Research Article: BCG Revaccination Does Not Protect Against Leprosy in the Brazilian Amazon: A Cluster Randomised Trial

Date Published: February 13, 2008

Publisher: Public Library of Science

Author(s): Sérgio S. Cunha, Neal Alexander, Mauricio L. Barreto, Emilia S. Pereira, Inês Dourado, Maria de Fátima Maroja, Yury Ichihara, Silvana Brito, Susan Pereira, Laura C. Rodrigues, Denis Daumerie

Abstract: BackgroundAlthough BCG has been found to impart protection against leprosy in many populations, the utility of repeat or booster BCG vaccinations is still unclear. When a policy of giving a second BCG dose to school children in Brazil was introduced, a trial was conducted to assess its impact against tuberculosis, and a leprosy component was then undertaken in parallel. Objective: to estimate the protection against leprosy imparted by a second dose of BCG given to schoolchildren.Methods and FindingsThis is a cluster randomised community trial, with 6 years and 8 months of follow-up. Study site: City of Manaus, Amazon region, a leprosy-endemic area in Brazil. Participants: 99,770 school children with neonatal BCG (aged 7–14 years at baseline), of whom 42,662 were in the intervention arm (revaccination). Intervention: BCG given by intradermal injection. Main outcome: Leprosy (all clinical forms). Results: The incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45).Conclusions/SignificanceThere was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. These results point to a need to consider the effectiveness of the current policy of BCG vaccination of contacts of leprosy cases in Brazilian Amazon region.

Partial Text: BCG vaccination is given routinely to neonates to prevent tuberculosis in Brazil and in most of the world. BCG also protects against leprosy, with estimates of protection ranging from 20% to 90% [1],[2]. In Brazil, in addition to routine BCG vaccination at birth to prevent tuberculosis, BCG is officially recommended for household contacts of leprosy cases. In 1994 the Brazilian Ministry of Health expanded its tuberculosis control policy to recommend the routine BCG vaccination of school age children (around 7–14 years old). Given the high coverage of neonatal vaccination, this was effectively revaccination for most children. A large cluster randomised trial (BCG-REVAC) was started in 1996 to assess the effectiveness against tuberculosis of BCG vaccination of schoolchildren [3],[4]. One of the trial sites was the city of Manaus, which is also endemic for leprosy. In this city the trial objective was then expanded to estimate the effectiveness on leprosy. This paper reports the results of the BCG-REVAC trial in preventing leprosy based on follow-up from January 1999 to August 2006.

Details of the methodology of the BCG-REVAC trial and of the leprosy component have been published elsewhere (regarding trial co-ordination, screening to detect leprosy cases before the trial, and sample size) [4],[5]. A CONSORT checklist is available in Text S1. We summarise here relevant methodological aspects.

The number of leprosy cases detected in the trial and number of children are shown in Figure 1. The baseline characteristics of the two allocation arms were similar regarding gender, age at entry into the trial (Table 1). A higher proportion of children in intervention arm were in schools located in areas that had higher incidence of tuberculosis and leprosy (NCDR) before the trial (bold numbers in Table 1).

This study found no evidence of protection of the second dose of BCG against all forms of leprosy among school children within 6 years and 8 months of follow-up. This remained after controlling for potential confounders and adjusting for effect of clustering. The confidence interval of 0.72 to 1.58 (for the all cases and the whole period, controlled for covariates and adjusted for clustering) is consistent with a vaccine protection of up to 28% and an increase in leprosy in those vaccinated up to 58%. We conclude that the results did not support the original hypothesis of a vaccine protection of 50%, and additional follow-up is thus not planned. There was no statistically significant vaccine protection against MB and PB cases, but this analysis was not powered to evaluate protection separately for clinical forms at this duration of follow up. We can speculate some alternative hypotheses why the expected protection by revaccination was not observed.



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