Vaccines on the Road to Recovery

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Improving manufacturing
But production of the vaccines could be a problem, according to a report published last year by the International AIDS Vaccine Initiative. The report cites two main challenges: a shortage of the manufacturing capacity needed to provide enough vaccine necessary for phase III clinical trials, and, once a vaccine is approved, a lack of large-scale manufacturing capacity and process development.
Even tried-and-true production processes can run into problems and underscore the vulnerability of the vaccine supply line. Late last year, British regulators shut down a Chiron plant in Liverpool, UK, that produced 48 million doses of the company's Fluvirin vaccine for use in the United States. A number of doses were found to be contaminated with a bacterium called serratia when the bulk vaccine was being put into individual vials, the FDA reported. Chiron announced in August that the FDA and British regulatory authorities were satisfied the company had addressed the problem and that the company would begin producing Fluvirin again.
Peter de Wild, MD, senior vice president for research and development at Sanofi Pasteur in Lyon, France, says more needs to be done to update vaccine production. "In terms of testing our products or designing them, technologies have evolved dramatically. In terms of actually making them, there has not been much change. It gives you some humility." Chiron's Byrett believes cell culture techniques will play more of a role in production as companies move away from growing vaccines in chicken eggs. "The annual flu jab will become much, much more straightforward because we won't depend on eggs." Using cell cultures would also be an improvement because it allows for much more rapid scale-up, something that could be vital in the event of a pandemic involving something like the H5N1 avian-flu strain. "If you've got a pandemic where it went from man to man, you would need to have a vaccine produced very rapidly and the eggs could very well be a rate-limiting step on that."
Scale up and storage
At a meeting of the American Chemical Society in March, researchers presented a plan for growing the virus for flu vaccine in mammalian cell culture instead of in eggs, an click the image to enlarge
approach that could cut production time from four to two months. Henry Wang, PhD, said a small cell culture facility would maintain the cells and then distribute them to a network of production facilities in the event of an emergency. Wang, a professor of biomedical and chemical engineering at the University of Michigan in Ann Arbor, said there are about a dozen approved facilities worldwide that use mammalian cell cultures to make drugs.
In September, GSK purchased a vaccine plant in Marietta, Pa., formerly owned by Wyeth. GSK plans to upgrade the 90-acre facility and use it to investigate new vaccine technology, including the development and production of tissue culture technology that will be used for seasonal and pandemic flu vaccines. The site has freeze-drying capabilities that will be used to enhance the shelf life and stability of many of the company's vaccines.
Companies are working on stability issues as well. In July, Avant Immunotherapeutics in Needham, Mass., and Harvard Medical School announced they had received $500,000 from the NIH to develop a thermostable version of CholeraGarde, their cholera vaccine. The freeze-dried preparation of CholeraGarde has been shown to be well tolerated and immunogenic in clinical studies, but it must be stored at ?20?C, necessitating a chain of cold storage to maintain vaccine stability and potency. The grant money will explore the use of VitriLife, a proprietary technology that confers thermostability to live bacterial vaccines, on CholeraGarde.
Advances in bioreactors could also help enhance vaccine production. The Wave Bioreactor from Wave Biotech, Bridgewater, N.J., is a system of disposable bioreactors that range in size from 0.1 to 5 liters to 100 to 500 liters that can be used in both research and development, and production. "In a traditional type of environment you have tanks and so forth that you have to clean and decontaminate and show that you've actually cleared everything of the previous drug or vaccine," says Vijay Singh, PhD, the company's founder and president. "Then you start the next production run, and that's about a two- or three-week turnaround for most companies. With a disposable, the advantage is that the only contact surface is a throwaway component, so you're done."
Singh says the use of bioreactors could become more prevalent as companies seek to move away from older vaccine production techniques that rely on trays, roller bottles, jugs, and chicken eggs, to newer techniques such as mammalian cell cultures. "Disposable bioreactors are becoming more interesting because you can make a fairly large volume in one vessel as opposed to having to deal with thousands of roller bottles." Singh says the disposables are currently being used mainly in research and development, but large companies are beginning to use them for vaccine production.
Other vaccines
As with AIDS, there are a number of vaccines in development for cancer, some preventative and some therapeutic. Gardasil, from Merck, and GSK's Ceravix are designed to prevent infection with HPV and related cervical cancer, cervical precancers, and genital warts. Cervical cancer is the second most common cause of cancer deaths among women. Gardasil will act against four strains of HPV, while Ceravix will act against the virus which triggers the cancer. "I think those will be products that will have a significant impact," says Chiron's Byrett.
Researchers at Cerus Corp., Concord, Calif., recently published a study in Nature Medicine outlining the potential of a new class of vaccines based on killed but metabolically active (KBMA) bacteria (Listeria monocytogenes) that could be used for cancer and infectious diseases. "This broke down a lot of dogma in the field because what we have been taught is that if Listeria is killed, it is immunologically inactive," says Tom Dubensky, PhD, vice president of research at Cerus and a study co-author. They were able to show that the opposite was true, not only with Listeria, but also with anthrax, so they are now working on a follow-up study looking at anthrax more closely. An editorial in the same issue of the journal stated that the new protocol "may have a leg up on the others as a cancer vaccine in an arena which Listeria has already shown considerable promise."
A number of companies are also trying to develop vaccines for avian influenza A (H5N1) and have been spurred in their efforts by announcements by the US, Britain, France, Canada, and Australia that they plan to stockpile H5N1 vaccine. In March, the National Institute of Allergy and Infectious Diseases announced that it had begun fast-track recruitment for a trial to investigate the safety of an avian flu vaccine manufactured by Sanofi Pasteur, and the company was awarded a $100 million contract from the US Department of Health and Human Services to manufacture the vaccine in bulk. PowerMed, a biotechnology company based in the United Kingdom, has developed a DNA-based avian flu vaccine that it says can be produced quickly and in large quantities. The experimental vaccine is expected to enter clinical trials by the middle of next year.
One product already on the market serves as an example of the public health impact a vaccine can make: Prevnar, the pneumococcal 7-valent conjugate vaccine developed by Wyeth. Prevnar, approved by the FDA in 2000, was the first conjugate vaccine to help prevent invasive pneumococcal disease caused by Streptococcus pneumoniae in infants and children up to two years. "Within a few years of the approval of Prevnar, there were dramatic reductions in thedisease in infants and young children where the greatest burden occurred," says Wyeth's Paradiso.
Sanofi Pasteur's de Wild says this trend could translate into other areas. "In terms of vaccinology, it's a striking observation that has become very apparent with the advent of pneumococcal conjugated vaccines and now we're seeing it with the meningococcal conjugated vaccines." Earlier this year, the FDA approved Sanofi Pasteur's Menactra, making it the first quadri-valent conjugate vaccine licensed in the United States for the prevention of meningococcal disease.
Despite advances with drugs like Menactra and Prevnar, there are still challenges. The main hurdle, says de Wild, echoing others in the industry, is not scientific, but societal. "The tolerance for any side effects is very close to zero?.Any perceived, and I insist on saying perceived, risk results in a lack of acceptance," he says. "It's driving an extremely conservative approach by the regulatory agencies." A more basic challenge is the lack of funding, says Haigwood. "The science and the technology are not there; that's why you need the funding. The funding is needed because we still have to figure out how to use, for example, the innate immune response, bacterial genetics, and what Toll-like receptors are doing."