Most pharma companies have shied away from vaccines for years, but scientific advances and additional funding are revitalizing the field.
Patrick McGee, Senior Editor
The last few decades haven’t been easy for vaccine manufacturers. Litigation fears, poor investment returns, and other factors have reduced their numbers in the United States from 26 in 1967 to just several major ones today, which includes GlaxoSmithKline (GSK), Sanofi Pasteur, Wyeth, Merck, and Chiron. Perceived fears about side effects and links to autism, while widely questioned by scientists, have also made companies skittish about the market.
But scientific advances and several impending approvals could change those dour perceptions. Two vaccines for the human papillomavirus virus (HPV) are in phase III trials and could have a major impact if approved. Two new vaccines could also become available to fight rotavirus gastroenteritis, which causes nearly 500,000 deaths annually in children under five, most of them in the world’s poorest countries. Merck’s Rotateq was submitted to the US Food and Drug Administration (FDA) in April, and GSK’s Rotarix should be submitted by the end of the year. And then there are vaccines being developed for diseases such as AIDS and cancer. While none have been approved, a number are in phase III trials and dozens of others are in development.
“The overarching trend is the new products that have been introduced over the last several years and the promise of those that are coming along in the near future,” says Peter Paradiso, PhD, vice president of new business and scientific affairs at Wyeth Vaccines, Collegeville, Pa. In addition to the momentum provided by new and innovative products, the field is also being energized by initiatives such as the Bill & Melinda Gates Foundation, which has provided hundreds of millions of dollars for vaccine research, particularly for diseases affecting the third world, says Kevin Byrett, MD, vice president of policy communications and corporate affairs for Chiron Corp., Emeryville, Calif.
The National Institutes of Health (NIH) is also helping jump start the field, says Nancy Haigwood, PhD, viral vaccines program director at the Seattle Biomedical Research Institute and a professor at the University of Washington. NIH will provide $20 million to $25 million in funding to each of three or four companies that can bring new vaccine approaches into phase I trials.
One disease that is decimating parts of the third world and is still a major problem in the developed world is AIDS. A number of vaccines are in various stages of development, and much research is focusing on new vectors, says Haigwood. “I think we’ve moved away from the point where we were a few years ago where there was a lot of optimism about DNA vaccines and attenuated pox virus vaccine, such as canary pox-type vectors, but there were rather disappointing results in phase I trials with these products,” says Haigwood, who designed and developed one of the first AIDS vaccines in the mid-1980s while at Chiron.
Many researchers have turned their attention to non-replication-competent and replication-competent vectors such as adenoviruses, Haigwood says. She cites the work of Marjorie Robert-Guroff, PhD, chief of immune biology of the retroviral infection section at the National Cancer Institute. Her research group is using adenovirus recombinants for delivery of AIDS vaccines, and their studies in chimpanzees have shown that live, replication-competent Ad-HIV recombinants, together with a viral envelope booster immunization, elicit humoral, cellular, and mucosal immune responses. They used a vaccine based only on the viral envelope, and further primate studies will compare the immunogenicity of replication-competent and -incompetent Ad-HIV recombinants.
Earlier this year, Targeted Genetics Corp., Seattle, reported safety data from a phase I clinical trial for tgAAC09, an investigational recombinant adeno-associated viral vector (rAAV)-based AIDS candidate. The phase I trial, the first ever to test a rAAV-based vaccine, found it was well tolerated and did not elicit significant immune response. AlphaVax, Research Triangle Park, N.C., developed its replicon vaccine (ArV), which is genetically derived from a modified alphavirus and can be used as a platform technology for vaccines. A number of companies are developing other vectors as well, Haigwood says.
Another key in vaccine research is the resurgence of interest in neutralizing antibodies, something she has worked on for the last 20 years. At the same time attenuated pox viruses and DNA approaches were being used, a belief emerged that neutralizing antibodies were not important and that perhaps all that was needed was good cellular immunity. But there is now “abundant evidence” that the only thing that can block infection at the start is antibodies. Funding trends support that view, she says, as more money is going into looking at cellular and neutralizing responses, “going back to the drawing board, if you will, on antibodies.”
A number of AIDS vaccines have moved beyond the exploratory phase and into clinical trials. In 2003, VaxGen, Brisbane, Calif., killed its AIDSvax program after announcing disappointing results from a phase III clinical trial. This year, Merck and the HIV Vaccine Trials Network initiated a proof-of-concept trial for Merck’s Adeno5-vectored trivalent vaccine candidate. Because most of the current vaccine candidates are similar to the Adeno5 vaccine, the trial will be an “extremely important” study for the entire field, states the recently released annual report from the AIDS Vaccine Advocacy Coalition.
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 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.
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 the disease 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.”
Filed Under: Drug Discovery