[This article was published in 2009 and updated in May 2012. Read the update here.]
Dengue fever is an increasing problem worldwide. The dengue fever virus is spread by the Aedes aegypti mosquito, which is highly adapted to urban conditions. A vaccine will be key to controlling the disease. The Pediatric Dengue Vaccine Initiative (PDVI) partnered with Brazil’s state-owned Instituto Butantan to rapidly develop a promising vaccine candidate.
Butantan, which supplies Brazil with most of its vaccines, is also receiving advice from PDVI contractee Global Solution for Infectious Diseases. The trio aim to develop the vaccine in the next few years and bring it to market at a low price. After approval, PDVI will continue to assist with planning for mass distribution. The development route taken by this vaccine represents a new model.
Previously, large pharmaceutical companies introduced vaccines in rich countries first. It took years for the vaccine to appear in resource-poor countries. With the dengue fever vaccine, both research and distribution will take place in a developing country with a strong interest in moving quickly against the disease.
The Dengue Fever Epidemic
Dengue fever is on the upswing in most tropical areas of the world, particularly south Asia and Latin America. The epidemic spread of the disease has made dengue vaccine research a pressing matter. Donald Francis, vaccine pioneer and executive director of Global Solutions for Infectious Diseases (GSID), thinks that the novel international collaboration behind dengue vaccine development represents a new paradigm. “There is a major evolution going on,” he says. “Vaccine development is moving from the industrial world and its enormous investments to the developing world where the diseases occur. The NIH [U.S. National Institutes of Health] used to license vaccines to rich country companies and then years later the vaccines would get to developing countries. Now the NIH is going directly to the developing countries. Both for-profit and nonprofit government entities are playing a role. They used to be “me too” operations making established vaccines. These groups are getting more interested in development.”
Isaías Raw (pronounced “rao”) is director of the Instituto Butantan as well as president of its research branch, the Fondação Butantan. Butantan is owned by the state of São Paulo, where dengue fever is “out of control,” says Raw. “Every summer [January through March] is worse than the last.” Brazil as a whole recorded 560,000 cases in 2007, with 158 deaths. In the first 35 weeks of 2008 — the latest period for which data are available — there were already 735,000 cases and 212 deaths. Aside from São Paolo state, Rio de Janeiro state and parts of the north are heavily affected.
Profiting from the NIH’s recent tilt toward developing-country vaccine producers, Instituto Butantan has obtained a license to a promising dengue fever vaccine from the agency. Efforts to create HIV or malaria vaccines involve northern agencies and companies collaborating to develop the candidate vaccines and then work with developing country researchers to conduct human testing. The location of vaccine manufacture has not yet come up in these cases but will most likely include developing-country producers that receive no-royalty licenses. The dengue fever vaccine collaboration gives the local partner much more authority. It yields project direction to Brazil’s Instituto Butantan as soon as the vaccine comes out of the NIH laboratories. This public Brazilian agency is the country’s main vaccine manufacturer. It will organize the human trials for the dengue vaccine, steer it through regulatory approval and bring it to market.
This is the first time that Butantan has attempted to develop a new vaccine from early human safety trials on. To provide technical support for this ambitious effort, Butantan called on the Pediatric Dengue Vaccine Initiative. PDVI is based in Seoul, South Korea. It is a branch of the International Vaccine Institute, which was established in 1987 under the aegis of the United Nations Development Programme.
According to Richard Mahoney, PDVI’s director, vaccine access, “We started in 2003, and became a coalescing force.” PDVI, among other things, organized regular meetings to bring experts together. These meetings provided a venue for real sharing of information and setting of standards. The Bill & Melinda Gates Foundation in 2003 granted PDVI $55 million to support its activities, including establishing vaccine trial sites in Asia and South America. PDVI thus became a leader in creating the global dengue vaccine effort along with such agencies as the World Health Organization.
Butantan, with PDVI’s assistance, hopes to implement an ambitious plan for rapidly moving from safety studies to largescale efficacy trials and mass rollout. PDVI has, in turn, brought in GSID as management and training consultants. “GSID has experience in scaling up vaccine trials. It sits down with Butantan and talks about technical requirements and then comes back and does an audit,” says Harold Margolis, PDVI’s director.
Butantan is able to move a vaccine from the development stage to distribution. Mahoney has great respect for its capabilities. He comments, “Brazil has made dengue a high priority, and we have made Butantan a high priority among developing country manufacturers for developing the vaccine.” Butantan is a government-owned, nonprofit entity but works like a private company. It is able to pump its revenue back into its facilities so as to maintain an efficient, high-quality operation.
PDVI Facilitates Vaccine Development
Developing a dengue vaccine should be a straightforward affair, but there are two serious obstacles. Dengue virus has four strains, designated dengue 1-4. The people at highest risk of life-threatening dengue hemorrhagic syndrome are those who were previously infected with one strain and are later infected by another. The solution to this problem is to create a vaccine that triggers long-term high antibody levels to each strain. Butantan’s NIH-licensed vaccine generally showed signs of provoking strong immunity in preliminary U.S. trials. Francis praises the NIH approach. He says, “Rather than the old-fashioned live-virus culture approach to create attenuated strains here they directly manipulate the genes and then clone the virus. It’s incredible.”
There is, however, a further issue. The immune response to each strain in the combined vaccine interferes somewhat with the response to the other strains. Multiple dosing promises to provide long-term immunity despite this interference. The optimum vaccine dose and schedule has to be worked out in carefully designed human trials. Here, PDVI has played a critical role in advising on appropriate trial design and the required lab capabilities.
PDVI has also worked with Butantan to assess potential trial sites, in the process evaluating local epidemiological information and research infrastructure. The initiative also did an elaborate computer analysis of the entire vaccine project, breaking it down into more than 320 individual tasks, including trials, building manufacturing capacity and regulatory approval. These analyses allow Butantan to navigate new territory for their institution, indicating the resources and time that would have to be allocated.
PDVI has been instrumental in clarifying the vaccine’s regulatory pathway with government officials at Brazil’s National Health Surveillance Agency — the equivalent of the U.S. Food and Drug Administration. Mahoney says, “One of the most important things we do is to bring detailed technical knowledge to discussions with the regulatory agency. We then help Butantan provide scientifically accurate and relevant information in its applications for clinical trials and, eventually, for marketing approval.”
Raw adds, “PDVI has a first-rate team of experts to analyze the results and plan the next step. Having PDVI shows outside recognition and gives the project more credibility.” That credibility is vital when seeking support from the state or from private funders.
Vaccine approval is, of course, only one step on the way to vaccine access. Vaccines in the past have been introduced first in rich countries and then very slowly made their way to developing ones. This process could take years. Recent vaccines, such as those for pneumococcal bacteria and human papillomavirus, have come to market at unprecedentedly high prices, making their use in resource-limited settings still more problematic. But there will not be much need for the dengue fever vaccine in areas able to support high prices. The vaccine will go straight to poor countries with small health budgets and poor distribution systems.
Yet there is no doubt that the vaccine will be highly advantageous in these nations: A 2004 Southeast Asia cost-effectiveness study found that a 95 percent effective dengue vaccine with a public sector price of 50 cents would be very cost effective. It is not clear if a price of 50 cents per dose can be achieved but PDVI’s free support work will help reach that target. Then too, the Instituto Butantan is state-owned. Part of its mission is to keep prices down. When explaining PDVI’s strategy, Mahoney says, “Butantan will be a low-cost manufacturer that just covers its costs. One of the little secrets of the vaccine business is that the major cost is in R&D, whereas production costs are low. Sometimes the cost of packaging is more than cost of making the vaccine.” PDVI is working with Butantan on an analysis of actual costs to establish a rational basis for the vaccine’s price.
Mahoney has long experience in reducing vaccine expense. As secretary of the International Task Force on Hepatitis B Immunization, he was one of the key personalities in bringing down developing nation prices for the hepatitis B vaccine. In 1986 the worldwide price for this vaccine was about $100 for the required three doses, and the U.S. private sector cost is still nearly $70 for children (more than $150 for adults). It is now available in resource-restricted settings for less than 90 cents for three doses, or under 30 cents per dose. (The older childhood vaccines typically cost less than 10 cents in less developed countries versus a U.S. public sector price of $10 to $20 per dose.)
Butantan intends to sell its dengue vaccine in other Latin American countries once it has obtained regulatory approval and has sufficient manufacturing capacity. Making the vaccine is just the first step toward mass immunization, which necessitates a multiphase introduction effort. Health care workers require training on the appropriate population and schedule for the vaccine. Health organizations need to conduct a community education effort to ensure public interest. Supply chain logistics have to be worked out in detail — is there enough cold storage space, for example?
Contemplating the post-approval phase of dengue vaccine development, Margolis says, “Nearly everyone in low- and middleincome countries receives vaccines through public programs. PDVI will work to get in place funding mechanisms through GAVI [Global Alliance for Vaccines and Immunization] and local country governments. We also will advise on technical implementation and help to conduct demonstration projects.”
A New Paradigm in Vaccine Development
PDVI is moving forward on several other fronts. In India, it is advising vaccine makers on developing the NIH vaccine. In Thailand, PDVI’s epidemiologic studies have helped French vaccine developer Sanofi Pasteur with its large-scale dengue vaccine efficacy trial. The Sanofi Pasteur dengue vaccine is the first to reach this advanced testing stage. If all goes well, the world will see several competing dengue vaccines by the middle of the next decade. The promise of multiple sourcing leaves PDVI hopeful. Mahoney and Margolis contend that competition among producers is a potent means of keeping prices down while keeping supply up.
In January 2009, the Instituto Butantan announced an agreement to develop a leishmaniasis vaccine with the Seattle-based Infectious Disease Research Institute. Although the vaccine will target the leishmania reservoir in dogs, the agreement in many respects parallels the Butantan-PDVI agreement for dengue fever. In both cases, Butantan, with the assistance of an international nonprofit partner, will adopt a vaccine concept and develop it into a marketed product.
Butantan is growing into an autonomous vaccine developer that can produce vaccines for diseases of local concern. It will be able to license vaccines for such diseases as malaria, tuberculosis and HIV when the National Institute of Allergy and Infectious Diseases and other research organizations find promising candidates. Butantan will then be in a position to ensure that these vaccines become accessible to the public in Brazil and other developing countries.
By David Gilden