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Vaccines for Tropical Diseases and Global Research Priorities Neglected Tropical Diseases and Vaccines in Development Measles, mumps, rubella, pertussis, polio, diphtheria, tetanus, and Hib are familiar, vaccine-controlled, diseases in developed countries. Populations in low-income countries not only confront these infections but also a number of infections unrecognizable to most Westerners: human African trypanosomiasis, visceral leishmaniasis, Chagas disease, hookworm, ascariasis, trichuriasus, schistosomiasis, lymphatic filariasis, onchocerciasis, dracunculiasis, trachoma, leprosy, and Buruli ulcer.1,2 These 13 neglected tropical diseases are known as the "poverty diseases" and are responsible for approximately 534,000 deaths annually.3 In addition to causing mortality, neglected tropical diseases (NTDs) can often be disabling and disfiguring. For example, lymphatic filariasis, commonly called elephantiasis, causes massive swelling in the arms, legs, breasts, and genitals. Dracunculiasis, known as guinea worm disease, leads to the emergence of 2-3 foot long parasitic worms from painful blisters in the skin. Along with causing emotional distress, they impair children's physical and cognitive growth (primarily from associated anemia).4, 5 Human parasitic diseases combine for approximately 100 million disability-adjusted life years ('DALYs,' the number of life years lost to premature death or disability), a total that exceeds the DALYs from diarrheal disease, lower respiratory infections, or HIV/AIDS.6 After HIV/AIDS, malaria, and tuberculosis, neglected tropical diseases, considered as a group, represents the fourth largest group of communicable diseases worldwide.7 The inadequacy of current available treatments adds a sense of urgency to the poverty diseases, as many of the first-line drugs are toxic, difficult to administer, over 50 years old, and gaining resistance.8 Vaccines, offer a promising alternative to standard treatments of poverty diseases.9 Neglected tropical disease vaccines could potentially prevent 60% of global disability resulting from infectious diseases. Of the 13 poverty diseases, vaccines are in development for hookworm, schistosomiasis, and leishmaniasis. Hookworm occurs in approximately 576 million people worldwide, with most morbidity attributed to anemia and protein malnutrition.10, 11 Children and women of reproductive age are particularly vulnerable. High rates of re-infection, decreased efficacy of existing drugs, and emerging drug resistance have spurred hookworm vaccine research.12 One hookworm vaccine has undergone Phase 1 clinical trials for safety and immunogenicity.13, 14 Plans are underway to conduct further testing.15 Schistosomiasis is a blood-fluke (worm) infection affecting approximately 200 million people worldwide.16 High infection rates occur near large bodies of fresh water, especially in Egypt, China, and Africa.17 Chronic consequences result from parasitic egg deposition in the bladder, intestines, and liver.18 Anemia, relentless pain, undernutrition, growth failure, and cognitive disabilities are symptoms particularly evident in children.19 Different vaccine development approaches are being analyzed to determine feasibility, safety, and efficacy, particularly for vaccine use in conjunction with existing treatment.20, 21 Leishmaniasis is a protozoan parasitic infection that can cause skin sores, fever, damage to the spleen and liver, and anemia. Worldwide prevalence is estimated at 12 million cases, with approximately 350 million people at risk for infection.22 Communities have sought protection against leishmaniasis for centuries, actively immunizing themselves in an ancient Middle Eastern and central Asian practice called leishmanization. In the process, an individual is inoculated with live parasites; mild disease results. The procedure is unrefined but has been government-sponsored in public health emergencies. In the early 1990s, Iran, a country with high prevalence of the disease, launched a vaccine development program.23 Several labs are working on a second-generation recombinant vaccine for use in conjunction with standard treatments.24, 25 Safety and immunogenicity have been demonstrated in Phase 1 clinical trials.26, 27 NTD Vaccine Financing: Problems and Potential Solutions The development of poverty disease vaccines faces significant economic challenges. With a limited market for such products, pharmaceutical companies lack the financial incentives to develop and produce vaccines for low-income countries - a key factor explaining why only 10% of global health research is devoted to conditions responsible for 90% of the global burden of disease.28 Neglected tropical disease vaccine research and development (R&D) has high risk and a low expected return on investment due to the poverty of relevant populations and major distortions in these disease markets.29, 30 Economist Ernst Berndt and attorney John Hurvitz delineate two key vaccine market failures that challenge the poverty diseases' vaccine development. First, because knowledge generated by research is a global public good and accessed by many countries, no single government has incentive to meet research costs through higher prices or direct funding.31 The second problem is "time inconsistency." After pharmaceutical companies have invested in vaccine R&D, public sector purchasers (i.e., government health ministries) have incentives to use their power as dominant purchasers to dictate low prices, maximizing access.32 Knowing this inevitable economic reality, pharmaceutical companies are less likely to make investments in products for these countries, as low prices often do not cover R&D costs, much less lead to profits.33 One solution, advance purchase commitments (APC), has the potential to guarantee commercial markets. In advance of product development, purchasers (governments of international organizations) agree to finance the purchase of vaccines for low-income countries. The market price is fixed and determined in advance.34 These commitments reduce uncertainty on returns and give investors confidence.35 However difficulties arise in the actual application of these schemes. A balance must be struck between the interests of 1) sponsoring donors, 2) potential vaccine developers and manufacturers (including investors), and 3) low-income countries.36 Conflicts can occur over pricing, contract design, product diversification, quantity guarantees, and long-term sustainability. In 2007 the Global Alliance for Vaccines and Immunization (GAVI) piloted an advance market commitment to facilitate the development and availability of a pneumococcal vaccine.37 The final price has not been determined, but it would initially be purchased at $5-$7 a dose and eventually decline to $2-$3.38 GAVI hopes to positively affect competition by participating in advance purchase commitments, stimulating R&D and creating viable markets in developing countries.39 Public-private partnerships (PPPs) have taken a prominent role in funding vaccine development and distribution in developing countries. The GAVI Alliance is an example of a PPP. GAVI's partners include United Nation agencies and institutions (UNICEF, WHO, the World Bank), civil society organizations (International Pediatric Association), public health institutes (Johns Hopkins), donor and implementing country governments, the Bill & Melinda Gates Foundation, other private philanthropists, vaccine industry representatives, and members of the financial community.40 PPPs are responsible for major transformations in the way new drugs and vaccines are developed - bridging commerce and philanthropy and applying a market-driven model to humanitarian initiatives. Despite growing partnerships with philanthropic organizations, commercial interests must confront ethical questions posed by both developed and developing countries. What obligations, if any, does industry have to both local and global communities? In a market economy, it is essential that pharmaceutical companies earn a profit before they can reinvest in products aimed at underdeveloped countries. Does this justify price inflation in developed countries? Ethics and economics overlap further in the question of what makes a "fair" price. As PPPs pilot advance purchase commitments, debates will continue over equity, access, and pricing. The ownership of the knowledge generated in research also presents legal hurdles as intellectual property issues come into play. -- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu) Continue to II. Vaccine Research Priorities and Obstacles to Access
1Yamey G & Hotez P (2007). Neglected tropical diseases. BMJ, 335: 269-70. |
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