Efficacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trial.

OBJECTIVE: To compare the incidence of tuberculosis over two years in infants vaccinated at birth with intradermal BCG or with percutaneous BCG. DESIGN: Randomised trial. SETTING: South Africa. PARTICIPANTS: 11,680 newborn infants. INTERVENTIONS: Infants were randomised by week of birth to receive Tokyo 172 BCG vaccine through the percutaneous route (n=5775) or intradermal route (n=5905) within 24 hours of birth and followed up for two years. MAIN OUTCOME MEASURES: The primary outcome measure was documented Mycobacterium tuberculosis infection or radiological and clinical evidence of tuberculosis disease. Secondary outcome measures were rates of adverse events, all cause and tuberculosis specific admissions to hospital, and mortality. RESULTS: The difference in the cumulative incidence of definite, probable, and possible tuberculosis between the intradermal group and the percutaneous group, as defined using study definitions based on microbiological, radiological, and clinical findings was -0.36% (95.5% confidence interval -1.27% to 0.54%). No significant differences were found between the routes in the cumulative incidence of tuberculosis using a range of equivalence of "within 25%." Additionally, no significant differences were found between the routes in the cumulative incidence of adverse events (risk ratio 0.98, 95% confidence interval 0.91 to 1.06), including deaths (1.19, 0.89 to 1.58). CONCLUSION: Equivalence was found between intradermal BCG vaccine and percutaneous BCG in the incidence of tuberculosis in South African infants vaccinated at birth and followed up for two years. The World Health Organization should consider revising its policy of preferential intradermal vaccination to allow national immunisation programmes to choose percutaneous vaccination if that is more practical. Trial registration ClinicalTrials.gov NCT00242047.

A new recombinant bacille Calmette-Guérin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers.

BACKGROUND: One strategy for improving anti-tuberculosis (TB) vaccination involves the use of recombinant bacille Calmette-Guérin (rBCG) overexpressing protective TB antigens. rBCG30, which overexpresses the Mycobacterium tuberculosis secreted antigen Ag85b, was the first rBCG shown to induce significantly greater protection against TB in animals than parental BCG. METHODS: We report here the first double-blind phase 1 trial of rBCG30 in 35 adults randomized to receive either rBCG30 or parental Tice BCG intradermally. Clinical reactogenicity was assessed, and state-of-the-art immunological assays were used to study Ag85b-specific immune responses induced by both vaccines. RESULTS: Similar clinical reactogenicity occurred with both vaccines. rBCG30 induced significantly increased Ag85b-specific T cell lymphoproliferation, interferon (IFN)-gamma secretion, IFN-gamma enzyme-linked immunospot responses, and direct ex vivo intracellular IFN-gamma responses. Additional flow cytometry studies measuring carboxyfluorescein succinimidyl ester dilution and intracellular cytokine production demonstrated that rBCG30 significantly enhanced the population of Ag85b-specific CD4(+) and CD8(+) T cells capable of concurrent expansion and effector function. More importantly, rBCG30 significantly increased the number of Ag85b-specific T cells capable of inhibiting intracellular mycobacteria. CONCLUSIONS: These results provide proof of principal that rBCG can safely enhance human TB immunity and support further development of rBCG overexpressing Ag85b for TB vaccination.