Ted Agres, Deputy Managing Editor, Washington Times

Illustration: Roger Schillerstrom

In November, President George W. Bush outlined a $7.1 billion strategy to expand domestic vaccine production capacity, detect and respond to influenza outbreaks, and stockpile treatments against the H5N1 avian influenza A virus, whose possible mutation into human-transmissible form has sparked fears of a pandemic.

As part of this emergency funding request, Bush asked Congress for $2.8 billion to develop cell-culture technologies to give companies "surge capacity" to rapidly produce pandemic flu vaccines. "By bringing cell culture technology from the research laboratory into the production line, we should be able to produce enough vaccine for every American within six months of the start of a pandemic," Bush said. "We must fund a crash program to help our best scientists bring the next generation of technology online rapidly."

But in reality, cell culture technology is far from new, having been used since the 1950s to manufacture vaccines against chicken pox, hepatitis A, measles, polio, and other well-defined diseases. But ramping up cell culture capabilities will have distinct benefits. Because it does not rely on vast quantities of specially prepared fertilized eggs, cell culture has the potential to shave several months off the egg-based six- to nine-month vaccine production cycle, a key advantage when the specific genetic makeup of the target virus—whether H5N1 or human influenza—is not known.

Cell culture is also free of certain risks associated with egg-based production, including shortages due to contamination by poultry-based diseases (including, potentially, H5N1 itself). For these reasons, cell culture has the potential for making commercial, on-demand vaccine manufacturing possible.

But before the promise can be achieved, several obstacles must be overcome. Cell culture-based vaccines are often derived from mammalian cells and run the safety risk of passing viruses or other contaminants into those immunized. Some cell lines are based on African green monkey (Vero) kidney cells and human retinal cells. Others come from Madin-Darby Canine Kidney epithelial cell lines (MDCK), derived from a healthy female cocker spaniel in 1958 and widely used in vaccine research. "While some lines of MDCK cells are not tumorigenic, others are highly tumorigenic," state briefing materials prepared by the Food and Drug Administration (FDA).

Because of these concerns, FDA is taking a cautious approach and, thus far, has required time-consuming oncogenicity testing to help determine risk. But the agency also seems to understand that time may be wasting. In November, the FDA invited Chiron Corp. in Emeryville, Calif., and Solvay Pharmaceuticals in The Netherlands to brief the agency's Vaccines & Related Biological Products Advisory Committee about their MDCK-based flu vaccines that they are developing.

The FDA appears comfortable that potential risks associated with tumorigenic cell substrates can be mitigated. "Although there is a perception that highly tumorigenic cells may carry greater risks than less tumorigenic cells, we are proposing that such risks can be mitigated by careful testing of the cells, validation of the production process for its capacity to remove adventitious agents, and limitation of residual DNA in the final product," the FDA said in a statement.

Solvay has already filed an investigational new drug application (IND) for its MDCK-based flu vaccine. In October, Chiron began a phase I/II clinical study of its MDCK-based flu vaccine and has completed enrollment of a second phase III study of investigational flu cell culture vaccine in Europe and is seeking approval by the European Medicines Agency. "Moving from egg-based to cell-based influenza vaccine production is an important step in enhancing our preparedness against pandemic influenza," said Walter Orenstein, associate director of the Emory Vaccine Center in Atlanta, in response to Chiron's advances.

The FDA wants to help streamline the approval process for companies developing influenza vaccines. Acting FDA Commissioner Andrew von Eschenbach told the Wall Street Journal that the agency hopes to shorten the review cycle for new influenza vaccines and drugs from 10 months to six to eight weeks. This could be done, he said, by working with industry and the National Institutes of Health (NIH) from the start of the vaccine and drug development process, rather than at the end. If requested, he said, the FDA will advise a company on setting up proper clinical studies and other technical aspects before an application is submitted.

But nonscientific obstacles also exist. Citing the "growing burden of litigation," Bush urged Congress to pass liability protection to encourage vaccine manufacturers to return to this market. For decades, the vaccine industry has been struggling with government-imposed price limits, liability lawsuits, problems in regulatory compliance, and limited manufacturing capacity.

Various vaccine-related measures were pending as the first session of Congress ended in December. Among them was the Biodefense and Pandemic Vaccine and Drug Development Act (S. 1873). The bill, sponsored by Sen. Richard Burr (R-N.C.), would establish a new government agency—the Biomedical Advanced Research and Development Agency (BARDA)—to fund and coordinate government R&D efforts into vaccines and countermeasures for bioterrorism and natural outbreaks. The bill would offer liability protection for vaccine manufacturers and a 10-year marketing exclusivity for companies, during which time competitors could not produce generic substitutes.

The Burr bill takes the place of the BioShield II legislation introduced by senators Joseph Lieberman (D-Conn.) and Orrin Hatch (R-Utah) in 2004. BioShield II attempted to create industry incentives to support Project BioShield, the Administration's mechanism to purchase $5.6 billion in vaccines and drugs over 10 years. But the BioShield II bill was controversial and died, in part, because it included a "wild card" patent provision that would have let pharmaceutical companies extend patent exclusivity on an unrelated blockbuster drug in exchange for developing bioterror therapies—a windfall potentially worth billions of dollars.