The cyclical fortunes that have characterized the vaccines business for decades have swung decidedly positive, with no indication that they will slip again any time soon.
Today, vaccine development and manufacturing, more than perhaps any other area of biotechnology, are characterized by innovation, even daring. Developers tackle not just the easy targets like seasonal influenza but the most intractable communicable and noncommunicable diseases as well.
The industry has received several shots in the arm from the emergence of potentially pandemic viral infections, the threat of bioterrorism, and the promise of vaccination against noninfectious diseases such as cancer and heart disease.
“For years vaccines were considered a competitive, high-risk business characterized by low prices and high-liability exposure,” says Mike Kowolenko, Ph.D., svp for biotechnology at Wyeth. “Advances in our understanding of infectious diseases and immunology have revitalized vaccine development. Today’s vaccines are, therefore, more cost-effective and scientifically driven.”
Vaccine manufacturing has tracked development and manufacturing trends in biotech but has lagged by several years. Today’s developers increasingly seek to upgrade their production and expression systems, in favor of new cell culture technologies. Vaccine makers are beginning to adopt newer analytic techniques as well as more formal quality practices and methodologies like process analytic technology (PAT) and quality by design.
“Biotech was a black box back in the seventies,” notes Dr. Kowolenko. “It only became less so once we gained knowledge and understanding of those tools that influence process outcomes. Vaccine makers are now beginning to apply lessons learned from biotech.”
Vaccine makers must continuously innovate through manufacturing efficiencies, by concentrating on difficult targets, or by adding significant value to existing products.
For example Wyeth is looking to improve on its Prevnar pneumococcus vaccine, which is heptavalent, by developing a 13-valent product. “To do so requires the ability to control polysaccharide expression in bacteria, and to purify and conjugate those antigens,” Dr. Kowolenko reports.
In vaccines, the entry of even two or three competitors quickly relegates products to commodity status. This is what has happened, cyclically, to manufacturers of seasonal flu vaccine.
“The low-hanging fruit in vaccinology has already been harvested,” says Vijay Samant, CEO of Vical, which focuses exclusively on DNA vaccines. “If you’re going to be a player, pick a target nobody is working on and either get a head start, come up with a high-efficiency process, or figure out a way to provide long-term immunity.”
Vical has a Phase II DNA-based cytomegalovirus vaccine for treating bone marrow transplant patients and is working on products to combat SARS, Ebola, West Nile, herpes, and human immunodeficiency viruses, in addition to programs on dengue, angiogenesis, and melanoma. It is also developing a vaccine to prevent hematopoietic necrosis virus, a pathogen that spreads from wild salmon, in which it is harmless, to farm-raised salmon, which it kills.
“Vaccines made outside the human body are limited to generating antibody-mediated responses,” Samant notes. “The same is true for vaccines produced in cell culture. The only thing that comes close to generating the response from DNA vaccines are live attenuated vaccines.”
Vical manufactures its vaccines through fermentation of E. coli in 1,000 to 2,000 liter bioreactors. Fermentation is more productive and easier to standardize, validate, and scale, and presents fewer matrix impurities than cell culture. Also, with DNA vaccines, processes tend to be of the platform variety, suitable for almost any vaccine product.
Manufacturing DNA vaccines in weeks rather than months may provide a significant advantage when dealing with emerging infectious diseases such as pandemic influenza. “The speed at which we can make the vaccine is, in part, due to the fact that we do not need to handle the pathogen itself,” explains Samant.
Vical recently announced preliminary clinical trial data suggesting that its DNA vaccines safely induce significant human immune responses against H5N1 pandemic influenza.
The 100-person Phase I study demonstrated that the company’s Vaxfectin® adjuvant-formulated vaccine produced potentially protective antibodies, as measured by hemagglutination inhibition titers, similar to those of conventional vaccines. The data also suggests that the vaccine induces immunity to strains of H5N1 influenza not matching that of the vaccine. Cross-strain protection is key for utilizing vaccine stockpiled against rapidly-mutating viruses.