed people in Asia and Turkey -- carries "a protein to which your immune system has never had to respond before," Campbell said. So it takes a heftier dose to prod an effective response. "We don't give [seasonal] flu vaccine to adults in multiple doses, but that's because most of us have seen influenza before."

By contrast, children younger than 9, who have not been immunized before, are routinely given two doses of the regular flu vaccine because their immune systems are "naive" to the many seasonal flu viruses older people have encountered.

Next up: trials in more vulnerable populations, including children ages 2 to 9, and in adults age 65 and older. Edelman, a professor of medicine, said he will oversee trials in the elderly at the University of Maryland, one of a number of sites for government-funded trials.

At the University of Maryland, the volunteers who received the H5N1 vaccine during the initial trials have since received a third booster dose to determine not just its safety, but whether it will improve their protection against the virus.

It's the avian flu's viral novelty that makes the H5N1 virus a pandemic threat. Most of us haven't been exposed to it, just as the world hadn't encountered the virus that triggered the 1918 pandemic.

The combination of an avian flu vaccine given along with the seasonal one hasn't been tested, "but theoretically it makes sense," Campbell said.

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One of the concerns, however, relates to the possibility of a mass inoculation revealing rare but serious side effects that would have gone undetected in clinical trials. Another is that the costly effort, even if safe, might be unnecessary.

"We would be giving folks something now that they didn't 'need,'" Gellin said in an interview Friday. "You could justify it if you had a scientific basis to show that when they needed it, this priming would work."

Another concern is that manufacturers lack the capacity to make a combined vaccine. The problem is that the regular flu vaccine contains several strains, which are made sequentially, Gellin said. Companies make their flu vaccines in eggs, and getting enough to make yet another strain may be a challenge.

With government approval, a manufacturer could drop one of the seasonal strains and replace it with an avian one, according to Alison Marquiss, a spokeswoman for Chiron Corp. in California.

And if a pandemic were imminent, they could stop production of the annual vaccines entirely and shift all production facilities to making the pandemic flu vaccine.

MedImmune Inc., the manufacture of FluMist, said through a spokeswoman that it would continue to look to the WHO for guidance, including on whether to target an avian strain in its formulation.

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Adding a pandemic strain to the mix would be much simpler with production based not on eggs but on cell culture.

"From our perspective, it underscores the importance and benefit of having alternative production methods," said Deborah Spak, a spokeswoman for Illinois-based Baxter International.

Baxter is working on an H5N1 vaccine that uses a cell culture derived from a line of kidney cells from monkeys -- the process Baxter used to produce smallpox vaccine recently stockpiled by the federal government.

"We are hoping to begin clinical trials ... this year," Spak said.

Scientists are thinking about an even bigger idea, which is to develop a single vaccine that might be effective against a broad array of flu strains.

"That's the broad sweep," Gellin said, noting that the flu viruses are all part of the same viral family. Finding a common component would eliminate the need to tailor the vaccine strain by strain.

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"That clearly is the greatest of the scientific challenges," he said. "If that could be achieved, then essentially the pandemic threat would dissolve."

juliana.bell@baltsun.com

frank.roylance@baltsun.com

To read archived coverage of issues dealing with avian flu, go to baltimoresun.com/avianflu.



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