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