Trial of BCG Vaccines in South India for Tuberculosis Prevention

The protective effect of BCG vaccination in man has been evaluated in a number of controlled trials. In these trials, the protection observed varied from none to 80 per cent. In view of these conflicting results, a large scale BCG trial was planned in India and the protective effect of BCG vaccinatiou evaluated in a controlled, double-blind, community trial near Madras in south India in a population of about 360,000 persons, In this trial, all individuals aged 1 yr and above were tested with 3 IU of PPD-S and 10 units of PPD-B, and simultaneously, BCG vaccines and placebo were allocated randomly to all those aged 1 mo and above. All individuals aged 10 yr and above were X-rayed, and from such persons whose photoftuorograllls were interpreted as abnormal two specimens of sputum were collected and bacteriologically examined. Intensive efforts were made, by means of regular follow-up surveys every 21/2 yr and more frequently, by selective case-finding among suspects and further by maintaining permauent diagnostic services for symptomatics, to identify all new cases of tuberculosis occurring in the community. Mutually exclusive random samples of the population were retested with tuberculin at 21/2 mo, 21/2; and 4 yr after the intake in order to evaluate the tuberculin sensitivity over time in the study population. The study population was charaterised by a high prevalence of tuberculous infection nd disease as also by a very high prevalence of uonspecific sensitivity. This report presents findings of the first 71/2 yr of follow-up. The, tuberculin sensitivity induced by BCG vaccination was highly satisfactory at 21/2 mo but waned considerably between 21/2 mo and 21/2 yr with no further waning in sensitivity thereafter. Incidence of infection was high in the study population. However, incidence of bacillary disease was more frequent among iuitial tuberculin reactors, especially among the older persons, than among uon-reactors of whom the majority were in the younger age groups. The distribution of new cases of pulmonary tuberculosis among those not infected at intake did not show any evidence of a protective effect of BCG. Certain hypotheses that may explain the findings have been discussed

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

Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guerin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK

Background Until recently, evidence that protection from the bacillus Calmette–Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK’s universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. Objectives To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Methods Two case–control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0–19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10–29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case–cohort analysis based on Cox regression. Results In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5–10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10–15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10–15 years after vaccination and 57% (95% CI 33% to 72%) 15–20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading. Limitations The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination. Conclusions Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading