The BCG vaccine is around 100 years old and is one of the most widely used vaccines globally.¹ The vaccine has a well established safety profile^2,3 and is considered highly cost-effective in most settings, especially in low-income countries with a high tuberculosis burden.⁴ However, there is considerable debate about the impact that BCG vaccination has on tuberculosis, particularly among older children and adults.^1,5,6

There are several crucial unanswered questions about BCG vaccination that have important implications for global tuberculosis epidemics and the development of supplemental vaccines. Whether BCG vaccination protects against pulmonary tuberculosis is unclear. There has been wide variability in estimates of the effectiveness of the BCG vaccine against pulmonary tuberculosis,^3,5,6 with some studies showing strong protection and others showing none. Several reasons for this heterogeneity have been proposed, such as sensitisation by environmental mycobacteria, the timing of BCG administration, and stringent tuberculosis testing.^3,6–8 Additionally, there is a paucity of data on the impact of BCG vaccination on mortality during childhood,^9,10 with several studies having been done in the pre-chemotherapeutic era, producing heterogeneous results.^11,12 More recent studies suggest potential sex-specific differences in the effectiveness of BCG vaccination.^13,14

In addition, the duration of protection against tuberculosis offered by BCG vaccination remains controversial. In the 1950s, a large randomised trial in the UK found that participants still had protection against tuberculosis 15 years after BCG vaccination.¹⁵ By contrast, a randomised trial of 250 000 participants done in Chengalpattu, India, found that the effect of infant BCG vaccination appeared to wane by 12·5 years of age.¹⁶ Other studies have shown BCG vaccination to offer sustained protection against tuberculosis into adulthood among US Native American and Norwegian populations.^17,18 These inconsistent results regarding the effectiveness of BCG vaccination in protecting against tuberculosis in later life have created controversy and confusion.

To attempt to improve our understanding of the effectiveness and longevity of BCG vaccination, we convened a large data consortium group of longitudinal cohort studies of tuberculosis-exposed contacts done during the past 20 years. Our primary aim was to investigate the age-specific impact of BCG vaccination at birth on all forms of tuberculosis and on pulmonary

We identified 14 927 original records from our database searches, of which we screened 9753 through an exclusionary keyword algorithm (figure 1). We tested the exclusionary words approach for accuracy by implementing the exclusionary algorithm on a random list of 100 titles that were also manually screened for eligibility to our study. Our exclusionary algorithm eliminated all articles that were excluded by manual screening with 100% specificity. We reviewed 512 full-text articles published on or after Jan 1, 1998 (figure 1). 80 study groups were contacted for individual participant data and study groups from 48 studies agreed to share their data, which were collated into a single database of 461 285 contacts of tuberculosis cases. 16 studies without data on BCG vaccination and six studies that were done in countries (the Netherlands, Australia, Canada, Germany, Spain, and the USA) that do not recommend BCG vaccination at birth were excluded. 26 studies from 17 countries were included in our systematic review and meta-analysis (figure 1; appendix pp 12–13). Included cohorts measured different outcomes of interest: 26 cohorts had information on the BCG vaccination status of tuberculosis contacts and any tuberculosis (n=68 552); 14 studies had information on BCG vaccination and the development of pulmonary (n=57 279) or extrapulmonary (n=56 183) tuberculosis; and four studies had data on BCG vaccination and subsequent mortality (n=18 175; table 1). 20 (77%) studies had a prospective study design. Studies were from geographically diverse settings in 17 countries (appendix p 47). The majority of participants were recruited in the Western Pacific region (n=35 947), the region of the Americas (n=17 205), and the African region (n=12 800; table 1). Studies assessing mortality were located in South Africa, Taiwan, Uganda, and Viet Nam. Most studies were located in a latitude from 10° to less than 20° (n=47 834) or from 20° to less than 30° (n=13 959); one study was done in a latitude of 40° or more (n=150).

Similar proportions of BCG-vaccinated versus unvaccinated participants were male (46·7% vs 40·2%; aOR 1·03, 95% CI 0·99–1·07), living with HIV (1·5% vs 2·4%; aOR 1·00, 0·77–1·30), or had a history of previous tuberculosis (3·8% vs 3·1%; aOR 1·05, 0·93–1·18). There was similar BCG vaccine coverage among the age groups younger than 15 years (9225 [87·5%] of 10 537 for ages <5 years, 9936 [88·5%] of 11 225 for ages 5–9 years, and 7847 [86·8%] of 9037 for ages 10–14 years), which was higher than the coverage in the older age groups (7984 [75·2%] of 10 612 for ages 15–24 years, 5159 [63·2%] of 8165 for ages 25–34 years, and 9535 [50·2%] of 18 976 for ages ≥35 years). Compared with unvaccinated participants, participants who were BCG-vaccinated had slightly higher rates of tuberculin skin test or IFNγ release assay positivity (aOR 1·09, 95% CI 1·01–1·17) and tuberculin skin test positivity (aOR 1·09, 1·01–1·17) but similar rates of IFNγ release assay positivity (aOR 0·97, 0·81–1·17).

Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all forms of tuberculosis was 18% (aOR 0·82, 95% CI 0·74–0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49–0·81; figure 2). Of participants aged 10 years or older, effectiveness was highest among those aged 35 years or older, but this increase did not reach statistical significance (figure 2).

Among participants with positive tuberculin skin tests or IFNγ release assays, BCG vaccination significantly protected against tuberculosis in all participants, participants younger than 5 years, and participants aged 5–9 years (figure 2). The vaccine was not protective among those without positive tests, unless they were younger than 5 years (0·54, 0·32–0·90; figure 2). The vaccine was significantly protective against tuberculosis among female participants (aOR 0·53, 0·36–0·79), but not among male participants (0·82, 0·55–1·23).

We did a range of secondary multivariable regression analyses of all tuberculosis, further adjusting for preventive therapy, index HIV status, index smear status, index cavitary status, WHO region, and country income status. No secondary variables modified the relationship between BCG vaccination and tuberculosis risk (appendix p 49). Findings stratified by IFNγ release assay (appendix p 23) and tuberculin skin test (data not shown) results separately (and not as a composite variable) were generally consistent with the analysis using the composite variable, although age-specific results were limited in those with IFNγ release assay tests due to small numbers of participants and events.

14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). Among 1394 tuberculosis cases in these cohorts, 1250 (89·7%) were pulmonary and 144 (10·3%) were extrapulmonary. BCG vaccination significantly protected against pulmonary tuberculosis events among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 95% CI 0·70–0·94) and among those with a positive tuberculin skin test or IFNγ release assay (0·80; 0·65–0·99; table 2; appendix pp 24–25). Protection against pulmonary tuberculosis was only present in children younger than 3 years (aOR 0·58, 95% CI 0·35–0·98; table 2). Vaccine effectiveness was higher among female participants (0·57, 0·32–1·03) than among male participants (0·92, 0·51–1·68). BCG vaccination was not protective against extrapulmonary tuberculosis events overall (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; aOR 0·96, 95% CI 0·65–1·41). For extrapulmonary tuberculosis, BCG vaccination produced a suggestive but statistically non-significant protective effect in children younger than 5 years (table 2). BCG vaccination was not effective at preventing extrapulmonary tuberculosis among female participants (aOR 0·66, 95% CI 0·34–1·11) or male participants (1·33, 0·78–2·28).

A multivariable model adjusting for tuberculin skin test or IFNγ release assay positivity at baseline showed that BCG vaccination remained protective for pulmonary tuberculosis (aOR 0·80, 95% CI 0·66–0·97) and not protective for extrapulmonary tuberculosis (0·73, 0·45–1·17; appendix p 48).

In four studies that followed up tuberculosis contacts for death, 18 175 participants were evaluated and 50 (0·3%) deaths occurred (35 [0·2%] of 16 780 vaccinated participants and 15 [1·1%] of 1395 unvaccinated participants). Among children younger than 15 years, increasing age was associated with a reduced risk of death (aOR 0·92 per year, 95% CI 0·86–0·98). Among participants aged 15 years or older, increasing age was strongly associated with death (aOR 1·08 per year, 1·08–1·09). BCG vaccination was significantly protective against death for all ages, for participants younger than 5 years, for participants aged 5–9 years, and for participants aged 10–14 years (figure 3). Among participants aged 15 years or older, there was no relationship between BCG vaccination and death (figure 3).

Heterogeneity was generally low (I²<50%; appendix p 18) and the majority of studies were rated as high or moderate quality (appendix pp 28–33).

The BCG vaccine is a crucial component of tuberculosis control and is given to more than 100 million newborn babies every year.^4,28 Nevertheless, there is continued debate concerning the ability of BCG vaccination to prevent tuberculosis and death.^3,5,9,10 Using individual-level data from 26 case-contact cohort studies comprising 68 552 exposed participants followed up for a median duration of 2·0 years, we found that infant BCG vaccination was effective in preventing all tuberculosis, pulmonary tuberculosis, and death, especially among younger children. When stratified by age, BCG vaccination at birth only significantly protected against all tuberculosis in children younger than 5 years. This effect was consistent in participants with either positive or negative tuberculin skin tests or IFNγ release assays. These results suggest that infant BCG vaccination, although important to young children who are at high risk of tuberculosis,^20,29–31 does not prevent adult-type cavitary tuberculosis and is therefore insufficient to impede the tuberculosis epidemic, providing further evidence that novel vaccines are urgently needed.

We found that infant BCG vaccination was protective against all forms of tuberculosis (18% effectiveness). Among the subset of 14 cohorts reporting specific forms of tuberculosis, we found evidence for a small, significant reduction in the rate of pulmonary tuberculosis with vaccination (19% effectiveness). For both of these outcomes, protection was concentrated in young children. Whether BCG vaccination protects young children from pulmonary tuberculosis is controversial and previous results have been heterogeneous.^1,3,4 Unfortunately, we were unable to investigate latitude as an important cause for this heterogeneity because the majority of studies included were done at latitudes of less than 30°. Among participants younger than 5 years who had recorded tuberculin skin test or IFNγ release assay results, children were slightly more protected from tuberculosis if they had negative (46% effectiveness) rather than positive (32% effectiveness) results, consistent with previous trials that have found a high BCG vaccine efficacy (59%) among tuberculin skin testnegative infants vaccinated at birth.⁸ This effect seemed to wane faster among participants with negative tests than among participants with positive tests, either due to the small numbers of participants who tested negative or a combination of vaccine-induced and infection-induced immunity. BCG vaccination did not generally protect from all tuberculosis for participants aged 5 years or older or from pulmonary or extrapulmonary disease when stratified by age group, although statistical power for the outcome of extrapulmonary disease was limited after age stratification. Importantly, vaccine effectiveness in people exposed to tuberculosis contacts, as included in the cohorts in this analysis, might differ from effectiveness in people from the general population.

We found marked protection from death among BCG-vaccinated children in our study. Protection persisted until participants were aged 14 years. Sex-specific differences in BCG effectiveness have been variably observed in previous studies.^10,13,14 In a previously published prospective birth cohort study, girls were more likely to benefit from BCG vaccination than were boys.¹³ However, a combined analysis of three randomised trials in Guinea-Bissau found that the efficacy of BCG vaccination was much greater in boys than in girls aged 0–1 month due to marked reduction in mortality among boys in the first month of life (largely driven by a reduction in sepsis).¹⁴ Our results extend this finding across a larger age range into adolescence. We were not able to identify specific mechanisms by which BCG vaccination might have reduced mortality, as causes of death were not reported by each study. Previous experimental and observational studies have found that BCG vaccination might provide non-specific or off-target immune protection against an array of other pathogens.^1,3,10 Although our results should be cautiously interpreted, they add to the sparse empirical evidence on the relationship between BCG vaccination and mortality in children. Furthermore, they affirm the value of BCG vaccination among children in tuberculosis-endemic settings and underscore the need to identify effective supplementary vaccines to protect against tuberculosis among adolescents and adults.^32,33

Our study has numerous strengths. Importantly, most studies included in the analysis were done in the past 10 years in countries with a high tuberculosis burden, including India, South Africa, China, Viet Nam, Indonesia, Uganda, The Gambia, and Brazil. By contrast, several previously published studies examining the protective effect of BCG vaccination only considered low-burden settings and the historical literature before 1950.^1,6 Several studies done during the past two decades have also provided further input.^17,34 77% of the cohorts examined in our analysis had a prospective design, thus decreasing potential recall biases and increasing confidence of proper case detection. In addition, many cohorts provided important secondary information, such as tuberculin skin test or IFNγ release assay results, HIV status, and histories of previous tuberculosis; these data were largely unavailable in previous studies.^1,3 The inclusion of these characteristics allowed us to investigate and explore variability across studies.

Our findings are subject to several limitations. First, the studies included were observational in nature and therefore exposure to BCG vaccination was not randomised. There is no longer clinical equipoise for a clinical trial on BCG vaccination. However, the availability of individual-level data on demographic and clinical information from contacts and index cases and cohort-level characteristics from each individual study allowed for adjustment. Despite adjustment, residual or unmeasured confounding is possible and might have biased our effectiveness values upwards. BCG vaccination might theoretically reflect health-care access and higher socioeconomic status, which could plausibly confound the risk of the outcomes we have measured. Our results showing a protective effect in young children and predominantly no effect among adolescents and adults, consistent with previous trials,⁶ suggest that this bias might be minimal. Second, we utilised the classifications of BCG vaccination used in each study, which were based on a BCG vaccine scar and vaccination records. Exposure misclassification might occur if a scar does not form. However, BCG scar formation is a sensitive indicator of vaccination status, and few vaccinated children from various settings do not show a scar years after vaccine administration.^35–37 Third, although our results were largely consistent when analysing by QuantiFERON-TB and tuberculin skin test status, sample size and statistical power were low. Fourth, our mortality analysis must be interpreted with caution. Due to the observational nature of the studies we included, vaccinated children might have had higher socioeconomic status and greater access to health care and have been more likely to have received other vaccinations compared with BCG-unvaccinated children, leading to overestimation of mortality benefit. Furthermore, the studies with mortality data were from a small number of settings, potentially impacting our results and their generalisability. Finally, because diagnosing extrapulmonary tuberculosis is challenging in many of the included settings and the type of extrapulmonary disease (eg, tuberculous meningitis or miliary tuberculosis) was often not reported, it is probable that extrapulmonary tuberculosis was underdiagnosed and we were unable to evaluate BCG vaccine effectiveness against specific forms of extrapulmonary tuberculosis.

In conclusion, using a combined analysis of 26 cohort studies comprising 68 552 participants, we have shown that infant BCG vaccination is effective at preventing all tuberculosis and death in young children. The protective effect of BCG vaccination against tuberculosis waned in participants aged 5 years or older, consistent with historical studies.⁶ These associations were not modified by evidence of M tuberculosis infection at baseline in these cohorts. These results suggest that protective immunity against M tuberculosis should be boosted after childhood.