Susan Martins Pereira

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

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.

BCG vaccine: efficacy and indications for vaccination and revaccination

OBJECTIVES To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications. SOURCES OF DATA A systematic review of the literature was made by searching PubMed and selecting studies carried out in the last 50 years. The studies were grouped according to their design (clinical trials, case-control studies, and meta-analyses) and the results were presented separately for each type of study. Other relevant topics such as BCG and HIV/AIDS, use of tuberculin skin test, issues related to vaccine scars and to the development of new vaccines were also reviewed. SUMMARY OF THE FINDINGS BCG vaccine has been used since 1921. However, the data concerning its use are variable and inconsistent. The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important. Nevertheless, results regarding pulmonary tuberculosis have been inconsistent, either showing no efficacy or a protective efficacy rate around 80%. There is some evidence that a second dose of BCG vaccine does not increase its protective efficacy. Studies have shown that BCG vaccine protects against leprosy. The development of new vaccines to replace BCG in the future has been investigated. CONCLUSIONS Despite the hope that a new vaccine against tuberculosis will be available in the future, BCG vaccine, in spite of its deficiencies, is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis, especially in countries where this disease has moderate to high levels of incidence.

Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial.

BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (-2 to 24%) as compared to 9% (-16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, -27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups.

BCG revaccination does not protect against leprosy in the Brazilian Amazon: a cluster randomised trial.

Background Although 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 Findings This 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/Significance There 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.

Vacina BCG contra tuberculose: efeito protetor e políticas de vacinação

OBJETIVO: A vacina BCG e utilizada desde 1921, embora ainda apresente controversias e aspectos nao esclarecidos. O objetivo do artigo foi analisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e as politicas de vacinacao adotadas. METODOS: Foi realizada revisao sistematica da literatura publicada em ingles e espanhol, abrangendo o periodo compreendido entre 1948 e 2006, na base PubMed. Os principais descritores utilizados foram BCG vaccine, BCG efficacy, BCG e tuberculosis. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clinicos, estudos de caso-controle e metanalises. RESULTADOS: O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite e elevado. No entanto, os resultados sao discordantes em relacao a forma pulmonar, variando de ausencia de efeito a niveis proximos a 80%. Estao sendo conduzidas pesquisas sobre novas vacinas candidatas a substituir a BCG ou serem utilizadas como reforco. CONCLUSOES: Ha evidencias de que a segunda dose da BCG nao aumenta o seu efeito protetor. Apesar de seus limites e da expectativa futura de nova vacina para tuberculose, a vacina BCG mantem-se como importante instrumento no controle dos efeitos danosos da doenca, sobretudo em paises com taxas de incidencia medias e elevadas.

Effect of the Brazilian conditional cash transfer and primary health care programs on the new case detection rate of leprosy.

Background Social determinants can affect the transmission of leprosy and its progression to disease. Not much is known about the effectiveness of welfare and primary health care policies on the reduction of leprosy occurrence. The aim of this study is to evaluate the impact of the Brazilian cash transfer (Bolsa Família Program-BFP) and primary health care (Family Health Program-FHP) programs on new case detection rate of leprosy. Methodology/Principal Findings We conducted the study with a mixed ecological design, a combination of an ecological multiple-group and time-trend design in the period 2004–2011 with the Brazilian municipalities as unit of analysis. The main independent variables were the BFP and FHP coverage at the municipal level and the outcome was new case detection rate of leprosy. Leprosy new cases, BFP and FHP coverage, population and other relevant socio-demographic covariates were obtained from national databases. We used fixed-effects negative binomial models for panel data adjusted for relevant socio-demographic covariates. A total of 1,358 municipalities were included in the analysis. In the studied period, while the municipal coverage of BFP and FHP increased, the new case detection rate of leprosy decreased. Leprosy new case detection rate was significantly reduced in municipalities with consolidated BFP coverage (Risk Ratio 0.79; 95% CI  = 0.74–0.83) and significantly increased in municipalities with FHP coverage in the medium (72–95%) (Risk Ratio 1.05; 95% CI  = 1.02–1.09) and higher coverage tertiles (>95%) (Risk Ratio 1.12; 95% CI  = 1.08–1.17). Conclusions At the same time the Family Health Program had been effective in increasing the new case detection rate of leprosy in Brazil, the Bolsa Família Program was associated with a reduction of the new case detection rate of leprosy that we propose reflects a reduction in leprosy incidence.

Abandono del tratamiento de la tuberculosis en Nicaragua: resultados de un estudio comparativo

OBJETIVO: Identificar factores relacionados con el abandono (desercion) del tratamiento de la tuberculosis en centros de salud de los departamentos de Managua y Matagalpa, en Nicaragua. METODOS: Se diseno un estudio de casos y testigos pareados por edad y por municipio de tratamiento. Se seleccionaron como casos 251 pacientes mayores de 15 anos que abandonaron el tratamiento antituberculoso y como testigos pacientes que concluyeron la farmacoterapia (razon 1:1) durante el periodo de enero de 1998 a diciembre de 2001. Se obtuvieron datos de aspectos demograficos y socioeconomicos, habitos de vida y caracteristicas de la atencion. Las variables se seleccionaron y agruparon utilizando un modelo teorico jerarquizado. Por medio de un analisis de regresion logistica condicional, se estimo la razon de posibilidades (odds ratio, OR), con un intervalo de confianza de 95% (IC95%). RESULTADOS: Son factores de riesgo de abandono de la farmacoterapia antituberculosa: sexo masculino (OR: 2,51; IC 95%: 1,63 a 3,94), residencia inestable o en la calle (OR: 3,08; IC95%: 1,57 a 6,49), cambio de domicilio durante el tratamiento (OR: 4,22; IC95%: 2,06 a 9,93), consumo de bebidas alcoholicas (OR: 5,25; IC95%: 2,43 a 12,94), uso de drogas ilicitas (OR: 5,25; IC95%: 2,43 a 12,94), dificultad de acceso a los servicios de salud (OR: 2,64; IC95%: 1,39 a 5,29) y un concepto negativo de la atencion recibida (OR: 5,33; IC95%: 1,52 a 28,56). CONCLUSION: Es indispensable establecer en los servicios de salud medidas que contribuyan a abatir el riesgo de abandono. Es importante recuperar la participacion social del sector de la salud mediante acciones comunitarias.

Design of the Brazilian BCG-REVAC trial against tuberculosis: a large, simple randomized community trial to evaluate the impact on tuberculosis of BCG revaccination at school age

This paper describes the design and baseline results of a large and simple randomized controlled trial of the protection against tuberculosis of a dose of Bacillus Calmette Guerin (BCG) vaccination given to school children in a population with a high coverage of neonatal BCG (The Brazilian BCG-REVAC trial). The study started in 1996 and is a pair-matched and stratified-cluster randomized controlled trial with no placebo. The study population consists of children aged 7-14 years enrolled in 763 state schools from the cities of Salvador and Manaus, Brazil. Schools were the unit of randomization. Identifying information was collected for 354,708 school children. The final study population, after exclusions on the basis of age, BCG scar readings and absence from school on the day of the study visit, consists of 242,401 children, of whom 125,403 are in intervention schools. Follow-up relies on ascertainment of cases diagnosed at the health services and notified to the tuberculosis control program surveillance system. Blindness is guaranteed during linkage and validation of cases. Analysis is planned for the next 12 months, where efficacy will be estimated by calculating incidence of tuberculosis in the vaccine and control groups, taking into consideration the cluster design. The intervention studied, a second BCG vaccination, is widely used, although the World Health Organization does not recommend it on the basis of absence of evidence of protection or lack of protection. The results of the trial will make it possible for BCG revaccination practice to be informed by evidence. This is an example of a large simple and relatively inexpensive effectiveness trial, resulting from good collaboration between academia and health and education services enabling developing countries to define policies that are relevant for their reality.

BCG (Bacille of Calmette-Guérin) revaccination leads to improved in vitro IFN-gamma response to mycobacterial antigen independent of tuberculin sensitization in Brazilian school-age children.

Tuberculin skin test (TST) response and cytokine production in finger stab-derived whole blood cultures from 136 BCG scar-positive school-age children were evaluated before and after BCG revaccination. Fifty-four percent of the children increased in vitro production of IFN-gamma after revaccination, and this increase was highly significant for previously unresponsive children (P<0.0001). No correlation was found between TST response and cytokine production. Our data suggest that the in vitro IFN-gamma response to mycobacterial antigens can be boosted by BCG revaccination and may contribute to the search of correlates of protection to be used for the evaluation of new mycobacterial vaccines.

Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial

BACKGROUND Neonatal BCG vaccination is part of routine vaccination schedules in many developing countries; vaccination at school age has not been assessed in trials in low-income and middle-income countries. Catch-up BCG vaccination of school-age children who missed neonatal BCG vaccination could be indicated if it confers protection and is cost-effective. We did a cluster-randomised trial (BCG REVAC) to estimate the effectiveness (efficacy given in routine settings) of school-age vaccination. METHODS We assessed the effectiveness of BCG vaccination in school-age children (aged 7-14 years) with unknown tuberculin status who did not receive neonatal BCG vaccination (subpopulation of the BCG REVAC cluster-randomised trial), between July, 1997, and June, 2006, in Salvador, Brazil, and between January, 1999, and December, 2007, in Manaus, Brazil. 763 schools were randomly assigned into BCG vaccination group or a not-vaccinated control group. Neither allocation nor intervention was concealed. Incidence of tuberculosis was the primary outcome. Cases were identified via the Brazilian Tuberculosis Control Programme. Study staff were masked to vaccination status when identified cases were linked to the study population. We estimated cost-effectiveness in Salvador by comparison of the cost for vaccination to prevent one case of tuberculosis (censored at 9 years) with the average cost of treating one case of tuberculosis. Analysis of all included children was by intention to treat. For calculation of the incidence rate we used generalised estimating equations and correlated observations over time. FINDINGS We randomly assigned 20,622 children from 385 schools to the BCG vaccination group and 18,507 children from 365 schools to the control group. The crude incidence of tuberculosis was 54·9 (95% CI 45·3-66·7) per 100,000 person-years in the BCG vaccination group and 72·7 (62·8-86·8) per 100,000 person-years in the control group. The overall vaccine effectiveness of a first BCG vaccination at school age was 25% (3-43%). In Salvador, where vaccine effectiveness was 34% (8-53%), vaccination of 381 children would prevent one case of tuberculosis and was cheaper than treatment. The frequency of adverse events was very low with only one axillary lymphadenitis and one ulcer greater than 1 cm in 11,980 BCG vaccinations. INTERPRETATION Vaccination of school-age children without previous tuberculin testing can reduce the incidence of tuberculosis and could reduce the costs of tuberculosis control. Restriction of BCG vaccination to the first year of life is not in the best interests of the public nor of programmes for tuberculosis control. FUNDING UK Department for International Development, National Health Foundation.