Vaccines Give Pharma Employment A Boost

For years, the global vaccine market has been at low ebb, but with current concerns about emerging diseases, the tide is rising quickly. New manufacturers are entering the field, and more established companies are revving up their vaccine programs. With these developments come career opportunities for chemical scientists who have well-honed skills and the desire to be at the forefront of a small, but crucial, sector of pharmaceutical research.

These days, the big players in vaccine research and manufacturing are Chiron, GlaxoSmithKline, Sanofi Pasteur, Merck, and Wyeth, which together hold 80% of the market. The remainder of the field is populated with smaller players like Acambis in Cambridge, Mass.; Baxter in Deerfield, Ill.; and Berna Biotech in Switzerland. According to IMS Health, a company that provides market data and analysis on the pharmaceutical industry, as of September 2005, the global vaccine market was valued at about $6 billion-or a little more than 1% of the total global pharmaceutical market-up from $2 billion in 1995.

Today's headlines are bolstering the vaccine market. "Concerns about bioterrorism and avian flu, for example, have resulted in lots of funding for vaccine development," says Janice M. Reichert, senior research fellow at Tufts Center for the Study of Drug Development, which is affiliated with Tufts University. "Billions of funding dollars are available through agencies like the Department of Health & Human Services, the National Institute of Allergy & Infectious Diseases, and the Department of Defense to develop vaccines for priority pathogens such as anthrax and dengue flavivirus and for avian flu."

Reichert observes a big medical need for innovative vaccines. "What struck me is that in the past 10 years there have been 60 to 70 novel, innovative protein therapeutics approved for serious or life-threatening diseases," she says. "By comparison, there have been only four novel vaccines approved in the same period, two of which, RotaShield for rotavirus and LYMErix for Lyme disease, were withdrawn. Another 11 vaccines were approved for indications where products already existed." Much more research needs to be done, Reichert says, but the low approval rates for novel vaccines make the economics of vaccine R&D difficult.

Nevertheless, manufacturers are investing more resources in vaccines and are having success. Prevnar, Wyeth's vaccine to treat pneumococcal diseases like bacterial meningitis and bacteremia in infants and young children, in 2004 became the first vaccine to reach $1 billion in sales. GlaxoSmithKline has more than 20 vaccines in clinical development and plans to launch five new vaccines by 2010 with a potential market value of $11 billion to $18 billion.

Reichert's research shows that vaccine development is distributed over a large number of companies, and clinical development is spread over a large number of targets. According to her database, 174 vaccines are in the current pipeline, most of which are in Phase I or Phase II clinical trials. Ninety companies are sponsoring these vaccines, two-thirds of which are in the U.S., 30% in Europe, and the remainder in other countries such as Israel, Cuba, and Australia. Anti-infective vaccines make up about half of the vaccines in development, and the remainder are therapeutic vaccines for diseases such as cancer and diabetes.

"Of the 40 companies that are working on anti-infectives, most are smaller biotech firms," Reichert says. "Vaccines are a big thing for biotech now." She adds that the near-term vaccines include some with blockbuster potential, such as Glaxo's Cervarix, the first vaccine to be 100% effective in protecting women against two strains of human papillomavirus that are linked to more than 70% of all cases of cervical cancer (Lancet 2004, 364, 1757). Cervarix has been granted "fast track" status by the Food & Drug Administration. In the meantime, Merck is developing its version of a cervical cancer vaccine, Gardasil, which has the potential to generate multi-billion-dollar sales.

On Another front, Sanofi Pasteur has several contracts with the U.S. government for developing a vaccine against the H5N1 avian influenza strain, which health authorities believe could cause a pandemic. Separately, in France, Sanofi Pasteur is developing an H5N1 vaccine for the European Union. And in both France and the U.S., the company is expanding its influenza vaccine manufacturing capability for seasonal influenza and in case a pandemic should occur.

At Wyeth, the discovery research group conducts the basic lab research that goes into the development of vaccines, and the development group takes the discoveries and scales them up into processes that can support the production of millions of doses. According to Ph.D. biochemist Peter Paradiso, vice president of new business and scientific affairs at Wyeth Pharmaceuticals in Collegeville, Pa., many functional areas are important for research within the discovery group, such as protein chemistry, carbohydrate chemistry, and the biochemistry of viruses and bacteria.

Wyeth has recently expanded its vaccine research beyond infectious diseases into illnesses like Alzheimer's disease for which vaccine development requires the skills of protein chemists and conjugation chemists. As part of the development group, "chemists and chemical engineers need to understand the chemistry and biochemistry of the development process to maintain the integrity of the product," Paradiso says.

"There are any number of paths that chemists can follow. There is a lot of chemistry and biology going on here," says Jim Robinson, vice president of industrial operations at Sanofi Pasteur. "In R&D, chemists and biologists work together on specific formulations to grow a virus or a bacteria. The biologists make sure the environment is ideal for growth, while the chemists assist to formulate the media."

Bacteria are grown in chemically defined media, and viruses are grown in living cells supported by chemically defined media, he explains. "For example, the influenza virus is grown either in a chicken embryo or a cell culture grown in situ. After the bacteria or virus has grown, the next step is to purify it by physical separation, for example, by filtration, which can be either a chemical or biological process," Robinson says.

Sanofi Pasteur employs many chemists and biochemists, and the area of heaviest concentration is in quality control. The quality control chemists test all the ingredients in the products to ensure that every reagent meets the specifications of the process that were proven clinically to work. "You have to follow the process every time because the biological function could be affected," Robinson explains. Product characterization can be more difficult than understanding how to make the product itself and involves the use of multiple analytical tools. The company could not accomplish this without a large science staff, he notes.

Wyeth's Prevnar, a vaccine to prevent pneumococcal invasive disease in infants, offers a good example of chemists and other scientists solving a problem together. Young babies who get meningitis from these bacteria can't make an immune response to a polysaccharide coating on the bacteria. So chemists came up with a chemical method to link the polysaccharide to a compatible carrier protein, Paradiso explains.

"Prevnar has seven distinct conjugates in it, each with its own chemistry requirements. The next generation of Prevnar will have 13. The expanded vaccine is being tested in adults and the elderly because pneumococcal disease is a serious cause of morbidity and mortality in the high-risk and elderly populations," he says.

One of the ways chemists are involved in vaccine development is in the creation of adjuvants. These are molecules that enhance the immunogenicity of a vaccine. Most of these use a form of aluminum phosphate, aluminum hydroxide, or aluminum oxide. A small protein may require something to stimulate the immune system and trigger an immune response. Robinson explains: "There are other things you can do to a small molecule, like lipidation, to form larger aggregates of product that the immune system can recognize."

"We use a lot of separation chemistry, computational chemistry, and conjugation chemistry," Paradiso says. In general, vaccine development requires identifying important antigens, expressing those antigens so that they are functional, and ensuring that the product maintains its functionality over time. All of these efforts involve chemical processes and testing. "There are aspects of delivery systems that appear to be more in the realm of biology," he says. "For example, producing viral vector systems or making viral particles," he says, "but you still need chemistry."

"There's a lot of immunochemistry involved as well," Robinson says, "where you measure the response to the biological agents that could be in a cell culture system. We've increasingly eliminated animal testing and replaced toxicology tests with cell culture assays for neutralizing toxins. If the cell survives, we know the toxin is eliminated."

Looking toward the future, "DNA vaccines are getting a lot of attention," Paradiso says. "These use the genes for vaccine antigens as the immunization source." Chemists need to be able to work with DNA and express the DNA products in a useful form. "If you can make DNA vaccines sufficiently immunogenic, they have the potential to revolutionize the field because of the broad applicability," he says.

Vaccine manufacturers are looking beyond pediatric and flu vaccines. According to the market research firm Business Insights, new vaccines for adolescents and adults will likely drive the growth of the vaccine market in the future. This growth will be largely driven by new disease targets for which there are no current vaccines, such as sexually transmitted diseases and cancer, and by infectious diseases like malaria.

At Sanofi Pasteur, the future pipeline is pretty clear. "Our focus is strictly vaccines, and we have vaccines for 24 out of about 100 infectious diseases," Robinson says. "Our goal is to get the other 76, because once you eliminate a major health threat, another one will become important. For example, we're developing a vaccine for dengue fever and for Group B meningococcus, the latter accounting for approximately one-third of meningitis cases in the U.S., according to the Centers for Disease Control & Prevention. Both are very important and will have a tremendous health impact."

Although the market is growing, those seeking employment in the field should know that the vaccine business still faces significant challenges: high capital costs, limited market potential, stringent regulatory requirements, potential liability issues, and other technical complexities. "There are issues that still need to be addressed," says Tufts Center's Reichert. Return on investment is still a question. Although most of the vaccine R&D and manufacturing are very similar to what is required for therapeutics, the overall consumer price of therapeutics, especially those for chronic conditions, is higher. "Vaccines are typically given in fewer and smaller doses; when you look at it from that perspective, the economics aren't there," Robinson says.

However, the vaccine future could be a bright spot for drugmakers because of opportunities offered by improved technology for developing and manufacturing vaccines, a growing market, a robust pipeline, and an investment in the nation's public health. "From our perspective, there's a tremendous value on a societal basis," Paradiso says. Vaccination has real public health value and importance because "you're preventing disease rather than treating it."

"What is exciting about this business is that there's great science being done, and there's also a great good that goes along with it," Robinson says. "The bottom line is the good we do."