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8
Additional Issues in the Selection of Priorities for Accelerated Vaccine Development

The final selection of candidates for accelerated vaccine development requires consideration of several factors in addition to the potential benefits described in previous chapters. As noted in Chapters 3 and 7, affordability (as represented by vaccine expenditures) can be included in the decision process as a second decision criterion, if desired. Various nonquantifiable factors also need evaluation. These include ethical issues, questions about industry activities on certain vaccines, the relative benefits of immunization versus other methods of disease control or treatment (if available), and the epidemic potential of the disease and interaction between diseases. Nonquantifiable factors could also include questions relating to the geographic (or geopolitical) distribution of benefits and the degree to which some of the evaluated diseases pose an immediate threat to U.S. travelers, personnel, and, by possible importation, to the general U.S. population.

EQUITY CONSIDERATIONS IN CALCULATING DISEASE BURDENS AND VACCINE BENEFITS

Age-Related Weights

The methods for comparing disease burdens (Chapter 4) and vaccine benefits (Chapter 7) allow different weights in the infant mortality equivalence scale to be placed on events that occur at various ages. These weights directly affect both disease burden values and calculations of the possible health benefits of vaccine candidates. For example, if the death of one child under age 5 is considered equivalent to the deaths of 10 persons over age 60, then a disease that kills 1,000 infants annually would be viewed as imposing the same disease burden as another disease that kills 10,000 elderly persons annually.

The model allows decision makers to assess the impact of various infant mortality equivalence trade-offs. The report on vaccines for important diseases in the United States (Institute of Medicine, 1985a) compared rankings calculated by using a median of committee members’ perspectives with those obtained by using an age-neutral perspective, in which lives at various ages had equal value. The rankings resulting from the two perspectives were almost identical for the diseases



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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries 8 Additional Issues in the Selection of Priorities for Accelerated Vaccine Development The final selection of candidates for accelerated vaccine development requires consideration of several factors in addition to the potential benefits described in previous chapters. As noted in Chapters 3 and 7, affordability (as represented by vaccine expenditures) can be included in the decision process as a second decision criterion, if desired. Various nonquantifiable factors also need evaluation. These include ethical issues, questions about industry activities on certain vaccines, the relative benefits of immunization versus other methods of disease control or treatment (if available), and the epidemic potential of the disease and interaction between diseases. Nonquantifiable factors could also include questions relating to the geographic (or geopolitical) distribution of benefits and the degree to which some of the evaluated diseases pose an immediate threat to U.S. travelers, personnel, and, by possible importation, to the general U.S. population. EQUITY CONSIDERATIONS IN CALCULATING DISEASE BURDENS AND VACCINE BENEFITS Age-Related Weights The methods for comparing disease burdens (Chapter 4) and vaccine benefits (Chapter 7) allow different weights in the infant mortality equivalence scale to be placed on events that occur at various ages. These weights directly affect both disease burden values and calculations of the possible health benefits of vaccine candidates. For example, if the death of one child under age 5 is considered equivalent to the deaths of 10 persons over age 60, then a disease that kills 1,000 infants annually would be viewed as imposing the same disease burden as another disease that kills 10,000 elderly persons annually. The model allows decision makers to assess the impact of various infant mortality equivalence trade-offs. The report on vaccines for important diseases in the United States (Institute of Medicine, 1985a) compared rankings calculated by using a median of committee members’ perspectives with those obtained by using an age-neutral perspective, in which lives at various ages had equal value. The rankings resulting from the two perspectives were almost identical for the diseases

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries studied. For this reason and because of limited resources, this report does not include such comparisons. However, those making decisions about vaccine priorities for developing countries might wish to explore the effects of various trade-offs in the ranking process. Effect of Infant Mortality on Fertility Control One example of a value judgment that could affect vaccine programs for developing countries is the belief that reducing infant and child mortality has a lower priority than alleviating adult morbidity, because the former simply perpetuates population growth and increases pressure on resources. At its extreme, this view suggests that rapid early death from infectious disease is preferable to slow starvation. Because population growth is a concern in many parts of the developing world, the committee addressed this concept directly. Reductions in infant mortality may result in a short-term decrease in fertility because breast-feeding a surviving child (if practiced) lengthens the time of postpartum reduced fertility (Bongaarts and Menken, 1983). The death of a child may influence its parents toward further births to “replace” the lost child. Lower infant and child mortality reduces the impact of any such “make-up behavior.” Analyses of parental behavior by Cochrane and Zachariah (1983) indicate that, in the short term, preventing an infant/child death averts an average of about 0.5 births. Thus, the reduction in mortality is not fully offset by a reduction in fertility, and some population growth will occur. The study by Cochrane and Zachariah (1983) did not address longer term trends that may result from changes in general community attitudes. Reduced child mortality is likely to reduce fertility because fewer births are required to meet family size preferences. This decrease is likely to lag behind the decrease in mortality, however, because changes in child survival may not be recognized immediately in the community, resulting in a delay that precedes widespread change in population behavior (Heer, 1983). The magnitude of population growth before the adjustment to lower fertility rates cannot be predicted with any certainty. However, it appears that mortality reduction is an essential prerequisite for fertility reduction (Gwatkin, 1984) . That some population growth will occur as mortality declines highlights the need for integration of agricultural and health program planning to avoid food shortages. The model proposed in this study allows the incorporation of various views on the weight that should be assigned to averting morbidity and mortality at various ages. Opinions were solicited from a range of public health professionals in developing countries; presumably, they are generally aware of the interactions between mortality reduction and fertility discussed above. None of the individual responses could be interpreted as highly favoring adult versus infant/child mortality reduction.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Lives Versus Cases Versus Days The infant mortality equivalence scheme allows decision makers to vary trade-off values within age groups as well as among them. It would be possible to construct a perspective in which all deaths were considered equal, but morbidity was weighted differently for various age groups. For example, days of hospitalization in adult life might be weighted more heavily than days of hospitalization in childhood. Analyses with such perspectives would be valuable in evaluating the stability of the final rankings under various assumptions. The Aggregate Nature of the Disease Burden Calculations Infant mortality equivalence values assigned to specific morbidity category/age group combinations do not differentiate with respect to sex, race, ethnic origin, socioeconomic class, place of residence, occupation, or life-style. However, diseases occur more frequently in some regions than in others, and within countries the incidence or prevalence of diseases varies across population groups. This analysis uses an aggregate “global” perspective in its ranking methodology. The committee does not imply that this is the only feasible approach; other organizations might find alternative perspectives better suited to their needs. One method for going beyond a single, global burden-of-illness comparison is to construct individual disease burden profiles for specific regions, countries, or other groupings, for example: major regions, such as Latin America, Africa, or Southeast Asia specific countries major regions within countries the poorest nations or groups middle-income developing nations women These multiple burden-of-illness profiles might not lead directly to new public policy recommendations, but they would serve as a reminder that the global profile developed here is an aggregate that obscures differential effects in definable regions, countries, or population groups. The multiple profiles also could help decision makers decide whether to devote special attention to the needs of specific regions or the more vulnerable groups, however those groups were defined. Table 8.1 shows that many of the diseases under consideration are not globally or uniformly distributed. Another method to meet the needs of specific groups might involve the portfolio approach described below.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE 8.1 Examples of Pathogens Disproportionately Affecting Certain Regions Patnogen Region of Highest Prevalence Other Regions Affected Dengue virus Endemic in south Asia, southeast Asia, west Africa, north Australia Isolated epidemics in Caribbean 1963, 1969; Central America 1977; Polynesia and Micronesia 1963, 1979 E. coli (enterotoxigenic) Worldwide   H. influenzae type b Worldwide   Hepatitis A virus Worldwide   Hepatitis B virus Worldwide, though higher prevalence in developing countries than developed world. High chronic carriage rates in southeast Asia, and sub-Saharan Africa   Japanese encephalitis virus Endemic in tropical Asia, Australia, and New Guinea   Mycobacterium leprae Tropical areas of India, southeast Asia, Pacific Islands, and Latin America   Neisseria meningitidis Meningitis belt across sub-Saharan Africa, Nile River valley Worldwide Parainfluenza viruses Worldwide   Plasmodium spp. Sub-Saharan Africa, south and southeast Asia, tropical Central and South America, Pacific Islands, and New Guinea   Rabies virus Developing countries Industrialized countries Respiratory syncytial virus Worldwide   Rotavirus Worldwide   Salmonella typhi Developing countries Industrialized countries Shigella spp. Developing countries Industrialized countries Streptococcus Group A Worldwide   Streptococcus pneumoniae Worldwide   Vibrio cholera Endemic in south and southeast Asia, Africa Occasional epidemics in southern Europe and the Middle East Yellow fever virus Tropical South America, sub-Saharan Africa  

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries The Portfolio Approach for Ranking Vaccines for Research and Development Support In establishing consistent methods for setting priorities for vaccine research and development support, some consideration should be given to ranking within a group (or portfolio) of candidate vaccines. It may not be desirable or appropriate to have a single priority list based on final numerical (expected benefits) scores for all possible vaccines that need developmental support. This concept is reflected in the committee’s charge to rank vaccines separately for the United States and for developing countries; also, as noted above, vaccines could be ranked by potential benefits for major regions of the world or for specific countries. Other groupings of vaccines also should be considered. Possible classification categories include the following: Stage of vaccine development* improvement of existing or available vaccines (e.g., cholera and yellow fever) vaccines at an advanced stage of development that are already in, ready for, or almost ready for clinical and/or field trials (e.g., Hemophilus influenzae type b, rotavirus, and Streptococcus pneumonia) vaccines at an early stage of development that require significantly more basic study before any large scale clinical or field trials would be possible (e.g., respiratory syncytial virus) Expected recommendations for vaccine use vaccines for routine pediatric care vaccines primarily for adults vaccines for the entire population vaccines for specific high-risk groups vaccines for pregnant or pregnable women to protect neonates A third classification scheme might be to integrate and combine the above groupings. The results, however, would be fairly cumbersome. The rationale for developing some kind of classification system is based on practical program and political considerations. For example, an objective scoring formula might give malaria vaccine development a very high priority because of the huge incidence and public health importance of the disease. Yet, the prospects for such a vaccine *   The committee has partially adopted this concept in choosing to define a limited slate of candidates for accelerated vaccine development and a separate list of pathogens for which more basic research is necessary before vaccine development even at stage 1c above is foreseeable (see Appendix A).

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries might depend on technological advances that are not expected for several years. Although the probability of successful development could be incorporated into the ultimate ranking, the selection of a balanced portfolio of vaccine candidates might be better served by setting priorities within categories divided by stage of development (the vaccines most advanced in development generally have the highest probability of success). However, development of an improved vaccine might score quite low by objective measures, while policy considerations indicate that this vaccine should receive high priority (see below for discussion of pertussis vaccine). Limited selected use vaccines, the “orphan vaccines,” will probably have to be ranked in a separate grouping if any of them is to receive developmental support. INTERDEPENDENCE OF VACCINE DEVELOPMENT EFFORTS The proposed system for ranking candidate vaccines treats the development process for each vaccine as independent of efforts in other areas. It does not attempt to assess the extent to which research and development for one project leads to procedures or techniques applicable to and accelerating the availability of other vaccines. This possibility needs to be evaluated in the final establishment of priorities. (In regard to the current analysis, research on the incorporation of genes for protective antigens into virus vectors, and the development of simple, safe techniques for the conjugation of polysaccharide antigens to proteins pursued for particular projects, may serve as models for a number of other vaccines.) Such projects may therefore be worthy of special consideration. INTERDEPENDENCE OF IMMUNIZATION EFFORTS Similarly, the proposed system treats the benefits of each project independently and does not incorporate the possibility that certain vaccines, once available, might benefit immunization efforts as a whole. Two examples suggest that consideration of these wider benefits might be warranted in some cases. The analysis of important diseases in the U.S. population indicated that the health benefits resulting from an improved pertussis vaccine would not compare favorably with those produced by a range of new vaccines (for diseases that are not now vaccine preventable). The committee concluded, however, that development of a less reaction-producing, possibly safer, pertussis vaccine deserves special treatment because of its potential for restoring U.S. public confidence in immunization programs. Although the fear of adverse effects from the pertussis vaccine may be less in the developing world, in part because of the greater threat represented by the disease, it is likely that such effects cause concern and may lead to failure to complete recommended immunization schedules. Hence, an improved vaccine would benefit immunization efforts as a whole.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Immunization programs will be logistically constrained by their most sensitive agents. Hence, improving the temperature stability of the most labile vaccines would contribute to immunization efforts generally. The committee evaluated the situation for the two vaccines presently perceived to be the most in need of improved temperature stability, namely poliomyelitis vaccine and measles vaccine. The committee judged that the prospects for substantial improvements in either of the vaccines in the near future were not promising. Therefore, they are not included in this analysis. it is, however, noteworthy that presently feasible adjustments to the formulation of poliomyelitis vaccine can improve its temperature stability but that these modifications are not universally utilized. Magnesium chloride stabilized vaccine—as produced in the United Kingdom, France, Belgium, and a number of other countries but not in the United States—retains potency in the field without refrigeration for 2 weeks with daytime temperatures sometimes reaching 42°C during this period (Peetermans et al., 1976). Utilization of this modification should obviously be evaluated for all situations where it might be beneficial. The difficulty in quantifying interactions between different vaccines within the general immunization effort led the committee to analyze each vaccine development project independently. However, the overall impact of a potential vaccine candidate should be considered by those who ultimately set the priorities. INDUSTRY INTEREST AND ACTIVITY: THE RESPECTIVE ROLES OF THE PUBLIC AND PRIVATE SECTORS The charge to the committee included consideration of how the level of industry interest in certain vaccines should affect the selection of candidates for accelerated development. The charge did not differentiate between U.S. and foreign companies. Presumably, potential profitability is the major motivating force for private sector activity in vaccine development throughout the world. The potential profitability of a vaccine for developing countries may depend, in part, on whether or not the vaccine also can be used in developed countries. If the disease is absent or of low prevalence in developed countries, companies may be unable to recoup research and development costs. In addition, manufacturers may be less willing to invest in a vaccine if the target population required for clinical trials is distant or difficult to identify. In the United States, one of the major deterrents to vaccine development is potential liability resulting from clinical trials or widespread use. The impact of this factor on the availability of vaccines for developing countries is difficult to predict; probably, it is less important than concerns about sales revenues. Industry’s willingness to manufacture vaccines that are licensed and to invest in research and development of new vaccines is addressed in the report, Vaccine Supply and Innovation, by the Institute of Medicine’s Committee on Public-Private Sector Relations in Vaccine Innovation (Institute of Medicine, 1985b). That study’s recommendations

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries may lead to changes in the factors that govern industry’s interest in vaccine innovation. The level of industry’s interest in specific vaccines also may change over time as new development techniques are refined. This committee probably was not aware of all pertinent vaccine-related activity in the private sector, either U.S. or foreign. Given this situation, no formal attempt was made to incorporate the level of industrial interest in individual vaccines into the mechanism designed for selecting priorities for accelerated development. The committee suggests, however, that decisions on implementation of an accelerated vaccine development program should incorporate a review of relevant activities in the private sector. This review should focus on (1) identifying projects for which mutual collaboration might facilitate industrial development of a needed vaccine and (2) identifying high-priority vaccines for which obvious disincentives exist (e.g., special liability issues or limited sales potential, resulting from small market size or particularly severe restrictions on the ability of potential recipients to pay for vaccines). Government funding of the development of such vaccines might make them more attractive to manufacturers. Periodic reassessment, preferably biennially, of this aspect of the program is particularly desirable because of rapid changes in the technology of producing new vaccines. INTEREST IN OTHER COUNTRIES OR INTERNATIONAL ORGANIZATIONS Opportunities for acceleration of vaccine development by U.S. collaboration with other countries and international organizations may also influence the final choices of vaccines for development. The committee recommends that government decision makers consider such opportunities in selecting projects to be pursued. OTHER DIEASE CHARACTERSTICS RELEVANT TO ESTABLISHING PRIORITIES Alternative Disease Control Measures The method devised ranks vaccine candidates on the basis of their potential health benefits. It does not address the relative benefits of disease prevention, control, or treatment by approaches other than immunization. In some situations, the availability of effective alternatives to immunization might be an important consideration in setting priorities for vaccine development projects. For example, if two vaccine candidates ranked similarly on potential health benefits and costs, vaccine development might be considered more urgent for the candidate for which alternative prevention, control, or treatment measures were less satisfactory.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Table 8.2 provides a summary of the current prevention, control, and treatment measures for diseases in this analysis. More complete information on many of these diseases is presented in Warren and Mahmoud (1984) and in a series of monographs on selective primary health care that will be published shortly by Walsh and Warren (in press). Some caution is warranted in assuming that vaccine development is less urgent if alternative prevention, treatment, or control measures are available. The history of vector control (with pesticides) and drug therapy for a wide range of diseases indicates that even with continued efforts, these measures may become less effective (or completely ineffective) because of increasing vector or pathogen resistance. For example, certain strains of Mycobacterium leprae recently have become resistant to dapsone, the principal drug used to treat leprosy for the past 20 years. The prevalence of drug resistance has increased in some areas from 1 to 2 cases per thousand in 1966 to as high as 100 per thousand in 1981 (Bloom, personal communication, 1985). Resistance to dapsone, compounded by the considerable expense of rifampicin and the generally unacceptable side effects (skin coloration) of clofazimine, necessitates the pursuit of preventive immunization strategies. It was not within the charge of this committee to address the relative merits of immunization versus other means of controlling diseases. It should be noted, however, that immunization generally has been shown to be one of the most cost-effective measures for improving health and that it is relatively free of the resistance problems afflicting vector control and drug therapy. Papers by Feachem and colleagues demonstrate the use of cost-effectiveness analysis in comparing alternative approaches to combatting particular diseases (Ashworth and Feachem, 1985; de Zoysa and Feachem, in press; Feachem, 1983, 1984; Feachem and Koblinsky, 1983, 1984; Feachem et al., 1983). For rabies, immunization of the major vector, domesticated or semi-domesticated dogs, could be part of an overall strategy of disease prevention. Although cheaper human-use vaccines with fewer side effects would provide considerable benefit, developing animal vaccines that are inexpensive and easily administered (e.g., through baits) may offer the major hope for reducing the incidence of rabies in many countries. This analysis addresses only the potential benefits of vaccines for human use. Epidemiologic and Clinical Features The proposed system for calculating a vaccine’s potential health benefits uses average annual incidence rates to develop disease burden estimates. This process might understate the importance of certain diseases that occur in epidemic form and produce severe clinical symptoms. A large epidemic of such a disease could overwhelm health care services in developing countries. Because of limited resources, these countries are often barely able to provide appropriate care under normal circumstances. The potential for widespread epidemics also might exacerbate public anxiety about such diseases. Table 8.3 summarizes

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries the potential impact of the candidate diseases on health care systems in developing countries. Potential for Disease Eradication The possibility that a disease might be eradicated has not been incorporated into the calculation of potential benefits, but it could be considered in the ultimate selection of priorities for vaccine development. Early investment in the attack on a theoretically eradicable disease might speed its ultimate elimination and hasten future savings. However, because the current prospects for global eradication of the candidate diseases are remote, this issue probably should not be a major component in the selection of priorities in the near future. Interaction with Other Diseases A further consideration in establishing vaccine development priorities is the extent to which particular disease consequences exacerbate (or are exacerbated by) other illness. The interaction between diarrheal disease and measles is probably the most significant example (Feachem and Koblinsky, 1983). Other interactions are suspected, for example, between viral respiratory infections and bacterial pneumonia, and between various diseases and malaria. In addition, all diarrheas pose the threat of nutritional debilitation, with exacerbation of other illnesses as a consequence. Because the committee judged that knowledge of these phenomena would not permit reliable quantification of their consequences, no adjustments were made of disease estimates. The phenomena should, however, be recognized and the strength of the evidence considered in the ultimate selection of priorities. FINDINGS, CONCLUSIONS, AND RECOMMENDATIONS Various legitimate perspectives exist of the relative undesirability of death and morbidity in different age groups. The method proposed for calculating expected benefits from various vaccines allows decision makers to observe the effects on the final rankings of adopting various perspectives. The determination of which weights to use is inherently a political or public policy decision, not a scientific one. Scientific evidence can be valuable, however, in assessing certain value judgments. For example, epidemiologic and demographic studies suggest that mortality reduction may be a prerequisite for fertility reduction in developing countries. If a long-term view is taken, this finding contradicts the suggestion that programs to reduce infant and child mortality should receive low priority because they contribute to undesirable population growth and increase pressure on scarce resources (although some growth may occur in the delay between mortality and

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE 8.2 Alternatives to Candidate Vaccines Pathogen Prevention or Control Measures Treatment Dengue virus Vector control,a personal protectionb Supportive care E. coli (enter otoxigenic) Potable water supply, improve sanitation, educational and behavioral change,c improve socioeconomic status Oral rehydration therapy, antibacterial agents for severe cases H. influenzae type b Improve crowded living conditions, increase air circulation, early anti-bacterials for severe acute respiratory illness Antibacterial agents (some problems with resistance), bronchodilators Hepatitis A virus Potable water supply, improve sanitation, education and behavioral change,c passive immunization of travelers Supportive care Hepatitis B virus Improve crowded living conditions, improve socioeconomic status, personal hygiene, vaccine for high-risk groups (expensive) Supportive care Japanese encephalitis virus Vector control,a control of nonhuman hosts, vaccine (slow antibody response) Supportive care Mycobacterium leprae Active case finding in endemic areas; rapid, appropriate treatment of cases; chemoprophylaxis; personal sanitation; and isolation of cases (all ineffective) Anti-mycobacterial agents (problems with development of resistance), patient education to prevent complications Neisseria meningitidis Respiratory isolation of cases, chemoprophylaxis of exposed persons, vaccine (limited serotype coverage), improve crowding and ventilation Antibacterial agents, supportive care Parainfluenza viruses Improve crowded living conditions, increase air circulation Supportive care, early antibacterial agents for secondary bacterial pneumonia Plasmodium spp. Vector control,a personal protection,b chemoprophylaxis for children and pregnant women to prevent falciparum malaria Anti-malarials (some problem with resistance), supportive care

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Rabies virus Animal control, post-exposure prophylaxis, vaccine (expensive, multiple doses), education to lessen risk of exposure Supportive care (disease usually fatal) Respiratory syncytial virus Improve crowded living conditions, increase air circulation Supportive care, early antibacterial agents for secondary bacterial pneumonia Rotavirus Potable water supply, improve sanitation, education and behavior change,c improve socioeconomic status Oral rehydration therapy Salmonella typhi Potable water supply, improve sanitation, case finding for carriers, education and behavioral changec Antibacterial agents (some problems with resistance), oral rehydration therapy for gastroenteritis Shigella spp. Potable water supply, improve sanitation, education and behavioral changec Antibacterial agents (resistance is becoming a problem) Streptococcus Group A Treatment of cases, improve crowded living conditions Antibacterial agents Streptococcus pneumoniae Improve crowded living conditions, increase air circulation, vaccine (limited effectiveness in highest risk group, under 2 yrs) early antibacterial agent treatment for acute respiratory infections Antibacterial agents Vibrio cholera Potable water supply, improve sanitation, education and behavioral change,c vaccine (limited efficacy) Oral rehydration therapy Yellow fever virus Vector control,a personal protection,b vaccine (expensive) Supportive care aVector control includes insecticide and larvicide spraying, standing water control. bPersonal protection includes vector avoidance and screening of buildings. cEducation and behavioral change includes personal hygiene, prolonged breast feeding, hygienic food preparation.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE 8.3 Impact of Epidemic Disease on Health Care Services Pathogen Epidemic Potential Burden on Health Care Services Dengue virus High High patient burden in epidemics of dengue fever, high burden per patient in dengue hemorrhagic fever epidemic, may be disruptive to medical services E. coli (enterotoxigenic) Moderate to high, poor water and hygiene, disaster/mass migration settings High burden in terms of patients during epidemic H. influenzae type b Low Low (individual patients may be a burden in terms of resources required) Hepatitis A virus Low in populations of low socioeconomic status (all persons exposed in early childhood), moderate to high in higher socioeconomic populations, food borne outbreaks Low Hepatitis B virus Low in most settings, higher in disaster/mass migration settings (high risk populations: drug abusers, homosexual men, dialysis patients) Moderate (cases may be severe and may have chronic sequelae) Japanese encephalitis High High in terms of number of patients during virus epidemic, severe and chronic cases may be disruptive to medical services Mycobacterium leprae Low Low Neisseria meningitidis High (especially in “meningitis belt” in Africa) High Parainfluenza viruses Probably high Moderate Plasraodium spp. High in areas of seasonal transmission, low in holoendemic areas, disaster/mass migration situations; epidemic potential in situations where (now chemical, but potentially vaccine) prophylaxis might be interrupted or ceased High during epidemic Rabies virus Low Low Respiratory syncytial virus High Moderate to high Rotavirus High, disaster/mass migration situations, populations of low socioeconomic status High Salmonella typhi High, disaster/mass migration situations, mostly water borne High Shigella spp. High, low socioeconomic areas, endemic in tropical areas High Streptococcus Group A Pharyngitis: high; others: low, except under conditions of crowding Low Streptococcus pneumoniae Moderate Moderate Vibrio cholera High in areas where protected water supplies not available, disaster/mass migration situations High, may be disruptive to medical services Yellow fever virus High High

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries fertility reduction). That some population growth will result from infant and child mortality reduction highlights the need for integration of agricultural and health planning to avoid food shortages. The method of ranking in this report uses an aggregate or global perspective, but the actual benefits from new vaccines will not be distributed evenly among regions, countries, socioeconomic groups, ethnic groups, age groups, or other population subsets. The committee’s method can provide useful information about the distribution of potential benefits, but the committee recommends that relevant equity issues should be addressed in a broader political/public policy forum. The portfolio approach could help focus the decision-making process. The proposed system treats each vaccine development project independently, but some projects may have a wider impact. For example, a pertussis vaccine that caused fewer reactions might help increase public confidence in immunization programs in general and decrease failure to complete recommended schedules. Specific diseases may also interact synergistically in causing mortality. These interactions are difficult to quantify, but they should be considered by those setting vaccine priorities. Other nonquantifiable factors that might affect project rankings include the availability of alternative measures of disease control or treatment, the potential impact of epidemic disease on health care facilities, and the opportunity for complete eradication of a particular disease. In implementing the program of accelerated vaccine development, decision makers periodically should review activity in the private sector to identify projects for which public-private collaboration might expedite development, and to identify industry-scientific disincentives to the development of high-priority vaccines. Additional governmental funding for these vaccines (e.g., for clinical trials) might make them attractive to commercial manufacturers. In the ultimate selection of a portfolio of candidates for accelerated vaccine development, information obtained from the analysis described in Chapters 3, 7, and 9 must be integrated with the nonquantifiable considerations discussed here. REFERENCES Ashworth, A., and R.G.Feachem. 1985. Interventions for the control of diarrheal diseases among young children: Prevention of low birthweight. Bull. WHO 63:165–186. Bloom, B. 1985. Personal communication, Albert Einstein College of Medicine, Bronx, New York. Bongaarts, J., and J.Menken. 1983. The supply of children: A critical essay. Pp. 27–60 in Determinants of Fertility in Developing Countries, Vol. 1, R.A.Bulatao and R.D.Lee, eds. New York: Academic. Cochrane, S.H., and K.C.Zachariah. 1983. Infant and child mortality as determinants of fertility: The policy implications. World Bank Staff Working Papers, No. 556. Washington, D.C.

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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries de Zoysa, I., and R.G.Feachem. In press. Interventions for thecontrol of diarrhoeal diseases among young children: Chemoprophylaxis. Bull. WHO. Feachem, R.G. 1983. Interventions for the control of diarrhoeal diseases among young children: Supplementary feeding programmes. Bull. WHO 61:967–979. Feachem, R.G. 1984. Interventions for the control of diarrhoeal diseases among young children: Promotion of personal and domestic hygiene. Bull. WHO 62:467–476. Feachem, R.G., and M.A.Koblinsky. 1983. Interventions for the control of diarrhoeal diseases among young children: Measles immunization. Bull. WHO 61:641–652. Feacham, R.G., and M.A.Koblinsky. 1984. Interventions for the control of diarrhoeal diseases among young children: Promotion of breast feeding. Bull. WHO 62:271–291. Feachem, R.G., R.C.Hogan, and M.H.Merson. 1983. Diarrhoeal disease control: Reviews of potential interventions. Bull. WHO 61:637–640. Gwatkin, D. 1984. Mortality reduction, fertility, decline, and population growth: Towards a more relevant assessment of the relationship among them. World Bank Staff Working Papers, No. 686. Washington, D.C. Heer, D.M. 1983. Infant and child mortality and the demand for children. Pp. 369–387 in Determinants of Fertility in Developing Countries, Vol. 1, R.A.Bulatao and R.D.Lee, eds. New York: Academic. Institute of Medicine. 1985a. New Vaccine Development: Establishing Priorities, Volume I. Diseases of Importance in the United States. Washington, D.C.: National Academy Press. Institute of Medicine. 1985b. Vaccine Supply and Innovation. Washington, D.C.: National Academy Press. Peetermans, J., G.Colinet, and J.Stephenne. 1976. Activity of attenuated poliomyelitis and measles vaccines exposed at different temperatures. Pp. 61–66 in Proceedings of a Symposium on Stability and Effectiveness of Measles, Poliomyelitis, and Pertussis Vaccines. Zagreb, Yugoslavia: Yugoslav Academy of Sciences and Arts. Walsh, J.A., and K.S.Warren, eds. In press. Strategies for Primary Health Care: Technologies Appropriate for the Control of Diseases in the Developing World. Chicago: University of Chicago Press. Warren, K.S., and A.A.F.Mahmoud, eds. 1984. Tropical and Geographical Medicine. New York: McGraw-Hill.