Partial Protection
by Elisa Ludwig
October 2007
The pharmaceutical industry may be in the midst of a vaccine renaissance, but development and distribution challenges remain constant barriers.
Scientific advances and increased funding have yielded new breakthroughs in vaccine development during the past few years. Yet, even in the midst of a “golden age” of vaccines, global public health does not reflect significant improvement. “We are in a new world but we still have public health challenges,” says Dr. Jon Andrus, lead technical advisor of the Pan American Health Organization’s (PAHO) Immunization Unit in Washington, D.C., USA, which coordinates technical assistance to countries in Latin America, the Caribbean and North America. “We now have rotavirus, HPV, pneumococcal and influenza vaccines, but many countries, in particular middle- and lower-income countries, have yet to introduce them.”
Moving Ahead: The Case of Influenza
With a possible influenza pandemic looming—whether avian (e.g., H5N1) or not—rapid development of influenza vaccines are a major area of interest for public health authorities as well as industry. “One of the technologies that has really jump-started the scientific capacity for influenza vaccine development is the use of reverse genetics,” says Kathleen Coelingh, Ph.D., senior director of scientific affairs at MedImmune in Gaithersburg, Md., USA. “We can now use genetic engineering to make these new strains—I like to paraphrase it as ‘better living through chemistry.’” Indeed, reverse genetics, which consists of identifying genes solely on their position within the genome itself, contributed to the creation of the WHO’s prototype strains for pandemic flu, released in 2006.
Vaccine production methods also are changing. With the existing flu vaccine, developed in the 1950s, each dose is created with a fertilized chicken egg, a lengthy process that can take months and makes it difficult for vaccine manufacturers to respond quickly to mutations in seasonal flu strains. But a 2006 US$ 1 billion award from the U.S. Department of Health and Human Services has provided incentives to five manufacturers (GlaxoSmithKline, MedImmune, Novartis, DynPort and Solvay) to develop cell-culture methods. “Cell-based production is more scalable and allows for better quality control,” says Alan Taggart, vice president of government project management at MedImmune. “It also relieves us from having to have a vast egg supply in the event of a pandemic.”
Another new strategy for developing flu vaccine is a DNA vaccine that contains isolated virus genes that are injected into human skin to produce an immunological response, and thus create protection against individual strains. Although DNA vaccines have been licensed for veterinary use, they remain unlicensed for humans. “That’s because the induction of antibodies by DNA vaccines has been poor for humans,” says Dr. Stanley Plotkin, executive advisor to the CEO with Sanofi Pasteur in Swiftwater, Pa., USA and emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia, Pa., USA. “However there are recent developments that may improve that situation, and we’ve seen that the DNA vaccines can prime the immune system for a boost by some other entity.”
A third new approach is nonliving antigen delivery systems such as virus-like particles (VLP) that stimulate an immune response without exposing the patient to an actual virus. An example of a VLP vaccine is Gardasil, the human papilloma virus (HPV) vaccine, launched by Merck in 2006. At Novavax, efforts are underway to develop a pandemic flu vaccine based on VLP. “We’re taking that validated technology platform and expanding it with new intellectual property to address targets such as the flu,” says Rahul Singhvi, Ph.D., CEO of Novavax in Rockville, Md., USA. Though Novavax is starting with seasonal and pandemic flu, the company eventually plans to branch out and target other diseases.
Promising Partnerships
The development of new adjuvants to boost vaccine effectiveness also has been promising. Adjuvants have the potential to stimulate the immune response as well as deliver greater vaccine potency. Novavax has partnered with an Indian company, Bharat Biotech, to evaluate the use of Novosome paucilamellar vesicle adjuvants.
Especially important to new vaccine development is increased funding and government support for vaccine research. In the past, many pharmaceutical companies shied away from the costs and risks associated with vaccine development (about half of vaccine manufacturers ceased production in the 1970s), but today, major players like Pfizer have returned to the vaccine market.
In the meantime, Novartis and GlaxoSmithKline recently expanded their vaccine R&D. The Global Alliance for Vaccines and Immunization (GAVI), a Geneva, Switzerland-based partnership sponsored by the WHO, the United Nations and the Bill and Melinda Gates Foundation, among others, also invested hundreds of millions of dollars in vaccine research. MedImmune is working on a five-year collaborative research and development agreement with the U.S. National Institutes of Health to build a large library of influenza vaccines corresponding to 14 strain types with pandemic potential. “We’re systemically working our way through this list of strains, making live attenuated vaccines for each, and then testing them in animals and evaluating them in human clinical trials,” Coelingh says.
Continuing Challenges
Despite many gains in the areas of technology and funding, vaccine development continues to face major challenges. The time it takes to develop a vaccine and bring it to market typically is more than a decade and is a huge and often unrewarding financial investment for industry, Plotkin says. An example is the live attenuated flu vaccine—LAIV, found in MedImmune’s FluMist — that was first developed in the 1960s but was finally licensed and released to the market in 2003. But after decades of research there are no vaccines for HIV/AIDS or malaria, diseases that are ravaging the developing world. According to a commentary in the May 2004 issue of Nature Immunology, some vaccines never would be developed without assistance from philanthropic institutions or incentives from government agencies.
“To set up the capacity for manufacturing costs a minimum of US$100 million and it takes three to four years to design, build and validate a facility,” Singhvi says. “If [manufacturers] want to launch a product in United States, [they] have to start committing capital with a major risk. The problem is that you’re going in with a certain forecast that could be wrong.” Furthermore, clinical trials for novel vaccines typically involve thousands of patients multiple trial sites and they can cost anywhere from US$50 to 300 million. Overall, the combination of financial and development risks can be daunting to manufacturers. “It is very difficult to translate a new vaccine from preclinical research to human trials. Many vaccine candidates use live organisms and when you’re introducing a live organism to a live population there is an enormous burden on the manufacturer to show that the product is safe,” Singhvi says.
There also are the ethical concerns that vaccine manufacturers face. After just one year in use, Rotashield, the first vaccine for rotavirus, was taken off the market in 1999 because of suspected risk of intussusception in 1 in 12,000 vaccinated infants. Many public health officials regarded the vaccine’s withdrawal as a tragic miscalculation of risk and benefit as 600,000 children died annually of the disease—largely in developing countries—before two new vaccines were introduced in 2006.
Taking it Public
Once licensed, vaccines must be deployed effectively around the world to protect against disease. With seasonal strains of the flu, estimating and adjusting the demand of each season can be difficult, and with only a few major producers, regulatory issues can slow the creation of vaccines. A recent example is the flu season of 2004, when British regulatory authorities suspended Chiron Corporation’s manufacturing license, the world’s second largest flu vaccine supplier, and created a vaccine shortage in the United States. “In general, there is a limited number of companies that produce vaccines,” Plotkin says. “The situation has recently improved somewhat, and there’s more R&D now, but from my point of view it’s still insufficient.”
Taggart agrees, and adds that supply and demand are the critical forces in more targeted vaccine development. “When you’re talking about vaccines, it’s a different dynamic than when you go to the store to buy Campbell’s soup. If the soup’s not there, you choose another brand. With vaccines, it costs quite a bit of money to manufacture these products and industry matches the supply with the demand,” Taggart says. “The goal is to increase demand for the seasonal influenza vaccine, and thereby increase manufacturing capacity to the levels needed for pandemic preparedness. This is key because an influenza vaccine manufacturer can only rapidly produce a very large quantity of vaccine during a pandemic outbreak if the required infrastructure is already in place.”
One way to address distribution issues is to rethink the manufacturing process. Novavax has developed a modular, portable method of manufacturing its vaccines in the field. “Instead of a facility with stainless steel tubing and tanks, we are using disposable plastic bags for manufacturing our product. As a result, [our product] can be made in a reasonably clean room in a relatively unsophisticated facility,” Singhvi says. The modular approach is the epitome of “just-in-time” manufacturing that can target a specific geographic area quickly, and minimize the time for vaccine delivery, he says.
Global Issues
Beyond manufacturing, the effort to bring vaccines to the developing world requires elaborate global coordination to address logistical concerns such as cold chain management and focused introduction efforts. Public health agencies need to establish disease burden and cost-effectiveness data, and help create the infrastructure to deliver the vaccines.
On the industry side, concerns about intellectual property protection have slowed international access to vaccines. “If different agencies and industry cooperate when it comes to these scenarios in global health, we can protect the global population, but it has to be worked through rather rapidly so that there are no barriers to getting the product out there as efficiently as possible,” Taggart says.
The cost of new vaccines also remains problematic, Andrus says. “The traditional approach with vaccines is to provide assistance to countries so that everybody can rally around to achieve a public health priority such as polio eradication, but the traditional approach used technologies that were relatively inexpensive. The new vaccines are, by orders of magnitude, much more expensive,” he says.
With its Revolving Fund for Vaccine Procurement, PAHO offers technical and monetary assistance to national governments to alleviate the financial burden of vaccines and stimulate a healthy marketplace. “Some countries have importation taxes so we are working to negotiate an exemption for the purchase of vaccines,” Andrus says. “We’re helping countries enhance their fiscal aid and creating legal avenues that will strengthen the sustainability of the vaccine introduction. We believe it’s really about strengthening the capacity at the national level to make evidence-based decisions to reflect the regional situation.” But these efforts require political commitment and ongoing partnership.
For pandemic influenza, PAHO’s immunization unit is working to create demand so that when the pandemic vaccine is created, manufacturers can produce an appropriate supply. “There’s enough data to show that seasonal vaccination of children is cost-effective and there are secondary benefits of reducing morbidity and mortality in older populations when vaccinated young children are no longer sources of infection,” Andrus says. “In the last three years the number of countries implementing seasonal influenza vaccination has almost tripled in the Americas. It’s important to understand these experiences and bridge that commitment to pandemic preparedness.”
Despite the progress, there is still much work to be done, Andrus says. The ability to make regional policy with vaccines that cost pennies per dose is a thing of the past, he adds. “We need to be focused and target our assistance to countries that need the help most. We have an opportunity to provide access to vaccines. We know that vaccines are a primary prevention strategy that really benefits everyone.”
Web Extra: Vaccine Partnership on the Korean Peninsula
The International Vaccine Institute (IVI) is an international center of research, training and technical assistance for vaccines needed in developing countries. The IVI was founded on the belief that health in emerging countries can be dramatically improved by the development, introduction and use of new and improved vaccines, and that these vaccines should be developed through a dynamic collaboration among science, public health and business.
Most recently, the Seoul, South Korea-based IVI worked in conjunction with the North Korean government, to prevent bacterial meningitis and Japanese encephalitis (JE) in North Korean children by improving the country’s diagnostic capacity and introducing new vaccines.
IVI will work with North Korea to introduce vaccines against JE and Haemophilus influenzae type b (Hib), which causes bacterial meningitis, on a pilot scale. This will involve a pilot Hib and JE vaccination campaign for 3,000 North Korean children, scheduled to begin in early 2008.
Over the past few years, North Korea prioritized its national routine immunization program. However, it has not yet introduced vaccines against Hib and JE, which are major causes of deaths and disabilities in emerging countries.
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