Articles
Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study

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Summary

Background

Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian-born individuals.

Methods

In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12–50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators.

Findings

Median follow-up was 41 years (IQR 32–49) for 83 421 BCG-unvaccinated and 44 years (41–46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3·3 per 100 000 person-years in unvaccinated and 1·3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26–65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24–80]; 10–19 years 58% [27–76]; 20–29 years 38% [–32 to 71]; 30–40 years 42% [–24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27–85), 10–19 years was 63% (32–80), 20–29 years was 50% (−19 to 79), and 30–40 years was 40% (−46 to 76).

Interpretation

Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated

Funding

Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine.

Introduction

BCG, the sole tuberculosis vaccine licensed for use in human beings, is an important part of tuberculosis control efforts.1 It provides, on average, 86% protection against miliary and meningeal tuberculosis in children.2, 3, 4 It also protects against pulmonary tuberculosis, although its effect varies geographically and seems higher further from the equator,5, 6, 7 ranging, for instance, from no evidence of protection in the Indian Tuberculosis Prevention Trial up to an efficacy of 78% in the British Medical Research Council trial.7 Reasons for such variability7, 8 include good efficacy if vaccination is done before infection with Mycobacterium tuberculosis or sensitisation by environmental mycobacteria.7, 9 BCG might also protect against tuberculosis infection itself,10, 11 suggesting a greater contribution to tuberculosis control than that previously assumed, although understanding of the immunological basis of BCG-derived protection remains low.12

BCG is one of the commonest vaccines, but the duration of effect against tuberculosis is unclear, even though this information could affect vaccination policies. The substantial decrease in tuberculosis incidence in the 1980s to 1990s led several countries to move from universal vaccination of infants (most western European countries) or schoolchildren (eg the UK and Norway) to targeted vaccination of infants at high risk of tuberculosis;13 whether BCG protection will last until young adulthood when the risk of pulmonary tuberculosis and transmission to others is high is unclear. Improved understanding of long-term changes in BCG protection might also be useful not only to develop and test new tuberculosis vaccines, but also to adapt vaccination schedules. BCG booster vaccine candidates are designed on the premise of enhancement of weak or waned pre-existing BCG-derived protection.14 Other tuberculosis vaccine candidates (recombinant BCG or other attenuated mycobacterium-based vaccines) are empirically inspired or derived from BCG,14 and the performance of BCG can inform their potential effect.

BCG protection can last for up to 15 years.15 Little information exists beyond that period because studies have either relatively short follow-up or few events if follow-up is long. Follow-up of participants in the Native American and Alaska Natives BCG trial16 showed significant BCG protection up to 40 years after vaccination, although these findings have not yet been substantiated elsewhere. We used a retrospective population cohort from Norway from which well preserved information from the tuberculin skin test (TST) and BCG status was available, with reliable linkage to good tuberculosis surveillance from 1962 to 2011, to assess BCG effectiveness for 40 years in the general population and a European setting.

Research in context

Evidence before this study

All ten published randomised trials of BCG were reviewed for evidence for the duration of BCG efficacy against tuberculosis by Sterne and colleagues in 1998. This review was complemented by a comprehensive systematic review by Abubakar and colleagues in 2012, which also included all observational studies. Abubakar and colleagues searched for articles in electronic medical databases up to May 31, 2009 (including MEDLINE, Embase, Cochrane Central Register, and others), and in trial registers and grey literature sources. Search terms for disease were “TB”, “tuberculosis”, “tubercle bacill*”, “M. tuberculosis complex”, “M. bovis”, “M. africanum”, “M. canetti”, “M. microti”, and “M. tuberculosis”, and for intervention were “BCG vaccine”, “BCG”, “BCG vacc*”, “BCG imm*”, and “Bacillus Calmette”. Details of all databases searched are published in the report. We repeated the search strategy in MEDLINE, Embase, Cochrane Central, and Web of Knowledge, but identified no new additions. Authors of the most recent review suggested that BCG is, on average, effective against tuberculosis if given to individuals not already infected with Mycobacterium tuberculosis or sensitised by environmental mycobacteria, and the vaccine can protect for 10–15 years. Pooled VE estimates (against all forms of tuberculosis disease) from trials were 60% (95% CI 37–74) for 0 to less than 5 years, 56% (17–76) for 5 to less than 10 years, and 46% (18–64) for 10–15 years. Seven of the ten trials provided some data for follow-up beyond 15 years after vaccination, but investigators of only one noted evidence of protection, whereas the others had too few events for meaningful estimates. Abubakar and colleagues also identified 22 relevant observational studies (consisting of five cohort, five case-population, nine case-control, and three cross-sectional studies), of which only four had some data for BCG effectiveness up to 20 years after vaccination. Authors of three of these studies suggested decreasing but persisting protection 15–20 years after vaccination. Overall, evidence is consistent with significant BCG-derived protection against tuberculosis for 10–15 years after vaccination, with waning over time; however, the vaccine effect beyond that period is uncertain.

Added value of this study

Long-term follow-up of participants in the Native American and Alaska Natives BCG trial suggested that BCG could protect against tuberculosis for up to 60 years. Our study is, to our knowledge, only the second (and the first from western European countries) in which some of these findings are replicated. Our results suggest a BCG protection of about 50% during 40 years, with some evidence of about 40% effectiveness 30–40 years after vaccination. The consistency between results from these two settings strengthens the hypothesis that BCG-derived immunity could persist for much longer than 10–15 years as previously assumed.

Implications of all the available evidence

A longer duration of protection than that currently thought would imply that BCG is potentially more cost effective and beneficial than was previously estimated. This finding could be relevant if countries revise their BCG vaccination policies in response to changing tuberculosis epidemiology, especially in low-incidence countries. The potentially long-lived effect of BCG should be investigated and taken into account in development of new tuberculosis vaccines, especially in view of our low understanding of immunity to M tuberculosis. The duration and changes in levels of BCG-derived protection would also be relevant to scheduling of vaccination if the new family of BCG-booster vaccines was successfully developed and introduced.

Section snippets

Study design and population

In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12–50 years who were TST negative to whom intradermal BCG vaccination was offered as part of the nationwide Norwegian mandatory mass tuberculosis screening and BCG vaccination programme that took place between 1948 and 1975.17, 18, 19 We only included those screened during the last round of the programme, which took place between 1962 and 1975, when data were computerised and all tuberculosis cases

Results

1 334 686 (77%) of 1 739 996 individuals registered in the tuberculosis screening database were eligible, of whom 1 025 621 (77%) were TST negative (figure 1). 940 484 (92%) of these individuals were vaccinated and 85 137 (8%) were unvaccinated. The final study sample included 83 421 (22%) TST-negative unvaccinated and 297 905 (78%) BCG-vaccinated individuals. Baseline characteristics are presented in table 1. BCG vaccinated individuals were more likely to be male and younger at enrolment than

Discussion

Findings from our study show that BCG vaccination was associated with an almost halving of the risk of tuberculosis during a 40 year period after vaccination. If examined by decades, we noted that BCG was associated with about a 60% reduction in risk during the first two decades after vaccination. VE was about 40% between 20 years and 40 years after vaccination, although the evidence was weaker. The vaccine seemed to reduce the risk of pulmonary tuberculosis, the infectious form of the disease,

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