For years, vaccine manufacturing has faced low prices and high liability, and companies have simply left the business, one by one. However, recent developments, notably concerns about Avian flu and a possible flu pandemic, have underscored the need for a vibrant, viable and competitive marketplace for vaccine products and technologies. The emergence of AIDS, SARS and West Nile Virus has only intensified concerns. Manufacturers who remain in the vaccine business are adopting multiple strategies, exploring simple steps like dilution and the use of new adjuvants, improving traditional manufacturing methods and exploring new ones such as cell culture vaccine manufacturing. At the same time, new vaccine media such as DNA vaccines are also being developed.
Last year, the U.S. flu vaccine shortage brought more attention to the issue of vaccine manufacturing, but in particular to flu vaccine manufacturing, which uses a complex method and occurs in fertilized chicken eggs. More than 70% of the global supply is produced in this manner by CSL, Ltd. (Parkville, Victoria, Australia), ID Biomedical (Northboro, Mass.), GlaxoSmithKline (London), Chiron (Emeryville, Calif.) and Sanofi Pasteur (Swiftwater, Pa.). “Eggs are the easiest medium for growing influenza virus, and provide a natural barrier against other pathogens,” says Vijay Samant, president of Vical (San Diego), a developer of DNA vaccines.
Egg-based flu vaccine production began about 35 years ago, and incremental improvements are made each year. Although manufacturers have slowly, steadily increased yields, the egg-based productivity well is running dry. “It would be unrealistic to believe that we’ll find ways to double yields, given current plant capacity,” says James Matthews, Ph.D., senior director, health and science policy, for Sanofi Pasteur U.S. At the same time, though, he says, “It would be a mistake to call the egg-based manufacturing method a dead end. It’s very predictable and reliable.”
To meet the growing demand for vaccine, Sanofi Pasteur has committed to doubling its manufacturing capacity and expanding its formulation and filling capabilities. If the company keeps its current plant — a big “if” at this point — its vaccine production will triple, but the new capacity is not expected to come online before 2009.
|Process development fermenters at Dowpharma's San Diego facility.
New technologies are being used to improve egg-based manufacturing efficiencies. One important example is disposable manufacturing equipment, which would help reduce cleaning and cleaning validation requirements and eliminate cross-contamination concerns. Since vaccines are not typically produced at a huge scale, the economic argument for using disposables is quite compelling, for both egg-derived and cell culture vaccines, says Hélène Pora, vaccine application development director at Pall Corp. (Saint Germain-en-Laye, France).
Dilution: how low can you go?
At the same time, studies are being conducted to determine the minimum effective dose of vaccines, especially for pandemic flu. The U.S. government, which is planning to stockpile close to eight million doses of an experimental vaccine against avian influenza by early 2006, has been encouraging production of agents to combat the deadly H5N1 strain, although no one knows how effective such a vaccine would be. Most experts believe immunization would require two inoculations, while a few hope that a mere fraction of the currently envisioned dose would be effective. Studies are under way on the feasibility of diluting the current stockpile to cover 120 million Americans. Even if fifteenfold dilution works, the U.S. will be far short of protecting all its citizens should a pandemic strain of bird flu emerge.
Vaccines often employ simple chemical agents, called adjuvants, to boost immunogenicity. Dowpharma (Midland, Mich.) is developing recombinant protein adjuvants for vaccines against influenza and other diseases. Dowpharma produces its LT protein adjuvant in Pseudomonas fluorescens.
Interest in adjuvants is on the rise as vaccine manufacturers seek to get more doses per unit vaccine. “All the major vaccine players are looking at adjuvant strategies for various vaccines, including flu,” says Kurt Hoeprich, Dowpharma’s business leader for vaccines.
Given the difficulty of substantially improving unit operations, manufacturers who use chicken eggs might focus on early-stage efficiencies, before the cultures are even set up. “Having the strains in hand and producing vaccine seed are the rate-limiting step,” says Kathy Coelingh, Ph.D., senior director for scientific and regulatory affairs at MedImmune (Gaithersburg, Md.). “Cutting down on this time will translate into clinical benefits.”
Rajeesh Beri, Ph.D., who manages process development at ID Biomedical, stresses the importance of having an alternative to egg-based manufacture, especially for flu vaccine. Certain influenza strains do not grow well in eggs. Moreover, a flu variant that originates in birds could kill chick embryos before sufficient virus was generated to create a product.
ID, which will soon be acquired by GlaxoSmithKline, is developing FluINsure, a nasally-delivered subunit vaccine. Subunit vaccines also offer the potential for rapid response to emerging viruses. ID also manufactures Fluviral S/F, a traditional egg-derived vaccine, and is developing NeisVac-C for meningitis C and a vaccine against group A strep in cell culture.
FluMist, MedImmunne’s lead nasal influenza vaccine product, is manufactured in chicken eggs, but the company has been investigating cell culture methods for some time. The potential benefits of growing viruses in mammalian cells are great, according to Coelingh, but it will take time to make the switch for seasonal flu.