Timeliness and risks to eggs in avian flu pandemic lead companies to seek other production methods
By Ishani Ganguli | March 31, 2006
The global spread of avian flu is putting additional pressure on vaccine developers to rethink their traditional techniques, which rely heavily on eggs to incubate vaccine stocks: The lethality of avian flu in poultry makes it unlikely that there will be 4 billion embryonated eggs available-the number needed to protect the 1.2 billion people at high risk-in the case of a pandemic, according to Suryaprakash Sambhara at the US Centers for Disease Control and Prevention.
Cell culture is emerging as a viable and versatile alternative to eggs for churning out large quantities of vaccine. Last November, President Bush asked Congress for $2.8 billion to develop such technologies, which have been used for decades to manufacture vaccines for well-defined diseases like measles, and while the transition from eggs to culture represents a "considerable investment," vaccine industry leaders like Chiron, GlaxoSmithKline and Sanofi are now jumping on board, said Richard Webby, a vaccine researcher at St. Jude's Children's Research Hospital in Memphis, Tennessee.
Solvay Pharmaceuticals has already been licensed in Europe to use Madin-Darby canine kidney (MDCK) epithelial cell lines for commercial production of human vaccines and has just built a BSL3 production site in the Netherlands, while Protein Sciences Corporation has developed its seasonal vaccine FluBlok to grow in insect cells. Others are working with cell lines from African green monkeys (Vero) or humans (PER.C6).
The other advantage of cell culture methods is speed. Because egg production methods take up to nine months, manufacturers must rely on distant predictions of how the virus will mutate as it traverses the world. Using cell culture methods, Solvay global senior vice president Harold Shlevin predicted it would take 2.5 months to "produce upwards of 180 million to 200 million doses of antigen" in case of a pandemic. "The whole scalability of the cell based vaccine production facility is a big advantage," he said.
Rather than directly inoculating live virus into cells, a technique used by Solvay and others which many say poses a risk of infecting workers, companies such as Lentigen Corporation are looking to viral vector delivery systems to speed up the process. Lentigen is currently validating the use of lentiviral vectors to deliver carefully chosen "genes of an avian or seasonal flu virus into [mammalian] cells for highly efficient production of a vaccine," said CEO Boro Dropulic.
The replication-incompetent vaccine product would be ready within four months of a pandemic strain's emergence, Dropulic predicted.
Protein Sciences uses baculovirus vectors to a similar end, while the CDC's Sambhara has developed adenoviral vectors for the same purpose, and he says his collaborators at Purdue University are currently negotiating with industry to manufacture the vaccine in cell cultures.
Protein Sciences COO Manon Cox said her company is working on using recombinant virus libraries to create trivalent vaccine primers, based on likely pandemic-causing strains, that could provide people with low level protection before a pandemic even arose. And once a pandemic strain is identified, they could match it to the correct vector in the library to produce the vaccine in weeks, she said."You want to have virus banks already ready in your freezer so you can pull it out and be ready."
Reverse genetics, in which researchers directly combine antigen genes from the target virus with genes from a master strain known to grow readily in eggs, has become a popular method of custom-designing seed strains. Classical reassortment strategies, in contrast, require scientists to mix target and master strains in hundreds of chicken eggs and screen for the most immunogenic and easily grown reassortment product.
The strategy has led to a number of clinical trials worldwide, according to Webby, whose team designed the seed strain for Sanofi Pasteur that recently produced disappointing results in phase III trials. For the highly pathogenic H5N1 strain, which would likely kill chicken cells before they could produce vaccine, such genetic manipulation is the only viable method, said Webby.
Regulatory issues remain a concern for some manufacturers. For example, in Europe and Australia, the status of the manipulated viruses as genetically modified organisms gives manufacturers another round of paperwork. But earlier this month, the FDA issued draft guidelines to help vaccine manufacturers expedite development for both pandemic and seasonal flu vaccines. The guidelines demonstrate how to adapt existing licenses to those for pandemic flu vaccines and navigate the accelerated approval process, which relies on biological indicators of immunogenicity rather than placebo-controlled trials.
GlaxoSmithKline's Fluarix was the first vaccine approved last year using the accelerated process, which Cox calls "very good for the FDA because they are able to take larger risks than they otherwise would."
"It's absolutely essential for the government to partner with companies as well as university scientists the way we have done over now several years," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. "We are simultaneously trying to optimize existing vaccines and?develop new vaccine platforms that will make vaccine production more flexible and more specific." Fauci said the government may provide liability protection to companies developing pandemic flu vaccines. For example, the Biodefense and Pandemic Vaccine and Drug Development Act (S. 1873), which has yet to be voted on by the US Senate, would offer liability protection for vaccine manufacturers and a 10-year marketing exclusivity for companies producing countermeasures, during which time competitors could not produce generic substitutes.
Links within this article
M.A. Hoelscher et al., "Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice," Lancet 367:475-81, February 11, 2006.
J.J. Treanor et al., "Safety and Immunogenicity of an Inactivated Subvirion Influenza A (H5N1) Vaccine," NEJM, 354:1343-51, March 30, 2006.
FDA recommendations press release
FDA pandemic flu vaccine recommendations
FDA seasonal flu vaccine recommendations
T. Agres, "US weighs biodefense measures," The Scientist, November 2, 2005