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9
Findings, Conclusions, and Recommendations
This chapter presents the results obtained from the priority assessment system described in the preceding chapters. Potential health benefits and potential vaccine expenditures have been calculated for each of the 29 vaccine projects.* The committee suggests that the potential global health benefit of a vaccine takes precedence in determining its initial ranking for accelerated development priority. The “affordability” of benefits, represented by the potential expenditures on vaccines, can be entered into the decision process, if desired, and the techniques for doing so are illustrated with the central analysis. The first rankings presented reflect assumptions made in the central analysis, presented in Chapters 1 through 7 and reiterated below. To illustrate the use of other assumptions (all considered plausible by the committee), several sets of sensitivity analyses have been performed. These examine the effects on the rankings of various discount rates and of alternative assumptions about the probability of successful development. The effect on the rankings of adopting alternative assumptions on the disease burden derivations is also examined for selected vaccines. The effect of adopting perspectives on the undesirability of morbidity and death different from the median set of values used in the central analysis is discussed. In addition, approaches for incorporating differential utilization into the rankings are explained.
The rankings discussed below should be used as a guide to the selection of development priorities after consideration of the assumptions and issues outlined in Chapters 3 and 8. The committee believes that one of the major strengths of this analysis is that it encourages examination of all judgments and assumptions involved in the decision process. New data should be incorporated as they become available.
*
The analysis covers 29 vaccine projects directed against 19 diseases. In some cases, there may be more than one promising approach; also, various vaccine candidates for a particular disease may not have the same anticipated target population.
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This model was developed to assist the National Institute of Allergy and Infectious Diseases (NIAID) and the U.S. Agency for International Development (AID) in their decision making. The priorities identified by this model are not appropriate for all circumstances, but it is hoped that the model or some modification of it may be useful to other groups, both in the United States and elsewhere, that are faced with similar resource allocation problems.
The Central Analysis
The central analysis described below incorporates the following:
vaccine and development characteristics described in Chapter 5, including predictions on the target population, efficacy, and vaccine cost
estimates of the burden of each disease, derived as described in Appendixes B, C, and D-1 through D-19
the assumption that utilization rates would not differ among vaccine candidates (because delivery of vaccines would probably be through the World Health Organization Expanded Program on Immunization [WHO-EPI])
estimates of the number of new entrants to the respective target populations, as described in Appendixes D-1 through D-19 and summarized in Chapter 7, Table 7.1
times to licensure and adoption, delay of vaccination benefits presented in Chapter 7, Table 7.2
calculations of each vaccine candidate’s potential health benefits and associated expenditures as described in Chapters 4 and 7
a 5 percent discount rate for future health benefits and costs
a perspective, for illustrative purposes only, on the undesirability of various morbidity conditions and mortality, derived from the median values of responses from a range of health professionals in developing countries
independent consideration of each disease and the development of each vaccine candidate (for each target population)
expression of health benefits in units considered equivalent in undesirability to the death of an infant (i.e., infant mortality equivalents, see Chapter 4)
FINDINGS
The results of the central analysis (Chapter 7) are shown in Tables 9.1 and 9.2.
The range of potential benefits from the various vaccine candidates, viewed as present-day investment options, is considerable,
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spanning over two orders of magnitude, as does the range of potential expenditures.*
The expenditures listed in Tables 9.1 and 9.2 do not represent the net costs of using a vaccine (which may be a cost saving if averted treatment costs outweigh development and vaccination program costs). Hence, they cannot be used in formal cost-benefit or cost-effectiveness analyses. However, they can be used to illustrate how priority rankings may differ if financial resources (mostly needed in the countries of use) become a concern.
The ranking based on health benefits in Table 9.2 would be the initial priority assignment if resource constraints were not a concern. As financial constraints become a concern, the potential health benefit values can be adjusted to reflect the expenditures that might be considered feasible to gain a unit of benefit—in this analysis an infant mortality equivalence unit (IME). At each level of “willingness to pay,” this adjustment represents the health benefit (IME units prevented) that could be obtained by spending an amount of money equivalent to the expenditures on a particular vaccine in a different manner, for example, on another vaccine. This is termed the net opportunity cost of resources. Specifically,
Table 9.3 shows, for the various vaccine candidates, the annualized present values of potential health benefits adjusted for opportunity costs at various levels of willingness to pay per IME averted. Positive values reflect the relative size of benefits for vaccines that are “affordable” at that level of willingness to pay. Negative values apply to vaccines that are not affordable at that level of willingness to pay, that is, the cost of obtaining a unit of health benefit with that particular vaccine exceeds the resources or willingness to pay. It must be emphasized that the values in Table 9.3 reflect the use of expenditures as a measure of affordability rather than net costs, as discussed above. Expenditures on some vaccines may return net cost savings.
Rankings developed from these adjusted values reflect, for each level of willingness to pay, both the size of the potential benefit and its affordability. Table 9.4 shows the rankings of vaccine candidates at various levels of willingness to pay.
If desired, expenditures on vaccine development and use may be incorporated into the ranking process as a decision criterion
*
Expenditures represent vaccine development cost and vaccine cost (but not delivery, which is assumed uniform) for the vaccination program (see Chapter 4).
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TABLE 9.1 Health Benefits and Expenditures Associated with Various Vaccine Candidates: Central Analysis
Pathogen (Target Population)
Vaccine Envisaged
Annualized Present Value of Potential Health Benefits (IME Units)
Annualized Present Value of Expenditures on Vaccines Necessary to Achieve Potential Health Benefits ($ millions)
Dengue virus
(Infants and children in endemic areas; travelers to endemic areas)
Attenuated live vector virus containing gene for broadly cross-reacting protective antigen
9,558
242
Escherichia coli
(enterotoxigenic)
(Infants < 6 months)
A combination of purified colonization factor antigens and possibly other antigens
126,454
722
Genetically engineered attenuated strains
145,260
69
Hemophilus influenzae type b
(Infants)
Conjugated polysaccharide
210,943
527
Hepatitis A virus
(Susceptibles of all ages; routine for preschool children)
Attenuated live virus
15,112
1,058
Polypeptide recombinant vaccine produced in yeast
14,392
4,029
Hepatitis B virus
(Areas with high perinatal infection: all infants at birth (if possible). Other areas: all infants, simultaneous with other vaccinations)
Polypeptide produced by recombinant DNA technology
213,192
8,859
Japanese encephalitis virus
(Children in epidemic and and endemic areas; foreign visitors to epidemic regions)
Inactivated virus produced in cell culture
3,232
614
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Mycobacterium leprae
(Immuno-prophylactic: all children in endemic areas. Immuno-therapeutic: all recently infected individuals)
Armadillo-derived M. leprae
88,481
271
Neisseria meningitidis
(Infants, 3–6 months)
Conjugated capsular polysaccharides, groups A,C,Y, and W135
13,754
708
Parainfluenza viruses
(Infants)
Trivalent, subunit vaccine (which must contain fusion proteins)
43,692
1,697
Plasmodium spp.
(All infants at risk, military personnel, travelers)
Plasmodium falciparum, synthetic or recombinant sporozoite antigen preparation
475,205
967
Multivalent synthetic or recombinant sporozoite antigen preparation (P. falciparum, P. vivax, P. ovale, P. malariae)
426,640
857
Rabies virus
(Individuals at high risk, plus post-exposure prophylaxis) (As above)
Vero cell
41,910
147
Glycoprotein produced by rDNA technology in mammalian cells
37,983
139
(Birth cohort in areas of high risk)
Attenuated live vector virus containing gene for protective glycoprotein antigen
8,260
16
Respiratory syncytial virus
(Infants)
Polypeptides produced by recombinant DNA technology
52,412
1,964
Attenuated live virus
59,559
983
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Pathogen (Target Population)
Vaccine Envisaged
Annualized Present Value of Potential Health Benefits (IME Units)
Annualized Present Value of Expenditures on Vaccines Necessary to Achieve Potential Health Benefits ($ millions)
Rotavirue
(Infants, 0–6 months)
Attenuated high passage bovine rotavirus
521,852
853
Attenuated low passage bovine rotavirus
450,795
655
Rhesus monkey rotavirus
450,795
656
Salmonella typhi
(Children; young adults at risk; travelers from developed countries to endemic areas)
Attenuated ga1E mutant S. typhi strain TY21a
431,471
358
Aromatic amino acid dependent strains of S. typhi
194,745
152
Shigella spp.
(Infants at birth; elderly for epidemic strains)
Probably plasmid mediated outer membrane protein invasion determinant (there are a small number of promising options needing investigation to determine best approach)
222,096
92
Streptococcus A
(Children, < 3–4 years)
Synthetic M protein segment (excluding portions cross-reacting with human tissue)
180,513
554
Streptococcus pneumoniae
(Infants)
Conjugated polysaccharides, polyvalent
1,363,943
1,310
Vibrio cholera
(Children, especially < 2 years)
Genetically defined live mutant V. cholerae (A−B+ or A−B−) with respect to toxin subunit synthesis
94,986
24
Inactivated antigens
65,548
44
Yellow fever virus
(Young children)
Attenuated live virus produced in cell culture
11,127
93
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TABLE 9.2 Benefits and Affordability of Various Vaccine Candidates
Vaccine
Annualized Present Value of Potential Health Benefits (IME units)
Vaccine
Annualized Present Value of Potential Expenditures ($ millions)
S. pneumoniae
1,363,943
Rabies (live vector virus)
15.5
Rotavirus (HPBRV)
521,852
V. cholera (attenuated live)
23.8
Malaria (monovalent)
475,205
V. cholera (inactivated)
43.6
Rotavirus (LPBRV)
450,795
E. coli (attenuated live)
69.2
Rotavirus (RMRV)
450,795
Shigella
91.6
S. typhi (Ty21a)
431,471
Yellow fever
93.0
Malaria (multivalent)
426,640
Rabies (glycoprotein)
138.7
Shigella
222,096
Rabies (Vero cell derived)
146.8
Hepatitis B
213,192
S. typhi (aa-strain)
152.2
H. influenzae b
210,943
Dengue
241.8
S. typhi (aa-strain)
194,745
M. leprae
270.6
Streptococcus group A
180,513
S. typhi (Ty21a)
358.0
E. coli (attenuated live)
145,260
H. influenzae b
526.6
E. coli (purified antigens)
126,454
Streptococcus group A
554.2
V. cholera (attenuated live)
94,986
Japanese encephalitis
614.0
M. leprae
88,481
Rotavirus (LPBVR)
655.4
V. cholera (inactivated)
65,548
Rotavirus (RMRV)
655.9
RSV (attenuated live virus)
59,559
N. meningitidis
708.1
RSV (glycoprotein)
52,412
E. coli (purified antigens)
722.3
Parainfluenza viruses
43,692
Rotavirus (HPBRV)
852.7
Rabies (Vero cell derived)
41,910
Malaria (multivalent)
856.8
Rabies (glycoprotein)
37,983
Malaria (monovalent)
967.3
Hepatitis A (attenuated live virus)
15,112
RSV (attenuated live)
982.8
Hepatitis A (polypeptide)
14,392
Hepatitis A (attenuated live)
1,058.0
N. meningitidis
13,754
Streptococcus pneumoniae
1,310.3
Yellow fever virus
11,127
Parainfluenza
1,697.1
Dengue virus
9,558
RSV (glycoprotein)
1,964.4
Rabies (live vector virus)
8,260
Hepatitis A (polypeptide)
4,029.0
Japanese encephalitis virus
3,232
Hepatitis B
8,859.3
Health benefits are expressed in units equivalent in undesirability to the death of an infant (IMEs) and are calculated using the median of IME perspectives from responding health professionals in developing countries.
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TABLE 9.3 Some Relationships Between Expenditures and Health Benefitsa
Pathogen (Target Population)
Vaccine Envisaged
Annualized Present Value of Potential Health Benefits (IME Units)
Annualized Present Value of Expenditures on Vaccines Necessary to Achieve Potential Health Benefits (dollars)
Dengue virus
(Infants and children in endemic areas; travelers to endemic areas)
Attenuated live vector virus containing gene for broadly cross-reacting protective antigen
9,558
241,803,765
Escherichia coli
(enterotoxigenic)
(Infants < 6 months)
A combination of purified colonization factor antigens and possibly other antigens
126,454
722,284,852
Genetically engineered attenuated strains
145,260
69,171,586
Hemophilus influenzae type b
(Infants)
Conjugated polysaccharide
210,943
526,603,421
Hepatitis A virus
(Susceptibles of all ages; children)
Attenuated live virus
15,112
1,058,021,429
Polypeptide recombinant vaccine produced in yeast
14,392
4,028,950,683
Hepatitis B virus
(Areas with high perinatal infection: all infants at birth (if possible). Other areas: all infants, simultaneous with other vaccinations)
Polypeptide produced by recombinant DNA technology
213,192
8,859,258,746
Japanese encephalitis virus
(Children in epidemic and and endemic areas; foreign visitors to epidemic regions)
Inactivated virus produced in cell culture
3,232
613,959,820
Mycobacterium leprae
(Immuno-prophylactic: all children in endemic areas. Immuno-therapeutic: all recently infected individuals)
Armadillo-derived M. leprae
88,481
270,619,575
Neisseria meningitidis
(Infants, 3–6 months)
Conjugated capsular polysaccharides, groups A,C,Y, and W135
13,754
708,114,155
Parainfluenza viruses
(Infants)
Trivalent, subunit vaccine (which must contain fusion proteins)
43,692
1,697,123,972
Plasmodium spp.
(All infants at risk, military personnel, travelers)
Plasmodium falciparum, synthetic or recombinant sporozoite antigen preparation
475,205
967,271,590
Multivalent synthetic or recombinant sporozoite antigen preparation (P. falciparum, P. vivax, P. ovale, P. malariae)
426,640
856,843,460
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Expenditure per IME Prevented
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $100,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $10,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $1,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $500/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $100/IME
25,298
7,140
–14,622
–232,246
–474,049
–2,408,479
5,712
119,231
54,226
–595,831
–1,318,116
–7,096,394
476
144,568
138,343
76,088
6,917
–546,456
2,496
205,677
158,283
–315,660
–842,264
–5,055,091
70,014
4,531
–90,691
–1,042,910
–2,100,931
–10,565,103
279,946
–25,898
–388,503
–4,014,559
–8,043,509
–40,275,115
41,555
124,600
–672,734
–8,646,066
–17,505,325
–88,379,395
189,944
–2,907
–58,164
–610,727
–1,224,687
–6,136,366
3,058
85,775
61,419
–182,138
–452,758
–2,617,714
51,483
6,673
–57,057
–694,360
–1,402,474
–7,067,387
38,843
26,721
–126,020
–1,653,432
–3,350,556
–16,927,548
2,035
465,532
378,478
–492,066
–1,459,338
–9,197,511
2,008
418,072
340,956
–430,203
–1,287,047
–8,141,795
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Pathogen (Target Population)
Vaccine Envisaged
Annualized Present Value of Potential Health Benefits (IME Units)
Annualized Present Value of Expenditures on Vaccines Necessary to Achieve Potential Health Benefits (dollars)
Rabies virus
(Individuals at high risk, plus post-exposure prophylaxis) (As above)
Vero cell
41,910
146,811,503
Glycoprotein produced by rDNA technology in mammalian cells
37,983
138,655,304
(Birth cohort in areas of high risk)
Attenuated live vector virus containing gene for protective glycoprotein antigen
8,260
15,506,192
Respiratory syncytial virus
(Infants)
Polypeptides produced by recombinant DNA technology
52,412
1,964,436,106
Attenuated live virus
59,559
982,843,053
Rotavirus
(Infants, 0–6 months)
Attenuated high passage bovine rotavirus
521,852
852,737,494
Attenuated low passage bovine rotavirus
450,795
655,395,369
Rhesus monkey rotavirus
450,795
655,895,369
Salmonella typhi
(Children; young adults at risk; travelers from developed countries to endemic areas)
Attenuated ga1E mutant S. typhi strain TY21a
431,471
358,039,747
Aromatic amino acid dependent strains of S. typbi
194,745
152,153,450
Shigella spp.
(Infants at birth; elderly for epidemic strains)
Probably plasmid mediated outer membrane protein invasion determinant (a small number of promising options need to be investigated to determine best approach)
222,096
91,603,782
Streptococcus A
(Children, < 3–4 years)
Synthetic M protein segment (excluding portions cross-reacting with human tissue)
180,513
554,167,844
Streptococcus pneumoniae
(Infants)
Conjugated polysaccharides, polyvalent
1,363,943
1,310,290,738
Vibrio cholera
(Children, especially <2 years)
Genetically defined live mutant V. cholerae (A−B+ or A−B−) with respect to toxin subunit synthesis
94,986
23,788,751
Inactivated antigens
65,548
43,571,553
Yellow fever virus
(Young children)
Attenuated live virus produced in cell culture
11,127
93,049,382
aUnadjusted annualized present values of potential health benefits represent a situation where resource constraints are not a concern: no vaccine candidate is affordable if the willingness to pay per IME averted is $100 or less.
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Expenditure per IME Prevented
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $100,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $10,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $1,000/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $500/IME
Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Cost at $100/IME
3,503
40,442
27,229
−104,901
–251,713
–1,426,205
3,650
36,596
24,117
–100,673
–239,328
–1,348,570
1,877
8,105
6,709
–7,246
–22,752
–146,802
37,480
32,768
–144,031
–1,912,024
–3,876,460
–19,591,949
16,502
49,731
–38,725
–923,284
–1,906,127
–9,768,871
1,634
513,325
436,578
–330,885
–1,183,623
–8,005,523
1,454
444,242
385,256
–204,600
–859,995
–6,103,158
1,455
444,237
385,206
–205,100
–860,995
–6,108,158
830
427,891
395,667
73,431
–284,608
–3,148,926
781
193,224
179,530
42,592
–109,562
–1,326,789
412
221,180
212,936
130,492
38,889
–693,942
3,070
174,971
125,096
–373,655
–927,823
–5,361,165
961
1,350,840
1,232,914
53,652
–1,256,638
–11,738,964
250
94,748
92,607
71,197
47,408
–142,902
665
65,112
61,191
21,976
–21,595
–370,168
8,362
10,197
1,822
–81,922
–174,971
–919,366
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TABLE 9.4 The Effect of Resource Constraints on the Ranking of Various Vaccine Candidates
Rank Based on Annualized Present Value of Potential Health Benefits Adjusted for Opportunity Costsa
Willingness to Pay (dollars) per IME Averted
Vaccine
Unrestricted
100,000
10,000
1,000
500
S. pneumoniae
1
1
1
5
–b
Rotavirus (HPBRV)
2
2
2
–
–
Malaria (monovalent)
3
3
6
–
–
Rotavirus (LPBRV)
4
4
4
–
–
Rotavirus (RMRV)
5
5
5
–
–
S. typhi (Ty21a)
6
6
3
3
–
Malaria (multivalent)
7
7
7
–
–
Shigella
8
8
8
1
2
Hepatitis B
9
13
–
–
–
H. influenzae b
10
9
10
–
–
S. typhi (aa-strain)
11
10
9
6
–
Streptococcus group A
12
11
12
–
–
E. coli (attenuated live)
13
12
11
2
3
E. coli (purified antigens)
14
14
16
–
–
V. cholera (attenuated live)
15
15
13
4
1
M. leprae
16
16
14
–
–
V. cholera (inactivated)
17
17
15
7
–
RSV (attenuated live virus)
18
18
–
–
–
RSV (glycoprotein)
19
21
–
–
–
Parainfluenza viruses
20
22
–
–
–
Rabies (Vero cell derived)
21
19
17
–
–
Rabies (glycoprotein)
22
20
18
–
–
Hepatitis A (attenuated live virus)
23
27
–
–
–
Hepatitis A (polypeptide)
24
–
–
–
–
N. meningitidis
25
26
–
–
–
Yellow fever virus
26
23
20
–
–
Dengue virus
27
25
–
–
–
Rabies (live vector virus)
28
24
19
–
–
Japanese encephalitis virus
29
–
–
–
–
aRankings are based on values shown in Table 9.3.
b– denotes not affordable at indicated willingness to pay.
equivalent to potential health benefits. In this case the principle of dominance applies: vaccines yielding greater potential benefits and lower expenditures are preferred. Procedures are discussed in Chapter 3. However, because the expenditures do not reflect overall net costs, the committee believes that initial rankings of candidates should be based on their potential health benefits.
Disease Burden Assumptions
A major factor in determining the ultimate ranking of a vaccine candidate is the total disease burden value (TDBV) used as the starting point in the calculations of potential benefit. The central analysis rankings reflect the committee’s best efforts, within its resources and the reliability and quantity of available data, to generate disease
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burden estimates. Some of the estimates rest on uncertain assumptions or extrapolations from limited data. Some specific examples may help demonstrate how the overall method differentiates between vaccine candidates even when the starting points are somewhat uncertain.
For the top-ranked vaccine candidate, S. pneumoniae, the total disease burden in the central analysis represents a set of assumptions, including some use of antibiotics (see Appendix D-17). A “preantibiotic” TDBV twice that used in the central analysis could have been used in calculations, but would have merely served to further separate S. pneumoniae vaccine from the runners-up. Using a different starting point for the derivation of the disease burden estimates (see Appendixes B and D-17)* yields a somewhat lower estimate of pneumococcal pneumonia, the major contributor to the S. pneumoniae disease burden. Ignoring bacteremia and otitis media, the approach in Appendix B yields estimates for the under 15 years age group that results in a disease burden value of 1,921,300 (versus 6,612,261 in the central analysis which derives from the estimates developed in Appendix D-17). Because the lower value represents the partial disease burden for the under 15 years age group, it is assumed that all of the disease is potentially preventable (i.e., VPI=1.0; see Appendix D-17). Using the lower DBV of 1,921,300 as the starting point in the analysis results in a value for the annualized present value of potential health benefits (APVPHB) of 713,367. This value still results in the candidate S. pneumoniae vaccine having highest priority. The effect of adopting alternative assumptions on the probability of success for this candidate is discussed below.
For certain diarrheal pathogens it can be argued that by the time the new vaccines are available, the disease burden will have been significantly reduced by the adoption of oral rehydration therapy (ORT), which averts dehydration deaths. For those pathogens where this scenario was plausible (E. coli and rotavirus), TDBVs were calculated from disease burden estimates which assumed that by the time of vaccine availability, ORT had reduced deaths by 50 percent. The effect of adopting these TDBVs in the analysis was examined. Even with the assumption that the disease amenable to reduction by these vaccines is reduced substantially (by about 50 percent), the degree of spacing between the other candidates resulted in these vaccines shifting only slightly in the rankings. The three rotavirus candidates dropped in the central analysis from positions 2, 4, and 5 to positions 5, 6, and 7 (total candidates = 29). The two E. coli candidates dropped from positions 13 and 14 to positions 15 and 16.
*
The approach in Appendix B starts from reports on overall acute respiratory infections in developing countries; these reports probably underestimate the actual incidence of disease. The approach in Appendix D-17 starts from the assumption that pneumococcal pneumonia incidence in developing countries is likely to be similar to that in developed countries in the 1920s; such rates are reasonably well documented.
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Individuals wishing to evaluate the effect on the ultimate rankings of adopting different assumptions on the magnitude of the disease burden can do so in crude fashion by adjusting the final APVPHB in accordance with their beliefs. For example, if they believe that the overall disease incidence is twice that used in the central analysis (but that rates for complications, sequelae, case-fatality rates, etc., are reasonable) the central analysis APVPHB value should be doubled. The rank of the new APVPHB value can then be determined. More complex disagreements with disease burden determination (e.g., favoring a different frequency of complications) requires recalculation of the disease burden estimates and the TDBV.
Target Population and Assumptions on Vaccine Preventable Illness
The bases for the various disease burden proportions that are judged to be vaccine preventable are described in Appendixes D-1 through D-19. The effect of alternative assumptions can easily be examined by substituting a new value in the calculation process shown in Table 7.4. Assumptions different from those in the central analysis may alter the ranking of vaccines. For example, 50 percent of the disease burden for hepatitis B vaccine is estimated to be preventable by delivering the vaccine at the usual WHO-EPI scheduled times. If vaccines were delivered universally at birth, some higher proportion would be preventable and the potential benefits would be raised proportionally.
The targeted population may markedly affect the potential expenditures. For example, delivery of the N. meningitidis vaccine to the entire birth cohort in the developing world (115.1 million births) would cost about $708 million. Focusing vaccine delivery on births in the African meningitis belt (13.1 million births) would reduce the cost by about 90 percent to $82 million. (Because this strategy would not protect against endemic or rare epidemic disease in other parts of the world, potential health benefits would also be less; see Appendix D-8).
Similarly, immunotherapeutic use of a vaccine for M. leprae—to curtail progressive disease in all recognized new cases—would cost $10.3 million as contrasted to immunoprophylactic use in the birth cohort at risk, which would cost $270 million. These strategies are, however, significantly different, and this commentary does not suggest that immunotherapy would be more “cost-effective.” To be useful, such a strategy would require substantially increased efforts at early case detection.
Discount Rate
The committee believes that incorporating a discounting procedure for future health benefits and expenditures is justified because it reflects the preference for benefits achieved sooner rather than later (a basic concept in the establishment of a program of accelerated vaccine development). The effect of placing more or less weight on
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achieving early benefits was examined by selecting discount rates higher (0.10) and lower (0.02) than in the central analysis. Results from analyses using these discount rates are compared to results from the central analysis in Tables 9.5 and 9.6.
In general, using discount rates of 10 percent or 2 percent would not substantially affect the structure of the ranking, although some vaccines are shifted slightly in position. Notable among these is hepatitis B, which drops from position 9 on health benefits to position 15 if a 10 percent discount rate is adopted. Although the development of this second generation vaccine is relatively advanced, it drops in position when a high discount rate is adopted (i.e., one that favors shorter term realization of benefits) because the delay of vaccination benefits for hepatitis B immunization is long.
Alternative Development Scenario: Probability of Success
The central analysis uses the probability of successful development indicated for each vaccine in Chapter 5. The effect of adopting a more optimistic but not unreasonable view was examined by assuming a 100 percent chance of successful development within a time period for likely time to licensure. Tables 9.7 and 9.8 show the results. Such an assumption would not substantially affect the overall rankings, but some vaccines shift slightly in position. Some vaccines with lower probabilities of success (e.g., malaria at 0.5) rise in the rankings relative to those whose probability of success was already closer to 1.0. The spacing of benefit values is such that, for certain vaccines (e.g., M. leprae) with a lower probability of success, the more optimistic assumption (p=1.0) raises the potential benefit value but does not change the ranking.
The committee performed another sensitivity analysis, by way of example, to show the effects of lowering the probability of successful development for a single, highly ranked, vaccine—S. pneumoniae (Table9.9). The original estimate, shown in Tables 9.1 and 9.2, was 80 percent. Elimination of this vaccine from the top half of the ranking on potential health benefits (Table 9.2) required assuming a probability of success less than 5 percent. Assuming a probability of success less than about 12 percent is required to eliminate it from the top five positions.
Assessing the Effect of Differential Utilization
Table 9.2 shows annualized present values of potential health benefits (APVPHBs) unadjusted for utilization because the committee assumed this factor would not differ among vaccines. If future applications of this or similar systems (e.g., for specific countries) must account for differential utilization, then the appropriate values for the annualized present values of expected health benefits can be obtained simply by multiplying the APVPHBs by the appropriate value for that proportion of the target population expected to receive the vaccine.
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TABLE 9.5 Sensitivity Analysis: Effect of Discount Rate on Annualized Present Value of Potential Health Benefits for Various Vaccine Candidates
Discount Rate
Central Analysis, 0.05
0.02
0.10
Vaccine
Rank
Value (IME Units)
Rank
Value (IME Units)
Rank
Value (IME Units)
S. pneumoniae
1
1,363,943
1
1,770,510
1
897,358
Rotavirus (HPBRV)
2
521,852
5
603,244
2
413,552
Malaria (monovalent)
3
475,205
3
663,218
5
278,319
Rotavirus (LPBRV)
4
450,795
6
568,450
3
310,708
Rotavirus (RMRV)
4
450,795
6
568,450
4
310,708
S. typhi (Ty21a)
6
431,471
2
686,085
7
204,973
Malaria (multivalent)
7
426,640
4
640,191
6
222,440
Shigella
8
222,096
10
323,742
9
121,310
Hepatitis B
9
213,192
8
554,897
15
45,926
H. influenzae b
10
210,943
12
281,875
8
132,474
S. typhi (aa-strain)
11
194,745
9
363,189
12
71,630
Streptococcus group A
12
180,513
11
317,684
11
72,869
E. coli (attenuated live)
13
145,260
13
211,741
10
79,342
E. coli (purified antigens)
14
126,454
14
184,238
13
69,070
V. cholera (attenuated live)
15
94,986
16
126,925
14
59,652
M. leprae
16
88,481
17
162,639
19
33,310
V. cholera (inactivated)
17
65,548
17
82,656
16
45,179
RSV (attenuated live virus)
18
59,559
18
75,104
17
41,051
RSV (glycoprotein)
19
52,412
19
66,092
18
36,125
Parainfluenza viruses
20
43,692
20
60,101
22
26,192
Rabies (Vero cell derived)
21
41,910
21
52,088
20
29,566
Rabies (glycoprotein)
22
37,983
22
47,207
21
26,795
Hepatitis A (attenuated live virus)
23
15,112
23
20,787
23
9,059
Hepatitis A (polypeptide)
24
14,392
24
20,379
24
8,235
N. meningitidis
25
13,754
25
20,049
25
7,513
Yellow fever virus
26
11,127
26
19,301
26
4,598
Dengue virus
27
9,558
27
15,646
27
4,334
Rabies (live vector virus)
28
8,260
28
5,630
28
2,969
Japanese encephalitis virus
29
3,232
29
5,215
29
1,500
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TABLE 9.6 Sensitivity Analysis: Effect of Discount Rate on Annualized Present Value of Expenditures to Achieve the Benefits of Various Vaccine Candidates
Discount Rate
Central Analysis, 0.05
0.02
0.10
Vaccine
Rank
Expenditure ($ million)
Rank
Expenditure ($ million)
Rank
Expenditure ($ million)
Rabies (live vector virus)
1
16
1
21
1
10
V. cholera (attenuated live)
2
24
2
29
2
18
V. cholera (inactivated)
3
44
3
51
3
34
E. coli (attenuated live)
4
69
4
96
4
42
Shigella
5
92
6
128
5
55
Yellow fever
6
93
5
107
6
75
Rabies (glycoprotein)
7
139
7
182
8
112
Rabies (Vero cell derived)
8
147
8
193
9
119
S. typhi (aa-strain)
9
152
9
195
7
103
Dengue
10
242
10
341
11
140
M. leprae
11
271
12
417
10
137
S. typhi (Ty21a)
12
358
11
390
12
312
H. influenzae b
13
527
13
663
14
364
Streptococcus group A
14
554
14
749
13
344
Japanese encephalitis
15
614
17
806
15
398
Rotavirus (LPBVR)
16
655
15
802
18
475
Rotavirus (RMRV)
17
656
16
802
19
476
N. meningitidis
18
708
18
945
17
447
E. coli (purified antigens)
19
722
20
1,021
16
415
Rotavirus (HPBRV)
20
853
19
957
23
709
Malaria (multivalent)
21
857
21
1,177
20
516
Malaria (monovalent)
22
967
23
1,236
21
653
RSV (attenuated live)
23
983
22
1,203
24
711
Hepatitis A (attenuated live)
24
1,058
24
1,373
22
697
Streptococcus pneumoniae
25
1,310
25
1,604
25
948
Parainfluenza
26
1,697
26
2,267
26
1,068
RSV (glycoprotein)
27
1,964
27
2,405
27
1,420
Hepatitis A (polypeptide)
28
4,029
28
5,383
28
2,542
Hepatitis B
29
8,859
29
9,664
29
7,700
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TABLE 9.7 Sensitivity Analysis: Effect of an Alternative Development Scenario on Potential Health Benefits
Predicted Probability of Successful Development (Central Analysis)
100% Probability of Successful Development
Vaccine
Rank
Value (IME Units)
Rank
Value (IME Units)
S. pneumoniae
1
1,363,943
1
1,704,929
Rotavirus (HPBRV)
2
521,852
4
579,836
Malaria (monovalent)
3
475,205
2
950,410
Rotavirus (LPBRV)
4
450,795
5
563,494
Rotavirus (RMRV)
4
450,795
5
563,494
S. typhi (Ty21a)
6
431,471
7
479,412
Malaria (multivalent)
7
426,640
3
853,280
Shigella
8
222,096
9
317,280
Hepatitis B
9
213,192
13
215,346
H. influenzae b
10
210,943
11
234,381
S. typhi (aa-strain)
11
194,745
8
317,491
Streptococcus group A
12
180,513
12
225,641
E. coli (attenuated live)
13
145,260
14
207,514
E. coli (purified antigens)
14
126,454
10
252,908
V. cholera (attenuated live)
15
94,986
16
126,647
M. leprae
16
88,481
15
176,963
V. cholera (inactivated)
17
65,548
17
100,843
RSV (attenuated live virus)
18
59,559
18
74,449
RSV (glycoprotein)
19
52,412
19
65,515
Parainfluenza viruses
20
43,692
20
54,615
Rabies (Vero cell derived)
21
41,910
21
46,567
Rabies (glycoprotein)
22
37,983
22
44,686
Hepatitis A (attenuated live virus)
23
15,112
25
15,907
Hepatitis A (polypeptide)
24
14,392
26
15,149
N. meningitidis
25
13,754
23
27,509
Yellow fever virus
26
11,127
28
11,713
Dengue virus
27
9,558
27
12,744
Rabies (live vector virus)
28
8,260
24
16,520
Japanese encephalitis virus
29
3,232
29
6,465
CONCLUSIONS
Final decisions on the number of vaccines and the particular vaccines selected for accelerated development must incorporate various nonquantifiable factors, as well as information provided by the rankings that were derived with the proposed system for calculating benefits and expenditures. The additional factors include:
goals of the responsible agency and its schedule for achieving them
ethical questions on the distribution of benefits among socioeconomic or age groups, countries, or regions
most appropriate points in the development process at which the agency can exert influence and the opportunity and need for such influence
extent of private sector activities
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TABLE 9.8 Sensitivity Analysis: Effect of an Alternative Development Scenario on Potential Expenditures
Predicted Probability of Successful Development (Central Analysis)
100% Probability of Successful Development
Vaccine
Rank
Expenditures ($ millions)
Rank
Expenditures ($ millions)
Rabies (live vector virus)
1
15.5
1
30.3
V. cholera (attenuated live)
2
23.8
2
31.3
V. cholera (inactivated)
3
43.6
3
66.8
E. coli (attenuated live)
4
69.2
5
98.0
Shigella
5
91.6
6
130.1
Yellow fever
6
93.0
4
97.9
Rabies (glycoprotein)
7
138.7
7
177.4
Rabies (Vero cell derived)
8
146.8
8
177.5
S. typhi (aa-strain)
9
152.2
9
304.2
Dengue
10
241.8
10
322.0
M. leprae
11
270.6
12
549.0
S. typhi (Ty21a)
12
358.0
11
397.8
H. influenzae b
13
526.6
13
585.0
Streptococcus group A
14
554.2
14
692.1
Japanese encephalitis
15
614.0
19
1,225.4
Rotavirus (LPBRV)
16
655.4
15
819.0
Rotavirus (RMRV)
17
655.9
16
819.5
N. meningitidis
18
708.1
21
1,414.7
E. coli (purified antigens)
19
722.3
22
1,443.3
Rotavirus (HPBRV)
20
852.7
17
947.4
Malaria (multivalent)
21
856.8
24
1,711.9
Malaria (monovalent)
22
967.3
25
1,933.3
RSV (attenuated live)
23
982.8
20
1,228.2
Hepatitis A (attenuated live)
24
1,058.0
18
1,113.7
Streptococcus pneumoniae
25
1,310.3
23
1,637.5
Parainfluenza
26
1,697.1
26
2,121.1
RSV (glycoprotein)
27
1,964.4
27
2,455.2
Hepatitis A (polypeptide)
28
4,029.0
28
4,240.9
Hepatitis B
29
8,859.3
29
8,948.7
opportunities to accelerate vaccine development through collaboration with other countries or international organizations
the desired balance of the development portfolio (e.g., pediatric versus adult vaccines, global versus regional diseases)
arguments for treating certain vaccine development projects as unique because of their potential for facilitating immunization programs in general (e.g., by eliminating constraints on delivery, such as poor stability) or by improving public confidence (e.g., by reducing adverse reactions)
the prospect that a particular project may serve as a useful model for a number of other desired vaccines
disease related factors, such as epidemiologic and clinical characteristics likely to overwhelm medical services, and the availability of alternative control strategies or safe and effective therapy
possible synergistic interaction with other diseases
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TABLE 9.9 Effect of Varying Probability of Success on the Health Benefits of S.pneumoniae Vaccine: Central Analysis
Probability of Success
Annualized Present Value of Potential Health Benefits (IME units)
1.0
1,704,929
0.9
1,534,236
0.8a
1,363,943
0.7
1,193,450
0.6
1,022,957
0.5
852,464
0.4
681,972
0.3
511,479
0.2
340,986
0.1
170,493
0.0
0
aProbability of success used in central analysis.
the immediate U.S. interest in diseases that may be imported into the United States, that threaten travelers or personnel stationed overseas, or that are existing problems in the United States
the affordability of the potential health benefit, if not already used formally in the decision process
These factors are discussed in more detail in Chapter 8 and elsewhere in the report.
The analyses presented in this chapter indicate that of the 29 projects considered, vaccines for S. pneumoniae, Plasmodium spp. (malaria; both monovalent and multivalent circumsporozoite protein based versions), rotavirus (all three candidates), S. typhi (Ty21a), and shigella consistently rank in the top 10 positions in priority lists based on potential health benefits, under a wide range of assumptions and resource availability.
Vaccines for hepatitis B and H. influenzae type b rank in the top 10 in the central analysis but are dislodged under certain assumptions. Vaccines for E. coli (either candidate) or the alternative candidate for S. typhi (an aromatic amino acid requiring stain) move into the top
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10 under certain assumptions: as willingness to pay drops to $1,000 or below per IME prevented, the ranking changes more significantly, as shown in Table 9.4, with vaccines for certain diarrheal diseases rising in the rankings.
A fairly consistent middle-tier of vaccines occurs in the ranking under a variety of assumptions. In addition to those candidates that will contend for higher ranking under certain assumptions, this middletier includes vaccines for Streptococcus group A, M. leprae, V. cholerae, respiratory syncytial virus, parainfluenza viruses, and rabies (Vero cell derived or glycoprotein).
Most of the vaccines that consistently rank low would prevent diseases that are often serious, but mostly restricted to relatively small regions of the developing world. In such areas they may have more benefit than the widespread diseases that rank higher when the developing world is considered as a whole.
Additional sensitivity analyses, discussed below, can be performed to identify elements that may alter decisions.
DISCUSSION
Scientific opinion differs on some of the judgments incorporated into the proposed method, and uncertainty surrounds some of the data. The system has been applied by using the best estimates and most reliable data the committee could obtain, given its resources. The attempt to be explicit about certain estimates should not be interpreted as indicating that precise, unanimous, or certain comparisons are possible with existing methods or data, when the lack of data makes expert judgment necessary. The implications of these information gaps and differences of opinion about estimates are discussed more fully in Chapter 1. In this light, the committee suggests additional analyses and research to provide further information on the key elements that may alter decisions.
Ideally, to fully assess the effect of alternative IME profiles on the rankings, calculations should be conducted using the whole range of individual sets of IME values. However, because of resource and time constraints, this was not possible in the present study. The perspective adopted to illustrate application of the system was the median set of values from responses of health professionals in developing countries. A median set of values derived from U.S. respondents differed somewhat from the perspective used (see Chapter 4, Tables 4.7 and 4.8).
It is also possible to develop hypothetical age-neutral perspectives as was done for the committee’s first report (Institute of Medicine, 1985). The committee, however, does not endorse either set of median values or the age-neutral perspective for policy formulation. The effect of adopting various IME values is discussed in Chapter 4.
Selecting or constructing a small number of profiles that have distinct differences from the committee median or the age-neutral set would be a practicable way to further examine how various opinions on the undesirability of disease conditions might affect vaccine rankings. For example, IME profiles could be developed that show more or less
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aversion to chronic or acute morbidity than the median set and a constructed age-neutral profile (i.e., for each morbidity category, calculate the geometric mean of median IME values across different age groups). The results of the ranking process with these profiles would then identify the extent to which differences of opinion regarding chronic or acute morbidity could alter rankings. (For a range of 14 important diseases in the United States, adopting a hypothetical age-neutral IME perspective, rather than the committee median that disfavored death and morbidity most in the 15–24 years age group, did not significantly alter the ultimate rankings [Institute of Medicine, 1985]).
Other sensitivity studies around the central analysis are also possible. These include the effect on the rankings of various predictions about the number of vaccine doses needed (which would affect expenditures on vaccines) or various predictions about individual vaccines (e.g., the probability of successful development of a vaccine).
The impact on rankings of using alternative assumptions for choosing the target population for some vaccines could also be tested, it would entail, however, more extensive recalculations, including reestimation of the disease proportion that is vaccine preventable.
RECOMMENDATIONS
The committee believes that a major strength of this analysis is that it encourages those using it to examine all judgments and assumptions about the selected vaccine preventable diseases. The committee recommends use of the proposed system by government decision makers. New candidates should be assessed as they become technically feasible and new data should be incorporated as they become available.
Data for disease comparisons are lacking in some areas and are of variable reliability in others. Further, data on the pathogen serotypes prevalent in particular regions may also be lacking.
Better data bases in these areas would facilitate making rational choices on vaccine development priorities and vaccine formulation. Therefore, NIAID and other national and international organizations should consider means to improve available epidemiological data on infectious diseases.
REFERENCE
Institute of Medicine. 1985. New Vaccine Development: Establishing Priorities, Volume I. Diseases of Importance in the United States. Washington, D.C.: National Academy Press.
Representative terms from entire chapter:
health benefits
