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Vaccines are needed against old and new infectious disease threats - polio and other childhood illnesses, bioterrorism and pandemic flu. They are also emerging for cancer immunotherapy and for treating addiction. While vaccines are among some of the most successful biotech products, their large-scale manufacture involves some special demands, such as maintaining a good working cell bank and gearing up for production on an 'as needed' basis.
If pandemic flu strikes this winter — and many health experts believe that such a catastrophe is only a matter of time — then vaccine companies will be under huge pressure to deliver supplies safely and on time. The news on the technology front is that US-based companies Protein Sciences and Novavax may be able to deliver the goods in less than 12 weeks after the start of a pandemic, using a new approach to vaccine manufacture involving recombinant DNA. This is interesting because it's only quite recently that players such as Novartis and GlaxoSmithKline announced big investments in animal cell technology for vaccine manufacture. It's generally acknowledged that the animal cell approach is safer, faster and more reliable than the traditional method of producing vaccines in chicken eggs (to say nothing of the logistics of handling thousands of eggs and managing the associated flocks of chickens). But could animal cell technology now be superseded by the recombinant DNA method in the race to get safe and cost-effective vaccines to the public?
Choosing the right technology for manufacture is only one of the demands on vaccine companies. While public attention tends to focus upon whether we have enough shots for a pandemic of the deadly strain of bird flu (H5N1) or whether we are prepared to deal with a bioterror outbreak of smallpox, there are many other opportunities in the vaccine sector. For instance, we should not forget the World Health Organization's bid to eradicate polio from the planet by universal immunization (much as it eliminated smallpox) or the constant fight against childhood diseases such as diphtheria, measles, rubella and whooping cough (pertussis). Vaccines are now being formulated against cancer such as Merck's cervical cancer vaccine Gardasil. Meanwhile, researchers are looking for effective vaccines against HIV/AIDS and hepatitis C, and believe they can even immunize against nicotine and cocaine addiction in the near future. Different vaccines, different markets and many challenges for manufacturers.
While innovation is the watchword in small molecules and most biologics, the world of vaccines tends towards conservatism. That is because the drivers of the market are somewhat different: vaccines are used on very large numbers of healthy people, many of them children. If a product is known to be safe — however old — then there will be little incentive for change. Therefore, the vaccines against tetanus and pertussis have remained more or less the same for many years. Nor is there really any room for generics or biosimilars. Yet, there are some sophisticated vaccines around too. Dr Crawford Brown, CEO of Eden Biodesign, which runs the National Biomanufacturing Centre (NBC) at Speke, near Liverpool (UK), points to Merck's Recombinax vaccine against hepatitis B as an important product. "The advent of the hepatitis B vaccine has to be seen as a seminal change for the industry. It is a well-defined product, which makes money, has a healthcare benefit and is safe," he says. "Merck and Smith Kline got a lot of momentum from showing that a recombinant vaccine could work and making it in yeast gave an efficiency of cost."
Brown, who has long experience in vaccine manufacture and is now supervising some vaccine projects at NBC, says that more recent inspiration can be found in Wyeth's Prevanor, which protects against seven strains of Pneumococcus infection. "This has probably been the most successful launch of any biotech product," he says. "It is a very complex product because it requires the isolation and blending of seven different strains. But it is a $1 billion product — one of biotech's few blockbusters."
Vaccine manufacture is broadly similar, in principle, to other biotech manufacturing operations, but with some important differences. For instance, it is generally done on a smaller scale because only microgram quantities are needed, and, therefore, disposables, rather than stainless steel, tend to be used throughout the manufacturing process. Process validation, product characterization and purity are particularly important in vaccine manufacture: "Purity is a particular challenge for vaccines, compared with small molecules," says Brown. "Some vaccine impurities have an immunomodulatory effect and act more like an adjuvant to the vaccine." In other words, vaccine impurities are more akin to an API than a mere nuisance that must be eliminated. Therefore, manufacturers have to think how to scale-up their production without losing the potency of the vaccine plus impurity mixture.
Vaccines also differ from conventional drugs in that they are generally stockpiled and are not used continuously. People do not worry about whether there is enough aspirin or atenolol to meet demand — it is made and consumed all the time. But they are concerned about whether there is enough smallpox or flu vaccine ready to meet a sudden surge in demand. Therefore, vaccine manufacture is flexible, rather than continuous. "You may need to produce a batch of vaccine that is then to be stored for several years," explains Brown. "The nature of production is discontinuous compared with other products." Some of these products go back a long way and there may be items of knowledge involved in their production that are hard to document in GMP and the chance of the people in the know being around when an old vaccine is next needed is small.
Meanwhile, cell banks required for vaccine manufacture may become depleted with time and a new working cell bank may be needed. "A working cell bank is rather like the Crown Jewels," Brown observes. "This is very different to small molecule manufacture where you are only concerned about raw materials — there is no equivalent risk. Expecting the cells to grow and perform as they did 10 years ago is a big ask."
But growing expertise in cell culture technology and bioprocessing is helping manufacturers to overcome these problems. Therefore, it should be possible to put many new vaccines into robust large-scale production during the next few years — not only to protect against infection, but also against cancer and other conditions as an alternative to conventional pharmaceutical drugs.