ArticlesEffect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial
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.
Section snippets
Participants
We used schools as the unit of randomisation, the study population consisting of children aged 7–14 years at study entry. The schools were government funded and located in two cities in Brazil: Manaus and Salvador. In Brazil some areas have a high prevalence of infection with environmental mycobacteria and others have a low prevalence of infection with environmental mycobacteria. Manaus was chosen for this study because a high rate of infection was expected in this city, owing to the latitude,
Results
Information was collected for 348 083 children from 763 schools (figure 1). About a quarter of these children were absent from the school on the day the team visited the schools for scar reading in control schools and scar reading and BCG vaccination in intervention schools: 24% (42 053/176 846) of the children in intervention schools and 27% (47 006/171 239) in control schools. We excluded children who were absent from school on the day of the visit. Another 58 310 children were excluded
Discussion
BCG revaccination in children aged 7–14 years did not have a protective effect. The incidence of tuberculosis during the study period, and the number of pulmonary and non-pulmonary cases by age, were similar in the intervention and control groups. BCG revaccination was ineffective against all forms of tuberculosis or against non-pulmonary tuberculosis. Revaccination efficacy was similar in certain, probable, and suspect cases, and when cases with insufficient data for validation were excluded.
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