Comparing cytokine production and clinical response following vaccination with BCG Moreau and BCG Russia strains in a Brazilian infant population.

INTRODUCTION: BCG is the only licensed vaccine against tuberculosis (TB) and, in Brazil, comprises part of the recommended vaccine schedule within the first month of life. Due to a local manufacturing shortage of BCG Moreau, BCG Russia was introduced in 2017 by the Brazilian Ministry of Health. OBJECTIVE: To evaluate differences in immune responses induced by BCG Moreau and BCG Russia in infants, in addition to scar formation. METHODS: The present case series involved 15 healthy infants who were vaccinated within the first seven days of life with one of two strains of BCG, then followed for 12 weeks or longer. Cytokine levels were measured before and after vaccination in whole blood culture supernatants previously stimulated in vitro with either BCG strain, heat-killed M. tuberculosis H37Rv or in the absence of stimulation. BCG scarring was also documented. RESULTS: Infants vaccinated with BCG Moreau exhibited increased background IL-2, IL-10 and IL-4 production, yet no differences were found in those vaccinated with BCG Russia. Although both strains induced higher levels of IL-2 and IFN-γ, elevated IL-6, TNF and IL-10 production was also seen in response to BCG Russia. In contrast, no specific responses were observed against heat-killed M. tuberculosis H37Rv, with the exception of increased IL-2 following BCG Moreau vaccination. Although documented in both groups, scarring was milder and less frequent following BCG Russia vaccination. CONCLUSIONS: Similar Th1 profiles were found following immunization with either type of BCG vaccine evaluated herein, with more pronounced cytokine production detected in response to the Russia strain. Overall, vaccination was well-tolerated and scarring evolved as expected for both BCG strains.

Investigating extradomiciliary transmission of tuberculosis: An exploratory approach using social network patterns of TB cases and controls and the genotyping of Mycobacterium tuberculosis.

Extradomiciliary contacts have been overlooked in the study of TB transmission due to difficulties in identifying actual contacts in large populations. Complex network analysis provides a framework to model the structure of contacts, specially extradomiciliary ones. We conducted a study of incident sputum-positive TB cases and healthy controls occurring in a moderate TB burden city. Cases and controls were interviewed to obtain data regarding the usual locations of residence, work, study, and leisure. Mycobacterium tuberculosis isolated from sputum was genotyped. The collected data were used to build networks based on a framework of putative social interactions indicating possible TB transmission. A user-friendly open source environment (GraphTube) was setup to extract information from the collected data. Networks based on the likelihood of patient-patient, patient-healthy, and healthy-healthy contacts were setup, depending on a constraint of geographical distance of places attended by the volunteers. Using a threshold for the geographical distance of 300 m, the differences between TB cases and controls are revealed. Several clusters formed by social network nodes with high genotypic similarity were characterized. The developed framework provided consistent results and can be used to support the targeted search of potentially infected individuals and to help to understand the TB transmission.

[Factors associated with geographic access to health services by TB patients in three State capitals in Northeast Brazil]. / Fatores associados ao acesso geográfico aos serviços de saúde por pessoas com tuberculose em três capitais do Nordeste brasileiro.

The aim of this study was to identify factors associated with geographic access to health services by tuberculosis patients in three State capitals in Northeast Brazil. The sample consisted of new tuberculosis cases reported in 2007. The study used data from the Information System on Notifiable Diseases and the National Registry of Healthcare Organizations. Addresses of households and health services were geocoded, and difficult access was defined as a distance greater than 800 meters from the household to the health service. Crude prevalence ratios were estimated, as well as adjusted prevalence ratios using Poisson regression. After adjusting the study variables, the only variable that remained associated with difficult access was primary healthcare units in Salvador, Bahia State (PR = 0.75; 95%CI: 0.720-0.794) and in Recife, Pernambuco State (PR = 0.402; 95%CI: 0.318-0.508). The study concluded that decentralization of primary care can help improve access to health services.

Fatores associados ao acesso geográfico aos serviços de saúde por pessoas com tuberculose em três capitais do Nordeste brasileiro / Factors associated with geographic access to health services by TB patients in three State capitals in Northeast Brazil / Los factores asociados al acceso geográfico a los servicios de salud para personas con tuberculosis en tres capitales del nordeste brasileño

O objetivo do presente estudo foi identificar fatores associados ao acesso geográfico aos serviços de saúde por portadores de tuberculose em três capitais do Nordeste do Brasil. A amostra foi composta por casos novos de tuberculose, notificados em 2007. Foram utilizados dados provenientes do Sistema de Informação sobre Agravos de Notificação, e do Cadastro Nacional de Estabelecimento de Saúde. Os endereços dos domicílios e das unidades de saúde foram georreferenciados e, utilizando a distância entre o domicílio e a unidade de atendimento de cada caso, foi considerado acesso dificultado quando esta distância foi maior do que 800 metros. Foram estimadas as razões de prevalência bruta e ajustada por meio de regressão de Poisson. Verificou-se que após ajuste com as variáveis estudadas, apenas a variável unidade básica, em Salvador, Bahia (RP = 0,75; IC95%: 0,720-0,794) e em Recife, Pernambuco (RP = 0,402; IC95%: 0,318-0,508), manteve associação com o acesso dificultado. O estudo concluiu que a descentralização do atendimento em unidade básica pode contribuir com a melhoria do acesso aos serviços de saúde.

The aim of this study was to identify factors associated with geographic access to health services by tuberculosis patients in three State capitals in Northeast Brazil. The sample consisted of new tuberculosis cases reported in 2007. The study used data from the Information System on Notifiable Diseases and the National Registry of Healthcare Organizations. Addresses of households and health services were geocoded, and difficult access was defined as a distance greater than 800 meters from the household to the health service. Crude prevalence ratios were estimated, as well as adjusted prevalence ratios using Poisson regression. After adjusting the study variables, the only variable that remained associated with difficult access was primary healthcare units in Salvador, Bahia State (PR = 0.75; 95%CI: 0.720-0.794) and in Recife, Pernambuco State (PR = 0.402; 95%CI: 0.318-0.508). The study concluded that decentralization of primary care can help improve access to health services.

El objetivo de este estudio fue identificar los factores asociados con el acceso geográfico a los servicios de salud para pacientes con tuberculosis en tres capitales del Nordeste. La muestra constó de nuevos casos de tuberculosis en 2007. El estudio usó datos del Sistema de Información de Enfermedades de Notificación Obligatoria y del Registro Nacional de Establecimientos de Salud. Las direcciones de los hogares y establecimientos de salud fueron geocodificados y, utilizando la distancia entre el hogar y la unidad de cuidados en cada caso, se consideró de difícil acceso cuando esta distancia era mayor de 800 metros. Se calcularon los cocientes de brutos y ajustados mediante la regresión de Poisson por razones de prevalencia. Se encontró que después de ajustar las variables estudiadas, sólo la unidad variable básica en Salvador (RP = 0,75; IC95%: 0.720-0.794) y Recife (OR = 0,402; IC95%: 0,318-0,508) se mantuvieron asociadas con difícil acceso. La conclusión es que la descentralización de la atención en las unidades básicas de atención puede contribuir a la mejora del acceso a los servicios de salud.

Tuberculosis and living conditions in Salvador, Brazil: a spatial analysis.

OBJECTIVE: To investigate spatial tuberculosis (TB) distribution patterns and the association between living conditions and incidence of the disease in Salvador, Bahia, Brazil. METHODS: An ecological study with neighborhood as the unit of analysis. Data was collected from the Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação, SINAN) and the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística, IBGE). Rates of TB incidence were transformed and smoothed. Spatial analysis was applied to identify spatial auto-correlation and "hotspot" areas of high and low risk. The relationship between TB and living conditions was confirmed by spatial linear regression. RESULTS: The incidence of TB in Salvador displayed heterogeneous patterns, with higher rates occurring in neighborhoods with poor living conditions in 1995 - 1996. Over the study period, disease occurrence declined, particularly in less-privileged strata. In 2004 - 2005, the association between living conditions and TB was no longer observed. CONCLUSIONS: The heterogeneous spatial distribution of TB in Salvador previously reflected inequalities related to living conditions. Improvements in such conditions and health care for the less privileged may have contributed to observed changes.

Tuberculosis and living conditions in Salvador, Brazil: a spatial analysis / Tuberculosis y condiciones de vida en Salvador, Brasil: un análisis espacial

OBJECTIVE: To investigate spatial tuberculosis (TB) distribution patterns and the association between living conditions and incidence of the disease in Salvador, Bahia, Brazil. METHODS: An ecological study with neighborhood as the unit of analysis. Data was collected from the Notifiable Diseases Information System (Sistema de Informação de Agravos de Notificação, SINAN) and the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística, IBGE). Rates of TB incidence were transformed and smoothed. Spatial analysis was applied to identify spatial auto-correlation and "hotspot" areas of high and low risk. The relationship between TB and living conditions was confirmed by spatial linear regression. RESULTS: The incidence of TB in Salvador displayed heterogeneous patterns, with higher rates occurring in neighborhoods with poor living conditions in 1995 - 1996. Over the study period, disease occurrence declined, particularly in less-privileged strata. In 2004 - 2005, the association between living conditions and TB was no longer observed. CONCLUSIONS: The heterogeneous spatial distribution of TB in Salvador previously reflected inequalities related to living conditions. Improvements in such conditions and health care for the less privileged may have contributed to observed changes.

OBJETIVO: Investigar las pautas de distribución espacial de la tuberculosis (TB) y la asociación de las condiciones de vida con la incidencia de esta enfermedad en Salvador, estado de Bahía (Brasil). MÉTODOS: Estudio ecológico que tomó el vecindario como unidad de análisis. Se recopilaron datos del Sistema de Información de Enfermedades de Notificación Obligatoria (Sistema de Informação de Agravos de Notificação, SINAN) y el Instituto Brasileño de Geografía y Estadística (Instituto Brasileiro de Geografia e Estatística, IBGE). Se transformaron y suavizaron las tasas de incidencia de la TB. Se aplicó análisis espacial para establecer la autocorrelación espacial y las áreas "conflictivas" de alto y bajo riesgo. Se confirmó la relación entre la TB y las condiciones de vida mediante regresión lineal espacial. RESULTADOS: La incidencia de la TB en Salvador mostró modelos heterogéneos, con tasas mayores en los vecindarios cuyas condiciones de vida eran desfavorables en 1995 y 1996. A lo largo del período de estudio, disminuyó la aparición de nuevos casos de la enfermedad, en particular en los estratos menos privilegiados. En el 2004 y el 2005, ya no se observó la asociación entre TB y condiciones de vida. CONCLUSIONES: La distribución espacial heterogénea de la tuberculosis en Salvador reflejaba anteriormente las desigualdades relacionadas con las condiciones de vida. Las mejoras de dichas condiciones y la atención de salud dirigida a los menos privilegiados pueden haber contribuido a los cambios observados.

Causes of variation in BCG vaccine efficacy: examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses.

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p<0.001) and Manaus (36%, 95% CI 11-53%, p=0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective.

Social inequalities and vaccination coverage in the city of Salvador, Bahia.

OBJECTIVE: To estimate the vaccination coverage in children born in the city of Salvador, analyzing these coverages by socioeconomic conditions. METHOD: A household survey on vaccination coverage was conducted with children born in 2005, in Salvador, Bahia, northeastern Brazil, who were aged between 18 to 36 months at the time of this study. Cluster sampling was performed in multiple stages. Census tracts were stratified using data from the national census conducted in 2000. Data was collected on socio-economic households. The sample size was defined by a specific methodology developed for immunization coverage surveys. The questionnaire was based upon the information contained in the vaccination cards. The estimated vaccination coverage in the various strata considered the sampling complex plan, weighting the observations according to the sampling fraction, the losses and the design effect. RESULTS: There was inequality in the socioeconomic strata analyzed, where the coverage rate was directly proportional to socioeconomic status. Strata D and E showed statistically significant differences when compared to stratum A. Regarding to the complete scheme, children living in strata D and E have significantly less coverage than those residing in strata B. For vaccines not included in the basic scheme, the differences are very marked, showing less than 3% in stratum D and E. CONCLUSIONS: Vaccination coverage for the complete schedule at the end of 18 months of age with valid doses, was unsatisfactory and shows significant differences among the socio-economic strata with poor coverage in the poorest groups.

Desigualdades sociais e cobertura vacinal na cidade de Salvador, Bahia / Social inequalities and vaccination coverage in the city of Salvador, Bahia

Objetivo: Estimar as coberturas vacinais alcançadas em crianças nascidas na cidade de Salvador, analisando essas coberturas por condições socioeconômicas. Método: Foi realizado um inquérito domiciliar sobre cobertura vacinal, na cidade de Salvador, capital do Estado da Bahia, Nordeste do Brasil, sendo incluídas crianças nascidas em 2005, que no momento do estudo apresentavam 18 a 36 meses de idade. Foi realizada amostragem por conglomerados em múltiplas etapas. Os setores censitários foram estratificados utilizando-se dados do censo demográfico realizado em 2000. Foram coletados dados socioeconômicos dos domicílios. O tamanho da amostra foi definido a partir de metodologia específica para inquéritos de cobertura vacinal. O questionário foi aplicado tomando por base as informações constantes na caderneta de vacinação. Foi estimada a cobertura vacinal nos diversos estratos considerando o plano complexo de amostragem, ponderando as observações segundo a fração amostral, as perdas e o efeito do desenho. Resultados: Observou-se desigualdade socioeconômica nos diversos estratos, com um gradiente diretamente proporcional entre cobertura vacinal e nível socioeconômico. As diferenças mostram-se estatisticamente significantes entre os estratos D e E comparado ao estrato A. Em relação ao esquema completo, as crianças residentes nos estratos D e E apresentam cobertura significantemente menor que aquelas residentes no estrato B. Para vacinas não incluídas no esquema básico, as diferenças são muito acentuadas, sendo inferior a 3% nos estratos D e E. Conclusões: A cobertura vacinal pelo esquema completo ao final dos 18 meses de idade, com doses válidas, foi insatisfatória e foram observadas ...

Objective: To estimate the vaccination coverage in children born in the city of Salvador, analyzing these coverages by socioeconomic conditions. Method: A household survey on vaccination coverage was conducted with children born in 2005, in Salvador, Bahia, northeastern Brazil, who were aged between 18 to 36 months at the time of this study. Cluster sampling was performed in multiple stages. Census tracts were stratified using data from the national census conducted in 2000. Data was collected on socio-economic households. The sample size was defined by a specific methodology developed for immunization coverage surveys. The questionnaire was based upon the information contained in the vaccination cards. The estimated vaccination coverage in the various strata considered the sampling complex plan, weighting the observations according to the sampling fraction, the losses and the design effect. Results: There was inequality in the socioeconomic strata analyzed, where the coverage rate was directly proportional to socioeconomic status. Strata D and E showed statistically significant differences when compared to stratum A. Regarding to the complete scheme, children living in strata D and E have significantly less coverage than those residing in strata B. For vaccines not included in the basic scheme, the differences are very marked, showing less than 3% in stratum D and E. Conclusions: Vaccination coverage for the complete schedule at the end of 18 months of age with valid doses, was unsatisfactory and shows significant differences among the socio-economic strata with poor coverage in the poorest groups. .

SNP typing reveals similarity in Mycobacterium tuberculosis genetic diversity between Portugal and Northeast Brazil.

Human tuberculosis is an infectious disease caused by bacteria from the Mycobacterium tuberculosis complex (MTBC). Although spoligotyping and MIRU-VNTR are standard methodologies in MTBC genetic epidemiology, recent studies suggest that Single Nucleotide Polymorphisms (SNP) are advantageous in phylogenetics and strain group/lineages identification. In this work we use a set of 79 SNPs to characterize 1987 MTBC isolates from Portugal and 141 from Northeast Brazil. All Brazilian samples were further characterized using spolygotyping. Phylogenetic analysis against a reference set revealed that about 95% of the isolates in both populations are singly attributed to bacterial lineage 4. Within this lineage, the most frequent strain groups in both Portugal and Brazil are LAM, followed by Haarlem and X. Contrary to these groups, strain group T showed a very different prevalence between Portugal (10%) and Brazil (1.5%). Spoligotype identification shows about 10% of mis-matches compared to the use of SNPs and a little more than 1% of strains unidentifiability. The mis-matches are observed in the most represented groups of our sample set (i.e., LAM and Haarlem) in almost the same proportion. Besides being more accurate in identifying strain groups/lineages, SNP-typing can also provide phylogenetic relationships between strain groups/lineages and, thus, indicate cases showing phylogenetic incongruence. Overall, the use of SNP-typing revealed striking similarities between MTBC populations from Portugal and Brazil.

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.

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 vaccine against tuberculosis: its protective effect and vaccination policies]. / Vacina BCG contra tuberculose: efeito protetor e políticas de vacinação.

OBJECTIVE: The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. METHODS: A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case-control studies and meta-analyses presented separately. RESULTS: The protective effect of the first dose of the BCG vaccine against tuberculosis in its miliary and meningeal forms is high. However, the results vary in relation to the pulmonary form of the disease, with some indicating zero effect and others levels of nearly 80%. Research is being carried out to develop new vaccines that could substitute the BCG or be used as a booster. CONCLUSIONS: There are evidences that the protective effect of the BCG vaccine does not increase with a second dose. In spite of its limitations and the expectation that a new tuberculosis vaccine will be developed in the future, the BCG vaccine remains an important tool in controlling the harmful effects of tuberculosis, particularly in countries with medium or high incidence levels of the disease.

Vacina BCG contra tuberculose: efeito protetor e políticas de vacinação / BCG vaccine against tuberculosis: its protective effect and vaccination policies

OBJETIVO: A vacina BCG é utilizada desde 1921, embora ainda apresente controvérsias e aspectos não esclarecidos. O objetivo do artigo foi analisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e as políticas de vacinação adotadas. MÉTODOS: Foi realizada revisão sistemática da literatura publicada em inglês e espanhol, abrangendo o período 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 clínicos, estudos de caso-controle e metanálises. RESULTADOS: O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é elevado. No entanto, os resultados são discordantes em relação à forma pulmonar, variando de ausência de efeito a níveis próximos a 80 por cento. Estão sendo conduzidas pesquisas sobre novas vacinas candidatas a substituir a BCG ou serem utilizadas como reforço. CONCLUSÕES: Há evidências de que a segunda dose da BCG não aumenta o seu efeito protetor. Apesar de seus limites e da expectativa futura de nova vacina para tuberculose, a vacina BCG mantém-se como importante instrumento no controle dos efeitos danosos da doença, sobretudo em países com taxas de incidência médias e elevadas.

OBJECTIVE: The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. METHODS: A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case-control studies and meta-analyses presented separately. RESULTS: The protective effect of the first dose of the BCG vaccine against tuberculosis in its miliary and meningeal forms is high. However, the results vary in relation to the pulmonary form of the disease, with some indicating zero effect and others levels of nearly 80 percent. Research is being carried out to develop new vaccines that could substitute the BCG or be used as a booster. CONCLUSIONS: There are evidences that the protective effect of the BCG vaccine does not increase with a second dose. In spite of its limitations and the expectation that a new tuberculosis vaccine will be developed in the future, the BCG vaccine remains an important tool in controlling the harmful effects of tuberculosis, particularly in countries with medium or high incidence levels of the disease.

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.

Vacina BCG: eficácia e indicações da vacinação e da revacinação / BCG vaccine: efficacy and indications for vaccination and revaccination

OBJETIVOS: Revisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e discutir as suas principais indicações e contra-indicações. FONTES DOS DADOS: Utilizando o PubMed, foi realizada uma revisão sistemática da literatura abrangendo um período de, aproximadamente, 50 anos. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clínicos, estudos de caso-controle e meta-análises. Outros tópicos relevantes, como a BCG e HIV/AIDS, o uso do teste tuberculínico, aspectos relacionados à cicatriz vacinal e ao desenvolvimento de novas vacinas, dentre outros, foram também revistos. SíNTESE DOS DADOS: A vacina BCG é utilizada desde 1921. Apesar disso, ainda apresenta controvérsias e aspectos não esclarecidos. O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é bastante significativa. No entanto, em relação à forma pulmonar, os resultados são discordantes, variando de ausência de efeito a níveis próximos a 80 por cento. Há evidências de que uma segunda dose da BCG não aumenta o seu efeito protetor. Estudos demonstram proteção da vacina contra a hanseníase. Pesquisas sobre novas vacinas que, no futuro, poderão vir a substituir a BCG estão sendo realizadas. CONCLUSÕES:Apesar da expectativa de que, no futuro, venhamos a ter uma nova vacina para a tuberculose, no presente e ainda por muitos anos, a vacina BCG, apesar de suas deficiências, mantém-se como um importante instrumento nos esforços para controle dos efeitos danosos da tuberculose, sobretudo em países em que essa doença ocorre em médias e elevadas taxas de incidência.

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.

[Dropout from tuberculosis treatment in Nicaragua: the results of a comparative study]. / Abandono del tratamiento de la tuberculosis en Nicaragua: resultados de un estudio comparativo.

OBJECTIVE: To identify factors related to dropping out from tuberculosis treatment in health centers in the departments of Managua and Matagalpa, in Nicaragua. METHODS: This study matched cases and controls (1:1 ratio) by age and by municipality of treatment. The 251 cases were patients over 15 years of age who had dropped out of tuberculosis treatment, and the 251 controls were patients who had completed pharmacotherapy, during the period of January 1998 to December 2001. Data were obtained on demographic and socioeconomic characteristics, lifestyle habits, and treatment characteristics. The variables were chosen and grouped using a hierarchical theoretical model. Conditional logistic regression analysis was used to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The risk factors for dropping out of tuberculosis drug treatment were: male gender (OR, 2.51; 95% CI, 1.63 to 3.94), an unstable living situation or being homeless (OR, 3.08; 95% CI, 1.57 to 6.49), changing residence during the treatment period (OR, 4.22; 95% CI, 2.06 to 9.93), consuming alcoholic beverages (OR, 5.25; 95% CI, 2.43 to 12.94), using illegal drugs (OR, 5.25; 95% CI, 2.43 to 12.94), difficulty in access to the health services (OR, 2.64; 95% CI, 1.39 to 5.29), and a negative opinion of the health care received (OR, 5.33; 95% CI, 1.52 to 28.56). CONCLUSIONS: It is essential for the health services in Nicaragua to develop measures to reduce the risk of dropout from treatment. In particular, it is important for the health sector to work with community groups that can support the health sector's activities.