Scientists Flying the Coop on Flu Vaccine Manufacturing

IN 2005, THE world faced a possible flu pandemic known as the avian flu. ThenPresident George W. Bush’s response was to invest $7.1 billion in preparedness funding that would give the U.S. more versatility to deal with potential biothreats, both natural and man-made. Yet, while the avian flu outbreak never produced to pandemic proportions and only $3.3 billion was invested, the money did pave the way for what looks to be a substantial improvement in vaccine production technology. That paved road has meandered somewhat, but what is finally emerging is a new recombinant flu vaccine that will outpace the current research to produce a mammalian cell-based flu vaccine and that eventually will replace the five-decades-old egg-based vaccine.

The Long and Winding Road

Traditional egg-based vaccine technology was once considered groundbreaking. And for more than 50 years, it has provided protection against influenza for 50 to 80 percent of the population. But a flu virus grown in chicken eggs has its complications. Vaccinating the entire population would potentially require 600 million eggs.If we were to experience an outbreak of avian flu, our egg-producing flocks could be depleted. Even more serious: A full-blown pandemic like the Spanish flu of 1918 would not be able to be contained and defeated by egg-based production; the process takes too long, and eggs don’t grow on demand. And, many people are allergic to eggs and can’t be vaccinated.

All of the major players in the vaccine industry have long recognized the need for a more expeditious vaccine production technology, which is why in the mid1990s, many embarked on the development of flu vaccine with mammalianbased cell cultures. In the mid-2000s, the Department of Health and Human Services (HHS) invested more than $1.5 billion in contracts with six manufacturers to develop it. Unfortunately, this technology hasn’t solved the expediency issue at all because it requires the same process to produce vaccines as does eggbased technology. While it has been reported that mammalian cell-based technology could reduce the time to produce vaccines by about 10 weeks, this is only the case if the strain is ready for production. A seed stock virus, which is used in egg-based and mammalian cell-based production, takes eight weeks to be modified to reduce pathogenicity in humans. Further hindering the expediency issue is that mammalian cell-based technology yield is about fourfold lower, meaning a much larger volume is needed. This is problematic because upfront costs for operational readiness of plants are much higher than the costs for egg-based systems. Large-scale egg-based facilities have been reported to cost $150 million to produce 100 million doses per season, compared to mammalian cell-based facilities, which cost up to $600 million to produce 50 million doses per season.

Along comes the solution: Insect cellbased production. This recombinant vaccine technology cuts 10 to 12 weeks off of the production time, and has the potential of a much higher yield, specifically a greater than 40-fold productivity in terms of doses of vaccine per liter of cell culture. Even more significant is the fact that the process provides an exact match to the wild-type influenza strain, meaning it is much more effective in preventing the flu. And, the vaccine is considerably cheaper to produce.

Leaders in Cell-Based Technology

A couple of the current leaders in recombinant vaccine production technology are Protein Sciences and Novavax. In June 2009, Protein Sciences Corp. was awarded a $35 million contract by the HHS when it was determined that the company was furthest along in developing a cell-based flu vaccine using its insect cell technology. And, if testing goes well, the HHS contract could be expanded over five years for a total of nearly $150 million.

The production of a recombinant flu vaccine, which Protein Sciences developed with the published genetic code of the flu virus that the CDC posts on its website, has not been without its challenges. According to CEO Dan Adams, the vaccine has been “about 12 years in the making.” Challenges have included trying to partner with a large pharma company (a deal that fell through), getting clinical studies in its initial stages funded by the National Institutes of Health, getting through larger Phase III trials, and convincing the FDA that insect cells are a safe and effective way to produce vaccines.

Protein Sciences turned out its first batch of doses (about 100,000) against the H1N1 flu last June, and they’re continuing to manufacture it. According to Adams, the FDA gave the company an approval date of January 2010. Adams predicts that in 2010, the company will produce a few million doses of flu vaccine. “If it’s the H1N1 vaccine, we could produce a lot more than that,” he explains. “We can make up to nine times as much pandemic vaccine.” In 2011, Adams says that the company will have large-scale plants in place and they’ll be able to produce as much flu vaccine as needed.

Protein Sciences isn’t alone. Novavax also has been developing an insect cellbased flu vaccine. According to Jim Robinson, vice president of technical and quality operations, their vaccine “is 20 times more productive than egg-based manufacturing processes. We plan on manufacturing in reactors that are 1,000 to 2,000 liters in volume.” Currently, Novavax is in Phase II studies, and they have a year or two of Phase III preparation and testing before licensing the product, Robinson says.

Both Robinson and Adams agree that the biggest challenge to producing recombinant flu vaccine is the manufacturing. “We’re still struggling with that a little bit,” says Adams, “but we are making a lot of progress.” Novavax has built a pilot/product launch facility for $5 million that will produce up to 30 million doses of pandemic vaccine in six months and has completed conceptual design for doses in six months, which would have an estimated cost of $40 million (versus 50 million doses for $600 million for mammalian cell-based production). The pilot plant will allow several million doses of vaccine to go out into the U.S. market after licensure while building a highcapacity plant, which Robinson says will take about two years to build and validate.

As of this writing, there is still not an approved vaccine that is produced in insect cells in the U.S.; however, one product is licensed in Europe. But with FDA approval of Protein Sciences’ vaccine and GlaxoSmithKline’s Cervarix vaccine for HPV,Robinson says Novavax should have the third such product under FDA review.

Better Late Than Never?

When the H1N1 flu threat hit, some say that the delay in producing a recombinant flu vaccine was a result of “faulty” government planning. But,Adams doesn’t necessarily believe that. “As the military guy says, you go to war with the one you got, not the one you want to have,” he says. The government “had to figure out how they were going to potentially meet an emergency. I can’t attack their logic.” But, he adds, right now, the country doesn’t have the “technology to churn out 600 million doses [of flu vaccine]. Everybody knows [egg-based production] is not a short- or long-term solution. If this had been a real pandemic virus, we’d be out of luck.”

The government’s logic may not have been that far off. All cell-based flu vaccines will progressively capture an increasing market share in the future, says Robinson, who believes that “if you follow traditional thinking, mammaliancell culture will replace eggs, but it will replace it slowly as capacity is available” — it may take 10 to 15 years to replace all the egg-based capacity. In the meantime, “recombinant flu vaccine has the potential to leapfrog mammalian cell technology as we can create capacity more quickly and for less capital.”