Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial

Summary

Background

Many countries offer a second BCG vaccination to prevent tuberculosis, although there is little evidence of whether this confers additional protection. BCG vaccination is routine in Brazil but BCG revaccination procedures vary by state. We studied revaccination efficacy in two Brazilian cities with tuberculosis prevalence representative of Brazil.

Methods

We did a cluster-randomised trial of the protection against tuberculosis from BCG revaccination in school-aged children who had had one BCG vaccination as infants. 767 schools in the cities of Salvador and Manaus, Brazil, participated; schools were the unit of randomisation. The study was open label with no placebo. Cases of tuberculosis were identified through record linkage to the Tuberculosis Control Programme. Revaccination status was masked during linkage and validation of cases. The incidence of tuberculosis was the primary outcome. Analysis was by intention to treat.

Findings

386 schools (176 846 children) were assigned BCG revaccination and 365 (171 293 children) no revaccination. 42 053 children in the vaccine group and 47 006 in the control group were absent from school on the day of the visit and were excluded. 31 163 and 27 146, respectively were also excluded because they had no BCG scar, two or more scars, or a doubtful scar on assessment. The crude incidence of tuberculosis in the intervention group was 29·3 per 100 000 person years and in the control group 30·2 per 100 000 person-years (crude-rate ratio 0·97; 95% CI 0·76–1·28). The efficacy of BCG revaccination was 9% (−16 to 29%).

Interpretation

Revaccination given to children aged 7–14 years in this setting does not provide substantial additional protection and should not be recommended. Follow-up is ongoing and needed to assess the effect of other factors on revaccination efficacy: time since vaccination, age at vaccination, and high or low prevalence of environmental mycobacteria.

Introduction

Tuberculosis is one of the ten main causes of death in the developing world.¹ Neonatal BCG vaccination is routine in many countries; exceptions include the USA and the Netherlands. Where routinely done, neonatal BCG coverage has been high since the 1980s.² BCG protection against tuberculous meningitis is estimated to be more than 80%,³ including in Brazil.4, 5, 6 Efficacy of vaccination against pulmonary tuberculosis varies and in trials ranged from no protection to very high protection; variations in the BCG vaccine used or in ethnicity of the vaccinated population do not explain variations in efficacy.⁷ Efficacy tends to be low in regions where there is high prevalence of environmental mycobacteria. Because environmental mycobacteria are immunologically close to Mycobacterium tuberculosis, they are thought to confer protection against tuberculosis.⁷

Whether a second BCG vaccination gives additional protection is not known.⁷ In the absence of scientific evidence that revaccination confers protection, WHO global programmes on tuberculosis and on vaccines do not recommend repeated BCG vaccination.⁸ A trial of the effect of a second BCG vaccination, which was done in Malawi, reported a 50% protective effect against leprosy but no effect against tuberculosis;⁹ this is consistent with a second dose conferring no protection in settings (such as Malawi) where a first dose confers no protection.¹⁰ BCG revaccination is routine in several countries, mostly in eastern Europe and Asia11, 12 and in some municipalities in Brazil. In the past decade, several countries have suspended their BCG revaccination programmes. Decisions to suspend revaccination were commonly made for economic reasons, without rigorous assessment of protection. A few studies have assessed revaccination¹³ by assessing secular trends in BCG vaccination and in tuberculosis incidence.14, 15, 16, 17

Effective BCG revaccination would offer a low-cost method for controlling tuberculosis. If revaccination is not effective, it is important that the reason for ineffectiveness is identified so that effective vaccines can be developed to be given after neonatal BCG. Much attention is being given to the development and future assessment of new vaccines against tuberculosis—more than 200 possible vaccine candidates have been identified.18, 19 Because there is no immunological marker of protection against tuberculosis, field trials with disease endpoints are needed to estimate the protective effect of a second dose of BCG or a new tuberculosis vaccine.20, 21 In this paper we report the results of a cluster-randomised trial involving more than 200 000 school-aged children which was done to estimate the efficacy of BCG revaccination against tuberculosis, and we discuss the implications for the design of trials of new tuberculosis vaccines. A full description of the study design,²² validity of scar reading,²³ parallel immunological studies,24, 25 and the frequency of adverse events,²⁶ are presented elsewhere.