Early vaccination with BCG-Denmark or BCG-Japan versus BCG-Russia to healthy newborns in Guinea-Bissau: A randomized controlled trial.

BACKGROUND Bacille Calmette-Guérin (BCG) vaccination remains a cornerstone against tuberculosis. Randomized controlled trials (RCTs) has demonstrated that BCG-Denmark lowers all-cause mortality, but a recent RCT found no effect of BCG-Russia. Observational studies indicate that the genetically divergent BCG strains have different effects. METHODS Parallel-group, open-label RCT conducted at the National Hospital in Guinea-Bissau. Healthy neonates were randomized 1:1 to BCG-Denmark (2,851 randomized, 2,840 analyzed) versus BCG-Russia (2,845 randomized, 2,837 analyzed). We hypothesized that BCG-Denmark would reduce morbidity (primary outcome) and mortality while inducing more BCG reactions and Purified Protein Derivative (PPD) responses (secondary outcomes). Halfway through the trial, production of BCG-Denmark was halted, and the trial continued comparing BCG-Japan (3,191 neonates randomized, 3,184 analyzed) with BCG-Russia (3,170 randomized, 3,160 analyzed). Mortality and morbidity data were collected by telephone, at home-visits and at the National Hospital and assessed in Cox-models providing 6-week Mortality Rate Ratios (MRRs) and hospitalization Incidence Rate Ratios (IRRs). RESULTS By age 6 weeks, there were 140 admissions among neonates vaccinated with BCG-Denmark and 130 admissions for BCG-Russia, IRR=1.08 (95% Confidence Interval: 0.84-1.37). For BCG-Japan there were 185 admissions versus 161 admissions for BCG-Russia, IRR=1.15 (0.93-1.43). The 6-week mortality did not differ, BCG-Denmark/BCG-Russia MRR=1.15 (0.74-1.81); BCG-Japan/BCG-Russia MRR=0.71 (0.43-1.19). BCG-Denmark and BCG-Japan induced more BCG scars and PPD reactions than BCG-Russia. CONCLUSION BCG strains did not affect morbidity. BCG-Denmark and BCG-Japan were more immunogenic than BCG-Russia by the measures traditionally viewed as surrogates for successful immunization. The implications of strain differences for tuberculosis protection and overall health warrant further study.