Benefits and costs of vaccination P. Dejonghe and B. Parkinson Vaccination programmes supported by the WHO and other organizations have dramatically reduced disease in developin9 countries, but there remains a need to extend coverage rates and expand the number o f vaccines included. In industrialized countries, where paediatric vaccination is almost universal, there will be an increasing opportunity to protect against diseases which occur in later years. Keywords:Vaccination; costs; benefits; EPI
INTRODUCTION Twenty years ago, nearly five million children died annually from measles, tetanus, whooping cough, diphtheria, tuberculosis or polio. Millions more were permanently disabled. In 1974, the World Health Organization launched the Expanded Programme on Immunization (EPI). By mid-1991, 80% or more of the world's children were being vaccinated against these diseases 1. It is estimated that the EPI is preventing some 3.2 million deaths each year from measles, pertussis and neonatal tetanus, and 440 000 cases of polio. Nevertheless, annual!y, there remain 1.7 million deaths from these same diseases, and 120 000 cases of polio 2. The human benefits of the reduction of infant mortality and morbidity are not disputed, and funds have been made available to support the vaccination programmes. In the case of the EPI, the vaccine component costs are probably around $150 million p.a., or $50 per life saved 3. However, vaccines are only a small part of the total cost of immunization (typically less than 10% ), and there has been a need to examine that they are being administered in the most cost-effective way. One such study was undertaken in Thailand in 1987, and showed that the cost per fully vaccinated child varied from $5.30 to $33.20. It was found that there was little difference between hospitals and health centres, and relatively little between fixed and outreach services. The main determinant was the vaccination session frequency, with the highest costs being incurred in health centres which had the most frequent sessions. There did not appear to be any correlation between session frequency and coverage. It was concluded that the best way to reduce costs would be to make better use of staff time by decreasing the frequency of the services offered4. Another study carried out in Ecuador in 1986 compared the costs using routine services based in fixed facilities with mass immunization campaigns. The costs per fully vaccinated child were $4.39 for the former and $8.60 for the latter. More importantly, however, the study SmithKline Beecham Biologicals, Rixensart 1330, Belgium
Rue de I'lnstitut 89,
0 ~ 10)(/92/13093£~04 © 1992 Butterworth-Heinemann Ltd
936
Vaccine, Vol. 10, Issue 13, 1992
illustrated that the necessary high coverage rates can only be achieved by use of special campaigns 5. The proportion of children vaccinated against D T P , by age, is shown in
Figure 1. VACCINATION COUNTRIES
IN INDUSTRIALIZED
In industrialized countries, a number of cost-benefit analyses on vaccines have been reported, and some of these are briefly reviewed below.
Poliomyelitis In the USA in 1952 over 20000 cases of polio were reported. Inactivated poliovirus vaccine (IPV) was introduced in 1955 and led to a dramatic decline in the incidence. Live attenuated (oral) polio vaccine (OPV) followed in 1961, and quickly replaced IPV, both in the USA and many other countries. A cost-benefit analysis yielded a return of 7 - 1 4 % . Another study in the former West German Republic indicated that for every DM spent on vaccination between 1962 and 1971, 90 DM were saved on treatment, care and rehabilitation costs 6. The success in polio elimination has led to the dilemma of which type of polio vaccine is preferable. The last case of indigenously acquired wild poliovirus disease in the USA was in 1979. However, an average of eight cases per year continue to be reported in association with the administration of OPV. Where there continues to be a risk of the introduction of wild polio virus (e.g. by immigration) OPV is preferable, but when such risk is eliminated then IPV would be safer (albeit more expensive).
Pertussis The issue of vaccine safety versus efficacy has been of even greater importance with pertussis, where there is a risk of encephalopathy and other less severe reactions. A benefit-cost analysis carried out in 1984 concluded that there were substantial excess benefits over costs (11:1). As the result of increasing attention from the media in the USA, and increasing lawsuits, manufacturers were forced to increase prices to cover spiralling
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson
Hepatitis B
I00
o~O
80
Campaigns
"o (~
~
ao
u
g
40
Routine
L X3 ~:
20
0
1
2
3
4
Age (completed years)
Figure 1
DTP coverage rates in Ecuador. (Source: Bulletin of the WHO,
1989)
Table 1
Immunization with MMR: results over 25 years in France Cases avoided
Complications
Sequelae
Deaths
Measles
9 million
2000 encephalitis
900
500
Mumps
8 million
25000 meningitis 1680 encephalitis
Rubella
Not calculated
500-3000
A plasma-derived vaccine against hepatitis B was introduced in the early 1980s, and because of its limited availability and relatively high price ($100 per course), there was an interest in using cost-effectiveness analysis to evaluate alternative vaccination strategies for populations at different risks of exposure to the virus. One such study considered a model whereby the population at risk were divided into three groups vaccinate all; screen for prior immunity and vaccinate only those who are susceptible; no vaccination but use of hepatitis B immune globulin after known exposure 8. Table 2 shows the results obtained. In this analysis only direct medical costs were considered, and the indirect costs of lost productivity were not. For populations with a high prevalence of prior exposure and a high annual attack rate (e.g. homosexuals), screening and vaccination of susceptibles was the best strategy. For populations with low prevalence and high annual attack rates (such as hospital health care workers), vaccination without screening was the least costly option. For populations with low prevalence and low annual attack rates (e.g. the general population of USA or most of Western Europe), neither screening nor universal vaccination were advocated. It is now nearly 10 years since these results were published, and certain of the assumptions need amendment (notably the price of the vaccine, which has fallen ). It is, perhaps, of no surprise that when implementing hepatitis B vaccination programmes in industrialized
Source: WHO Weekly Epidemiological Record, 1992
insurance costs. A reanalysis in 1985, which took $2.68 per dose of DTP (cf. 11 cents in 1984), and worst-case estimates of encephalopathy risk, gave a benefit:cost ratio of 1.1:1. Subsequently a federal levy has been imposed to establish a compensation fund, pushing prices to a level where vaccination is no longer cost-saving, although it still confers considerable excess health benefits 6.
Measles, mumps, rubella In industrialized countries, infants are also usually vaccinated against measles, mumps and rubella. A study was published in 1988 on the effects of using this triple vaccine in France 7. The estimated number of cases, complications, sequelae and deaths avoided over a 25 year period are given in Table 1. Measles and mumps both pose significant public health problems. Rubella is a more benign disease, except for the sequelae of congenital rubella. A range is given for the latter, since epidemics tend to occur irregularly. There is also a need to vaccinate the backlog of adolescent girls, which should bring the number of cases avoided close to the higher figure. The estimated cumulative net benefit is shown in Figure 2. Initially the total costs (cost of the diseases borne by the community, plus the vaccination costs) increase, but after 6 years they begin to fall, and after 17 years the investment in immunization will have been recovered. These results, which exclude vaccinating the backlog (which would give additional benefits), yield a return of 4.5% p.a.
Table 2 Medical care costs of strategies for vaccinating three representative populations Net medical care costs per person
Homosexuals
Surgical interns
General population
Prevalence of exposure Annual attack rate
High High
Low High
Low Low
No vaccination Vaccinate all Screen/vaccinate
$97 $105 $66
$106 $104 $114
$2 $100 $115
Source: Reference 8
"-~ o
±
1500 1000 500
% o -500 _i000~ u -1500 z
I
I
I
I
I
I
I
I
I
I
I
I
2
4
6
8
10
12
lq
16
18
20
22
24
N u m b e r of years
Figure 2 years
Benefit of MMR immunization in France projected over 25
Vaccine, Vol. 10, Issue 13, 1992
937
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson 300 ~7
250 tn
200
/
"0
150
E
/ /,/ ,/ / / / / ,/ ,/ / ,/ / /
100 50 0
J/
HH
¢ 1976
1978
1980
1982
1986
198q
Year Figure 3 HBV cases compensated by FOD 1975-1986, showing actual (~1) versus projected ( V ) figures. (Taken from Ref. 9)
Table 3 Belgian FOD 1981-1986
hepatitis vaccination costs and savings
FB million Vaccine costs
160
Savings: T e m p o r a r y w o r k incapacity Permanent impairment Death pensions
173 26 2
Total savings
41
countries, hospital health care workers were the first risk group to be addressed. In Belgium, hepatitis has been recognized since 1969 as an occupational disease for staff involved in nursing, care of the disabled, preventive medicine and laboratory activities, and for which compensation is paid by the insurance Fund for Occupational Disease (FOD). The number of such cases increased rapidly in the 1970s, and in 1981 vaccination against hepatitis B started experimentally. In 1983 the F O D was authorized to pay for hepatitis B vaccination, and this was the first time that professional risk insurance was allowed to invest directly in preventive action rather than in compensation for damage. The F O D agreed to reimburse vaccination for staff, including students, working in a number of hospital departments, and in other fields where there was risk. Figure 3 shows the number of HBV cases that were compensated during the period 1975-1986, together with the number that would have been expected without vaccination. The latter were established by extrapolation of the actual number in the years 1975 1980. The compensation paid by the F O D depends on the incapacity of the affected individual. For most there is a temporary work incapacity, for which there is a minimum of 4 months salary. For those suffering from chronic hepatitis or cirrhosis, an average compensation of 50% of salary is paid. Death compensation of 30% of salary is payable to surviving relatives of the victim. Over the period 1981 1986, it is estimated that vaccination prevented 30 cases of chronic hepatitis and cirrhosis, and four deaths. The financial repercussions are shown in Table 3.
938
Vaccine, Vol. 10, Issue 13, 1992
The net benefit of FB 40 million represents only the saving to the FOD, and excludes medical costs, which would be borne by the health insurance funds, and the costs of absenteeism, which would be borne by the employer 9. Vaccination of occupationally at-risk employees has been undertaken in many other countries. Recently legislation has been introduced in the USA and France, requiring such employees be offered vaccination by their employers. Another risk group are infants of carrier mothers. In North America programmes have been implemented to screen pregnant women living in populations with a high incidence of infection, and to provide either post or pre-exposure immunization to their infants. Unfortunately, the selective vaccination of risk groups has not fundamentally reduced the incidence of the disease. This has led to the consideration of whether universal immunization of infants is the only feasible approach for control. The Centers for Disease Control (CDC) commissioned a cost benefit analysis, which indicated that such a programme in the USA would cost the public sector $105 million p.a. Of this $62 million were for screening and vaccination. In the absence of such a programme direct costs of $72 million p.a. would be incurred, together with a further $300 million for indirect productivity loss. Thus the programme would not be cost saving, but would confer considerable health benefits ~°. There are two factors that strongly influence the cost-effectiveness of infant vaccination programmes. Not surprisingly, one is the cost of the vaccine. The other is the prevalence of the disease. The overall prevalence in the USA is thought to be 0.2%, with certain populations having up to 15%. It has been shown that at 0.9%, such programmes become cost-effective6. In Italy, where the prevalence is 3.2%, there has been a greater incentive to consider universal vaccination programmes. Last year, legislation was introduced, enabling the vaccination of both infants and adolescents. However, it is in developing countries that hepatitis B is the greatest problem, causing an estimated 1-2 million deaths p.a. The W H O has recommended that hepatitis B vaccine be integrated into the EPI.
CONCLUSIONS In developing countries, the EPI has had a significant impact on infant mortality and morbidity. The high coverage rates necessary to achieve and sustain such results have required a combination of both routine and special campaigns. There is an opportunity and a need to make better use of the infrastructure that has been established. The marginal cost of adding further vaccines (e.g. yellow fever, hepatitis B) is low. In industrialized countries, paediatric vaccines have been widely accepted for many years. There is a lower recognition of the value of vaccines which protect against diseases occurring later in life, or against the long-term sequelae of diseases which may be caught in childhood. Both governments and industry will need to take a longer term view. Governments will need to recognize that policies enacted may take many years to produce an impact on public health. Industry will need to show that discounted benefits are worthwhile.
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson
REFERENCES 1 World Health Organization. Expanded Programme on Immunization, Summary for the European Region. WHO Information System, 1991, pp2 3 2 World Health Organization. Week. Epidemiol. Rec. 1992, 3, 11-12 3 Smithkline Beecham Biologicals estimate 4 World Health Organization. Bull. WHO 1989, 67(2), 181-188 5 World Health Organization. Bull. WHO 1989, 67(6), 649-662
Koplan, J.P. The benefits and costs of immunizations revisited. Drug Information J. 1988, 22, 379-383 7 World Health Organization. Week.Epidemiol. Rec. 1989,19, 142 144 6
8
Mulley, A.G., Silverstein, M.D. and Dienstag, J.L. Indications for use of hepatitis B vaccine, based on cost-effectiveness analysis. N. Engl. J. Med. 1982, 307, 644-652 9 Lahaye, D., Baleux, C., Strauss, P. and van Ganse, W. Cost-benefit analysis of hepatitis B vaccination. Lancet 1987, ii, 441 443 10 Centers for Disease Control. Analysis by Battelle Human Affairs Research Center, presented to CDC Immunization Practices Advisory Committee, October 1990
Vaccine, Vol. 10, Issue 13, 1992
939
INTRODUCTION Twenty years ago, nearly five million children died annually from measles, tetanus, whooping cough, diphtheria, tuberculosis or polio. Millions more were permanently disabled. In 1974, the World Health Organization launched the Expanded Programme on Immunization (EPI). By mid-1991, 80% or more of the world's children were being vaccinated against these diseases 1. It is estimated that the EPI is preventing some 3.2 million deaths each year from measles, pertussis and neonatal tetanus, and 440 000 cases of polio. Nevertheless, annual!y, there remain 1.7 million deaths from these same diseases, and 120 000 cases of polio 2. The human benefits of the reduction of infant mortality and morbidity are not disputed, and funds have been made available to support the vaccination programmes. In the case of the EPI, the vaccine component costs are probably around $150 million p.a., or $50 per life saved 3. However, vaccines are only a small part of the total cost of immunization (typically less than 10% ), and there has been a need to examine that they are being administered in the most cost-effective way. One such study was undertaken in Thailand in 1987, and showed that the cost per fully vaccinated child varied from $5.30 to $33.20. It was found that there was little difference between hospitals and health centres, and relatively little between fixed and outreach services. The main determinant was the vaccination session frequency, with the highest costs being incurred in health centres which had the most frequent sessions. There did not appear to be any correlation between session frequency and coverage. It was concluded that the best way to reduce costs would be to make better use of staff time by decreasing the frequency of the services offered4. Another study carried out in Ecuador in 1986 compared the costs using routine services based in fixed facilities with mass immunization campaigns. The costs per fully vaccinated child were $4.39 for the former and $8.60 for the latter. More importantly, however, the study SmithKline Beecham Biologicals, Rixensart 1330, Belgium
Rue de I'lnstitut 89,
0 ~ 10)(/92/13093£~04 © 1992 Butterworth-Heinemann Ltd
936
Vaccine, Vol. 10, Issue 13, 1992
illustrated that the necessary high coverage rates can only be achieved by use of special campaigns 5. The proportion of children vaccinated against D T P , by age, is shown in
Figure 1. VACCINATION COUNTRIES
IN INDUSTRIALIZED
In industrialized countries, a number of cost-benefit analyses on vaccines have been reported, and some of these are briefly reviewed below.
Poliomyelitis In the USA in 1952 over 20000 cases of polio were reported. Inactivated poliovirus vaccine (IPV) was introduced in 1955 and led to a dramatic decline in the incidence. Live attenuated (oral) polio vaccine (OPV) followed in 1961, and quickly replaced IPV, both in the USA and many other countries. A cost-benefit analysis yielded a return of 7 - 1 4 % . Another study in the former West German Republic indicated that for every DM spent on vaccination between 1962 and 1971, 90 DM were saved on treatment, care and rehabilitation costs 6. The success in polio elimination has led to the dilemma of which type of polio vaccine is preferable. The last case of indigenously acquired wild poliovirus disease in the USA was in 1979. However, an average of eight cases per year continue to be reported in association with the administration of OPV. Where there continues to be a risk of the introduction of wild polio virus (e.g. by immigration) OPV is preferable, but when such risk is eliminated then IPV would be safer (albeit more expensive).
Pertussis The issue of vaccine safety versus efficacy has been of even greater importance with pertussis, where there is a risk of encephalopathy and other less severe reactions. A benefit-cost analysis carried out in 1984 concluded that there were substantial excess benefits over costs (11:1). As the result of increasing attention from the media in the USA, and increasing lawsuits, manufacturers were forced to increase prices to cover spiralling
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson
Hepatitis B
I00
o~O
80
Campaigns
"o (~
~
ao
u
g
40
Routine
L X3 ~:
20
0
1
2
3
4
Age (completed years)
Figure 1
DTP coverage rates in Ecuador. (Source: Bulletin of the WHO,
1989)
Table 1
Immunization with MMR: results over 25 years in France Cases avoided
Complications
Sequelae
Deaths
Measles
9 million
2000 encephalitis
900
500
Mumps
8 million
25000 meningitis 1680 encephalitis
Rubella
Not calculated
500-3000
A plasma-derived vaccine against hepatitis B was introduced in the early 1980s, and because of its limited availability and relatively high price ($100 per course), there was an interest in using cost-effectiveness analysis to evaluate alternative vaccination strategies for populations at different risks of exposure to the virus. One such study considered a model whereby the population at risk were divided into three groups vaccinate all; screen for prior immunity and vaccinate only those who are susceptible; no vaccination but use of hepatitis B immune globulin after known exposure 8. Table 2 shows the results obtained. In this analysis only direct medical costs were considered, and the indirect costs of lost productivity were not. For populations with a high prevalence of prior exposure and a high annual attack rate (e.g. homosexuals), screening and vaccination of susceptibles was the best strategy. For populations with low prevalence and high annual attack rates (such as hospital health care workers), vaccination without screening was the least costly option. For populations with low prevalence and low annual attack rates (e.g. the general population of USA or most of Western Europe), neither screening nor universal vaccination were advocated. It is now nearly 10 years since these results were published, and certain of the assumptions need amendment (notably the price of the vaccine, which has fallen ). It is, perhaps, of no surprise that when implementing hepatitis B vaccination programmes in industrialized
Source: WHO Weekly Epidemiological Record, 1992
insurance costs. A reanalysis in 1985, which took $2.68 per dose of DTP (cf. 11 cents in 1984), and worst-case estimates of encephalopathy risk, gave a benefit:cost ratio of 1.1:1. Subsequently a federal levy has been imposed to establish a compensation fund, pushing prices to a level where vaccination is no longer cost-saving, although it still confers considerable excess health benefits 6.
Measles, mumps, rubella In industrialized countries, infants are also usually vaccinated against measles, mumps and rubella. A study was published in 1988 on the effects of using this triple vaccine in France 7. The estimated number of cases, complications, sequelae and deaths avoided over a 25 year period are given in Table 1. Measles and mumps both pose significant public health problems. Rubella is a more benign disease, except for the sequelae of congenital rubella. A range is given for the latter, since epidemics tend to occur irregularly. There is also a need to vaccinate the backlog of adolescent girls, which should bring the number of cases avoided close to the higher figure. The estimated cumulative net benefit is shown in Figure 2. Initially the total costs (cost of the diseases borne by the community, plus the vaccination costs) increase, but after 6 years they begin to fall, and after 17 years the investment in immunization will have been recovered. These results, which exclude vaccinating the backlog (which would give additional benefits), yield a return of 4.5% p.a.
Table 2 Medical care costs of strategies for vaccinating three representative populations Net medical care costs per person
Homosexuals
Surgical interns
General population
Prevalence of exposure Annual attack rate
High High
Low High
Low Low
No vaccination Vaccinate all Screen/vaccinate
$97 $105 $66
$106 $104 $114
$2 $100 $115
Source: Reference 8
"-~ o
±
1500 1000 500
% o -500 _i000~ u -1500 z
I
I
I
I
I
I
I
I
I
I
I
I
2
4
6
8
10
12
lq
16
18
20
22
24
N u m b e r of years
Figure 2 years
Benefit of MMR immunization in France projected over 25
Vaccine, Vol. 10, Issue 13, 1992
937
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson 300 ~7
250 tn
200
/
"0
150
E
/ /,/ ,/ / / / / ,/ ,/ / ,/ / /
100 50 0
J/
HH
¢ 1976
1978
1980
1982
1986
198q
Year Figure 3 HBV cases compensated by FOD 1975-1986, showing actual (~1) versus projected ( V ) figures. (Taken from Ref. 9)
Table 3 Belgian FOD 1981-1986
hepatitis vaccination costs and savings
FB million Vaccine costs
160
Savings: T e m p o r a r y w o r k incapacity Permanent impairment Death pensions
173 26 2
Total savings
41
countries, hospital health care workers were the first risk group to be addressed. In Belgium, hepatitis has been recognized since 1969 as an occupational disease for staff involved in nursing, care of the disabled, preventive medicine and laboratory activities, and for which compensation is paid by the insurance Fund for Occupational Disease (FOD). The number of such cases increased rapidly in the 1970s, and in 1981 vaccination against hepatitis B started experimentally. In 1983 the F O D was authorized to pay for hepatitis B vaccination, and this was the first time that professional risk insurance was allowed to invest directly in preventive action rather than in compensation for damage. The F O D agreed to reimburse vaccination for staff, including students, working in a number of hospital departments, and in other fields where there was risk. Figure 3 shows the number of HBV cases that were compensated during the period 1975-1986, together with the number that would have been expected without vaccination. The latter were established by extrapolation of the actual number in the years 1975 1980. The compensation paid by the F O D depends on the incapacity of the affected individual. For most there is a temporary work incapacity, for which there is a minimum of 4 months salary. For those suffering from chronic hepatitis or cirrhosis, an average compensation of 50% of salary is paid. Death compensation of 30% of salary is payable to surviving relatives of the victim. Over the period 1981 1986, it is estimated that vaccination prevented 30 cases of chronic hepatitis and cirrhosis, and four deaths. The financial repercussions are shown in Table 3.
938
Vaccine, Vol. 10, Issue 13, 1992
The net benefit of FB 40 million represents only the saving to the FOD, and excludes medical costs, which would be borne by the health insurance funds, and the costs of absenteeism, which would be borne by the employer 9. Vaccination of occupationally at-risk employees has been undertaken in many other countries. Recently legislation has been introduced in the USA and France, requiring such employees be offered vaccination by their employers. Another risk group are infants of carrier mothers. In North America programmes have been implemented to screen pregnant women living in populations with a high incidence of infection, and to provide either post or pre-exposure immunization to their infants. Unfortunately, the selective vaccination of risk groups has not fundamentally reduced the incidence of the disease. This has led to the consideration of whether universal immunization of infants is the only feasible approach for control. The Centers for Disease Control (CDC) commissioned a cost benefit analysis, which indicated that such a programme in the USA would cost the public sector $105 million p.a. Of this $62 million were for screening and vaccination. In the absence of such a programme direct costs of $72 million p.a. would be incurred, together with a further $300 million for indirect productivity loss. Thus the programme would not be cost saving, but would confer considerable health benefits ~°. There are two factors that strongly influence the cost-effectiveness of infant vaccination programmes. Not surprisingly, one is the cost of the vaccine. The other is the prevalence of the disease. The overall prevalence in the USA is thought to be 0.2%, with certain populations having up to 15%. It has been shown that at 0.9%, such programmes become cost-effective6. In Italy, where the prevalence is 3.2%, there has been a greater incentive to consider universal vaccination programmes. Last year, legislation was introduced, enabling the vaccination of both infants and adolescents. However, it is in developing countries that hepatitis B is the greatest problem, causing an estimated 1-2 million deaths p.a. The W H O has recommended that hepatitis B vaccine be integrated into the EPI.
CONCLUSIONS In developing countries, the EPI has had a significant impact on infant mortality and morbidity. The high coverage rates necessary to achieve and sustain such results have required a combination of both routine and special campaigns. There is an opportunity and a need to make better use of the infrastructure that has been established. The marginal cost of adding further vaccines (e.g. yellow fever, hepatitis B) is low. In industrialized countries, paediatric vaccines have been widely accepted for many years. There is a lower recognition of the value of vaccines which protect against diseases occurring later in life, or against the long-term sequelae of diseases which may be caught in childhood. Both governments and industry will need to take a longer term view. Governments will need to recognize that policies enacted may take many years to produce an impact on public health. Industry will need to show that discounted benefits are worthwhile.
Benefits and costs of vaccination: P. Dejonghe and B. Parkinson
REFERENCES 1 World Health Organization. Expanded Programme on Immunization, Summary for the European Region. WHO Information System, 1991, pp2 3 2 World Health Organization. Week. Epidemiol. Rec. 1992, 3, 11-12 3 Smithkline Beecham Biologicals estimate 4 World Health Organization. Bull. WHO 1989, 67(2), 181-188 5 World Health Organization. Bull. WHO 1989, 67(6), 649-662
Koplan, J.P. The benefits and costs of immunizations revisited. Drug Information J. 1988, 22, 379-383 7 World Health Organization. Week.Epidemiol. Rec. 1989,19, 142 144 6
8
Mulley, A.G., Silverstein, M.D. and Dienstag, J.L. Indications for use of hepatitis B vaccine, based on cost-effectiveness analysis. N. Engl. J. Med. 1982, 307, 644-652 9 Lahaye, D., Baleux, C., Strauss, P. and van Ganse, W. Cost-benefit analysis of hepatitis B vaccination. Lancet 1987, ii, 441 443 10 Centers for Disease Control. Analysis by Battelle Human Affairs Research Center, presented to CDC Immunization Practices Advisory Committee, October 1990
Vaccine, Vol. 10, Issue 13, 1992
939
