Is Bacillus Calmette–Guerin Revaccination Necessaryfor Japanese Children?1

Mahbubur Rahman, MBBS, MPH, Ph.D.,*,2 Miho Sekimoto, M.D.,* Kenji Hira, M.D., Ph.D.,*Hiroshi Koyama, M.D., Ph.D.,* Yuichi Imanaka, M.D., MPH, Ph.D.,† and Tsuguya Fukui, M.D., MPH, Ph.D.*

Preventive Medicine 35, 70–77 (2002)doi:10.1006/pmed.2002.1043

†Department of Healthcare Economics and Quality Manage

Background. Bacillus Calmette–Guerin (BCG) revac-cination has been implemented in Japan amongtuberculin-negative first grade primary and firstgrade junior high school students for decades. Contro-versies regarding the effectiveness of BCG revaccina-tion and low incidence of tuberculosis (TB) amongJapanese children prompted this study.

Methods. Cost–effectiveness and cost–benefit analy-ses were conducted for a cohort of schoolchildren whounderwent revaccination during 1996. The study pop-ulation was a hypothetical cohort comprising 1.35 mil-lion first grade primary school and 1.51 million firstgrade junior high school students enrolled in 1996 atlocations throughout Japan. Assuming 50% vaccineefficacy for revaccination, a 10-year duration of pro-tection, and 5% annual discount rate, we calculatedthe total hypothetical number of TB cases averted, thecost and number of immunizations per TB caseaverted, and the benefit–cost ratio for the program.

Results. The revaccination program for 1996 school-children cohort would prevent 296 TB cases over a10-year period at a cost of US$ 108,378 per caseaverted. About 4,963 immunizations would be re-quired to prevent one child from developing TB. Thebenefit–cost ratio remained at 0.13 with baseline as-sumptions and ranged from 0.05 to 0.29 and from 0.02to 0.74 for one-way and two-way sensitivity analyses,respectively.

Conclusion. BCG revaccination among schoolchil-dren is not supported by available scientific and eco-nomic data. Based on the results of this study, currentBCG revaccination policies in Japan and other coun-tries should be reexamined. © 2002 American Health Foundation

and Elsevier Science (USA)

1 Supported by grants from the Japan Society for the Promotion ofScience (JSPS), Tokyo Japan (P98150).

2 To whom reprint requests should be addressed at Department ofGeneral Medicine and Clinical Epidemiology, Kyoto University

700091-7435/02 $35.00© 2002 American Health Foundation and Elsevier Science (USA)All rights reserved.

nt, Kyoto University School of Public Health, Kyoto, Japan

Key Words: Bacillus Calmette–Guerin (BCG); tuber-culosis; revaccination; cost-effectiveness analysis;cost–benefit analysis; Japan.

INTRODUCTION

In addition to universal Bacillus Calmette–Guerin(BCG) vaccination for infants, revaccination is alsobeing practiced in Japan among the tuberculin-negative schoolchildren of first grade primary and firstgrade junior high schools. But efficacy of BCG vaccina-tion is a matter of international debate [1,2]. There arewide-ranging variations in the efficacy of BCG vaccine,from a detrimental effect to more than 90% protectivebenefit in prospective trials and case–control studies[3,4] and 50% in a meta-analysis of the literature [5].On the other hand, a study on the efficacy of BCGrevaccination showed very little or no protection at allagainst tuberculosis (TB). Revaccination seemed to de-crease childhood and adolescent TB in Hungary [6] andPoland [7], but not in Chile [8]. In a recent randomizedcontrolled trial, BCG revaccination failed to show anyprotection against pulmonary TB [9]. The analysis re-ported here was designed to estimate cost and numberof immunizations required to prevent a case of TB andthe benefit–cost ratio of the BCG revaccination pro-gram in Japan.

MATERIALS AND METHODS

Costs of Revaccination Program

BCG revaccination in Japan is a nationalgovernment-run program. The analysis is conductedfrom the perspective of actual cost incurred by thisprogram and estimated from the data on expenditurefor BCG revaccination program in Kyoto city. The costsof this program include the cost of the purified protein

*Department of General Medicine and Clinical Epidemiology, K

Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku,Kyoto 606-8507, Japan. Fax: 81-075-751-4211. E-mail: rahman@kuhp.kyoto-u.ac.jp.

to University Graduate School of Medicine, Kyoto, Japan; and

derivative (PPD) testing kit, the cost of BCG vaccinestogether with injection materials (multiple puncturedisk), and personnel costs. Other costs were estimated

yome

according to the third-party payer’s viewpoint [10]. Thecosts of treating side effects caused by BCG andfollow-up of PPD-positive infants were based on pub-lished reports and expert opinion [11–13]. All the costswere based on 1999 Japanese yen.

Since the revaccination programs are school based,the indirect costs, such as loss of work for parentsaccompanying children to health centers for vaccina-tion, are not incurred. Indirect costs for loss of work forparents accompanying children either to treat side ef-fects incurred by BCG or to follow up PPD-positivestatus, were not included in this analysis. The relevantcost and epidemiological parameters are listed in Table1. Using the notations in Table 1, cost is expressed asfollows:

Cost of revaccination program � N � PV � CBCG

� 100,000 � N�PV � PP�CPPD

� 100,000 � CSE � Cfu.

Effectiveness of Revaccination Program

The effectiveness of this program relies totally on thenumber of TB cases averted by vaccination. The num-ber of TB cases prevented by revaccinating schoolchil-dren was estimated with the following formula devel-oped by Rahman et al. [16]:

Ptb �N � PV � VE�1 � PV � VE�

� �K�1

d Itk

�1 � r� k�1 ,

where P tb is the number of TB cases prevented by BCGrevaccination, N represents the number of schoolchil-dren of a cohort in 100,000 (either first grade primaryschool or first grade junior high school students), VE isvaccine efficacy for revaccination, PV is the proportionof the cohort being vaccinated (only percentage oftuberculin-negative children), I tk is the incidence of TBamong the revaccinated cohort at the kth year afterrevaccination, “r” is discount rate, and “d” is durationof protection against TB after revaccination. Details onthe origin of the formula mentioned above are given inthe Appendix.

All first grade primary school and first grade juniorhigh school students enrolled in 1996 in Japan wereconsidered as a hypothetical cohort to compare “BCGrevaccination” and “no revaccination at all” to estimatethe number of TB cases prevented (P tb) by the vacci-nation program. The above formula was used sepa-rately for first grade primary school and first gradejunior high school students.

In addition to cases directly averted by the vaccina-tion program, some were averted by a break in thetransmission chain. We assumed that the prevalence ofTB would be 0.65% among contacts of TB patients andthat the average number of contacts per TB patientwould be 3 until identified as a TB case [17]. Therefore,the number of cases averted by breaking the transmis-sion chain would be equal to P ttb � P tb � 3 � 0.0065.Thus the net number of TB cases averted by the vac-cination (Pntb) program was equal to P tb � P ttb.

TABLE 1

Parameters Used for Economic Evaluation of BCG Revaccination Program along with Baseline ValuesObtained from Relevant References

Symbol used Parameter Baseline value

VE Vaccine efficacy against TB in revaccination [5] 50%d Duration of BCG vaccine efficacy after revaccination [14] 10 yearsN Number of first grade primary school students enrolled in 1996 in Japan [15] 1.35 million

Number of first grade junior high school students enrolled in 1996 in Japan[15]

1.51 million

PV Proportion revaccinated among first grade primary school students [11,15] 0.66Proportion revaccinated among first grade junior high school students [11,15] 0.38

I tk TB incidence among the cohort in Japan [11]:5–9 years 1.1 per 100,00010–14 years 1.4 per 100,00015–19 years 6.8 per 100,00020–24 years 20.2 per 100,000

Iuk Hypothetical incidence of TB among the nonrevaccinated per 100,000 —I vk Hypothetical incidence of TB among the revaccinated per 100,000 —CBCG Cost per BCG revaccinationa US$ 11.8CPPD Cost per PPD injectiona US$ 3.7CSE Costs for treating patient having BCG side effects (per vaccine) —C fu Costs for follow-up of PPD-positive patients (per subject) —P tb Number of TB cases averted by revaccination among first grade primary school

students and first grade junior high school students—

Vn Number of vaccines required to prevent a single TB case —r Discount rate 5%

a Costs estimated by the information provided by Kyoto City Municipality Office, Kyoto, Japan 110 Yen � 1 US$.

71BCG REVACCINATION IN JAPAN

The number of immunizations (Vn) required to pre-vent one case of TB is expressed as follows

Vn �total number of vaccines �PV � N � 100,000�

net total number of TB cases averted�Pntb � Ptb � Pttb�

.

Benefits of Revaccination Program

The direct benefit of vaccination would be the treat-ment costs saved on future cases. Indirect benefits, i.e.,averted loss of work output of the parents of pediatricTB patients due to hospitalization, were estimated ac-cording to the average per capita income of Japanesepopulation [18]. According to Japanese law, one cannotenter the job market before completing 9 years ofschooling. Since some of the averted cases would occuramong older age groups, we calculated economic loss of70 days (average length of stay of TB patient) absencefrom work for 17- to 22-year-old averted TB cases,although all the persons in these age groups are notlikely to enter the job market.

Data Acquisition and Assumptions

Vaccine efficacy. Strictly speaking, vaccine efficacy,a crucial factor in advocating the BCG vaccinationprogram, is uncertain, with estimates ranging fromnegative to more than 90% [3]. We used 50% as base-line value, as derived from meta-analysis [5]. However,because of the wide-ranging uncertainty, we analyzedour data using values for overall BCG vaccine efficacyof 10, 25, 75, and 90%.

Cost to treat a pulmonary TB case. Based on somepublished parameters [19] and expert opinion, the costof treating pulmonary TB in a 10-year-old child (70-dayhospital stay, monthly outpatient visit, four chest x-rayfilms, three sputum or gastric lavage specimens forAFB, two PPD tests, eight blood counts and ESRs,eight blood chemistries, one chest CT per two TB pa-tients, two urine analyses, and cost of drugs) has beenestimated to determine the benefit–cost ratio of revac-cination.

Duration of protection. We assumed that after re-vaccinating the 1996 cohort of first year primary andfirst year junior high schools students, protectionagainst TB would continue for up to 10 years, sincethere is no good evidence that the BCG vaccine pro-vides protection beyond this time frame [14].

Number of schoolchildren in a cohort. There were1.35 million first grade primary school and 1.51 millionfirst grade junior high school students enrolled in 1996in locations throughout Japan, as estimated from apublished report [15].

Incidence of TB among revaccinated cohort (Itk).Since the revaccination program for school studentshas continued in Japan for years, the future incidenceof TB among the students after revaccination is con-sidered the same as that among students vaccinatedbefore. The present study assumes that the future TBincidence of first grade primary school and first gradejunior high school students enrolled during 1996 wouldbe equal to that for the age groups 6–16 and 12–22 in1996 (since 10 years was considered the duration ofprotection).

Incidence of TB among nonrevaccinated cohort (Iuk).The hypothetical incidence of TB (Iuk) among a cohortof the same size not revaccinated can be calculatedusing the incidence of TB in the revaccinated cohort(I tk), vaccine efficacy (VE), and proportion of revacci-nated (PV) population (see Appendix).

Proportion of cohort being revaccinated. The pro-portions of first grade primary and first grade juniorhigh school students who underwent BCG revaccina-tion were calculated from published reports [11,15].

TB mortality. We assumed that TB-related deathwould not occur for 10 years after revaccination be-cause no such event has been reported among the pop-ulation of the 6- to 22-year-olds in recent years inJapan.

BCG side effects. Very little information is avail-able on the side effects of BCG revaccination in Japan.Although 0.5% of the first grade primary school stu-dents and 0.9% of the first grade junior high schoolstudents were reported to have lymphadenopathy asfound in a snap survey [12], very few of them visitedphysicians. Since treatment of BCG side effects is sup-ported by the government, every adverse effect of BCGis reported to the appropriate authority. Accordingly,only 19 cases of BCG side effects (lymphadenopathy,local ulceration, and fever) among children aged 6–15years were reported in a year [12]. We assumed thesame rate among the schoolchildren. The incidences ofother extremely rare but severe side effects such asBCG osteomyelitis or disseminated BCG infection werenot included in this analysis since no relevant data areavailable.

RESULTS

Cost of Revaccination Program

The total cost associated with revaccination programwas US$ 32.1 million. The major components of costwere, in declining order, personnel (US$ 19.1 million),BCG vaccines (US$ 5.0 million), multiple puncturedisks (US$ 3.9 million), PPD test kits (US$ 3.1 million),PPD follow-up (US$ 1.0 million), and treatment of BCGside effects (US$ 1,159).

72 RAHMAN ET AL.

Number of TB Cases Averted

The estimated total number of TB cases averted byrevaccinating 2.86 million first year primary and jun-ior high school students enrolled in 1996 is 296. Of 296cases, 90 would be averted in the first 5 years afterBCG revaccination, with the remaining 206 appearingin the last 5 years.

Benefits of Revaccination Program

Benefits of the revaccination program have been cal-culated from the treatment costs saved for the avertedTB cases among the cohort of schoolchildren. AboutUS$ 2.7 million would be saved as treatment costs byaverting 296 TB cases.

Indirect Benefits

The major indirect benefit, that is, loss of work out-put due to tuberculosis morbidity, is estimated to beUS$ 1.6 million.

Number of Immunizations and Cost of Preventing aSingle Case of TB

The calculated cost and total number of immuniza-tions required to prevent one case of TB were US$108,378 and 4,963 injections, respectively. In otherwords, about 20 TB cases would be prevented by vac-cinating 100,000 schoolchildren.

Cost of Treating a Pulmonary TB

Based on some published parameters and expertopinion, the cost of treating a pulmonary TB in a 10-year-old child is estimated to be around US$ 11,576,which is much less than our estimated cost for preven-tion (US$ 108,378).

Benefit–Cost Ratio

Economic costs of revaccination far exceeded thebenefits. The benefit–cost ratio was 0.13 for baselineestimates.

First versus Second Revaccination

Separate analyses were undertaken to elicit andcompare costs, cost to prevent one case of TB, benefits,and benefit–cost ratios between the first and secondrevaccinations (Table 2). Since TB incidence is higheramong the older age groups, more TB cases would beaverted among them, and thus, the benefits andbenefit–cost ratio would be higher for revaccinationamong first year junior high school students thanamong first year primary school students. Similarly,the cost of preventing a case of TB is lower in theformer group than the latter.

Sensitivity Analyses

Sensitivity analyses (one- and two-way) examinedthe robustness of the estimates based on the underly-ing assumptions but none have shown benefits greaterthan costs (Figs. 1–3). The major uncertainties such asvaccine efficacy and duration of protection were pro-portionally related to benefit–cost ratio and inverselyrelated to cost and number of immunizations to pre-vent one case of TB (Figs. 1, 2). Variation of factors likevaccine efficacy, duration of BCG protection, and TBincidence rate change the benefit–cost ratio but failedto bring the ratio near 1 even after considering themost favorable vaccine efficacy and duration of protec-tion and higher TB incidence (Fig. 1). These factorsalso did not reduce the cost of preventing one case ofTB to the cost of treating a TB case (Fig. 2). Doublingthe TB incidence rates, for instance, would changecosts and number of immunizations to half of baselinevalues, and change the benefit–cost ratio from 0.13 to

TABLE 2

Comparative Features of Revaccination Program between First Grade Primary School Students andFirst Grade Junior High School Students

CategoryFirst grade

primary school studentsFirst grade

junior high school students

Year of enrollment 1996 1996Number of students (in million) 1.35 1.51Number of BCG revaccinations (in millions) 0.89 0.58Number of TB cases averted:

0–5 years after revaccination 35 556–10 years after revaccination 56 150

Cost to prevent one case of TB (US$) 197,865 68,482Number of immunizations required to prevent a single TB case 9,773 2,819Total estimated costs of the program (million US$) 18.1 14.0Total benefit of the program (million US$) 1.36 2.93Benefit–cost ratio 0.08 0.21

73BCG REVACCINATION IN JAPAN

0.27. The cost of treating a TB case might vary fromcase to case. So we included costs that were double andtriple the baseline value, and found only slight changesin benefit–cost ratios (Fig. 2). Variation in the discountrate (0–10%) impacted the cost of preventing a case ofTB and the benefit–cost ratio minimally (Figs. 1, 2).

DISCUSSION

The cost (US$ 108,378) of preventing a single case ofTB appears to be very high when compared with thecost (US$ 11,576) of treating a single patient (pulmo-nary TB). Benefit–cost ratios remain well below 1 evenafter considering highly favorable conditions (highervaccine efficacy and duration of protection) for revac-cination (Fig. 3). The cost for BCG revaccination inJapan is about US$ 32.1 million annually, whereasmaximum benefits in two-way sensitivity analysis re-mained at US$ 23.6 million (considering 90% vaccineefficacy and 300% treatment cost compared with ourbaseline estimates). However, the cost per TB patient

treated could be more expensive than the estimatedfigure if the prevalence of drug-resistant TB (includingmultiple-drug-resistant cases) increased.

The limitations of this study are those attributable tothe veracity of the data sources and to the manner ofinterpreting the results. There is no established reporton BCG revaccination efficacy in Japan. Therefore, weused the data derived from meta-analysis of multiplestudies conducted in countries other than Japan as thebaseline value for vaccine efficacy. In addition, sinceTB-related mortality has not been reported among 6- to22-year-olds in Japan in recent years, conventionalindices of cost-effectiveness such as cost per life yeargained are not appropriate. Therefore, the study re-sults are described as the cost of preventing one case ofTB and benefit–cost ratios.

Tuberculous meningitis (TBM) sometimes yields avariety of complications including permanent disabil-ity. Its prevention could be an important reason tocontinue revaccination. Since this disease is not re-

FIG. 2. One-way sensitivity analyses on cost to prevent one case of TB by vaccine efficacy, duration of BCG protection, TB incidence, anddiscount rate. TB treatment cost in future does not have any impact on cost to prevent a case of TB, so we did not include it in sensitivityanalyses.

FIG. 1. One-way sensitivity analyses of benefit–cost ratio on vaccine efficacy, duration of BCG protection, TB incidence rate, TBtreatment cost, and discount rate.

74 RAHMAN ET AL.

ported among the schoolchildren, revaccination doesnot have any role in its prevention.

A recent study revealed that BCG vaccination low-ered the incidence of asthma and other atopic disordersamong Japanese children by modification of immuneprofiles (by lowering IgE levels) [20]. Of course, thebenefit from this new finding depends on the incidenceof atopic disorders and the efficacy of BCG in loweringit. This benefit, if included in our calculation, couldchange the ratio to some extent. But due to the lack ofreliable data this benefit could not be incorporated intothe benefit–cost ratio.

Although we assumed the efficacy of BCG revaccina-tion to be 50% in a baseline estimate, revaccinationdata generated from other countries did show lower orno efficacy. A study from Finland reported very low orno efficacy in BCG revaccination [21]. A recent study, acontrolled trial from Malawi, concluded that BCG re-vaccination provided no protection against TB [9].Moreover, it was shown to be harmful in HIV-infectedindividuals, in whom the actual risk of pulmonary TBincreased. Furthermore, the World Health Organiza-tion also has a negative attitude regarding revaccina-tion in its new recommendation [22].

BCG side effects can occasionally be life-threatening.Two patients with severe combined immunodeficiencysyndrome have been identified among BCG vaccineesin their infancy during the last 10 years in Japan[23,24]. Two severe disseminated BCG infections werealso reported among schoolchildren after revaccina-tion, one of whom died [25,26]. The costs required tocontrol and compensate severe adverse outcomes (such

as BCG osteomyelitis and disseminated BCG infection)could be very high and were not included in our anal-ysis because of their rarity and the lack of frequencydata. If those costs were included, the cost of prevent-ing a single case of TB would be higher and thebenefit–cost ratio lower than the baseline values. Inaddition, frequent minor side effects of BCG can resultin more compensation claims in the developed coun-tries like Japan, and thus cost–effectiveness woulddecrease further.

Chemoprophylaxis of PPD positives (elicited by tu-berculin screening before BCG revaccination) wouldprevent a proportion of TB cases as reported [27], butwe did not include it in the analysis. Thus, if thosewere included, the cost of preventing a single case ofTB would be somewhat lower and the benefit–costratio a little bit higher than the estimated values.

Japan’s BCG revaccination policy focuses on thoseschoolchildren who did not have their first BCG shot inearly childhood and also on those who have PPD-negative test results. The former category comprisesonly about 5% of the total cohort while the latter com-prises 66% of first grade primary schoolchildren and38% of first grade junior high school students [11].Since postvaccinal conversion status is not an indica-tion of immunity against TB [28], justification of revac-cination on the basis of tuberculin testing results is notvalid. Again, the cost effectiveness of universal BCGvaccination also did not appear feasible [16]. Thus,BCG revaccination for 5% unvaccinated children alsohas become controversial. So, considering the very lowincidence of TB among children �15 years (2.1 per100,000, whereas in the United States it is 3.1) [29] inJapan, lack of evidence of the effectiveness of BCGrevaccination, results of economic evaluation elicitedfrom this study, the controversy over TB immunity andpostvaccinal conversion status, and the unfavorablecost effectiveness of universal BCG vaccination in Ja-pan, BCG revaccination appears to be an inefficient TBprevention strategy in Japan.

Our study suggests that discontinuing the BCG re-vaccination program would cause net financial savingswhich ought to be invested in other priority sectors.Comprehensive tuberculin testing in contact tracingand control of microepidemics appear to be priorityareas for elimination of TB in Japan.

We conclude that, from an economic point of view,based on the best available data and estimates, BCGrevaccination is not favorable in the current Japanesesituation.

APPENDIX

In a cohort where the incidence of TB among revac-cinated and nonrevaccinated individuals is I v and Iu,vaccine efficacy (VE) for that cohort would be

FIG. 3. Two-way sensitivity analyses of benefit–cost ratio.

75BCG REVACCINATION IN JAPAN

VE � �Iu � Iv�/Iu � 100 �as percentage�, (1)

VE � �Iu � Iv�/Iu �as proportion�. (2)

Where the proportion of revaccinated individuals is PVand the population of the cohort is N, the total numberof TB cases in that cohort in a given year (kth year) isequal to the total number of TB cases among the re-vaccinated plus the total number among the nonrevac-cinated. Let us assume I tk is the incidence of TB. So,

N � Itk � Ivk � PV � N � Iuk � �I � PV� � N

or

Itk � Ivk � PV � Iuk � �1 � PV�

� �1 � VE�Iuk � PV � �1 � PV�Iuk �from Eq. 2�

� Iuk�1 � PV � VE�

or

Iuk � Itk/�1 � PV � VE� (3)

Without the BCG revaccination program, the inci-dence of TB would be Iuk among the cohort. So thenumber of TB cases prevented (P tbk) in a given yearwould be

Ptbk � N�Iuk � Itk�

� N�Itk/�1 � PV � VE� � Itk �from Eq. 3�

� �N � Itk � PV � VE�/�1 � PV � VE�(4)

� �N � Itk � PV � VE�/�1 � PV � VE�.

So during 10 years (duration of protection of BCGrevaccination against TB) the total number of TB casesprevented would be equal to

Ptb � �N � It1 � PV � VE�/�1 � PV � VE�

� �N � It2 � PV � VE�/�1 � PV � VE�

� · · · �N � It10 � PV � VE�/�1 � PV � VE�

�N � PV � VE�1 � VE � VE�

� �k

10 Itk

�1 � r� k�1

ACKNOWLEDGMENTS

We are indebted to Takateru Izumi (Professor Emeritus, KyotoUniversity) for his help with the development of research protocol; toToru Mori (The Research Institute of Tuberculosis) for his usefulsuggestions; to Mr. Toru Yoshikawa (Kyoto City Corp.) for providingvaluable information; to Mr. Yoshinori Hattori (Osaka Sangyo Uni-versity) for his contribution to the methodology; and to Ms. Yoshiko

Kazami (The Research Institute of Tuberculosis) for her help inliterature review and collection.

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