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.

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.

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.

[Sensitivity and specificity of the BCG scar reading]. / Sensibilidade e especificidade da leitura da cicatriz vacinal do BCG.

OBJECTIVE: To validate the BCG scar as a marker of BCG vaccination status. METHODS: A cross-sectional survey was carried out among 53,348 schoolchildren aged 6-14 years who underwent BCG scar examination as part of a large BCG vaccine trial taking place in the city of Manaus, Brazil. Results of BCG scar reading were compared with information on vaccine status of their vaccination cards or provided by parents or guardians. Double-reading was performed in a sub-sample. Data analysis was conducted using Stata 7 and Kappa coefficient. RESULTS: Of 52,348 schoolchildren studied, vaccine status information from parents/guardian letters was available for 29,254 and from vaccination cards for 4,947. There was found a high agreement between the double-readings of the scars (Kappa=0.81). When the agreement between letter and card information was the gold standard, the sensitivity of BCG scar readings was 96.6% (95%CI 96.0-97.1) and the specificity was 71.1% (95%CI 55.7-83.7). The sensitivity was 96.1%, 97.3% and 95.3% for children vaccinated up to one month of age, four months and one year, respectively. CONCLUSIONS: Sensitivity and specificity did not show an association with the child's age at the scar reading. BCG scar was a good marker of BCG vaccination status regardless of age - from the first years of life up to 14 years old.

Sensibilidade e especificidade da leitura da cicatriz vacinal do BCG / Sensibility and speficity of the BCG scar reading

Objetivo: Validar a utilizaçäo da cicatriz vacinal de BCG como um indicador de vacinaçäo. MÉTODOS: Foi realizado um estudo transversal em 52.348 escolares, entre 6 e 14 anos de idade, que possuíam exame de cicatriz vacinal do BCG e que participaram de um ensaio clínico randomizado e controlado na cidade de Manaus, Brasil. Os dados da leitura da cicatriz vacinal foram comparados com a informaçäo sobre a vacinaçäo passada fornecida pelos cartöes vacinais ou informaçäo dos responsáveis. Em uma subamostra foi realizada leitura dupla com cálculo do coeficiente Kappa. Para análise dos dados utilizou-se o Stata 7. RESULTADOS: Do total de 52.348 escolares estudados, 29.254 possuíam informaçäo sobre cicatriz vacinal coletada por meio de carta aos pais, e 4.947 possuíam história de vacinaçäo coletada pelo cartäo de vacinas. Observou-se elevada concordância entre a dupla leitura de cicatriz vacinal (Kappa =0,81). A sensibilidade da leitura de cicatriz vacinal foi 96,6 por cento (95por cento IC 96,0-97,1) e a especificidade foi 71,1 por cento (95 por cento IC 55,7-83,7) quando o padräo ouro utilizado foi a concordância entre a carta aos pais e a informaçäo do cartäo de vacinas. A sensibilidade foi de 96,1 por cento, 97,3 por cento e 95,3 por cento para crianças vacinadas até um mês de idade, até 4 meses e até um ano de idade, respectivamente. CONCLUSOES: Os valores encontrados para sensibilidade e especificidade foram independentes da idade da realizaçäo da leitura de cicatriz vacinal. O exame da cicatriz vacinal mostrou ser um bom indicador para avaliar a situaçäo vacinal referente ao BCG

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.