A Chicken-and-Egg Problem: How to
Speed Up Production of Flu Shots
October 31, 2005 By Charles Piller, latimes.com
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.
Chiron spun off PowderMed last year, including executives
and researchers at the original PowderJect, as a privately
held company dedicated to producing powder-based vaccines.
PowderMed has 36 employees and has raised $35 million in venture
capital.
Another advantage of DNA vaccines is that they can be given
without a needle. PowderMed uses a painless "gene gun"
— much like the device used by Dr. McCoy on the TV series
"Star Trek." A high-speed puff of compressed helium
implants the gold powder into the skin. The devices are so
easy to use that the company plans to train grocery clerks
to give vaccines.
Nevertheless, DNA vaccines are running well behind cell-culture
methods in the competition to replace egg-based methods of
flu vaccine production, said Aaron Geist, an analyst with
Robert W. Baird & Co. who has a doctorate in microbiology
and virology.
"The standard manufacturing capacity of cell culture
has been proven in the biotechnology market," Geist said.
"We have yet to see the feasibility of DNA vaccines in
scientific studies to determine if or when they will hit the
commercial market."
Dr. Gary Nabel, director of vaccine research for the National
Institute of Allergy and Infectious Diseases, compared egg-based
manufacturing to the traditional QWERTY typing keyboard layout
— awkward and inefficient, yet so widely used that moving
to a new method would be staggeringly hard.
So for the time being manufacturers will try to increase
egg-based vaccine efficiency with "adjuvants" —
chemical additives that boost immune response so that a lower
dose has the same benefit. Chiron reported positive results
Friday for early trials of an experimental adjuvant vaccine
for H9N2, another common bird flu virus that can infect humans.
"We like DNA vaccines because they are so simple,"
Nabel said, noting that his agency funds more than $30 million
in DNA vaccine research for several diseases. "But it's
not quite ready for prime time."
Nabel also cautioned against being seduced by what seemed
at first like a miracle solution.
In 1976, swine flu virus was mistakenly seen as a pandemic
strain. The government rushed a vaccine into circulation that
was later believed to have caused hundreds of cases of Guillain-Barre
syndrome, a rare paralytic disorder.
"The ghost of swine flu is out there," Nabel said.
"We're trying to balance the risk of the pandemic, the
risk of the vaccine not working, the risk of side effects."
Such cases led to stringent regulations that increase safety
but delay promising strategies. Given low profit margins in
the vaccine business, few drug companies can justify the long-term
risk.
"You're talking about a billion-dollar project for not
a very high-profit product," said Dr. Paul Offit, a vaccine
expert at Children's Hospital of Philadelphia.
Despite the obstacles, one fact remains: With egg-based manufacturing
methods, if pandemic flu strikes, the supply of vaccine would
run out virtually overnight.
Offit and others have called for urgent action on all fronts.
Nabel endorsed the concept.
"In three to five years we'll say we finally stared
this problem in the face and found the solution," he
said. "DNA would be part of it."
