Vaccine system remains antiquated
New production techniques are mostly years away from being implemented
Tuesday, November 24, 2009
After a lethal bird flu virus emerged in Asia, U.S. officials launched an intense effort to build new defenses against a pandemic, including replacing an antiquated vaccine system, which depends on millions of chicken eggs.
But six years later, as Americans from Washington to California line up to get inoculated against the swine flu, the slow progress toward developing better ways to make a vaccine has become glaringly obvious.
This lag and the shortage of H1N1 vaccine have focused attention on the status of government efforts to develop state-of-the-art techniques to make flu and other vaccines, including those needed to protect against bioterrorism, and the nation's dependence on a process that is notoriously slow and unreliable.
Several new technologies are showing promise. Spurred by $487 million in federal funding, a sprawling new vaccine factory is opening in North Carolina Tuesday that will produce shots using dog cells instead of chicken eggs. A Connecticut biotech company has also applied to sell a vaccine employing a radically different approach involving a genetically engineered virus infecting insect cells -- a strategy a Rockville firm is testing to inoculate people against the swine flu in Mexico. Dozens of other high-tech approaches are also moving through the pipeline.
While several companies are trying to ready their new techniques in case the H1N1 pandemic worsens, most of these remain years away from contributing significantly to the world's capacity to respond to a deadly new pathogen.
"If this pandemic had come next year, we might have had some of these vaccines licensed and we would have been able to use them -- our investments might have borne fruit," said Robin Robinson, of the Health and Human Services Department. "But unfortunately they didn't help us this year. Others still have a ways to go."
The most immediate solution to the vaccine shortage would be adjuvants -- compounds that boost the immune response, allowing limited stock to be stretched into more doses. H1N1 vaccine with adjuvants is available in Europe, Asia, the Middle East, Canada and Mexico. The United States has decided against using adjuvants because the Food and Drug Administration has not fully reviewed them. Officials worried that a new product would make people even more nervous about the inoculation.
For decades, flu vaccine has been produced by identifying which strains of flu virus were most likely to be circulating, tinkering with microbes in the laboratory to create "seed" virus, injecting that virus through the fragile shells of newly fertilized chicken eggs and waiting several days for the microbes to grow.
The process takes six to nine months and is highly unpredictable. The H1N1 seed virus initially grew inside the eggs at only about a third to a quarter of the expected rate, accounting for most of the lag in production.
"It's a time-honored but nonetheless fragile technology," said Anthony S. Fauci of the National Institute of Allergy and Infectious Diseases.
In addition, the process relies on having access to millions of eggs -- each egg typically produces one to three doses of vaccine. If the next pandemic is caused by a virus that kills birds, like the H5N1 avian flu virus that emerged in 1997 in Hong Kong and reemerged in 2003, any process dependent on chickens would be vulnerable.
Pharmaceutical companies, however, have had little incentive to invest in new technologies. Flu vaccine is relatively cheap and the market is capricious -- millions of doses often end up being discarded because of tepid demand. The long, expensive process of getting new vaccines approved creates another disincentive.
"We're behind the curve in embracing new technology because we're exceedingly cautious," said Scott Gottlieb, a former deputy FDA commissioner now at the American Enterprise Institute.
But in 2006 the federal government awarded $1.3 billion to six companies to develop flu vaccines using cells to grow the virus instead of eggs, although three recipients have dropped out or stalled.
"You just take the cells out of the freezer right away and ramp up production," said Andrin Oswald of Novartis. The Swiss company already makes flu vaccine using dog kidney cells for Europe and Japan at a factory in Germany; on Tuesday, it will cut the ribbon on a massive new facility in Holly Springs, N.C., that will eventually be able to produce 150 million doses of vaccine in six months for the United States. But the factory will not be ready to start making vaccine until 2011 at the earliest.
Baxter International won approval last month to sell an H1N1 vaccine in Europe that uses a decades-old line of African green monkey kidney cells, and it is working on a vaccine for the United States.
But the Deerfield, Ill., company has not said yet whether it will build a U.S. factory, which the federal government required in the contracts. Britain's GlaxoSmithKline spent $300 million on a facility in Marietta, Pa., but it remains in the earliest stages of development.
Sanofi Pasteur shelved its efforts after studies indicated the cell-based vaccine it was developing was not superior to the traditional vaccine it makes at its new $200 million facility in Swiftwater, Pa. Solvay dropped out after deciding to expand its production capacity in The Netherlands instead of building a U.S. factory. MedImmune of Gaithersburg put its program on hold after the FDA demanded additional studies that the company argued were unnecessary.
Even if cell-based vaccines eventually make it to the U.S. market, no one sees them as a long-term solution. They may shave weeks off the production time, which this year would have made a significant difference. But they still require lengthy production schedules for purification and testing.
More promising is a new generation of vaccines that do not depend on growing the virus. Instead, they exploit the latest in genetic technologies to use the viral DNA to quickly churn out key proteins to elicit a protective immune response.
Protein Sciences of Meriden, Conn., has applied to the FDA for approval to sell a vaccine made by genetically engineering flu genes into a worm virus, which then infects cells from caterpillar ovaries to produce the necessary proteins to make vaccine.
"The other approaches are evolutionary. Ours is revolutionary," said Daniel D. Adams, the company's chief executive.
After being turned down for government funding for years, the company last spring won a five-year, $147 million contract from HHS to develop the vaccine. An FDA advisory panel Thursday voted that the vaccine appeared to be effective in adults but more studies were needed, including to make sure it worked in children and was safe.
Novavax of Rockville is testing a similar vaccine on 4,000 people in Mexico in the hopes of getting an H1N1 vaccine approved by Mexican regulators.
VaxInnate of Cranbury, N.J., for example, produced an experimental H1N1 vaccine using genetically engineered E.coli bacteria, and Vical of San Diego just won a $1.25 million contract from the Navy to develop an H1N1 vaccine that involves injecting DNA sequences from the virus directly into people.
But these remain probably years away from producing a marketable vaccine, and given the skittishness of many Americans about the traditional shots and even the newer nasal spray, it remains unclear how many would feel comfortable with vaccines produced using insect cells, bacteria, animal kidney cells or other new approaches.
"It will be a uphill road in convincing people that it's safe and effective and represents an advance," said Gregory Poland, a flu vaccine expert at the Mayo Clinic.
Many experts say that while these approaches potentially offer a much quicker and easier way to produce large amounts of vaccine, they do not represent the ultimate solution.
That goal, they say, would be to produce a "universal vaccine," which would not have to be altered each year to match whatever strain of the virus is circulating.
"That would be the home run of flu vaccines," said John Treanor, a University of Rochester flu vaccine expert.
Other experts said the federal government should also take steps to guarantee vaccine makers that it would buy any excess vaccine and subsidize excess vaccine production capacity.
"Imagine if this was 1918-like influenza and lots more people were dying and we had no vaccine. We would see the world coming to a screeching halt," said Michael T. Osterholm, director of the University of Minnesota's Center for Infectious Disease Research and Policy. "This should be a wake-up call that we need to have an intervention that allows us to stay in control. Right now the virus is in charge."