Bird Flu, Part IV: Flying the Coop for New Vaccine Technology

The "chicken and the egg" approach to mass-producing influenza vaccines may soon fly the coop.

Although the tried-and-true — yet slow — process of making vaccines from flu viruses grown in fertilized chicken eggs is currently the only method approved in the United States, various drug companies and other corners are working on the next generation of vaccines using what's called "cell-culture technology."

The hope is that cell culture can help create vaccines faster, especially in the face of a pandemic flu — whether it be the H5N1 bird flu virus or another strain.

Editor's note: This is the fourth in a five-part series on avian influenza that will be featured all this week on

Click here to read Part I, "Bird Flu: All You Ever Wanted to Know About the Coming Pandemic."

Click here to read Part II, "Do Antivirals Give Us a False Sense of Comfort Against Pandemic Flu?"

Click here to read Part III, "Congress Ponder Liability Protection for Vaccine Makers."

"Making vaccine has sometimes been compared to farming," Dr. James Matthews, senior director for science and health policy at Sanofi Pasteur U.S., a division of the pharmaceutical giant Aventis Pasteur, told

"Like a farmer cultivating a crop, the inactivated influenza virus must first be grown before being harvested," explained Matthews. "Each virus has its own growth characteristics — some grow quickly, others slowly; some produce a large amount of virus, others a small amount."

In laying out his national plan to protect America against pandemic avian influenza, President Bush encouraged the use of cell-culture techniques, which could bring vaccines to the U.S. market faster. He's requested $2.8 billion from Congress for a crash program using the technology.

"New cell-culture technology should allow manufacturers to create capacity to produce enough vaccines for every American within six months of the start of a pandemic," Bush said Nov. 1

Using chicken eggs, it takes about nine months to make a flu vaccine, from the moment a new strain is identified to the day the vials ship out to health-care providers.

The current approach, which has been used for over 50 years, requires about 270 million eggs to make the roughly 90 million doses of flu vaccine in a given year, according to the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Hundreds of thousands of chickens need to be cooped up year-round just to lay those eggs.

"Basically we haven't really advanced much in new tech for the last 60 years," said Dr. Paul Offit, chief of the division of infectious diseases at the Children's Hospital of Philadelphia. "The problem with eggs is [that] only chickens grow eggs, so you're limiting steps."

Cell culture, on the other hand, can create a theoretically limitless amount of vaccine.

"To get it to mass scale where you make tens of millions of doses [of vaccines] is a big deal," Offit added.

Currently, the three flu strains identified by the World Health Organization as those most likely to spread around the world in any given year are injected into separate fertilized eggs, where the viruses multiply.

The viruses are eventually harvested from the eggs, purified and killed.

Vaccine makers then "split" the viruses using a detergent, releasing each strain's surface antigens. Fluids containing the dead viruses and their antigens are mixed together to make one dose of seasonal flu vaccine.

When the vaccine is injected into a recipient, the surface antigens trigger his immune system to make antibodies against them, conferring at least partial immunity to the original viruses.

With the cell-culture method, the virus is grown on specially selected cell lines instead of eggs. This can reduce the start-up time to get a vaccine into production from four weeks to two. Furthermore, people with egg allergies, barred from getting regular flu shots, can tolerate cell-culture vaccines.

Placing viruses in mammalian cells such as monkey or dog kidney cells allows vaccine makers to produce more pure doses in less time; they aren't limited in how much vaccine they can grow by the number of eggs they have to work with.

"We need to be able to bring our ability to manufacture [vaccines] into the 21st century. Egg-based cultures work, and they're reliable but they have a major disadvantage of lack of surge capacity," NIAID Director Anthony Fauci said Monday.

Several companies, including Sanofi Pasteur, Chiron and Protein Sciences Corp., are working on cell-based vaccine technology. ID Biomedical Corporation of Northborough, Mass., was awarded a $9.5 million contract from the NIAID to study cell culture.

But Bush doesn't anticipate a complete switch to cell-based technology until at least 2010. Some companies agree that timeline may be accurate.

"We view cell culture as being a longer-term prospect that will take years before it is approved for actual manufacturing in the U.S.," said Matthews of Sanofi Pasteur. "It is a promising technology but one still in development. Until then, we must rely on egg-based manufacture. There is no quick fix for improving current influenza vaccine manufacturing methods."

Sanofi Pasteur was awarded a $97 million contract from the U.S. Department of Health and Human Services to speed up the production process of cell-culture flu vaccines and the design of a manufacturing facility in the United States that could facilitate the production of 300 million flu vaccines annually. The majority of that contract is expected to be completed by 2008.

Chiron is conducting clinical trials of its seasonal flu vaccine in Europe, where they will file for approval for that product next year. That company has also begun studies of its cell-culture flu vaccine in the United States; Chiron produces those vaccines from viruses propagated in the Madin-Darby Canine Kidney cell line. Company representatives say vaccines made for the H5N1 strain via the traditional egg method will be available in the United States the first half of 2006.

Snipping a Little Genetic Code Here and There

Protein Sciences Corp. of Meriden, Conn., already has a cell-culture vaccine based on a flu strain's genetic code, one that's nearly ready for market.

"We're way ahead of the field," Protein Sciences President Daniel Abrams told "Making a pandemic vaccine for us is no different than making scrambled eggs … There's no danger working with a genetic code, and in the age of genomics, we can use the genetic code much faster than you can get a virus out of CDC that they feel comfortable releasing."

Scientists at Protein Sciences isolate ovary cells from the fall armyworm, a tropical caterpillar, and grow them in a fermenter, where they grow and divide.

The cells are later "infected" with the genetic code for the protein that is characteristic of the harmful virus. The company doesn't work with the actual pandemic flu virus.

"We take the virus that only infects these fall armyworms. … We isolate that virus, and then what we do is, we snip off the genetic code that the virus carries normally in nature and we substitute for it the code we get from the CDC, which codes for the protein that is characteristic for the virus," Abrams explained.

The maximum amount of protein for the virus is produced in two to three days. The infected cells die off, and the remaining three proteins are further purified. A little salt water is added, and the substance is put into a vaccine. This method results in purer proteins in less time than with the chicken-egg technique.

"It's a very pure, very straightforward vaccine. We use the ovary cells to make the protein because they don't know any different. They don't know they shouldn't be making the protein," Abrams said.

Protein Sciences has been granted accelerated approval status by the Food and Drug Administration to use its vaccines in clinical trials. The company's goal is to have the vaccine ready for market by 2006.

Many in the medical community say it's not whether more modern-day techniques can more effectively make vaccines, but whether there's the will in Washington and in the pharmaceutical industry to do it.

"From a scientific basis, the prospect of cell-culture technology replacing chicken-embryo egg techniques is really within grasp," said Dr. Brian Currie, vice president and senior medical director at Montefiore Medical Center in the Bronx, N.Y. "It's a real likelihood that can be developed in short order … The problem is not the technology, but implementing the technology."

One problem is that the FDA, which is currently heavily invested in egg technology, needs to approve any new vaccine-making method, and that method's side effects, before the vaccine can be used.

There is also little incentive for pharmaceutical companies to pay the up-front production costs to mass-produce vaccines. And if the U.S. government stockpiles vaccines, companies can't count them as being sold for a profit until they are actually distributed.

What isn't sold to governments to be stockpiled is left to be sold by the industry at marginal prices.

Another problem, Currie said, is getting academia, government and industry together to churn out vaccines.

"When you look at drug development, [something] like 90 to 95 percent of new drugs come out of pharmaceutical companies, not academia," Currie said. "All of the new technology for vaccine production seems to be coming out of academia, not the pharmaceutical industry. I think we keep disincentivizing the pharmaceutical industry from wanting to invest in new technology and research."

Respond to the Writer is taking an in-depth look at the initiatives, strategies and policies being employed to prepare the United States and the world against the next pandemic flu.

Click back to Monday to read about what state and local governments are doing to prepare for a possible influenza pandemic, in the Politics section.