Vaccine Manufacturing Reborn

Innovation is shortening time to market, reducing capacity requirements and improving yields

By Angelo De Palma, Ph.D., Contributing Editor

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After years of suffering as the pharmaceutical industry’s stepchild, vaccines are regaining their rightful place as wonder drugs, and profitable ones at that. Emerging indications, worldwide markets, and premiums supported by innovative manufacturing have set the stage for a vaccine renaissance.

Vaccine manufacturing graphic
Adjuvants have a substantial impact on vaccine efficacy and in conserving manufacturing capacity.

Based on its burgeoning clinical-stage pipeline, GlaxoSmithKline (GSK; Rixensart, Belgium) expects its vaccine sales will at least double over the next 10 years. The company is banking on its Cervarix vaccine (against human papillomavirus, a cause of cervical cancer) to drive sales near-term. Several products currently in the pipeline are expected to reach the market over the next several years. In 2005, GSK committed itself to launching five new vaccines in five years, beginning with Cervarix and its Rotarix anti-rotavirus product. The company also is focusing on products for influenza, meningitis, oncology and allergy. All told, the company has 33 vaccines in preclinical through Phase III/filed, nine of them in late-stage testing. GSK expects at least half of its vaccine sales growth to accrue from vaccines currently in the development pipeline.

“Our biggest challenge in continuing our growth will be expanding our manufacturing capacity over the next four to five years, and obtaining approvals for the many vaccines within the major markets which are increasingly global,” comments John Picken, VP for industrial operations, North America at GSK Biologicals (Laval, Québec). It is common for vaccine manufacturers to seek approvals simultaneously in their countries of domicile and overseas.

GSK believes its future vaccine successes lie with novel, biological adjuvants. Pipeline products containing these new immunostimulants include Cervarix, which uses a biological adjuvant produced through fermentation. The adjuvant used in Cervarix is already incorporated into another vaccine marketed in Europe.

Although biologically “adjuvented” vaccines are approved as single products, each component commands its own manufacturing and purity controls, and the adjuvants must pass regulatory muster. Even though their manufacture is straightforward, biological adjuvants are unfamiliar to regulators as well as to their developers.

The impact of adjuvants on vaccine efficacy and in conserving manufacturing capacity is substantial. Early vaccines for pandemic flu lacking an adjuvant required two 90 microgram doses to induce an immune response. By adding adjuvant GSK vaccine reduced the effective dosage to 3.8 micrograms. “If the vaccine industry had to produce a flu vaccine that required 90 micrograms per dose we would never have enough capacity to supply the market’s needs,” Picken noted. GSK observed a similar effect with its malaria vaccine. Sixty-five percent of GSK’s vaccine pipeline depends on adjuvant systems.

Pfénex rising

At one time the word “adjuvant” was synonymous with alum and related aluminum-based compounds whose mechanisms of immune stimulation are still only poorly understood. Today, vaccine manufacturers increasingly look to biological adjuvants for their innate ability to jump-start the immune response to vaccines. Vaccine developers employ adjuvants strategically to increase vaccine efficacy, sometimes quite dramatically, and thereby lower the production cost per dose. In many cases vaccines simply do not work without an adjuvant.

Dowpharma has seen its adjuvants business triple since 2005, due in large part to the success of its Pfénex (pronounced “phoenix”) platform protein expression technology. The company expects high growth to continue based on existing projects.

Because it uses bacteria rather than animal cells to produce vaccines, Pfénex requires relatively short development and scaleup times. Kurt Hoeprich, commercial director for biopharma at Dowpharma, claims many protein-based adjuvants are difficult to express in traditional cell culture. And since they contain no animal pathoges such as viruses and prions, bacteria-derived adjuvants are ideal for injected vaccines. “Developers will use bacterial expression systems if at all possible because of speed, cost of goods advantages,” Hoeprich says.

Along with Pfénex, Dowpharma employs its “rapid strain identification” method to evaluate the manufacturability of a vaccine in a given strain of Pseudomonas fluorescens (the Pfénex “bug”) in eight weeks or less. “We can examine so many different ways of making a target simultaneously, that our odds of finding a high-yield system in eight weeks are extremely high.” Hoeprich credits the ability of rapid strain identification to assess up to thirty different production strains simultaneously as the “driving force” behind the success of Pfénex. All told, a manufacturing-worthy process takes about six months to develop, during which time Dow provides preclinical-grade material. The process is then licensed back to the customer. Dowpharma operates sixteen pilot-scale fermenters at its San Diego, California location but performs no GMP manufacturing.

During this past year, the first Pfénex-derived protein antigen entered U.S. clinical trials and should be in Phase II by the time you read this.

Dowpharma’s flagship customer continues to be vaccine developer Iomai (Gaithersburg, Md.), which went public in 2006. Iomai champions needle-free, patchbased vaccine delivery and has products in early clinical testing for traveler’s diarrhea, pandemic influenza, and seasonal flu. Iomai’s patch-based vaccines are stable at room temperature for up to six months, which means no cold-chaining or refrigeration.

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