Economic evaluation of universal BCG vaccination of Japanese infants

Mahbubur Rahmana, Miho Sekimotoa, Isamu Takamatsub, Kenji Hiraa, Takuro Shimboa, Kyoichiro Toyoshimab and Tsuguya Fukuia

a Department of General Medicine and Clinical Epidemiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
b Division of Pediatrics, Osaka Prefectural Habikino Hospital, Habikino City, Osaka, Japan.

Correspondence: Tsuguya Fukui, Department of General Medicine and Clinical Epidemiology, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: fkts{at}kuhp.kyoto-u.ac.jp

Abstract

Background The international controversy surrounding the use and effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine and the low incidence of tuberculosis (TB) among Japanese children prompted this study.

Methods We compared ‘universal BCG vaccination’ with ‘no vaccination at all’ using a cost-effectiveness analysis. The study population was a hypothetical cohort comprising a total of 1.2 million infants born in 1996 at locations all over Japan. A model was developed to calculate the number of TB cases prevented by the vaccination programme. Assuming 40–80% overall vaccine efficacy (64–86% for TB-meningitis) and 10 years of protection, we calculated the cost and number of immunizations required to prevent one child from developing TB, the total number of TB cases averted by vaccination and total costs required for the programme.

Results Based on an assumption of flexible vaccine efficacy (40–80%), we estimated that 111–542 TB cases including 10–27 of TB-meningitis would be prevented during the 10 years after BCG vaccination among the cohort of infants born in 1996. About US$35 950–175 862 or 2125–10 399 immunizations would be required to prevent one child from developing TB. Sensitivity analyses covering a wide duration of protection, incidence of TB, vaccine coverage and discount rate, revealed that other than vaccine efficacy, the cost of preventing a single case of TB is highly sensitive to the duration of BCG protection and TB incidence.

Conclusion The cost per case of TB prevented is heavily dependent on vaccine efficacy and the duration of protection, and is high compared with the cost of treating one child who has developed TB.

Keywords Bacillus Calmette-Guérin (BCG), tuberculosis, Japan, Vaccine, cost-effectiveness analysis

Accepted 26 July 2000

Efficacy of Bacillus Calmette-Guérin (BCG) vaccination is a matter of international debate.1,2 It varies from detrimental to over a 90% protective benefit in prospective trials and case-control studies;3 and 50% in a meta-analysis of the literature.4 The efficacy was lowest in the Madras trial, in which BCG vaccination failed to protect against pulmonary tuberculosis.5

Japan has had a policy of universal BCG vaccination of infants against tuberculosis (TB) since 1951.6 Children aged 6 and 12 also undergo BCG revaccination, although the effectiveness of this practice is not well-established. The average incidence of TB has decreased from 698 per 100 000 in 1951 to 33.7 per 100 000 in 1996.7 Improved social and economic circumstances since World War II have played an important role in reducing the incidence of TB in Japan. Universal vaccination is not practised in regions where the incidence of TB is low, such as the USA and some western European countries. These countries target high-risk groups. Although the overall incidence of TB is much higher in Japan than in other developed countries, the paediatric incidence is much lower, at 2.1 per 100 000 compared with 3.1 per 100 000 in the USA.6 This situation reflects the fact that individuals infected before the 1940s and the ageing population are mostly responsible for the persistent incidence of TB in Japan.8 The criteria established by the International Union Against Tuberculosis and Lung Disease (IUATLD)9 to discontinue universal BCG vaccination have already been met in Japan (Table 1Go). Fulfilment of these criteria, along with the low paediatric TB incidence in Japan, has stimulated a debate in Japan as to whether or not universal vaccination should be retained. The analysis reported here was designed to compare the cost and number of immunizations required to prevent a single case of TB by the universal BCG vaccination programme with the alternative of no vaccination.


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Table 1 International Union Against Tuberculosis and Lung Disease (IUATLD) criteria for discontinuing Bacillus Calmette-Guérin (BCG) vaccination and Japanese status
 
Materials and Methods

Costs of universal vaccination programme
Since universal vaccination in Japan is a national government-run programme, the analysis was conducted from the perspective of actual cost incurred by this programme and estimated from the data on expenditure on the BCG vaccination programme in Kyoto city. The cost of this programme includes the cost of the purified protein derivative (PPD) testing kit, the cost of BCG vaccines together with injection materials (multiple puncture discs) and personnel costs. Other costs were estimated according to the third party payer's viewpoint.10 The costs of treating side effects caused by BCG and follow-up of PPD positive infants were based on published reports and expert opinion.7,11,12 Indirect costs, such as loss of work for parents accompanying children to health centres either for vaccination or for treating side effects incurred by BCG, were not included in this analysis. The relevant cost and epidemiological parameters are listed in Table 2Go. Using the notations in Table 2Go, cost is expressed as follows:


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Table 2 Parameters of cost-effectiveness analysis of Bacillus Calmette-Guérin (BCG) vaccination programme against tuberculosis (TB) and cited baseline values
 

(1)

Effectiveness of universal vaccination programme
Effectiveness of this programme is assessed by the number of TB cases averted by vaccination. We developed a model with which to calculate the total number of TB cases prevented by vaccinating a given cohort based on the population number in the cohort (in 100 000), vaccine efficacy, duration of protection, current TB incidence, vaccine coverage and discount rate. Because discounting health benefits in cost-effectiveness analysis is a controversial issue, we performed discounted and undiscounted analyses. All infants born in 1996 in Japan were considered a hypothetical cohort with which to compare ‘universal vaccination’ with ‘no universal vaccination at all’ to estimate the number of TB cases prevented (Ptb) by the vaccination programme. We developed the following formula to calculate the numbers of averted TB cases (Ptb).


The same formula was used to estimate the number of averted TB-meningitis (TBM) cases, using different values for vaccine efficacy and incidence of TBM. Since the efficacy of the vaccine against overall TB and TBM differs (usually higher in preventing TBM), extra TBM (Pextb) averted were added to Ptb. In addition to cases directly averted by the vaccination programme, some were averted by a break in the transmission chain. We assumed that the prevalence of TB would be 0.65% among contacts of TB patients and that the average number of contacts per TB patient would be three until identified as TB case.17 Therefore, the number of cases averted by breaking the transmission chain would be equal to Pttb = (Ptb + Pextb) x 3 x 0.0065. Thus the net TB number averted by the vaccination (Pntb) programme was equal to Ptb + Pextb + Pttb.

The number of immunizations (Vn) required to prevent one case of TB will be:


Data acquisition and assumptions
Vaccine efficacy
Because of wide-ranging uncertainty, we analysed our data using values for overall BCG vaccine efficacy of 40%, 60%, and 80%. Separate calculations also used 64%4 and 86%13 efficacy against TBM.

Duration of protection
We assumed that after vaccinating the 1996 infant cohort, protection against TB would continue for up to 10 years since there is no good evidence that the BCG vaccine provides protection beyond this time frame.14

Number of infants in a cohort
There were 1.207 million infants born in 1996 in Japan.15 This is considered a hypothetical cohort with which to calculate the number of TB cases averted by the vaccination programme.

Incidence of TB among vaccinated cohort (Itk)
Since the universal vaccination programme for infants has continued in Japan for years, the future incidence of TB among the infants born in 1996 is considered the same as that among infants born before 1996 and vaccinated. The present study assumes that the future TB incidence of the 1996 cohort would be equal to that in the age groups 0–4 and 5–9 years old in 1996.

Incidence of TB among unvaccinated cohort (Iuk)
A hypothetical incidence of TB (Iuk) among a cohort of the same size if unvaccinated, can be calculated using the incidence of TB among the vaccinated cohort (Itk), vaccine efficacy (VE), and proportion of the vaccinated infants (PV). Logically, the incidence of TB among unvaccinated infants (about 5% in Japan) within the universal vaccination cohort would also be the same as that of the hypothetical unvaccinated cohort.

Proportion of cohort being vaccinated
The proportion of infants born in 1996 who underwent BCG vaccination was 0.955.7,15 One report indicates that PPD-positive infants, an estimated 1.4% of the total cohort,7 were not vaccinated. We assumed that 95% of the cohort was vaccinated and that the TB incidence among PPD-positive infants would be the same as that in the unvaccinated cohort.

TB mortality
We assumed that TB-related death would not occur for 10 years after vaccinating the cohort because no such event has been identified among the population of the 0–9-year-olds in recent years in Japan.

BCG side effects
Information on the side effects of BCG vaccination in Japan was extracted from the report by Mori et al.11 Prevalence of overall lymph node swelling was 1.06%, while the estimated rates of lymphadenopathy, suppurative adenitis and surgical treatment for lymphadenitis after BCG vaccination were 0.73%, 0.02% and 0.006%, respectively. The incidence of other extremely rare but severe side effects such as BCG osteomyelitis or disseminated BCG infection were not included in this analysis since no relevant data are available.

Results

Cost of vaccination programme
The total cost associated with the vaccination programme was US$19.5 million. The major components of costs were in declining order, personnel (US$10.0 million), BCG vaccines with multiple puncture discs (US$6.98 million) and PPD test kits (US$0.98 million). Cost for treating side effects of BCG vaccinations was US$1.18 million (about US$1 per immunization) and that for follow-up of PPD-positive patients was US$0.46 million.

Number of TB cases averted
The estimated total number of TB cases averted by vaccinating 1.2 million infants born in 1996 would be 111–542 including 10–27 cases of TBM and 2–10 cases averted by breaking the chain of transmission (Table 3Go). Of the 111–542 cases, 80–387 would be averted in the first 5 years after BCG vaccination with the remaining 31–155 in the last 5 years.


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Table 3 Total number of averted tuberculosis (TB) cases, cost and number of immunizations required to prevent one case of TB after vaccinating 1996 infant cohort in Japan
 
Number of immunizations and cost of preventing a single case of TB
The calculated cost and total number of immunizations required to prevent one case of TB were US$35 950–175 862 and 2125– 10 399 injections, respectively (Table 3Go). In other words, 10–47 TB cases would be prevented by vaccinating 100 000 infants.

Sensitivity analyses
Sensitivity analyses tested the robustness of the estimates based on the underlying assumptions (Table 4Go). The major uncertainty was vaccine efficacy, which was included as a flexible range (40–80%) in the baseline estimates. Other than that, variations in the duration of BCG protection and TB incidence affect the cost and number of immunizations required to prevent a single case of TB. Changing the duration of BCG protection from 10 to 5 years increased the cost and number of immunizations to 37–39% above baseline values. The average TB incidence rate, although recently stable among Japanese children, shows marked regional variation. If it is half of the baseline value, the costs and number of immunizations required to prevent a single TB case would be doubled (Table 4Go). Cost effectiveness was improved by higher vaccine coverage and when discounting was omitted (Table 4Go).


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Table 4 Sensitivity analyses of cost (in US$) of preventing a single case of tuberculosis (TB)
 
Discussion

The cost of preventing a single case of TB is determined by vaccine efficacy, duration of BCG protection, TB incidence and vaccine coverage. However, BCG vaccine efficacy itself is a highly controversial issue. If the BCG vaccine was ineffective, there would be no reason to continue the vaccination programme. Even with flexible vaccine efficacy (40–80%), as used in this analysis as a baseline estimate, the cost of preventing a single case of TB (US$35 950–175 862) appears to be high. That cost is likely to exceed that required to treat a single patient with TB. Based on some published parameters17 and experts' opinion, the cost of treating a 2-year-old child with pulmonary TB would be around US$10 500, which is considerably less than our estimated cost of preventing that child contracting TB. The costs of preventing a single case of TB and of treating an infected patient become comparable only when vaccine efficacy is 80% and associated with either 20 years of protection or a doubled TB incidence rate (Table 4Go). Since only 10–27 of the averted cases would be TBM, they contribute only a small amount to the ratio of the cost of treatment compared with that of prevention.

It is known that BCG side effects can occasionally be life-threatening. Two patients with severe-combined-immunodeficiency syndrome have been identified among BCG vaccinees during the last 10 years in Japan.18,19 The cost required to control and compensate adverse outcomes could be very high and are not included in the analysis. Similarly, the cost associated with the treatment of other occasional side effects of BCG vaccinations (e.g. BCG osteomyelitis and disseminated BCG infection) are not included in our analysis because of their rarity and inadequate data. If those costs were included, the cost of preventing a single case of TB would be higher than baseline values.

The limitations of this study are those attributable to the veracity of the data sources and to the manner of interpreting the results. We used data derived mostly from meta-analyses of multiple studies conducted in countries other than Japan. In addition, since TB-related mortality has not been recently identified among the 0–9 years age group in Japan, conventional indices of cost effectiveness, such as cost per life year gained, are not appropriate. Therefore, the study results are described as the cost of preventing one case of TB.

The efficacy of the BCG vaccine in Japan could be different from that determined from meta-analyses of studies conducted in other countries. In fact BCG efficacy varies widely within and between countries. The inter-country variation in BCG efficacy is statistically explainable by the latitude of countries.20 Atypical mycobacteria that accrue natural protection against TB are highly prevalent at lower latitudes, therefore BCG could do little to protect against TB in countries at such geographical locations. The reverse is true for countries at higher latitudes. Considering the latitude of Japan (35°) actual vaccine efficacy could be around 40–60%, which represents a cost of US$85 348–175 862 to prevent a single case of TB, which is 8 to 16 times higher than the cost required to treat one patient who has developed TB.

Universal BCG vaccination of newborns or infants is no longer practised in most low-risk countries. In fact, BCG is only recommended for high-risk groups in the USA, and universal vaccination was discontinued in Sweden, Austria, Switzerland, Israel, as well as in selected areas of the Czech Republic and Germany many years ago.2124 Australia and New Zealand do not have a general BCG vaccination programme.25 However, in France, UK and Norway general BCG vaccination is recommended at 6, 11 and 13 years of age, respectively.26 In a recent study, universal BCG vaccination of neonates in the UK was recommended in areas where the average incidence of TB is over 40 per 100 000 population.27

The incidence of TB is an important determinant of the cost of preventing a single case of TB. The paediatric TB incidence varies by region in Japan.7 Nineteen of 47 administrative units (prefectures) have a TB incidence that is about 50% or less than the national average, that of 11 units is 150–200% and that of the remaining 17 units is almost equal to the national average. Therefore, the cost of preventing a single case of TB would be double in prefectures where the incidence is 50% or less of the national average, while it would be half in those prefectures where the incidence is double. Thus, a BCG vaccination programme could be formulated for each prefecture based on incidence data.

The high overall average TB incidence in Japan is due to high incidence among the elderly. Epidemics of TB in eastern Japan between 1910 and 1920 and in western Japan during the 1940s, the high risk of TB infection (4%) up to World War II,6 and lower socioeconomic conditions before the war, were responsible for the high infection rates of the past. However, the incidence of TB declined rapidly until 1982, and then plateaued and remained at 33–40 per 100 000 in the last few years.7 The paediatric TB incidence in Japan is comparable to that of the USA or most western European countries where universal BCG vaccination is no longer practised. Almost 75% of the paediatric TB cases in Japan are thought to have been contracted from individuals with active TB.28 Such paediatric patients are amenable to appropriate preventive measures such as contact examination and chemoprophylaxis, which could further decrease the current rate. Thus the cost effectiveness of universal vaccination would also decline. Therefore, a high average incidence of TB in Japan does not necessarily justify continuing the universal vaccination programme.

Universal BCG vaccination in Japan does not appear to be cost effective from an economic viewpoint. The cost effectiveness of selective BCG vaccination for high-risk groups (e.g. contacts of TB cases, homeless people, and immigrants from countries with a high prevalence of TB) should be analysed and compared with that of the universal vaccination programme.

Appendix

In a cohort where the incidences of TB among the vaccinated and unvaccinated cohorts are Ivk and Iuk, vaccine efficacy (VE) for that cohort would be:


Where the proportion of vaccinated is PV and number of population is N (in 100 000), the total number of individuals who develop TB in that cohort in a given year (Kth year) would be equal to the total number who developed TB among the vaccinated plus the total number of the same among the unvaccinated. Let us assume Itk is the average TB incidence.


If a BCG vaccination programme does not exist, then the incidence of TB would be Iuk among the cohort. The number of TB averted (Ptbk) in a given year would then be:

During 10 years (duration of BCG protection) the total number of TB averted would be equal to:

(while ‘r’ is annual discount rate)


KEY MESSAGES

  • Estimates of the efficacy of BCG vaccine are highly variable.
  • Japan has already met the International Union Against Tuberculosis and Lung Disease criteria to discontinue the universal BCG vaccination programme.
  • Paediatric TB incidence in Japan is similar or comparable to other low-risk countries where universal vaccination is discontinued.
  • Based on 40–80% vaccine efficacy, 2125–10 399 BCG immunizations or US$35 950–US$175 862 are required to prevent one child from developing TB, whereas the cost of treating one child with pulmonary TB is about US$10 500.
  • Cost of preventing one child from developing TB is highly sensitive to vaccine efficacy and duration of BCG protection.

 

Acknowledgments

The findings of this study were presented at the 32nd Annual Meeting of Society for Epidemiologic Research on 11 June 1999, Baltimore, USA.

This work was supported by grants from Japan Society for the Promotion of Science (P98150). We are indebted to Dr Takateru Izumi (Emeritus Professor, Kyoto University) for his help with the development of the protocol; to Dr Toru Mori (The Research Institute of Tuberculosis) for his useful suggestions; to Mr Toru Yoshikawa (Kyoto City Corporation) for providing valuable information; to Mr Yoshinori Hattori (Osaka Sangyo University) for his contribution in methodology section; and to Ms Yoshiko Kazami (The Research Institute of Tuberculosis) for her help in literature review and collection.

Contributors

MR initiated the research, gathered data, conducted data analysis, and wrote the paper. TF participated in all processes and is guarantor for this paper. MS and KH participated in data analysis and discussion. IT, KT, and TS participated in design and discussion.

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