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

Abstract

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.

Fig 1 Diagnostic algorithm for confirmation of tuberculosis in infants. Those who underwent investigations on the ward were admitted directly from their homes and were relatively well. Those requiring in-patient treatment for unrelated conditions were admitted for investigation of tuberculosis after hospital discharge and resolution of coexistent illness

Fig 2 Participant flow. *Some infants received vaccine through the alternative route to that allocated for operational reasons—for example, born shortly before midnight but vaccinated next morning, after allocation route changed. Sixty three (0.54%) infants received BCG by non-allocated route; 29 (0.50%) in intradermal group, 34 (0.58%) in percutaneous group. †10% random sample surveyed and less than 5% could not be traced. ‡Differential loss to follow-up by group cannot be calculated as out migration surveys did not collect this information

Fig 3 Percentage difference (95.5% confidence intervals) in cumulative incidence of tuberculosis over two years by end point