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A Chicken-and-Egg Problem: How to Speed Up Production of Flu Shots

October 31, 2005|Charles Piller | Times Staff Writer

If bird flu erupts into a pandemic, the world will need a lot of vaccine in a hurry. That would be virtually impossible with the current flu-vaccine manufacturing method, which is little changed since the 1940s.

Several companies have bird flu vaccines in development, though none is yet commercially available. Chiron Corp. of Emeryville, Calif., and Paris-based Sanofi-Aventis have begun clinical trials with vaccines that could be ready next year.

But flu vaccines traditionally are grown in millions of fertilized chicken eggs, a process that takes at least six months. The lengthy production cycle makes it hard for drug makers to keep up with mutating flu strains and limits the amount of vaccine they can produce quickly.

The egg-based method is particularly problematic for bird-flu vaccines because the disease threatens chickens, which provide the essential raw material.

So pharmaceutical companies are developing two methods -- using cell cultures and DNA cloning -- that could speed things up. But each faces hurdles in gaining official approval.

The best-known alternative is to grow vaccines in cell cultures, a decades-old technology already used for vaccines against chicken pox, hepatitis A and polio. Partly by removing the step of procuring huge stores of specially prepared eggs, it makes on-demand manufacturing possible.

Culturing flu vaccine strains using human, monkey or canine cells within sealed vats "can cut the production cycle to about four months, perhaps a little better," while vastly increasing yield, said Lei Zhong, an analyst with Banc of America Securities who holds a doctoral degree in immunology.

Annual flu vaccine preparations begin in February and shots are ready in October. Cell culture vaccines could be available by July, and if a new flu strain suddenly emerged, an updated vaccine could be produced before the flu season peaked.

Chiron, Sanofi-Aventis and other companies have produced experimental cell-culture flu vaccines, and a European product may hit the market as early as next year, Zhong said.

But analysts said a U.S. product was still at least three years away because of more-demanding regulations.

Other vaccine makers and experts are putting faith in a second alternative to egg-based vaccines, one that involves a radical shift into genetic engineering.

Peter Dunnill, chairman of biochemical engineering at University College London, said DNA vaccine production, a technique invented a decade ago, eventually could yield 500 million doses of flu vaccine from a single lab in as little as three weeks and could cut the entire production cycle to three months.

PowderMed Ltd., a biotech in Oxford, England, and San Diego-based Vical Inc. have shown that DNA vaccines hold promise for fighting flu outbreaks.

DNA vaccines are far from proven, said Dr. Stanley Plotkin, an emeritus professor of pediatrics and microbiology at the University of Pennsylvania and consultant to Sanofi Pasteur, the vaccine unit of Sanofi Aventis. But animal studies show intriguing potential for stronger immunity and the prospect that one vaccine could confer a degree of immunity to a range of flu viruses.

PowderMed clones the gene for hemagglutinin, a protein on the surface of flu viruses, within the common lab bacterium E. coli. The flu DNA is purified, dried and coated onto microscopic specks of gold, forming a powder.

In clinical trials of an experimental vaccine for common flu with 36 subjects, the company's vaccine worked well, with no serious side effects. The company said it would soon test a vaccine for H5N1, a bird flu strain.

Vical received a federal grant to develop a bird flu vaccine last month and hopes to advance to human trials with an experimental vaccine within two years.

The company plans to target the virus' surface proteins as well as "conserved core proteins" -- internal parts of the virus that are less changeable, said company spokesman Alan Engbring.

The approach could produce a vaccine that would still have some benefit as the flu virus mutated, or allow faster development of a new vaccine if H5N1 evolved into a pandemic strain, he said.

If large-scale trials succeed, the DNA method could offer some of the same advantages as the cell-culture method -- with cost savings.

"The expense associated with DNA vaccines is much lower than with the other methods," said Eric Schmid of SG Cowen Securities in New York.

The DNA and cell culture methods are also easier to keep clean than a factory full of eggs.

PowderMed knows the issue firsthand. In May 2003, Chiron Corp. agreed to buy British vaccine maker PowderJect Pharmaceuticals for about $878 million. A month later, PowderJect's plant in Liverpool, England, was cited by regulators for contamination. It was the start of problems that led to the plant's temporary closure last year and sparked a crisis in the U.S. flu vaccine supply.

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