BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control

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1 For reprint orders, please contact BCG vaccination and leprosy protection: review of current evidence and status of BCG in leprosy control Expert Rev. Vaccines 9(2), (2010) Corinne SC Merle, Sergio S Cunha and Laura C Rodrigues Author for correspondence Department of Epidemiology and Population Health, Tropical Epidemiological Group, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK Tel.: Fax: corinne.merle@lshtm.ac.uk The bacillus Calmette Guérin (BCG) vaccine, initially developed to provide protection against TB, also protects against leprosy; and the magnitude of this effect varies. Previous meta-analyses did not provide a summary estimate of the efficacy due to the heterogeneity of the results. We conducted a meta-analysis of published data including recently published studies (up to June 2009) to determine the efficacy of BCG protection on leprosy and to investigate whether age at vaccination, clinical form, number of doses, type of study, the latitude of study area and year of publication influence the degree of efficacy and explain the variation. In the light of the results, we argue for more emphasis on the role of BCG vaccination in leprosy control and research. Keywords: bacillus Calmette Guérin BCG efficacy efficiency leprosy meta-analysis review vaccine protection Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae, primarily affecting the peripheral nerves and skin. Among infectious diseases, leprosy is a leading cause of permanent physical impairment. Three major endemic countries (India, Brazil and Indonesia) account for 81% of all new cases [1]. Globally, the annual detection of new cases continues to decline, from a peak of more than 763,000 in 2001 to 254,525 in 2007 [1]. The basic principles for leprosy control are based on early diagnosis and treatment with multidrug therapy (MDT). Although bacillus Calmette Guérin (BCG) vaccination was originally developed as a vaccine against TB, it has also been demonstrated to offer protection against leprosy [2 4]. Its protective effect has been shown in various studies, ranging from 20 to 90%, and its role in reducing the incidence of leprosy is mentioned in various reports of the WHO, such as the last one on the strategy for further reducing the disease burden due to leprosy [101]. Since the level of protection is variable (as is BCG protection against pulmonary TB) none of the reviews aimed to produce estimates of the potential impact of BCG vaccination on leprosy burden and control [2 4]. The reasons for the variation in protection are not known. Several questions about BCG vaccination and leprosy remain unanswered, including the duration of protective immunity, whether the protective efficacy in multi bacillary forms is different to paucibacillary ones, whether age at vaccination affects protection and whether latitude is related to the level of protection (as it is for TB) [5]. In this review, we aim to give an update on current evidence, point to a lack of evidence regarding these questions and, in light of the results, we discuss the current and future status of BCG vaccination in leprosy control. Methods Literature search A systematic bibliographic search of the medical literature published from 1 January 1960 until 1 June 2009 was conducted through electronic databases including Medline and Latin America & Caribbean Health Sciences (LILACS). The search was performed using and combining the following index terms: BCG efficacy, BCG effectiveness, leprosy protection, protective effect and leprosy vaccine. In addition, a systematic manual search of bibliographies /ERV Expert Reviews Ltd ISSN

2 Merle, Cunha & Rodrigues of every relevant study retrieved from the electronic search and from review articles was performed. The contents of all potential articles identified through the literature search were reviewed independently by two investigators (Merle and Cunha). Inclusion & exclusion criteria All human studies, experimental or observational, published in English, Portuguese, Spanish or French, and measuring the efficacy or effectiveness of BCG vaccination in preventing leprosy cases were considered for inclusion in the meta-ana lysis. Crosssectional studies, studies based on comparison of before after intervention, or studies where efficacy was assessed on serum conversion or skin test outcomes instead of leprosy disease were not included. For trials, we selected only controlled trials with a clearly defined placebo (or nonintervention) group. To be included in the analysis, case control studies had to define the criteria for selecting cases and controls, and the method for determining their BCG vaccination status. If multiple reports of a single study were published, the most complete (in terms of duration of follow-up or study population) was included. Selection criteria were defined before the literature search was performed in order to avoid selection bias. Data collection The authors and year of publication, the study characteristics (i.e., study design, target population, study period, study area, type of vaccine used and number of BCG doses received), vaccine effect estimates (rate ratio or risk ratio [RR] or odds ratio [OR]) and their corresponding 95% confidence intervals provided by the reports were extracted. Adjusted (rather than crude) estimates were considered if available. When the RR and/or OR and their confidence intervals were not available, they were estimated from the raw data in the reports. Data analysis Characteristics of study design and study population, separately for trials, case control studies and cohorts were described. Vaccine efficacy, defined as 100 (1-RRs or ORs), were calculated. A meta-ana lysis was conducted, aiming: To summarize BCG effect estimates (pooled estimate and separate ones for each type of study design); To assess the presence of heterogeneity; To try to identify possible sources of heterogeneity. Information on vaccine efficacy specific to clinical forms (paucibacillary and multibacillary forms) or for specific age groups (younger or older than 15 years at vaccination) were also summarized in two meta-analyses, including a subset of studies with relevant data. Since leprosy is a disease with low incidence, RRs or ORs are numerically similar and so estimates of protection, whether ORs or RRs (from different types of study), were analyzed together, as suggested by Greenland et al. [6]. We proposed to estimate pooled effects using a fixed-effects model (based on the inverse variance method [7]) when there was no significant hetero geneity, and a random-effects model with their respective 95% confidence intervals if evidence of heterogeneity in results was found. The significance cutoff value of 0.1 was used to decide whether or not there was heterogeneity [8]. We developed a random-effects regression model to investigate the source of heterogeneity in the efficacy of the BCG vaccine reported in individual studies and for the two sub-meta -analyses mentioned earlier. Meta-regressions were weighted with the inverse of the standard error of the estimates, and the between-study variance estimated through restricted maximum likelihood [9]. Regression analyses were limited to five variables potentially associated with BCG efficacy based on the literature review as well as data availability and accuracy: latitude of study area (as a continuous variable corresponding to degree from equator line), study design (trials vs observational studies), dose of BCG received (one dose vs more than one dose), the target population of the study (general population vs contacts of leprosy patients) and the year of publication (as a continuous variable). Finally, we used a funnel plot approach, as well as Begg s and Egger s tests, to investigate potential publication bias or bias for other reasons in this meta-ana lysis. All the analyses were performed using Stata version 10. Results A total of 272 titles or abstracts were examined (242 citations in Medline and 30 in LILACS). We identified 28 suitable studies that were included in the analysis: five trials [10 14], six cohort studies [15 20] and 17 case control studies [18,21 36]. A study conducted in Venezuela by Convit et al. was excluded as it did not estimate vaccine protection [37], but rather investigated killed Mycobacterium leprae plus BCG, compared with BCG alone. Another observational study conducted in India by Chaudhury et al. was excluded because it compared three groups vaccinated with different vaccines (one being BCG alone) but had no unvaccinated group [38]. A trial in Vietnam by Truoc et al. was excluded because the intervention allocation was not satisfactory [39]. Finally, two randomized control trials, one in Malawi conducted by the Karonga group [40] and a cluster-randomized trial conducted by Cunha et al. in Brazil [41] were not included in the main metaana lysis as they assessed the efficacy of BCG revaccination only and did not estimate the efficacy of one dose of the BCG vaccine. Tables 1 & 2 describe the characteristics of all the studies included in the meta-analysis, along with the point estimate of BCG vaccine efficacy against leprosy. BCG protection against leprosy Figure 1 shows the efficacy by type of study and overall, sorted by latitude in a forest plot obtained in the meta-analysis. Vaccine protection in experimental studies (n = 5) ranged from 20 [12] to 48% [10] for the general population and was approximately 80% for individuals who had contact with a leprosy case [13]. Combining data from the five trials using a random-effects model (instead of a fixed-effects model due to significant heterogeneity of the results) gave a RR for leprosy protection of 0.59 (95% CI: ) equivalent to an overall vaccine 210 Expert Rev. Vaccines 9(2), (2010)

3 BCG vaccination & leprosy protection Review Table 1. Characteristics of the trials and cohort studies used in the meta-analysis and estimates of vaccine protection of BCG against leprosy (n = 11). Study (year) Study area Followup years Trials Stanley et al. (1981) Bagshawe et al. (1989) Lwin et al. (1985) Tripathy et al. (1983) Gupte et al. (1998) Cohort studies Fine et al. (1986) Ponnighaus et al. (1992) Matos et al. (1999) Cunha et al. (2004) Goulart et al. (2008) Duppre et al. (2008) Uganda (Soroti) Papua New Guinea Source population Individuals (n) Leprosy cases (n) Latitude Vaccine used Vaccine protection % (95% CI) 8 Contacts 16, Glaxo 80 (72 86) [13] 16 General Japan 48 (34 59) [10] Myamar 14 General 25, Glaxo 20 (12 28) [12] India 12 General 191,696 10, French (2) Danish (1) Ref. 24 (21 28) [14] India 8 General 171, India 34 (13 50) [11] Malawi 5 General 79, NA 57 (24 74) [18] Malawi 4 General 91, NA 49 (33 61) [20] Brazil 4 Contact NA 62 (33 78) [16] Brazil 4 School children 112, NA 41 (12 60) * [15] Brazil 5 Contact NA 53 (41 87) [19] Brazil 5 Contact NA 59 (27 77) [17] * BCG protection for the historical cohort. BCG protection among scar-negative contacts prior BCG vaccination. BCG: Bacillus Calmette Guérin; NA: Not available. protection of 41%. All cohort studies showed significant protection of BCG against leprosy. The pooled estimate using a fixedeffects model was 0.42 (95% CI: ), corresponding to an overall vaccine protection of 58%. Overall, 14 out of the 17 case control studies showed a statistically significant vaccine protection varying from 20 [28] to 90% [27]. Among the case control studies, the only study restricted to contacts showed an overall vaccine protection of 56% (95% CI: 27 74) [25], but in this study the population received one or more doses of BCG. Owing to the heterogeneity of the results, we used a randomeffects model to pool the estimates, which produced a combined OR of 0.40 corresponding to an overall vaccine protection of 60% (95% CI: 51 70%) (Figure 1). Meta-regression In univariate meta-regression, the proportion of variation in BCG protection explained by each of the variables was: the latitude of the study area: 1.2%; the number of doses of BCG: 6.8%; the target population (whether contacts or general population): 25.6%; the year of publication: 45.8%; and the type of study: 51.15%. When combining all covariates in the random multivariable meta-regression model, there was no statistical evidence that the number of doses of BCG, the latitude or the years of publication were contributing to the heterogeneity of the BCG efficacy between the studies. There was still some evidence that the type of study design interfered with the results. The BCG efficacy was found to be larger in observational studies than in trials: 0.40 (95% CI: ) versus 0.59 (95% CI: ) (p = 0.09) (Table 3). The only aspect that significantly explained the heterogeneity of the results after adjustment was the target population of the study, whether they were contacts of leprosy cases or the general population. BCG efficacy seemed to be significantly higher among contacts of leprosy patients than among the general population (p = 0.03). Vaccine protection & clinical forms Table 4 presents vaccine efficacy estimates by clinical forms (i.e., paucibacillary and multibacillary forms). This analysis only included studies that reported BCG protection separately by clinical forms

4 Merle, Cunha & Rodrigues Table 2. Characteristics of the case control studies used in the meta-analysis and estimates of vaccine protection of BCG against leprosy (n = 17). Study (year) Fine et al. (1986) Abel et al. (1990) Muliyil et al. (1991) Rodrigues et al. (1992) Baker et al. (1993) Convit et al. (1993) Orege et al. (1993) Thuc et al. (1994) Boelens et al. (1995) Lombardi et al. (1996) Bertolli et al. (1997) Zodpey et al. (1998) Zodpey et al. (1999) Zodpey et al. (2005) Kerr-pontes et al. (2006) Rahete et al. (2007) Zodpey et al. (2007) Study area Case Controls Latitude Vaccine used Vaccine protection n Source n Source % (95% CI) Malawi 260 Survey All population Ref. Community 9 56 Glaxo 36 (16 51) [18] Vietnam 50 Health service 50 Hospital Pasteur 48(-15 77) [21] India (Vellore) 397 Community 669 Community Copenhagen 20 (-10 41) [28] Brazil 62 Health service 186 School Moreau 81 (63 90) [31] Malawi 145 Community 290 Community Glaxo 64 (42 77) [22] Venezuela 90 Survey contact 3641 Survey contact 7 06 NA 56 (27 74) [25] Kenya 69 Health service 238 Community 0 06 Glaxo 81 (67 90) [29] Vietnam 177 Health service 354 Community Saigon- Pasteur, Canadian and Japanese 29 (-10 55) [32] Indonesia 115 NA 326 Community 5 07 NA 76 (39 90) [24] Brazil 97 Health service 385 Community Moreau 90 (78 96) [27] Myanmar 245 Health service 245 Community NA 66 (44 80) [23] India 314 Health service 314 Hospital Danish 71 (59 79) [36] India 212 Survey 212 Survey Danish 60 (31 76) [34] India 364 Survey 364 Survey Danish 54 (39 66) [33] Brazil (NE) 226 Health service 857 Community 7 12 NA 52 (30 67) [26] India (Raipur) 201 Health service 201 Community NA 35 (-04 60) [30] India (Nagpur) BCG: Bacillus Calmette Guérin; NA: Not available. 292 Health service 292 Health service NA 62 (45 74) [35] Taking all studies together, there was greater variability of the BCG vaccine effect against paucibacillary forms, whereas the estimates for multibacillary forms were more homogeneous. The pooled protections were 76% (95% CI: 69 83%) for multibacillary forms and 62% (95% CI: 51 73%) for paucibacillary forms. After adjustment for two covariates: number of dose of BCG delivered and type of study design in a random-effects meta-regression model, we failed to find a statistically significant difference in BCG protection against multibacillary and paucibacillary leprosy forms. Vaccine protection & age at vaccination In all trials, vaccine protection was reported to be larger for subjects vaccinated at younger age compared with those vaccinated after 15 years of age. In all the cohort studies, BCG vaccination was given to children under 15 years of age. There are, therefore, no estimates available for the subgroup of subjects over 15 years of age. For case control studies, despite the fact that the study population of several studies had a broad age range, estimates by age at vaccination were not provided or were not clear enough 212 Expert Rev. Vaccines 9(2), (2010)

5 BCG vaccination & leprosy protection Review Study Year of publication Latitude of trial area ES (95% CI) % Weight Trial Stanley et al Bagshawe et al Tripathy et al Gupte et al Lwin et al Subtotal (l-squared = 98.1%, p = 0.000) 0.20 (0.14, 0.28) 0.52 (0.41, 0.66) 0.76 (0.72, 0.79) 0.66 (0.50, 0.87) 0.80 (0.72, 0.88) 0.59 (0.34, 0.84) Cohort Cunha et al Fine et al Ponnighaus et al Boulart et al Duppre et al Matos et al Subtotal (l-squared = 0.0%, p = 0.521) 0.59 (0.40, 0.88) 0.43 (0.26, 0.76) 0.51 (0.26, 0.76) 0.27 (0.13, 0.59) 0.41 (0.33, 0.63) 0.38 (0.22, 0.67) 0.42 (0.34, 0.51) Case control Orege et al Boelens et al Kerr-pontes et al Convit et al. Fine et al. b Thuc et al Abel et al Muliyil et al Baker et al. Bertolli et al Rodrigues et al Zodpey et al. c Rahete et al Zodpey et al Zodpey et al. d Zodpey et al. b Lombardi et al Subtotal (l-squared = 80.0%, p = 0.000) 0.19 (0.10, 0.33) 0.24 (0.10, 0.61) 0.48 (0.33, 0.70) 0.44 (0.26, 0.73) 0.66 (0.49, 0.84) 0.71 (0.45, 1.10) 0.52 (0.23, 1.15) 0.80 (0.59, 1.10) 0.36 (0.23, 0.58) 0.34 (0.20, 0.56) 0.19 (0.10, 0.37) 0.46 (0.34, 0.61) 0.65 (0.40, 1.04) 0.29 (0.21, 0.41) 0.38 (0.26, 0.55) 0.40 (0.24, 0.69) 0.10 (0.04, 0.22) 0.40 (0.30, 0.49) Overall (l-squared = 94.6%, p = 0.000) Note: weights are from random-effects analysis 0.45 (0.34, 0.56) RR or OR No protection Figure 1. Forest plot displaying a fully Bayesien meta-analysis (random-effects model) of the effect of BCG vaccine on leprosy overall, stratified by type of study design and sorted by the latitude of the study area (n = 28). BCG: Bacillus Calmette Guérin; ES: Point estimate (OR or RR); OR: Odds ratio; RR: Risk ratio. to be taken into consideration in the meta-ana lysis. BCG vaccine effects (RRs and ORs) against leprosy by age at vaccination for the study included in the meta-ana lysis are shown in Table 3 with corresponding pooled-effect estimates by type of study design; the overall pooled efficacy for BCG given before the age of 15 years was 57%. There were not sufficient data for subjects vaccinated after 15 years of age to allow meta-regression in order to investigate the difference in BCG protection according to age at vaccination. Publication bias Begg s funnel plots were used to investigate publication bias. The plot shows evidence of publication bias with a p value of for the correlation between the point estimate and its standard error. When stratifying according to the type of study design, evidence of bias of the estimates was essentially limited to case control studies (Begg s test and Egger s test concordant with p = 0.03 and p = 0.02, respectively). Figure 2 gives a summary of the results of the Begg s and Egger s tests and presents the funnel plot for case control studies. It shows a clear asymmetry in the funnel plot, suggesting that small case control studies with a low efficacy were less likely to be published than those finding a large efficacy. Discussion There is consistent evidence that BCG protects against leprosy. However, the magnitude of such a protection varies greatly in different studies and is estimated to be approximately 41% (95% CI: 213

6 Merle, Cunha & Rodrigues Table 3. Meta-regression model to explain heterogeneity in the efficacy of BCG vaccine against leprosy (n = 28). Study characteristics considered in the meta-regression model Dose of BCG BCG efficacy (95% CI) in subgroup analysis 1 dose of BCG 55% (42 67) doses or more 59% (50 68) 0.43 Type of study Experimental studies 41% (16 66) 0.09 Observational studies 60% (52 67) 0.09 Target population studied General population 53% (41 64) * 0.03 Contact subject 68% (56 80) 0.03 Latitude of study area 0.29 Years of publication of the study %) for trials and 60% (95% CI: 51 70%) for observational studies. We investigated whether the hetero geneity of the results was influenced by the latitude of the study area, the number of BCG doses delivered, the year of publication of the study, the study design and whether the population was general or contacts of leprosy cases. Although there were differences, perhaps owing to a lack of power, we did not find statistically significant evidence that the heterogeneity of the results across all studies was explained by latitude of the study area, the number of BCG doses received or the year of publication of the study. There is some evidence of variation of the BCG efficacy depending of the study design, with an estimated higher protective effect in observational studies compared with trials, and some indication of publication bias in case control studies. Finally, we found a statistically significant higher protective effect of the BCG vaccination if studies were conducted among household contacts instead of the general population, even after adjustment for the number of doses of BCG received, the type of the study design, the year of publication and the latitude of the study area. We did not find statistical evidence of a difference in protection against multibacillary and paucibacillary clinical forms. The available data did not permit a reliable analysis to be carried out to assess the difference of vaccine protection conferred for children vaccinated before 15 years of age compared with later vaccination. Heterogeneity in the protective efficacy of BCG There is overwhelming evidence that BCG can offer protection against leprosy, but that the level of protection varies. Owing to the heterogeneity, we used a random-effects model instead p-values (metaregression model) * 30% BCG efficacy (95% CI: 20 40) for experimental studies and 59% BCG efficacy (95% CI: 50 68) for observational studies. 80% BCG efficacy (95% CI: 73 87) for experimental studies and 62% BCG efficacy (95% CI: 52 72) for observational studies. Continuous variable. BCG: Bacillus Calmette Guérin. of a fixed-effects model to investigate the reasons behind the hetero geneity. Factors considered for the meta-regression and other aspects that could influence the findings are discussed in the following sections. Importance of the study design A debate continues in the literature as to whether one should include observational studies in a meta-ana lysis [42,43], if results from different study designs should be combined or analyzed separately [44], and whether if observational and interventional studies disagree, the trials are always right. The existence of unknown and unmeasured confounding factors in observational studies is the main criticism. Furthermore, trials and observational studies aim to answer different questions: except by pragmatic trials, most randomized controlled trials are concerned with vaccine protection under controlled conditions, close to ideal conditions, and so with vaccine efficacy. Observational studies are concerned with estimates of vaccine effectiveness and protection under routine conditions. We found in our meta-analysis that 48% of the heterogeneity of the results could be explained by the type of study. Therefore, pooled estimates have to be considered with caution. We decided to present them separately for trials and observational studies and to adjust on this factor when conducting the meta-regression. Other methodological aspects specific to some study designs may explain the difference in efficacy depending on the study design. Length of follow-up is an important factor to take into consideration. In various experimental or cohort studies [11,12,16,17,41] an increased risk of leprosy has been noticed among the population exposed to BCG during the first year of follow-up. The explanation offered for this paradoxical finding is that BCG vaccination may induce the emergence of leprosy clinical manifestations among asymptomatic infected individuals during the initial period of follow-up. It is worth distinguishing whether vaccine unmasks clinical symptoms among people who would ultimately develop the disease later without vaccination, or whether it triggers clinical symptoms among people who would not have developed the disease if they were not vaccinated. There is currently no evidence to support one view or the other. However, in practice, this implies the need for a sufficient follow-up period of the study population in order to draw reliable conclusions about BCG protection. It may explain the variability of efficacy estimates from one study to another depending on the length of the follow-up period. The reliability of BCG scar reading to ascertain whether or not BCG vaccination has been performed is a matter of concern in observational studies, and it has been studied by various teams. Rodrigues et al. found an overall good specificity (90%) and sensitivity (98%) of scar reading in Brazil [45]. In Malawi, Floyd et al. 214 Expert Rev. Vaccines 9(2), (2010)

7 BCG vaccination & leprosy protection Review also found that BCG scar reading is overall a highly sensitive and repeatable indicator of BCG vaccination (93 and 94%, respectively) but when focusing on the population of infants vaccinated when younger than 1 month of age, they found that less than 80% had still recognizable scars 4 years later [46]. Given that most vaccinations in the world are administered soon after birth, this low sensitivity may lead to an underestimation of BCG protection in observational studies in which vaccination status is inferred from the presence or absence of a distinctive BCG scar. Paradoxically, in our meta-ana lysis we found a higher BCG vaccine effectiveness in observational studies compared with vaccine efficacy observed in trials (as was the case in other trials [2,4]), which should be the opposite if the measurement of vaccine protection was biased by misclassification of previous BCG exposure. Even if BCG scar reading is not a perfect indicator of previous BCG vaccination, it cannot explain the difference in terms of BCG protection noticed between observational studies and trials. Number of doses of BCG vaccination & benefits of revaccination We found no statistical difference in BCG protection between studies where patients are vaccinated once (55%; 95% CI: 42 67%) and studies where patients are vaccinated twice or more (59%; 95% CI: 50 68%), with a p value of It is unlikely that the variability of the BCG efficacy between studies could be explained by the number of BCG doses received by the study population in one study compared with another. There is also no consistency on whether revaccination always provides additional protection. The two large trials conducted had very different results: a recent cluster randomized trial conducted by Cunha et al. among 99,770 school children 7 14 years of age and followed for 6 years in Brazil found an incidence rate ratio of leprosy of 0.99 in the revaccinated group compared with the control group (95% CI: ), indicating no obvious gain of protection with revaccination [41]. By contrast, Fine et al. found in a randomized controlled trial conducted in northern Malawi that a second BCG vaccination affords 49% protection (95% CI: 0 75%) against leprosy [40]. The main difference between these two studies is the nature of the revaccinated population, which was restricted to school children in the study in Brazil and involved a broader age range of infants to adults in Malawi. Revaccination might give additional protection to adults for whom the efficacy of the first vaccination waned with time but, as shown by Cunha et al., there might be no benefit of revaccination when it is performed in school children. More studies need to be undertaken in order to draw a reliable conclusion; the level of vaccine protection from revaccination may vary from place to place. Exposure to environmental mycobacteria Many species of bacteria of the genus Mycobacterium are found in the external environment, such as water and soil. There is growing evidence that the exposure of a population to other mycobacteria might interfere with the efficacy of the BCG vaccine against TB and leprosy [47]. Individuals exposed to environmental mycobacteria (EM) could have some degree of acquired natural immunity against leprosy, and BCG may not offer additional protection to these individuals already exposed to EM. Therefore, the observed vaccine protection may depend on the prevalence of infection by EM in the study population, which varies in different regions throughout the world, and may explain in part the variation of the BCG protection from one study to another. There is no perfect variable that can embody the degree of exposure to EM. High humidity and temperature, as is found in tropical areas, favor the growth of such EM. Therefore, as investigated by Fine et al. for BCG protection against TB, we tried to adjust the results on vaccine protection on the latitude of the study area, considered as a proxy measure of myco bacterial exposition. We failed to find any relationship between the protection offered by BCG and the latitude of the study area, although all leprosy studies are carried out in tropical areas and thus there may not be enough variation in the case of leprosy studies; latitude contributes to only 4.3% of the heterogeneity. However, it is worth mentioning that humidity and temperature (likely to influence EM prevalence) do vary in different areas at the same latitude. Study population & vaccination of high-risk populations We found that BCG efficacy was significantly more important in studies when BCG vaccination was targeting household close contacts who are at higher risk of infection compared with the ones conducted in the general population (66% of protection for household close contacts versus 53% for the general population). It is noteworthy that leprosy has a long incubation period and it is difficult to define a clear date of onset. The main issue faced by the investigators conducting intervention among a contact population is the risk of misclassification of cases and controls. Duppre et al. found 28 new leprosy cases (21 cases in the BCG-vaccinated group) during the first 2 10 months of their study [17]. They made the assumption that these new cases were either within the incubation period or were mistakenly not diagnosed at the time of recruitment into the cohort study, and that BCG vaccination accelerated the natural history of Mycobacterium leprae infection in subjects infected prior to vaccination. Furthermore, it is not always easy to quantify the level of exposure of contacts and there might be variation in the definition of contact from one study to another. Lastly, the summary estimates found in this meta-ana lysis were heterogeneous, which obliged us to consider random-effects model estimates that give greater weight to less-precise studies and might therefore have undesired effects on the summary risk estimates. In summary, although we are still unable to explain the variation in estimates, these findings clearly show the effect of BCG in preventing leprosy, and suggest a role for routine BCG vaccination of all leprosy close contacts in addition to treatment of index cases. There is a need for further studies measuring the impact of such a strategy in order to guide vaccination policy in endemic countries, for example, cost effectiveness analyses and chemoprophylaxis followed by BCG vaccination. Publication bias & other factors We found some evidence of publication bias, especially among case control studies, which seems to show that small case control studies demonstrating low protection might be missing in 215

8 Merle, Cunha & Rodrigues Table 4. Vaccine effect (rate ratio and odds ratio) and 95% confidence intervals by study and clinical forms or age at vaccination. Study (year) Clinical form Age at vaccination Ref. Paucibacillary Multibacillary <15 years of age 15 years of age Trials Rate ratio (95% CI) Rate ratio (95% CI) Rate ratio (95% CI) Rate ratio (95% CI) Stanley et al. (1981) 0.20 ( ) NA 0.20 ( ) NA [13] Bagshawe et al. (1989) 0.53 ( ) 0.5 ( ) 0.46 ( ) 0.66 ( ) [10] Lwin et al. (1985) NA NA 0.76 ( ) NA [12] Tripathy et al. (1983) NA NA NA NA [14] Gupte et al. (1998) NA NA 0.63 ( ) 0.68 ( ) [11] Test of overall heterogeneity p < Not applicable p = p = 0.9 Pooled estimates 0.36 ( ) * 0.5 ( ) 0.41 ( ) 0.67 ( ) Cohort Rate ratio (95% CI) Rate ratio (95% CI) Rate ratio (95% CI) Rate ratio (95% CI) Fine et al. (1986) NA NA 0.43 ( ) Not applicable [18] Ponnighaus et al. (1992) 0.51 ( ) 0.16 ( ) 0.51 ( ) Not applicable [20] Cunha et al. (2004) 0.74 ( ) 0.33 ( ) 0.59 ( ) Not applicable [15] Goulart et al. (2008) NA NA 0.27 ( ) Not applicable [19] Duppre et al. (2008) 0.74 ( ) 0.15 ( ) 0.41 ( ) Not applicable [17] Test of overall heterogeneity p = 0.21 p = 0.51 p = 0.29 Pooled estimates 0.64 ( ) 0.23 ( ) 0.45 ( ) Case control studies Odds ratio (95% CI) Odds ratio (95% CI) Odds ratio (95% CI) Odds ratio (95% CI) Fine et al. (1986) NA NA 0.64 ( ) NA [18] Abel et al. (1990) 0.20 ( ) NA NA NA [21] Muliyil et al. (1991) NA 0.25 ( ) NA NA [28] Rodrigues et al. (1992) NA NA 0.19 ( ) NA [31] Baker et al. (1993) 0.26 ( ) 0.50 ( ) 0.36 ( ) NA [22] Orege et al. (1993) 0.17 ( ) 0.24 ( ) 0.19 ( ) NA [29] Thuc et al. (1994) 0.58 ( ) 0.90 ( ) 0.71 ( ) NA [32] Boelens et al., (1995) 1.00 ( ) 0.18 ( ) 0.24 ( ) NA [24] Lombardi et al. (1996) 0.10 ( ) 0.09 ( ) 0.10 ( ) NA [27] Bertolli et al. (1997) 0.26 ( ) 0.43 ( ) NA NA [23] Zodpey et al. (1998) 0.33 ( ) 0.21 ( ) NA NA [36] Zodpey et al. (1999) 0.55 ( ) 0.28 ( ) NA NA [34] Zodpey et al. (2005) 0.43 ( ) 0.32 ( ) NA NA [33] Test of overall heterogeneity p = 0.03 p = 0.66 p = Pooled estimates 0.28 ( ) * 0.23 ( ) 0.40 ( ) * Random-effect pooled estimate. Fixed-effect pooled estimate. NA: Not available. 216 Expert Rev. Vaccines 9(2), (2010)

9 BCG vaccination & leprosy protection Review Table 4. Vaccine effect (rate ratio and odds ratio) and 95% confidence intervals by study and clinical forms or age at vaccination (cont.). Study (year) Clinical form Age at vaccination Ref. All studies combined Test of overall heterogeneity Paucibacillary Multibacillary <15 years of age 15 years of age p = p = 0.75 p = 0.21 Pooled estimates 0.38 ( ) * 0.24 ( ) 0.43 ( ) * Random-effect pooled estimate. Fixed-effect pooled estimate. NA: Not available. this meta-analysis because they are unpublished. This might partly explain the overestimation of BCG efficacy reported in observational studies compared with trials. Many other factors may be suggested to explain the variability of BCG efficacy from one study to another. In short, these include: variation of Mycobacterium leprae strain in terms of growth pattern and drug resistance, variation of the vaccine BCG strain used, variation in the methods of administration and storage of BCG vaccines, problems with the follow-up of vaccinated and unvaccinated patients in long follow-up studies, variable susceptibility/genetics of the recipients, variable nutritional status, and the presence of coinfections with other organism such as helminths. Fine listed factors interfering with BCG efficacy against TB and most of these would also apply for leprosy [48]. Although there is evidence that all these factors might theoretically interfere with BCG efficacy, these are just hypotheses, and lack any conclusive proof. Protection of BCG against paucibacillary & multibacillary clinical forms We found that BCG protects against paucibacillary leprosy as well as multibacillary leprosy. Mulyil et al. hypothesized that BCG may shift cases from the multibacillary to the paucibacillary end of the leprosy spectrum by causing a shift in the overall cellmediated immune response, thus increasing the risk for milder and transient forms of leprosy while protecting against more serious forms, such as the multibacillary ones [28].Thus the drop in numbers of paucibacillary cases due to BCG vaccination might be masked by the change in the multibacillary paucibacillary shift. We did not find statistical evidence to support this hypothesis, even if there is a suggestion of low BCG protection for paucibacillary leprosy (62%; 95% CI: 51 72%) compared with multibacillary leprosy (76%; 95% CI: 69 83%). There is a lack of power due to the small number of studies that provide separate estimates for the paucibacillary and multibacillary forms (13 out of 28) and these have wide confidence intervals. There is also the problem of classification of the borderlines cases [12]. When comparing the percentage of patients vaccinated with BCG among multibacillary and paucibacillary cases, significant differences were found by Rodrigues et al. and, recently, by Schuring et al. [49] with a lower frequency of BCG vaccination among the multibacillary patients compared with the paucibacillary patients. This seems to support the hypothesis of a multibacillary paucibacillary leprosy shift due to BCG vaccination, but more studies need to be conducted in order to verify this. Age at vaccination & BCG efficacy Vaccine protection was reported to be higher in subjects vaccinated at a younger age compared with later vaccination (>15 years of age) in the trial in Papua New Guinea [10] and in the trial of Gupte et al. in India (Table 4) [11]. Among the observational studies, all subjects were vaccinated via routine BCG programs at a young age, which do not allow estimates to be obtained for a comparison with subjects vaccinated after 15 years of age. Therefore, there are not enough data to explore whether vaccination is more efficient when given at a younger age. Length of the protective efficacy of BCG Little is known in the literature concerning the duration of the protection conferred by BCG against leprosy. In all trials, there was a small decline in the vaccine protection observed at the end of the follow-up period, which was up to 16 years in the trial in Papua New Guinea. In a case control study conducted by Zodpey in India where BCG vaccination is performed during infancy, patients older than 20 years of age were less protected against leprosy compared with younger subjects but the protection was still not negligible and estimated to be approximately 43% [33]. This is clear evidence that protection can still be present 20 years after vaccination. Rodrigues et al. found similar results in a case control study in Brazil a country where BCG is also administered routinely during infancy with a BCG protection of 84% for the age group years, 54% for ages years and surprisingly 32% in the group 40 years of age or older [45]. In conclusion, BCG protection wanes with time but may last for 30 years and possibly longer. Place of BCG in the leprosy control strategy In conclusion, there is very solid evidence of BCG protection against leprosy among the general population, and this protection might be even higher in populations at a higher risk of leprosy, such as household contacts. That protection, however, might vary in different sites, and the reasons for variability probably also vary in different settings and are not completely known. BCG 217

10 Merle, Cunha & Rodrigues Type of study n Begg s test p-value Egger s test p-value Trial Cohort studies Case control Overall < Begg s funnel plot with pseudo 95% confidence limits 0-1 log[rr] Standard error of log[rr] Figure 2. Begg s and Egger s tests results and funnel plot for the case control studies. log[rr]: Log of the relative risk. protection wanes with time but the duration of the protective effect appears to be substantial. BCG is widely used in endemic countries to protect children against severe TB disease. Its role in leprosy control is recognized, although not always explicitly mentioned. Indeed, there is an often stated misconception that there is no vaccine against leprosy. The fact that leprosy continues to exist despite BCG vaccination can be perfectly explained by the variability of its protection in several settings due to previous infection with EM, and the waning in the protection with age combined with vaccination being performed most in infancy. If the leprosy rate is still high in endemic areas with BCG vaccination, this rate will probably be still higher where vaccination is not done. Meima et al. attempted to predict leprosy incidence by 2020 with using various scenarios under the assumption that early case-finding and treatment are sustained until 2020 [50]. These scenarios were made under the assumption of 95% BCG coverage, which is if focusing on the three main high-burden countries overestimating the BCG coverage in India and Indonesia (87 and 89%, respectively, in 2008) but underestimating the BCG coverage in Brazil, which is estimated to be approximately 99% [102]. The BCG protection estimate used in this analysis is 50%, which is close to the pooled estimate we found in this meta-analysis. For the scenarios without BCG vaccination, the average annual decline in incidence projected for ranges from 1.6 to 8.3% (corresponding to the need of 8 43 years to halve the leprosy incidence). By contrast, for the same scenarios with BCG vaccination, the average annual decline in incidence ranges from 4.9 to 10.0% (corresponding to the need of 7 14 years to halve the leprosy incidence). In other words, the scenarios with BCG with the least and most favorable projections have 57 and 39% lower leprosy incidences in 2020 than in corresponding scenarios without BCG vaccination. These results advocate for the maintenance of good BCG coverage in high-burden countries. Furthermore, all these scenarios make the assumption that current leprosy control measures early diagnostic and multidrug treatment are sustained until The diagnosis of leprosy is clinical. In many endemic countries, leprosy control activities have been integrated into general health services, but with the 218 Expert Rev. Vaccines 9(2), (2010)

11 BCG vaccination & leprosy protection Review decline of the disease [1] and the emergence of other pressing health problems such as HIV/AIDS and TB, the challenge for the future is to sustain political commitment and to maintain services, especially at peripheral levels, for leprosy control activities. Maintaining expertise in leprosy control among healthcare workers with qualified personnel able to make a correct diagnosis and to treat leprosy cases on time is challenging, particularly in countries with a low endemicity. BCG vaccination, which is easy to deliver and which seems to provide long-lasting protection against leprosy, might play an even more important role in the future if the sustainability of an efficient leprosy control program is not completely fulfilled. Concerns might be raised regarding the safety of using BCG in contacts in areas where there is a high prevalence of immunosuppression due to HIV infection. Indeed, there is evidence that BCG can produce disseminate infection and more serious adverse events when given to immunocompromised HIV-infected children. There is less information for adults, probably because BCG is mostly given to children, but investigation of HIV status should be considered before vaccinating adult contacts in areas where HIV prevalence is high. Lastly, since the 1960s, the prevalence of leprosy has declined dramatically, but there are still areas with high endemicity. The strategy to decrease the leprosy incidence probably needs to be implemented at multiple levels, with routine interventions, such as BCG vaccination during infancy, for the general population, and more targeted interventions among high-risk populations, such as household close contacts of index cases. As shown by Dupre et al. and Goulart et al. in two recent cohort studies conducted among household close contacts [17,19] and supported by our meta-ana lysis, BCG protection may be particularly important when targeting close leprosy contacts. Recently, Schuring et al., who conducted a cluster-randomized controlled trial in Bangladesh, showed that there is an additional effect of immunoprophylaxis when BCG is associated with rifampicin prophylactic treatment of close contacts [49]. Rifampicin protection was estimated to be approximately 58% (95% CI: 30 74%). The protective effect dramatically increased to 80% (95% CI: 50 92%) when rifampicin chemoprophylaxis was associated with BCG vaccination. This is the first time that an additive effect has been demonstrated between these two preventive strategies. Further research need to be conducted in different endemic countries to confirm these results. Expert commentary The key finding of this analysis is that there is consistent evidence of BCG protecting against leprosy wherever it is studied. BCG does not make leprosy an immunopreventable disease, in the sense that the disease cannot be controlled with the BCG vaccine alone; other measures are required, but in the light of the present findings, it is undeniable that BCG confers protection against leprosy. The level of protection varies. Even using strict inclusion criteria for this meta-analysis in order to maximize the homogeneity of the studies pooled together, we were not able to identify the reasons behind the variation in BCG efficacy against leprosy and therefore we could not estimate a global BCG protective effect. The heterogeneity of the results is probably real, and a pooled estimate of efficacy across different geographic zones would not be interpretable. It is up to each national program to assess the degree of potential protective benefit that may be expected with BCG vaccination in their area or country. This protection seems to be particularly high among close contacts of index cases and may be considerably increased if associated with other preventive strategies, such as chemoprophylaxis with rifampicin. Leprosy control requires complex interventions. Sustainability of the leprosy services with early diagnosis and early treatment of the cases are a necessity, but chemoprophylaxis of contacts and BCG vaccination should also be considered as potential key interventions in the global leprosy control strategy. Consideration of the role of BCG in leprosy control should influence any discussions of replacement of BCG by newer, more TB-specific vaccines. Five-year view The push for the elimination of leprosy leads to a reduction of cases worldwide but might also have led to a premature perception that leprosy is no longer a public-health concern, with potential repercussions on the priority given to leprosy within health services and in research funding. In the countries where the incidence of leprosy has decreased dramatically, it is likely that in the next 5 years, the emphasis on leprosy control will continue to center on how to sustain leprosy services given the reduction in the number of cases, and how to maintain the expertise among healthcare workers, particularly if leprosy control is integrated into primary care services; how to promote early diagnosis and treatment, including contact tracing for early identification and prevention of new cases; how to prevent disability and enhance rehabilitation; and how to fight stigma. Neonatal BCG vaccination has been part of routine vaccination to prevent TB in places where leprosy is common. Indeed, the BCG vaccine was invented whether the leprosy world asked for it or not; and it has not been necessary to consider the need for neonatal BCG vaccination to prevent leprosy, or to measure the impact it has had in reducing leprosy. Developed countries that have suspended BCG vaccination to all but those groups at a high risk of TB took the decision on the basis of cost per case of TB prevented. Any similar discussion in less-developed countries should include the impact on leprosy and leprosy-related disability in the cost efficacy balance. There is a fierce search for a TB vaccine that works when BCG does not; with at least one candidate vaccine in human trials. This raises many issues for leprosy. Associated immunological research on the mechanism of immunological protection against TB might be useful in aiding further understanding of immunity to leprosy and the role of BCG, and in making informed decisions about the best use of BCG for leprosy control. A new vaccine against TB will most likely be given as a booster to BCG but may conceivably also replace BCG. An important question from the leprosy field will be whether a new vaccine against TB protects against leprosy. A vaccine that is as protective 219

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