Flu Vaccine Production Relies on Quaint System

Posted on Sun, Oct. 24, 2004
Vaccine Production Relies on Quaint System
MARILYNN MARCHIONE
Associated Press

SWIFTWATER, Pa. - The quaint system of producing flu vaccine based on seasonal egg-laying has harsh implications for what would happen if new batches had to be made in a hurry to fight a super-strain pandemic. At best, it would take half a year.

And since chicken flocks for next year's vaccine are already established and plants already run at full capacity, it's unclear how much Aventis Pasteur or any single company can goose up production to cover a shortfall like this year's loss of Chiron Corp.'s vaccine.

As Chiron executive Dr. Kevin Bryett said in an interview two weeks before its British factory was shut down: "If the market was to change dramatically, it is almost impossible to turn up production. The primary issue is access to the eggs. Large numbers of birds cannot be obtained immediately. It's not something you can just go down to the shop and buy, eggs off the shelf."

A visit to Aventis, America's only flu shot maker, reveals how much fragile Americans depend on an eggshell-fragile system to protect them from a killer disease. The Associated Press was allowed inside last week for a rare, firsthand look.

As the nation struggles with a historic shortage of flu vaccine, the last batches of this year's supply are being bottled at a slickly run, modern factory in the Pocono Mountains.

A little to the west, in Amish country, next year's doses are already in the works. At the moment, they have two legs and soft, downy feathers. By January, they'll be laying millions of eggs for flu shots.

There is far more horse-and-buggy to vaccine production than just the Amish wagons that creak past Pennsylvania chicken farms.

Vaccines are biological products, not chemicals that can be cranked out in times of need.

The viruses they're made from need cells in which to grow. Yellow fever and flu are the only vaccines that use eggs for this - not the kind that come from the store but those produced under strict pharmaceutical conditions.

Flu also is the only vaccine made fresh every year. In late February or early March, the World Health Organization picks its three strains based on the virus going around. If it acts too soon, newly emerging strains can be missed, as Fujian was last year.

If it waits too long, vaccine makers must race against the biological clocks of hens, which only lay eggs for nine months until they're too old, then rush through a several-months-long process to make enough vaccine before the flu season starts.

"We're constrained on the front end and the back end. No other vaccine has that kind of time pressure," said Aventis spokesman Len Lavenda.

Dr. Anthony Fauci, the government's top vaccine scientist, acknowledged the difficulty.

"The ability to have surge capacity when something goes wrong, to turn on a dime and try and correct it, is difficult," he said in an interview Thursday.

Aventis starts making vaccine more than a year in advance, around August on nearly 50 farms throughout Pennsylvania.

"They're fairly small operations," many with only 10,000 birds, said Sam Lee, a 40-year-old chemical engineer who is the company's operations team leader.

White leghorn hens are used. The exact type is a company secret. The breeder holding the patent supplies the eggs, which take 21 days to hatch and become chicks.

They're moved in late September into buildings where they can move freely as opposed to cages and coops, and spend three months maturing into hens.

Egg-laying starts in late December, typically one a day. How many eggs it takes to make a flu shot is another Aventis secret, but Chiron's Bryett said: "If you're very lucky, you'll get three doses per egg." That's for a single flu strain; three strains go into each dose of vaccine.

The fertilized eggs are collected by two large egg producers, who incubate them for seven to 12 days and then bring them to Aventis. Eggs delivered in January would hatch into chicks if not used for vaccine, so manufacturers often gamble and start making whichever of the three flu strains WHO seems most likely to choose.

"Any production before February is done at the company's risk," Lee said.

A machine punches a tiny hole in each shell and a needle inoculates the chick embryo with a single flu strain. The virus is allowed to multiply for about three days.

Then the eggs are broken, and the fluid around the embryo containing the virus is collected and purified. Formaldehyde is added to inactivate the flu virus, and a machine spins the mixture to separate out the part containing virus.

Once again, eggs are needed: A sample of the spun solution is put back in the eggs to see if any virus grows - a test to ensure the germ was inactivated. A few more processing steps turn it into a lot, or batch, of several hundred thousand doses of a single strain.

Next comes sterility testing where vaccine is spread onto lab dishes and checked to see if it contains contaminating bacteria.

"We haven't had a contamination in years," Lee said.

It's not known whether this step is where Chiron's vaccine was discovered to be tainted with serratia bacteria or if it happened later.

As Aventis tests for sterility, samples also go to the Food and Drug Administration, which doesn't start its testing until late May or early June because it has to brew specific chemicals each year to test specific strains.

After that, three viral strains are combined to form the trivalent vaccine. Four weeks of potency and sterility testing follow, then packaging into single-dose syringes and 10-dose vials and quality checks for potency.

The last doses are made by the end of September. Chicken farms are free to sell old birds and must do a mandatory cleanout and disinfection to get ready to start the whole process all over again.

As cumbersome as this egg-based vaccine recipe may seem, "it has been over the years a reliable, time-tested and reasonably efficient way to get virus grown," Fauci said.

"Changing that requires genuinely a very, very large investment" to make a product sold only once a year and for a pittance compared to expensive cholesterol pills and other drugs that people take every day, said Dr. William Schaffner, a Vanderbilt University flu expert who advises the government on vaccines.

"Vaccines in general and flu in particular are undervalued. Prices are not at the level they should be to attract new investments," Aventis' Lavenda agreed.

Aventis has partnered with a company in the Netherlands, Crucell, to research using human and animal cells in place of eggs. These so-called cell cultures could be maintained indefinitely and ramped up on demand whenever vaccine is needed.

It's pricey technology, but cost isn't the only obstacle. Some worry that the genetic material of these cells might interact with the flu viruses, creating dangerous hybrids and undercutting the purpose of the vaccine.

"If it changes the virus, obviously, that would not be desirable," Chiron's Bryett said.

Such technology is at least a couple years away, said Fauci, whose office is funding many such studies.

"There are safety issues, consistency issues," he said. "That's the reason why you do research on it. If it was just sticking the virus in a cell culture and go, we would have done it a long time ago."

So we're stuck with eggs for next year and probably several more.

The government has plans in the works to encourage chicken farmers to maintain year-round flocks so eggs would be available anytime in case a new single-strain vaccine had to be made to fight a pandemic.

"Right now we don't have the capacity to reliably create all the vaccine we would need in that situation," Dr. Julie Gerberding, director of the federal Centers for Disease Control and Prevention, said in a news conference earlier this year.

"It is clear that we need to substantially expand our options," including looking at whether the vaccine really needs to be updated every year, Dr. John Treanor, another government vaccine adviser from the University of Rochester, wrote in a recent New England Journal of Medicine article.

Public health officials have worried much about bioterrorism, a threat of unknown proportions. Instead, Treanor writes, the nation has been caught offguard and threatened by a long familiar foe, "a virus that predictably - in each and every year - causes major mortality and morbidity."