Scientists have already created a live, attenuated version of the H9N2 bird flu virus, which first appeared in Hong Kong in
1999. Animal results for the H9N2 vaccine have been "encouraging," Coelingh says. With the H5N1 strain, researchers at MedImmune
and NIAID are using recombinant-DNA technology to pluck the genetic code for part of the bird flu and graft it to the backbone
of the MDV. The company hopes to start clinical tests on H5N1 sometime early next year.
As MedImmune and NIAID scientists test more strains of influenza with the MDV, they can expect to offer more protection for
the population. "We're very hopeful because our seasonal FluMist data indicate that this live, attenuated vaccine does indeed
protect against drift variants," Coelingh says, referring to new, unexpected mutations.
GSK also has invested in new vaccine technology. In September the company announced the acquisition of a facility in Marietta,
Penn., which is trying to replace chicken eggs, the substrate used for manufacturing vaccines since the 1950s, with a cell
culture. The new process could cut production time by two months. GSK also bought Seattle-based Corixa over the summer and
announced plans in September to purchase Vancouver-based ID Biomedical, which has a vaccine production contract with the Canadian
government that runs through 2011. The moves increase the vaccine-production clout of a company whose third-quarter vaccine
sales have risen by 20 percent, to nearly $700 million.
Then there is Chiron, now part of the Swiss pharmaceutical giant Novartis, which received a $62.5 million contract from the
Department of Health and Human Services (HHS) in October to produce a bird flu vaccine using adjuvants, or chemical agents
that are added to vaccines to enhance immune response. Chiron's research on adjuvants in the early- to mid-1990s led to the
production of MF59, an adjuvant used in the company's seasonal flu vaccine Fluad (commercially available in Europe and other
countries but not in the United States). After the H5N1 strain of avian flu surfaced in Hong Kong in 1997, Chiron produced
an adjuvanted H5N3 vaccine that offered cross-protection against H5N1. The company ran a series of tests and published its
findings in Lancet in 2001, then again in Vaccine in 2003. In April of this year Chiron published updated results in another
paper in The Journal of Infectious Diseases.
When H9N2 emerged in 1999, Chiron was again on the scene to make a vaccine for the new strain. "The key message is we've worked
on a number of potential pandemic-like strains," says Rob Budge, a Chiron spokesman. "And the point of that work is you can
take learnings from that as to how you would construct an optimal vaccine against a pandemic."
Chiron delivered its H9N2 vaccine to NIAID in March and expects to deliver an H5N1 vaccine either this month or early next
Fifty years ago, there were six flu-vaccine manufacturers in the United States. Today there is one, Maryland-based MedImmune.
Companies around the world currently manufacture enough vaccine to protect about 900 million people, or less than 15 percent
of the global population. The United States receives about 80 million to 100 million doses of flu vaccine each year, which
leaves roughly two-thirds of the country unprotected.
"The infrastructure has crumbled," says Paul Offit, MD, a vaccine expert at the Children's Hospital of Philadelphia. "There
were protections [against lawsuits] put in place for pharmaceutical companies in the mid-80s, but it was too little too late.
I mean, there was just a big exodus from vaccines."
Offit notes that about 36,000 people die of flu each year, "and we don't give enough flu vaccine to prevent epidemics."
Vaccine makers steadily left the market in the latter half of the 20th century due to dwindling demand and rising litigation
costs, but that trend is about to change. On November 1, President Bush announced at NIH in Bethesda, Md., that is he asking
Congress to "remove one of the greatest obstacles to domestic vaccine production: the growing burden of litigation."
Bush also outlined a $7.1 billion plan calling for better monitoring of the virus, stockpiling antivirals, manufacturing vaccines,
and preparing governments and agencies for an outbreak.
"I'm very encouraged by the enthusiasm and all the hard work," says Coelingh, who worked 10 years at NIAID before joining
MedImmune in 1994. "As far as I can tell, the expressed intention on the part of policymakers is that we will be moving toward
a universal vaccination recommendation in the United States within the next few years."
The bird flu scare, at least for the moment, is forcing pharma and policymakers to work together. After all, a little fear
can go a long way.
COMBATING A DISEASE as nimble and adaptive as influenza requires scientists to mine for alternative methods of production
and revolutionary new products. Here are some ways in which scientists have ventured beyond the conventional in constructing
a bird flu defense:
DNA vaccines: UK-based PowderMed is working on DNA vaccine technology that injects the flu virus's nucleotides—usually the ones that code
for the protein hemagluttin—directly into a person's Langhans cells in the skin. The person's cells then read that DNA and
transcribe it into viral proteins, which allows the body to develop an immune response. The biggest advantage of a DNA vaccine
is its short production cycle—about two weeks, compared with the six to eight month cycle required for conventional vaccines.
PowderMed is expected to start Phase II trials early next year (the company is currently lobbying for funding for its vaccine
delivery device, shown above). San Diego-based Vical is also working on a DNA vaccine.
Cell-culture vaccines: Several companies, including Chiron, ID Biomedical, and Crucell, a Dutch biotech company, are developing methods for vaccine
production using cell cultures instead of embryonic chicken eggs. Mammalian cell substrates can shave one to two months off
the egg production time.
Protein vaccines: Novavax—in partnership with Wave Biotech—is working on a Virus-Like Particle (VLP) vaccine. The VLP is comprised of three
co-expressed virus proteins—hemagluttin, neuraminidase, and matrix M1—that are injected into the body. The VLP lacks genetic
material so it cannot replicate, but animal studies have shown that it triggers an immune response.
Novavax has worked on this product since 2000, and it hopes to get clinical data next year. VLP vaccines have a six-week production
cycle, according to Rahul Singhvi, the company's president and CEO.
Viral-vectored vaccine: Researchers at Purdue University have been working on an adenoviral-vector vaccine for H5N1 for the past three years. The
production process involves attaching part of the bird flu gene, extracted through standard molecular techniques, to a relatively
benign, widely circulating virus called the adenovirus. The vaccine is then injected into the host, where it replicates influenza
proteins without harming the host. Lead researcher Suresh Mittal says his team has been tweaking the delivery system (the
"adenoviral vector") for the past 10 years. Preclinical results with H5N1 are due later this month.
Nanoviricides: Also called "chemical viruses," these are chemically synthesized agents that destroy specific targets while remaining invisible
in their hydrophilic shells to the host's immune system. They are the "cloak and dagger" operatives of medicine, slipping
into viruses for the kill before sacrificing themselves in a tidy "post-op cleanup" that leaves no residue or side effects.
That's the vision of Anil Diwan, president of Nanoviricides, a seven-month-old company based in West Haven, Conn. Diwan, who
has been developing nanoviricide technology for the past 13 years, acknowledges that his peers in the scientific community
ridicule him for believing he can synthesize a drug akin to a "guided missile." But even so, he remains confident that nanoviricides
will be commercially available within the next five years (Diwan says animal studies last month showed nanoviricides were
safe to use). "There is a real need to find a different approach," Diwan says. "To find a different way of attacking the virus