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Commentary
Nature Medicine  11, S12 - S15 (2005)
Published online: ; | doi:10.1038/nm1225

Introducing new vaccines into developing countries: obstacles, opportunities and complexities

John Clemens & Luis Jodar

The authors are at the International Vaccine Institute, Seoul, Korea.

Correspondence should be addressed to John Clemens jclemens@ivi.int
Infectious diseases are thought to account for nearly 25% of all deaths worldwide, and extract a disproportionate toll in developing countries1. Moreover, infectious diseases are now appreciated to be major causes of the poverty and economic underdevelopment that characterize the world's poorest countries2. Development and deployment of new vaccines to prevent infectious diseases in developing countries have therefore become high priorities in the global health agenda.
Modern biology has yielded a large array of promising new vaccine approaches and candidates with breathtaking potential for disease prevention in developing countries. A recent survey of new vaccine candidates under development found that over 350 candidates against 88 different pathogens are being developed by companies, universities and research institutions, and many of these new vaccine candidates are directed against diseases of the Third World3. In this Commentary, we review current trends that may affect whether the most promising of these vaccine candidates will eventually be used in programs for the poor in developing countries, and how the generation of evidence has become an increasingly important determinant of vaccine introduction.

Obstacles to vaccine introduction
At the end of the last millennium several worrisome trends suggested that many newly developed vaccines might never be used in public health programs in developing countries. First, although in the late 1980s delivery of basic childhood vaccines—bacille Calmette-Guérin (BCG) against tuberculosis, polio vaccine, diphtheria-tetanus-pertussis vaccine and measles vaccine—by the Expanded Programme on Immunization (EPI) had risen to achieve worldwide coverage of about 80% of infants, these gains faltered thereafter, especially in sub-Saharan Africa, where in 2000 less than 50% of infants had received their third dose of diphtheria-tetanus-pertussis vaccine4. This trend underscored the difficulties that would be encountered in adding new vaccines to programs in settings such as developing countries.

Second, an increasing divergence between vaccine products used in the industrialized versus developing worlds arose in the 1990s (Table 1)5. This divergence included newer generation vaccines, such as vaccines against hepatitis B and Haemophilus influenzae type b (Hib). Such vaccines had become commonplace in the industrialized world, yet were not being used widely in the developing world largely because of their expense6, creating pessimism about the likelihood that newly developed vaccines would be introduced in the developing world. Moreover, several vaccines and vaccine formulations that had formerly been used jointly in industrialized and developing country populations ceased to be recommended in industrialized countries. For example, whole-cell pertussis vaccine had largely been replaced by acellular pertussis vaccine in the industrialized world, but continued to be used in the developing world, because of its low cost. This trend threatened to reduce the supply of many vaccines recommended for the developing world, as major vaccine producers tailored their portfolios to vaccines for the industrialized world.

Table 1. Divergence of recommendations for infant vaccines
Table 1 thumbnail

Full TableFull Table
Third, there was little incentive for the vaccine industry in the industrialized world, the major source of innovative vaccines, to develop new vaccines against diseases that were largely limited to the developing world, as industrialized world markets were more lucrative7. Examples of these diseases included malaria, tuberculosis, shigellosis, enterotoxigenic Escherichia coli diarrhea, cholera, typhoid fever, invasive group A meningococcal disease, dengue fever, hepatitis E, leishmaniasis and schistosomiasis.

Fourth, several factors, including the increasing stringency of regulations imposed by national vaccine licensing authorities, had increased the costs of clinical development pathways for licensure of vaccine candidates to hundreds of millions of dollars7. This meant that new generation vaccines would have to cost dollars per dose in order for industry to recover an adequate return on its investment—in contrast to the pennies per dose cost of the traditional EPI vaccines—and it was not clear how these costs would be borne for developing country populations.

Fifth, it had become increasingly common to find that vaccines performed less well in developing country populations than in populations residing in the industrialized world8, 9, 10. These disparities meant that trials of vaccines in developing countries were needed before their introduction in these settings. But trials in developing countries were not a priority for large producers in the industrialized world, and, if they were undertaken, they were typically deferred for years after vaccine licensure in industrialized countries, leading to delays in vaccine introduction.

Opportunities for vaccine introduction
Against this backdrop of obstacles, there have been several encouraging recent developments. To overcome the disincentives to industry of creating new vaccines for the developing world, governments in the industrialized world have traditionally used 'push mechanisms.' Push mechanisms are aimed at lowering the risks and costs to industry of research and development, and include such actions as providing grants for product development, supporting the costs of clinical trials, strengthening of field sites in developing countries, providing research and development tax credits and expediting the regulatory and licensing process11. Recently, these push mechanisms have been infused with increased funding, partly because of the recognition that infectious diseases are major threats to global security, that infectious diseases can spread rapidly from the tropics to the industrialized world and that several diseases of importance to the developing world are also potential bioterrorism threats.

In addition, foundations have recently become major contributors to these efforts. Particularly noteworthy is the Bill and Melinda Gates Foundation, which in recent years has funded major research and development programs for new vaccines against HIV/AIDS, malaria, tuberculosis, hookworm, leishmaniasis, group A meningococcus, cholera, shigellosis, typhoid fever, dengue fever, Japanese encephalitis, rotavirus, Hib, and pneumococcus (www.gatesfoundation.org).

Another hopeful development has been the emergence of public-private partnerships (PPPs)12. PPPs are typically coordinated by freestanding nonprofit organizations that raise money from the public sector and use this money to leverage efforts by both the public and the private sectors to develop and produce affordable vaccines for the developing world. PPPs have achieved several successes, including accelerating the development of vaccines against such scientifically daunting challenges as malaria13.

A recent trend for some of these entities has been to function as virtual vaccine companies, with in-house laboratory, clinical and regulatory expertise to coordinate and guide development activities among diverse partners. Examples of organizations taking on this expanded role include the International AIDS Vaccine Initiative (www.iavi.org), the AERAS Global TB Vaccine Foundation (www.aeras.org), and the Malaria Vaccine Initiative (www.malariavaccine.org). To help safeguard against conflicts of interest that might favor candidates whose development is being guided in-house over those being developed externally, independent advisory committees have been established for prioritization of candidates, development of 'go−no go' criteria at key points in the developmental process and assessment of the data at these decision points.

Particularly important has been the creation of the Global Alliance for Vaccines and Immunization (GAVI)14. GAVI is a voluntary alliance of major agencies, institutions and companies involved with developing or providing vaccines for developing countries and has three closely linked goals: (i) to improve vaccine delivery and vaccine safety, with payments to countries pegged to the number of children actually vaccinated; (ii) to introduce vaccines beyond the traditional EPI vaccines, including vaccines against hepatitis B, yellow fever, Hib and newer combination vaccines; and (iii) to increase the pipeline of new vaccines for future introduction by supporting research and development. An innovative feature of GAVI is that it has incorporated 'pull mechanisms' to guarantee purchase of vaccines for developing countries through creation of a Global Children's Vaccine Fund. In its first five years, beginning in 1999, the Fund received a donation of $750 million from the Bill and Melinda Gates Foundation, together with matching donations that increased the Fund to well over $1 billion. These resources have had an important effect not only in strengthening the delivery of the traditional EPI vaccines, but also in significantly raising coverage rates with hepatitis B vaccine, a vaccine whose introduction into country EPI programs had languished for many years despite clear international recommendations for its inclusion. In early 2005, a $750 million donation was again made by the Gates Foundation, and ensuing pledges by governments of the United Kingdom and Norway have again increased the current Fund to over $1 billion.

Even with a Global Children's Vaccine Fund, there must be an adequate global capacity to produce needed vaccines. As noted earlier, the divergence of vaccines between developing and industrialized countries has progressively slanted the product portfolios of international vaccine producers away from developing country requirements. A fortunate development has been the emergence of high quality vaccine producers and capable national regulatory authorities in the developing world. In Brazil, Cuba, India and Indonesia certain manufacturers have been prequalified by the World Health Organization to supply EPI vaccines for purchase by United Nations agencies5. Because of their location in the developing world and because of the commercial viability of selling vaccines to developing country markets, these new companies are beginning to fill the void left by the increasing departure of international companies from production of vaccines tailored to developing countries. Moreover, several of these producers are engaged in the development of vaccines against infectious diseases of local public health importance, such as invasive Hib disease, malaria, rotavirus diarrhea, shigellosis and Japanese encephalitis, often with technology transfer from sources in the industrialized world.

Complexities of vaccine introduction
Because resources for push and pull mechanisms are finite, decision-makers in the public sector are increasingly demanding evidence as a prerequisite for financial investments into vaccines for developing countries. Evidence is also required for advocacy efforts to convince policymakers that resources should be expended.

What types of evidence are needed? As shown in Figure 1, several types of uncertainties often remain about whether to introduce a new vaccine into developing countries, even when the conventional pre-licensure sequence of clinical studies for a vaccine has been successfully undertaken. Evidence from vaccine trials done in the industrialized world cannot be automatically generalized to developing-world populations. Clinical trials in developing countries, even for vaccines that have proved safe and protective in industrialized country populations, have therefore become a sine qua non in the package of evidence needed for decisions about introducing new vaccines into developing countries. Recognition of the delays incurred by sequential testing of vaccines in industrialized and developing countries has motivated the public sector to sponsor trials of promising new vaccines in developing countries in parallel with trials in the industrialized world, as illustrated by current clinical development programs for vaccines against rotavirus and HIV15, 16.

Figure 1. Residual uncertainties requiring evidence.
Figure 1 thumbnail

Evidence is needed to address several types of uncertainties that may persist even when the three phases of a clinical development program have been successfully undertaken.



Full FigureFull Figure and legend (42K)
Policymakers often find that there are inadequate data about whether the burden of the targeted disease is sufficient to warrant the introduction of a new vaccine. These uncertainties are exacerbated for targeted diseases that show major geographical variations in incidence, such as Hib17; diseases whose burdens are incompletely measured with routine diagnostic tests, such as pneumococcal pneumonia; and infections for which major disease burdens result from their long-term effects, such as Japanese encephalitis, human papilloma virus and hepatitis B18.

Moreover, even for a vaccine found to be safe and protective in clinical trials in the developing world, evidence is often needed to address doubts whether the vaccine will perform equally well when given to the wide spectrum of subjects and under the realistic conditions of public health programs, and whether the introduction of the vaccine will be programmatically feasible19. For example, for an effective vaccine against HIV/AIDS to have a near-term impact, it will have to be given to adolescents just before the onset of sexual activity; yet there is relatively little experience with delivery of vaccines to these age groups in the developing world20.

In addition, evidence may be needed to address doubts about the acceptability of the vaccine to populations and policymakers in the developing world, and about whether the demand for a vaccine will be strong enough that governments or even users would pay for the vaccine, should such payments prove necessary to ensure the financial sustainability of vaccine introduction. Studies of these perceptions can be illuminating. For example, a recent survey of policymakers and opinion leaders in seven developing Asian countries about views on demand for present and future vaccines against cholera, shigellosis and typhoid fever found that although there was high demand for vaccines against typhoid fever and shigellosis for the general populations of these countries, the demand for cholera vaccine was only for restricted populations at high risk. The study also found that $1 per dose was the maximum acceptable price most frequently cited for new generation vaccines against these diseases21.

Because new vaccines for developing countries will generally cost considerably more than traditional EPI vaccines, economic evidence is needed to assess the balance between the costs saved from prevention of disease by vaccination on one hand, and the expense of vaccine acquisition and delivery on the other. These economic analyses require not only credible data about the actual costs incurred in a country's health programs, but also the delineation of realistic program options for introducing a new vaccine in a country's public and private sectors22.

The Hepatitis B Vaccine Task Force was a pioneering effort to provide the multidisciplinary evidence needed to address these many uncertainties6. Additional programs have now emerged with support from the public sector. One of the first of these newer programs, the Diseases of the Most Impoverished (DOMI) Program, funded by the Bill and Melinda Gates Foundation, is providing this sort of evidence for new generation vaccines against cholera, shigellosis and typhoid fever23.

A matrix of studies is being undertaken by the DOMI Program to inform the introduction of Vi polysaccharide vaccine, the vaccine against typhoid fever given highest priority by the Program for near-term introduction (Table 2). The evidence needed to inform policy on introducing Vi vaccine is being generated through prospective, population-based disease burden studies as well as meta-analyses of published and unpublished studies of disease burden; observational epidemiological studies; clinical trials; and demonstration projects of licensed vaccines, designed to assess their feasibility, acceptability, costs and impact when deployed in real-life public health programs. Nested within the disease burden studies and demonstration projects are behavioral and economics studies of population demand for Vi vaccine, willingness to pay for the vaccine and actual costs of typhoid illness and Vi vaccine delivery. Policy analyses of potential program options for vaccine introduction—which may vary from country to country—are being conducted to provide a framework for the economic analyses. Because the strength of the case for introducing Vi vaccine will probably differ substantially for different countries with endemic typhoid, the DOMI Program has been designed to provide evidence at the country level for decision-making. Countries judged to be potential early adopters of Vi vaccine have been targeted for the complete ensemble of studies. An important feature of this matrix of studies was that it was designed in response to the data needs expressed by policymakers during a survey of DOMI's partner countries at the outset of the Program21.

Table 2. Development of a matrix of evidence in the DOMI program to help evaluate at the country level whether to introduce Vi vaccine
Table 2 thumbnail

Full TableFull Table
The DOMI Program is but one example of a new genre of multi-country, multidisciplinary programs of research designed to inform decisions about introducing new vaccines into developing countries. For example, in recognition of the need for evidence to accelerate the rational introduction of new generation vaccines that have been recently licensed or are near licensure, GAVI has initiated major programs of research, which go by the acronym ADIP (Accelerated Development and Introduction Plan). The research agendas of the ADIPs will generate the evidence needed for decisions about introducing new generation vaccines against rotavirus and pneumococcus14, 24.

Comment
Recent developments have countered the pessimism at the end of the last millennium about whether attractive new vaccines could realistically be introduced into developing countries. Despite these developments, resources for introducing new vaccines and sustaining their use in developing countries are still comparatively scarce, and will probably not ever be sufficient to support the use of all new generation vaccines of potential public health utility. Wise use of these funds demands several types of evidence to inform policy decisions.

The recent emergence of multi-country, multidisciplinary programs to generate this needed evidence is encouraging, yet several challenges remain. Much work is required to provide simplified, inexpensive and valid methods for obtaining crucial data at the country level, such as the burden and costs of disease. Research is also needed to create an intellectual framework to synthesize diverse types of relevant evidence so that the comparative merits of alternative vaccines (and other interventions) can be assessed and communicated to policymakers.

Another challenge stems from the dual use of evidence as a tool to inform rational policy and as a mechanism to advocate for a particular vaccine. Recent programs designed to generate needed evidence have been narrowly focused on one or a few diseases and vaccines, and those working in these programs often become champions for the introduction of vaccines considered in their portfolios. Although many of the greatest public health triumphs of vaccines have resulted from the efforts of such champions, it is important that decisions about using new vaccines come from objective and rational consideration of evidence rather than a contest of wills. Establishment of 'honest brokers' capable of undertaking and communicating objective comparisons will be important to help ensure rational deployment of new vaccines in developing countries in the future.

Published online: 5 April 2005.

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Competing interests statement:  The authors declare that they have no competing financial interests.

SUPPORTED BY:
Office of AIDS Research
Antigenics
Chiron Vaccine
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