Vaccine Manufacturing Reborn - Pharmaceutical Technology

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Vaccine Manufacturing Reborn
Drugmakers hatch new manufacturing paradigms in the wake of the 2009 H1N1 influenza pandemic.

Pharmaceutical Technology
Volume 10, Issue 34, pp. 40-46

Neither fish nor fowl

"This is where we come in," says VaxInnate's Shaw. "We can ramp up very quickly and cost effectively." The possibility of bringing new ideas to an old product has produced what Björn Lundgren, vaccine marketing manager for GE Healthcare Bio-Sciences (Uppsala, Sweden), a producer of equipment and reagents for vaccine manufacturing, calls an "R&D playground." Several biotech firms are banking on recombinant technologies as the future for influenza vaccine production.

Rather than reproduce entire virus particles, recombinant technologies like VaxInnate's produce selected viral proteins from the infectious strain, the sequence for which can be obtained from CDC. VaxInnate produces the viral surface protein hemagglutinin (HA) in the bacterium Escherichia coli, which Shaw calls "a prodigious producer of protein." Prodigious enough, in fact, that at the current selling price, the company can realize a profit, he says. However, until recently, E. coli seemed an odd choice in which to express the highly glycosylated HA protein, because the bacterium does not glycosylate its proteins.

As it turns out, says, Shaw "[HA] doesn't have to be glycosylated." VaxInnate harvests its protein and refolds it in urea, he says. When combined with an adjuvant, the protein seems effective in the company's early-stage clinical trials.

Medicago (Quebec, Canada) produces virus-like particles—including recombinant HA—in plant cells, which do glycosylate their proteins but in a manner different from mammalian cells. That hasn't seemed a problem, though, says Nathalie Charland, the company's product portfolio director, who says that initial clinical studies uncovered no deleterious immune responses to the plant-glycosylated protein. Both companies believe they can produce pandemic-scale quantities of their vaccine within three weeks of receiving the seed-virus sequence from CDC.

Recombinant proteins do have one drawback, however. They tend to be less immunogenic than are whole viruses, and therefore require some kind of adjuvant to boost potency. Says Mark Tomai, head of vaccine business development for 3M (St. Paul, MN), "The type of vaccine dictates whether and what type of adjuvant is required."

Both the Medicago and VaxInnate formulations include adjuvants. The Medicago adjuvant is part of the plant-cell membrane that envelopes the virus as it buds off from the plant cell. VaxInnate uses flagellin, a bacterial protein that binds to toll-like receptors on immune cells and activates them. There has been some concern, notes Tomai, that toll-like-receptor ligands distribute throughout the body causing nonspecific and unwanted immunological effects. VaxInnate circumvents that by coupling adjuvant and antigen, which, says Shaw, prevents adjuvant molecules from "swimming around on their own," and instead directs the immune response specifically against the antigen.

Novavax manufactures a trio of viral proteins inside insect cells, producing a virus-like particle, which Singhvi says closely resembles the actual virus in electron micrographs. He adds that without adjuvant, the preparation has elicited a strong immune response in Phase II clinical trials. Like the others, Novavax's production costs are competitive with traditional vaccine manufacturing, says Singhvi. "That's why we believe we can enter the market without being pushed out based on cost," he says.

Beyond recombinant proteins there are DNA vaccines, such as the one under development by San Diego-based biotech company Vical. Plasmid DNA containing a viral gene sequence and formulated with Vaxfectin, the company's proprietary lipid-based adjuvant, is injected, and the recipient's own cells manufacture the immunogenic proteins. The vaccine, says, Vijay Samant, Vical's president and CEO, provided a lasting immune response to H5N1 in Phase I clinical trials.

"It's hard to predict which technology will be the winner," says Lundgren. Choosing one and standardizing it, he thinks will be the real key to manufacturing an effective, scalable, and low-cost influenza vaccine.

See an online bonus interview with Novartis's Matthew Stober, global head of technical operations.


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