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M A N U FA C T U R I N G A N D P U B L I C H E A LT H SUPPLEMENT ARTICLE Considerations for Combination Vaccine Development and Use in the Developing World José Luis Di Fabio and Ciro de Quadros Division of Vaccines and Immunization, Pan American Health Organization, Washington, DC As more vaccines are developed and become available, combination vaccines will provide a way of delivering multiple antigens to avoid multiple injections and complications in the regular immunization schedules. The advantages of combination vaccines are that they decrease the discomfort of vaccine recipients and parents and also reduce the delivery cost of vaccines. We address some of the issues related to the use of combination vaccines in the developing world. Which vaccines are needed? Do developing countries have the appropriate infrastructure to deliver them? Can vaccines become affordable for countries with low incomes? And what is really needed to achieve the goal of providing developing countries with new vaccines of epidemiologic significance in a timely fashion? Vaccines are the most cost-effective public health tool available for the prevention and control of infectious disease [1]. Their use has had an enormous impact on disease, as seen with smallpox eradication, as well as with polio eradication in the Americas and major advances toward its global elimination. Similarly, measles is on the verge of eradication in the Americas [2], and sharp decreases in tetanus, diphtheria, and whooping cough cases are reported worldwide. However, there is still disparity with regard to vaccine use and coverage among regions of the world, associated principally with access to health care services. In the developing world, populations with poor access to health care services either are rural and lack adequate communication systems or are urban and generally are located on the outskirts of large cities that have a poor sanitary infrastructure. More than 80 million cases of childhood disease (measles, polio, tetanus, diphtheria, and whooping cough) and 1.5 million deaths due to these diseases are still reported every year. Inadequacies in vaccine deliv- Reprints or correspondence: Dr. José Luis Di Fabio, Program of Vaccine Technology Access, Div. of Vaccines and Immunization, Pan American Health Organization, 525 23rd St. NW, Washington, DC 20037-2895 ([email protected]). Clinical Infectious Diseases 2001; 33(Suppl 4):S340–5 2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3312S4-0014$03.00 S340 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros ery, communication, and transportation infrastructures are generally the most relevant problems. Although new, cost-effective, and sustainable strategies for reaching the unreached are being planned, new approaches for guaranteeing delivery of most of the antigens must be also designed. One important approach is combination vaccines [3]. Combination vaccines have the enormous advantage of providing the ability to administer several antigens in a single shot, thus decreasing the discomfort for vaccine recipients and parents and reducing the cost of the delivery process. In addition, because fewer syringes are required, safer administration with syringes and needles can be attained [4]. This strategy has been used for many years to deliver bacterial vaccines (diphtheria-tetanus-pertussis vaccine [DTP], meningococcal and pneumococcal vaccines) and viral vaccines (measles-mumps-rubella vaccine [MMR]). ADVANTAGES TO THE USE OF COMBINATION VACCINES Most of the vaccines developed and in use to date are delivered by injection and require several doses to induce complete immunity. Thus, in the typical immunization schedule for children, several injections and multiple visits to health care clinics, doctors, or vac- Table 1. in 1998. Mortality due to communicable diseases worldwide No. of deaths Total High-income countries Middle- and low-income countries Respiratory diseases 3,500,000 310,000 3,190,000 HIV/AIDS 2,285,000 32,000 2,253,000 Diarrheal diseases 2,200,000 7000 2,193,000 Childhood diseases 1,650,000 10,000 1,640,000 Tuberculosis 1,500,000 18,000 1,482,000 Malaria 1,110,000 0 1,110,000 143,000 4000 139,000 Disease Meningitis Others 1,000,000 50,000 950,000 Total 13,388,000 431,000 12,957,000 NOTE. Data are from [7]. cination posts are required. The discomfort that the injection represents for the child and parent adds to other difficulties in ensuring compliance with the entire immunization schedule. One of the key strategies for simplifying immunization has been the development of combination vaccines. There are several examples, such as DTP and MMR, that have been used for many years in the immunization programs, and some more recent ones, such as the combination of Haemophilus influenzae type b conjugated vaccine (Hib) with DTP [5], of varicella vaccine with MMR, and of hepatitis B vaccine (Hep B) with DTP [6]. There are several advantages to the use of combination vaccines in developing countries: • • • • Decreases the number of needle sticks and thus the discomfort of child and parent. Decreases the number of contacts required to administer multiple antigens and thus increases coverage in areas where access to health care is limited. Makes delivery of vaccine more cost-effective. Increases safety of immunization by decreasing the number of needles and syringes needed. have yielded the most significant improvements in child health in the last few decades, 11.5 million children still die each year from diseases for which vaccines are available at low cost: measles, polio, neonatal tetanus, diphtheria, and whooping cough. Hepatitis B, hepatitis C, human papillomavirus, and Helicobacter pylori are pathogens responsible for deaths due to infection-related cancers (liver and cervical cancer) or chronic diseases (gastric ulcers and cancer), which account for nearly 6 million deaths each year. Table 2 shows the major global burden of diarrheal and respiratory diseases that occur primarily in the developing world. Thus, there is a simple answer to the question of which combination vaccine would be useful or appropriate for the developing world: any vaccine that can be delivered will have a major impact. The greatest impact can be obtained with combination vaccines directed against the most common diarrheal pathogens, such as rotavirus, Salmonella, Shigella, and Vibrio cholerae, or respiratory pathogens, such as Streptococcus pneumoniae, respiratory syncytial virus, and influenza virus [9]. Many of these important vaccines are in the development pipeline, and some are close to final clinical trials, licensing, and availability [10]. But because the most important players in the development of these vaccines are the commercial manufacturers, vaccines for diseases that represent a burden to the developed world move faster through the pipeline, because they represent a higher profit margin. Vaccines directed at respiratory pathogens, for example, are closer to becoming available than vaccines aimed at diarrheal diseases, in direct association with the major burden in mortality and morbidity that respiratory diseases place on high-income countries. Nevertheless, when available, these vaccines will also have a key effect on mortality and morbidity in the developing world. INFRASTRUCTURE AND DELIVERY When safe and effective combination vaccines become available, one of the principal problems will be to deliver the vaccines to those who most need them. By 1999, vaccine coverage Table 2. Morbidity due to communicable diseases, infectionrelated cancer, or chronic diseases worldwide in 1997. EPIDEMIOLOGIC CONSIDERATIONS Although extraordinary medical advances have been made during the 20th century, a significant component of the global burden of illness still is attributable to infectious diseases, malnutrition, and complications of childbirth. In 1998, nearly 20 million deaths worldwide were linked directly to communicable diseases, infection-related cancer, or chronic diseases. These conditions are concentrated in the poorest countries, and they affect populations within those countries that are living in poverty (table 1). Despite the fact that immunization programs Disease No. of cases Respiratory diseases Diarrheal diseases Childhood diseases Tuberculosis 390,000,000 (new cases) 4,000,000,000 (new cases) 80,000,000 (new cases) 7,400,000 (new cases) Meningitis 1,500,000 (all cases) Hepatitis B 350,000,000 (all cases) Hepatitis C 170,000,000 (all cases) NOTE. Data are from [8]. Combination Vaccines for the Developing World • CID 2001:33 (Suppl 4) • S341 with the original 6 Expanded Programme on Immunization (EPI) vaccines reached a global average of 70%–80% of the population. However, there are great differences in coverage between regions, within regions, and within individual countries (table 3). Combination vaccines alone will not solve the problem, unless major efforts are made to improve the vaccine delivery infrastructure, such as in transportation, the Cold Chain, and human resources, which can ensure improvements in coverage. The ideal formulation for a combination vaccine would be an orally administered, multicomponent combination to be given as a single dose at birth. Other formulations would include combinations to be orally administered at the same time as the other, standard vaccines. The new generations of combination vaccines are injectable and are delivered on the same schedule as DTP. These vaccines are in already-combined formulations (DTP-Hib, DTP–Hep B) or formulations to be combined at the moment of administration (DTP ⫹ Hib, DTP–Hep B ⫹ Hib) [12–14]. In general, national immunization programs purchase vaccines through yearly bid solicitations and assign the purchase to the manufacturers, which can then provide quality vaccines at the lowest prices. If we consider the use of combination vaccines in the regular immunization program, this issue becomes critical. Is a country bound to continue the use of the initial combination vaccine if no other alternatives are possible? Should the industry reach a consensus on a standardized formulation composed of a group of basic vaccines such as DTP, Hep B, Hib, and some other priority vaccines (the so-called universal combination)? Some logistical problems are already being generated with the use of Hib, which comes in different formulations—liquid or freeze-dried, in combination with DTP, or reconstituted with DTP or DTP–Hep B. COST ISSUES The US$14 required for the program delivery costs involved in fully immunizing a child with the original 6 EPI vaccines (BCG, diphtheria, tetanus, pertussis [DTP], poliovirus, and measles vaccines) also can be applied to the delivery of new vaccines, such as Hib, pneumococcal and meningococcal conjugated vaccines, varicella vaccine, and hepatitis A vaccine, that cost 1–3 orders of magnitude more than the current ones. Thus, the availability of these new, more expensive vaccines will focus attention increasingly on the relative value of alternative disease-prevention measures. However, even at higher prices, vaccines will remain one of the most cost-effective means of preventing diseases and avoiding treatment costs. Governments are prepared to pay a higher price for treatment (drugs and tertiary care) than for prevention. The main challenge is to overcome the perception that vaccines must be cheap and, at the same time, to promote S342 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros Table 3. Vaccine coverage in countries with the highest and lowest rates of vaccination, by World Health Organization region, 1998. Range of vaccine coverage, % of population Region BCG OPV3 DTP3 Africa 25–99 24–95 23–96 Americas 82–100 72–100 70–97 Eastern Mediterranean 33–100 24–99 24–99 Europe 87–100 88–99 70–99 Southeast Asia 64–94 70–97 37–94 Western Pacific 56–100 64–99 55–98 NOTE. DTP3, diphtheria-tetanus-pertussis vaccine (3 doses); OPV3, oral poliovirus vaccine (3 doses). Data are from [11]. vaccine affordability. It is necessary to take into account not only the price of vaccination and the country’s relative wealth but also the benefit that the use of vaccines can have in protecting the individual, the group, and, most important, society, in comparison with other health interventions [15]. Introduction of new vaccines will greatly increase the national immunization budgets in countries, and specific actions will be required to guarantee sustainability of the programs once they are initiated. To maintain continuous support from country decision-makers for these improvements in immunization programs, appropriate information has to be generated from the surveillance systems, initially to evaluate the possible impact of vaccine introduction and later to monitor the impact. The responsibility for making the decision to use new vaccines will go beyond the health sector and will include other sectors, such as ministries of economy, finance, industry, commerce, foreign affairs, and international cooperation. Advocacy has to be directed to these other decision-makers, as well as to multilateral and bilateral agencies, so that they can appreciate the potential value of vaccines. EXPERIENCE IN THE REGION OF THE AMERICAS After the United States, in 1990, and Canada, in 1991, the next country in the Americas to introduce Hib was Uruguay, in 1994 [16]. By 1996, Chile had also included Hib in the regular immunization program [16]. At that time, the Pan American Health Organization (PAHO) started active promotion of surveillance of H. influenzae type b disease, as well as evaluation of the possible introduction of the vaccine in the national immunization programs. The decision was reinforced by results from clinical studies with Hib in The Gambia that indicated that H. influenzae type b can be responsible for up to 20% of radiologically confirmed cases of pneumonia [17]. Since then, dramatic changes have occurred, and, in the year 2000, 190% of the birth cohort in the Americas had been vaccinated or had Hib in the vaccination schedule (figure 1). Two major decisions made by the PAHO led to the current situation. At the PAHO’s directing council meeting in 1997, member states were urged to strengthen surveillance in preparation for the introduction of new vaccines (such as Hib, Hep B, and MMR), as well as to develop appropriate strategies to introduce these vaccines. At its 1997 meeting, the PAHO Technical Advisory Group on Vaccines and Immunization recommended the following: (1) use of Hib in the regular immunization programs; (2) establishment of well-structured surveillance systems to monitor illnesses due to H. influenzae type b and measure the impact of this pathogen; and (3) use of the PAHO Revolving Fund for joint purchases of vaccine. It was of great importance that 2 countries in the region, Uruguay and Chile, had already introduced the vaccine; they provided examples for the other countries of the use and impact of the vaccine in reducing disease burden. One of the principal deterrents for introduction of the vaccine had been the price, although that had been steadily dropping. With the consolidation of Hib vaccine procurement via the PAHO Revolving Fund, prices have dropped considerably. These lower prices have allowed other countries to make the decision to use the vaccine in standard immunization programs. A combination vaccine that includes DTP, Hep B, and Hib is now available. Many countries have rapidly adopted this combination, because it facilitates the introduction of 2 new vaccines (Hep B and Hib) simultaneously into the immunization program. This has been the case for Mexico, Nicaragua, Bolivia, Guyana, and Panama. The combination simplified the delivery of both vaccines in countries that were already using them, such as Costa Rica, or facilitated the introduction of Hep B into the standard immunization program of countries that were already using Hib, such as Uruguay, Honduras, and Peru. Governments in the Americas have once more demonstrated a high level of political and financial commitment to vaccines. Even countries with low incomes, such as Nicaragua, Honduras, and Guyana (table 4), have considered that the required level of investment in health care expenditures was worthwhile, considering the benefits and impact of immunization of children against hepatitis B and H. influenzae type b. The availability of general information on disease burden and the incorporation of economic evaluation and opportunity costs relative to other interventions facilitated the decisionmaking process for vaccine introduction. Advocacy to the Ministry of Health and Ministry of Finance has developed awareness of and commitment to immunization in society and among national decision-makers. New strategies and approaches for vaccine financing were used in the region of the Americas. Figure 1. Evolution of Haemophilus influenzae type b vaccine (Hib) introduction in the Americas and use of diphtheria-tetanus-pertussis, hepatitis B, and H. influenzae type b conjugated vaccine (DTP ⫹ Hep B ⫹ Hib) by the year 2000. Combination Vaccines for the Developing World • CID 2001:33 (Suppl 4) • S343 Table 4. Country Financial commitments to vaccination in Latin American countries in 1999. GNP per capita, in US$ Total GNP, in millions of US$ Investment in pentavalent vaccine Health care expenditures, percentage of GNP Percentage of health care a expenditures Percentage of b total GNP Nicaragua 410 2024 5.3 1.71 0.090 Honduras 740 4675 2.8 1.64 0.046 Guyana 800 684 Bolivia 970 7900 3.8 0.93 0.035 Peru 2610 65,850 2.2 0.44 0.010 Costa Rica 2680 10,530 6.0 0.15 0.009 Panama 3080 8660 4.7 0.16 0.007 Mexico 3700 360,025 2.8 0.24 0.007 Uruguay 6130 20,290 1.9 0.16 0.003 0.027 NOTE. The cost of 3 doses of pentavalent vaccine was US$10.50. GNP, gross national product. Data are from [18]. a Percentage of the total health expenditures represented by purchase of the 3 doses of pentavalent vaccine for the birth cohort. b Percentage of the total GNP represented by purchase of the 3 doses of pentavalent vaccine for the birth cohort. These approaches ranged from allocation of the required resources in the regular immunization budget to consolidation of resources from different levels (national, provincial, municipal, private, etc.) to negotiation of loans with development banks, partner agencies, or vaccine manufacturers. TAKING ADVANTAGE OF OPPORTUNITIES PROVIDED BY VACCINES There are 2 main questions related to the availability of combination vaccines for the developing world: How can vaccines developed specifically for marketing to high-income countries be made affordable for use in developing countries? And how can vaccines of special epidemiologic importance for the developing world be developed? Cost of developing the vaccine. The cost of developing a vaccine is estimated to be in the tens of millions of US dollars, and a large percentage of these costs are used to fund clinical trials. These trials are becoming more complex and thus more expensive as they address the tighter safety requirements placed by regulatory agencies [19–21]. These requirements become even more important in countries where disease burden, medical care, and risk factors are such that the possible risks associated with the vaccine may overrule the intrinsic benefits of the vaccine. An example has been the licensing of rotavirus vaccine in the United States [22] and its recent withdrawal from the market because of associated adverse events [23, 24]. The same issue plays an important role in the decision by manufacturers not to embark on the development of vaccines that are a priority for developing countries, even though they S344 • CID 2001:33 (Suppl 4) • Di Fabio and de Quadros may also be of some interest in developed countries, for example, for travelers or other risk groups. International organizations (World Health Organization, PAHO, United Nations Children’s Fund, foundations, bilateral agencies, and other institutions) can become involved and subsidize the clinical trials, with the commitment of the industry to produce the vaccines, but investment is still required for production facilities, and the manufacturer may not be willing to take the risk if a market is not ensured. Private-sector market in the developing countries. It may be estimated that at least 15% of the population living in developing countries are from middle and higher socioeconomic strata. Additionally, an average of 40%–50% of the total health care expenditures in the developing world are private expenditures that cover direct household spending, private insurance, charitable donations, and direct service payments by private corporations. This indicates the existence of a sizable market in the developing world that can be targeted for new vaccines developed initially for the lucrative industrialized markets, thus increasing the market demand and speeding the filtering down of these vaccines to developing countries. Similarly, these markets could be targeted initially for vaccines of regional importance, as long as epidemiologic studies confirmed the vaccine need in these populations. This latent demand could motivate industry to make the investments needed for vaccine production. Interaction between commercial vaccine manufacturers and local vaccine producers. Most of the outputs (patents, intellectual property rights) from vaccine research and development technologies are under the control of the major commercial vaccine manufacturers, including manufacturers of vaccines that are of enormous importance to the developing world but of no commercial value to developed markets. Under these conditions, without a major incentive to continue further development, these new vaccines will not become available. The international community can promote successful ventures between commercial manufacturers and competent local vaccine producers [25, 26]. This interaction can lead to the production and use of “developing market” vaccines by local manufacturers in direct association with major commercial manufacturers, who, in turn, can benefit from the technological experience and results of the corresponding clinical trials and vaccine use. The commercial manufacturer may use this information to produce the vaccine for the developed-world market. Combination vaccines will become fundamental tools in improving public health, preventing millions of deaths and illness due to devastating diseases. The major task ahead requires the participation of a multiplicity of partners, including governments, researchers, the vaccine industry, public vaccine manufacturers, regulatory agencies, international organizations, and the public in general. Notwithstanding the difficulties, one can look into the future with optimism: the example of the region of the Americas shows that new vaccines can be introduced and used by countries regardless of their income. This success depends on countries’ placing enough value on the benefit of vaccines to make the vaccines available to their populations. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. References 1. International Bank for Reconstruction and Development. World Development Report 1993: investing in health. Washington, DC: International Bank for Reconstruction and Development, 1993. 2. 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