By Jeanne Whalen, David Hamilton, Marilyn Chase (WSJ)
Updated: 2005-10-28 14:51

RIXENSART, Belgium -- When his neighbors on the outskirts of Brussels stop him to ask what they should do about bird flu, Emmanuel Hanon tells them not to panic but to be concerned.

He should know. He is on the front lines of ensuring that the outbreak of avian flu, which began in Asia and has spread to poultry in Europe, never becomes a pandemic, spreading from human to human around the globe, as some experts fear it might.

Dr. Hanon, the 36-year-old head of viral-vaccines research at U.K. drug giant GlaxoSmithKline PLC, is one of a small field of researchers world-wide racing to develop vaccine against H5N1, the bird-flu virus. H5N1 has killed some 60 people over the past two years -- a tiny fraction of the 250,000 to 500,000 people who die every year from regular flu.

So far, the virus has been passing from bird to bird and from bird to human. It doesn't yet appear to have mutated to a form that could pass from human to human. But scientists fear it will, and because humans have no natural immunity to H5N1, the search for a vaccine has emerged as one of the world's most pressing pharmaceutical-research priorities.

GlaxoSmithKline is searching for a vaccine that might offer broad immunity, protecting against any human-to-human strain of H5N1 that may emerge. Glaxo said yesterday that clinical trials would begin shortly for a H5N1 vaccine that it hopes will prove effective in a pandemic. Results should be available in next year's second quarter.

An H5N1 vaccine would be "one of the major weapons we have for our preparedness for an ultimate flu pandemic," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, a unit of the National Institutes of Health that is working closely with companies to try to develop a bird-flu vaccine.

"The good news is that even a mismatched vaccine would probably be better than no vaccine, but the bad news is that it is going to be difficult to be confident of making an exact match" for any human-to-human strain, says John Treanor, an expert in virology at the University of Rochester in Rochester, N.Y.

So far, just one avian-flu vaccine has withstood clinical testing: Over the summer, a team of researchers from Sanofi-Aventis SA of Paris, the U.S. National Institutes of Health and St. Jude Children's Research Hospital in Memphis, Tenn., created a vaccine designed to protect against the spread of H5N1 among humans. The U.S. government has placed an order valued at $100 million.

Even so, that vaccine isn't considered optimal in the event of a human-to-human pandemic, because two doses of it are required to spark a robust immune reaction. In a pandemic, authorities would rely on emergency "ring vaccination," rushing vaccine to people around the site of an outbreak. "Anything more than one dose isn't practical" for that, says Robert Belshe, a vaccine researcher at St. Louis University in St. Louis.

See complete coverage of avian flu, including a map of H5N1's reach, plus an in interactive graphic on the science of the virus and a look back at major flu epidemics.Yesterday, the U.S. placed a $62.5 million order for avian-flu vaccine from biotechnology company Chiron Corp. of Emeryville, Calif. Oddly, Chiron's vaccine hasn't yet been tested; the company plans to deliver 8,000 doses for testing next month. "It's a matter of industry and government working together to get as much in place for preparedness as possible," a Chiron spokeswoman said.

Meanwhile, PowderMed, a tiny Oxford, England, concern, also is in the race. Governments, too, are working on it: Hungary recently claimed its scientists had developed a prototype vaccine.

Scientists say it is hard to predict how long it will take to develop an effective bird-flu vaccine. Glaxo's Dr. Hanon says he is experiencing "productive stress." "I am doing everything I can to convince people to go as fast as possible," he says.

Speaking to reporters yesterday, Glaxo Chief Executive J.P. Garnier said, "We're pulling out all the stops to do everything we can to be ready to help various governments to have their planning in place at the time, and if, there is a catastrophic event."

The economics of making vaccines aren't very appealing: Demand is unpredictable, the manufacturing process is slow, and the product is perishable. With blockbuster drugs, companies carefully guard new products with patents, but patent protection for vaccines is complicated. In the event of a global flu pandemic, the World Health Organization could void any vaccine patent protection in the interest of vaccinating as many people as possible.

With few big U.S. drug companies manufacturing vaccines these days, the world has precious little ability to make them. Factories today can produce, at most, a combined 300 million doses of flu vaccine of any kind -- about enough to give only 4.6% of the world's population one flu shot, according to Wood Mackenzie, a consulting firm. GlaxoSmithKline said yesterday it plans to convert more of its manufacturing capabilities to produce pandemic flu vaccines, if needed.

One indication of demand for a bird-flu vaccine is the surge in demand for Tamiflu, an antiviral drug made by Roche Holding AG of Switzerland, and the only readily available treatment for avian flu. Even though it is just a treatment, not a vaccine, governments world-wide and even some individuals have been stockpiling the medicine. Roche this week said it had temporarily suspended shipments of Tamiflu to private-sector recipients in the U.S. to ensure that enough is available for use during the regular influenza season.

Scientists make flu vaccines using a technique that is more than 50 years old: They take a small amount of the targeted virus and inject it into thousands of fertilized hen eggs, where the virus multiplies. Each egg is cracked and the virus harvested. Chemicals inactivate and purify the virus, which is then blended into a vaccine and bottled in vials. Vaccines go stale quickly, and small changes in a virus's makeup can render them useless.

At Glaxo, Dr. Hanon leads a pandemic-flu team of about 25 scientists, many of whom are attempting to mix the right combination of liquids together to form an adjuvant. The right adjuvant would make a flu vaccine effective against a broader range of virus strains. It also could potentially help circumvent the scarcity in manufacturing capacity by bolstering the power of a vaccine and stretching it into more doses.

Sanofi, meantime, is trying to add a powerful adjuvant to its vaccine. Marie-Jose Quentin-Millet, head of research and development for Sanofi in France, led a conference call this week with nine researchers in Lyon, France, and Swiftwater, Pa., to discuss the best way to add the adjuvant. Her team also is studying ways to make vaccines using cell cultures instead of eggs, which could shave several weeks off production times.

Chiron is also working on making vaccines in cultures of canine liver cells. Earlier this week, Chiron said it began studies aimed at gaining U.S. regulatory approval of the method. It is already conducting a second late-stage test of the method in Europe, and has expressed hope that the U.S. Food and Drug Administration might accept its European data as well.

One prospect for speeding up vaccine production time is a new technology from PowderMed. Its experimental, DNA-based vaccine would skip the process of re-creating the virus in chicken eggs. Instead, scientists would pluck the vital genes from the circulating flu virus and plug them into a pre-existing vaccine template. With this technology, PowderMed says it could build a factory capable of producing 150 million flu doses in three months. Such a factory would cost about $300 million to build.

But John Beadle, PowderMed's chief medical officer, says the technology has been a tough sell. Potential funders say it is too experimental. "I find it quite scary that my friends and family will not get a vaccine," he says. "The capacity just makes it impossible that they'll get one."