Science in the Triangle

The flu vaccine manufacturing plant that Novartis is about to finish about 20 miles southwest of North Carolina’s Research Triangle Park promises better and faster protection for humans without the carnage to chicken offspring.

Measuring twice the size of a Super Wal-Mart store, the plant (photo below) will be the first in the U.S. to use millions of factory-grown cells rather than millions of fertilized chicken eggs to make seasonal and pandemic flu vaccine. With a production capacity of up to 150 million doses per year and room for expansions on the 167-acre site, the Novartis vaccine manufacturing plant in Holly Springs will also be one of the largest.

Company officials expect that the first dose made in Holly Springs will be sold in 2011 - a milestone in U.S. flu vaccine manufacturing, which has relied on fertilized chicken eggs since the end of World War II.

On Tuesday, Novartis offered a rare look inside the facility. Gov. Beverly Perdue, Congressman David Price and Kathleen Sebelius, U.S. secretary of health and human services, toured the facility. Daniel Vasella, chief executive of Novartis, and Dr. Andrin Oswald, head of Novartis’ vaccines and diagnostics division, were on hand to host the guests.

“It’s the beginning of modern cell-based flu manufacturing,” Oswald (photo at right) said during a media briefing. “This facility is a promise for the next 20 to 40 years.”

Cells cultured in the laboratory and grown in a series of ever larger tanks have been used to make biotech medicines for more than a decade. The Triangle, the center of the North Carolina biotech hub, got its first commercial biotech manufacturing facility in 1997, when Boston drugmaker Biogen Idec opened its cell-based production plant in RTP.

Cell cultures are also used to make some vaccines, including those protecting against polio, hepatitis B and types of the human papilloma virus that can cause cervical cancer. But the handful of companies that make flu vaccines have long been reluctant to switch from chicken eggs to cell cultures.

Flu vaccines aren’t profitable enough to justify the large investment necessary to build cell-based production facilities, said Novartis CEO Vasella. (Photo at right)

The Holly Springs plant required more than $1 billion in investments - about $600 million from Novartis and $487 million from the U.S. Department of Health and Human Services.

Without the public-private partnership, Vasella said, “a $1 billion investment would be a real stretch” for Novartis.

Announced about 10 months ago, the partnership followed four years after Swiss-based Novartis bought Chiron, the second largest supplier of U.S. flu vaccine, for about $5 billion.

Like other large pharmaceutical companies, Novartis wanted to beef up its vaccine business. But the company also saw the Chiron deal as an opportunity to pursue cell-based production technologies, Vasella said.

In 2004, quality problems with Chiron’s egg-based production method caused a shortage of seasonal flu vaccine supplies in the U.S. The same year, the first avian flu virus to infect people emerged in Asia. The virus, also known as H5N1, killed half of the about 250 people it infected over the next two years before its advance stopped in Europe.

The 2004 shortage of U.S. seasonal flu vaccine supplies and the threat of a deadly avian flu epidemic alarmed federal public health officials and led to the partnership that made construction of the Holly Springs facility possible, Vasella said.

Novartis officials said they hope the H1N1 virus (photo at left), which arrived in the U.S. in April and has killed nearly 4,000 nationwide, will help them with an immune response booster, or adjuvant, they want to make at the plant.

The adjuvant not only reduces the amount of H1N1 pandemic vaccine needed per shot by 75 percent, clinical tests have shown it also gives better protection for young children and the elderly.

Like the cell-based pandemic flu vaccine, Novartis’ adjuvant still requires regulatory approval in the U.S. Both are approved in Europe, the adjuvant for more than a decade.

The Food and Drug Administration, long reluctant to consider approving a vaccine adjuvant because of safety concerns, now is at least talking about what it would take to bring it to market, Oswald said.

In the past year, Novartis has tested pandemic flu vaccine with an adjuvant in the U.S. and started collecting data from the tests, said Russell Thirsk, head of Novartis’ U.K. vaccine manufacturing site in Liverpool.

While FDA approvals for the cell-based vaccine and the adjuvant are far from guaranteed, Novartis officials said there is a chance.

Last week, Protein Sciences was sent looking for more safety data for its cell-based seasonal flu vaccine. But the Connecticut biotech company uses insect cells to grow the one crucial protein that produces an immune response. Novartis’ approach is less experimental, using canine kidney cells the company has long cultured in the lab and inactivated virus.

The current shortage of H1N1 pandemic vaccine - brought on by the virus’ slower-than-expected growth in chicken eggs - could also become a factor.

Cell cultures grow much faster than chicken embryos, are available on demand and don’t pose the risk of allergic reactions to the vaccine. Also, the virus produced in eggs is slightly altered.

At the Holly Springs plant the steps of making flu vaccines with the help of cells is spread across three floors: from growing the cells in tanks holding up to 5,000 liters, about 1,250 gallons, to infecting the cells, harvesting and inactivating the virus and filling up to 600 vials per minute on a packaging line that is equipped with the latest technology available.

The plant already employs about 200. The work force is projected to increase to 350 by 2013.