November 01, 2005
Tuesday

Of the many worries raised by the H5N1 bird flu, nothing can top modern medicine's reliance on a rickety system that makes influenza vaccine from chicken eggs and has repeatedly failed in the annual bouts against ordinary strains.

Fearing that a pandemic capable of killing millions of people could spring from the avian flu, researchers are studying a range of choices aimed at stretching vaccine supplies, finding new ways to make traditional shots or leaping to new methods of immunization only now being tested in humans.

"Our main weapon in the armamentarium against influenza is a vaccine," said Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases. "The fragility of the influenza enterprise is real, and we must address it."

The Department of Health and Human Services is investing $165 million to build a stockpile of 20 million doses of an experimental H5N1 vaccine, but there is no certainty the egg-based serum will work. Bird flu won't spread easily among people unless it mutates. Those same genetic changes could render the stockpiled vaccine a mismatch - triggering a mad race to make a new one.

The fate of millions may rest in the daily work of an army of laying hens, enlisted to deliver billions of eggs to vaccine factories around the globe. But if that same virus also sweeps through the world's henhouses, there may not be enough chickens left to lay the eggs.

In this milieu of unknown risks and extraordinarily high stakes, both government researchers and private industry are mulling over vaccine alternatives.

Fifteen years ago, Dr. Stephen Johnston, now a professor at Arizona State University, developed what he called a "gene gun." With a burst of compressed helium gas, the gun blasts a microscopic dose of gold particles into the upper layers of skin tissue, which are rich in disease-fighting white blood cells.

Piggybacked onto each speck of gold are segments of DNA - the genetic blueprints of living things - that once inside these cells cause them to make proteins that rev up the immune system.

Today, British entrepreneurs backed by venture capitalists are testing a version of Johnston's gene gun. The device by PowderMed Ltd. of Oxford can deliver a DNA vaccine that carries the blueprints for protein found on the outer surface of the flu virus. The vaccine can be formulated to mimic the surface proteins - known as hemagglutinin antigens - of any flu virus.

Just like the antigens harvested and purified from vaccine strains grown in eggs, these proteins stimulate antibodies that will destroy any similar-appearing flu virus that enters the bloodstream.

In a small study last year, PowderMed's gold-borne vaccine raised protective antibodies against a common flu in 12 volunteers. A larger trial of the technology is slated for next year. In August, PowderMed announced that it also had developed a DNA vaccine against the H5N1 strain - ready only for testing in animals. The first human tests of that vaccine may begin in mid-2006.

PowderMed's prowess in following through with its technology is yet to be proven. The management team had previously owned the troubled egg-based vaccine facility in Liverpool that was sold to Chiron Corp. in 2003. The plant was subsequently shut down last year because of persistent contamination, but Chiron has solved those problems and will be making H5N1 vaccine at the same facility.

Should PowderMed's new technology prove effective, the company claims its vaccine would hold an extraordinary advantage over egg-based serums - only 2.6 pounds of DNA would be needed to immunize the entire U.S. population. Using standard biotechnology industry processes, it all could be manufactured in three months - compared with a year for making 80 million doses of vaccine from eggs.

The rush to develop a vaccine for the H5N1 strain is driven by the chilling theory that the bird flu now spreading throughout the avian world could mutate into one that reprises the 1918 Spanish influenza, which killed an estimated 50 million people.

"We really do need an entirely new approach to vaccine manufacturing," said PowderMed chief medical officer Dr. John Beadle. "The 1918 pandemic killed most people in the first six months. An egg-based vaccine won't even be produced in time to make an impact."

If tests prove the DNA vaccine works, the trickier part of this technology would be in making enough of the disposable plastic gene guns. PowderMed's planned factory capacity would yield in three months only enough for 75 million two-dose immunizations. The handheld guns - each with a tiny reservoir of pressurized helium - are also inherently more costly than a standard syringe. However, because the DNA vaccine itself would be much cheaper than an egg-based product, PowderMed executives contend that the overall cost would be competitive.

A different approach to DNA vaccines is being pursued by Vical Inc., a small San Diego company run by former executives of Merck & Co. Here, there is no reliance on unorthodox gold beads and helium-powered guns - the vaccine is injected into the muscle by hypodermic needle.

The vaccine itself contains three components of a flu virus - the surface antigen, as well as two proteins found in the influenza virus core.

One advantage of including core proteins, according to Vical Chief Executive Vijay Samant, is that they do not mutate as quickly as surface antigens, so a vaccine against one strain of influenza might work against others.

Although the surface antigens raise protective antibodies, core proteins stimulate a second line of antiviral defense known as cellular immunity. Specialized white blood cells detect and destroy the body's own tissues that have been infected by a virus - preventing them from churning out copies of the unwelcome invader.

A vaccine that stimulates both antibodies and cellular immunity would in theory provide broader and more long-lasting protection against flu viruses. Vical has secured a $2.9 million grant from the National Institutes of Health to develop flu vaccines using the technology, which is also being used to develop immunizations against the Ebola virus and HIV, the virus that causes AIDS.

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