Early Vaccination With Bacille Calmette-Guérin-Denmark or BCG-Japan Versus BCG-Russia to Healthy Newborns in Guinea-Bissau: A Randomized Controlled Trial.

Frederik Schaltz-Buchholzer, Morten Bjerregaard-Andersen, Christian Bjerregård Øland, Christian Golding, Elise Brenno Stjernholm, Ivan Monteiro, Peter Aaby, Christine Stabell Benn

Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2021;71(8):1883-1893

PMID: 31677386

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Abstract

BACKGROUND

Bacille Calmette-Guérin (BCG) vaccination remains a cornerstone against tuberculosis. Randomized controlled trials (RCTs) have 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

This was a parallel-group, open-label RCT conducted at the National Hospital in Guinea-Bissau. Healthy neonates were randomized 1:1 to BCG-Denmark (2851 randomized, 2840 analyzed) vs BCG-Russia (2845 randomized, 2837 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 (3191 neonates randomized, 3184 analyzed) with BCG-Russia (3170 randomized, 3160 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 and 130 admissions among neonates vaccinated with BCG-Denmark and BCG-Russia, respectively (IRR, 1.08 [95% confidence interval {CI}, .84-1.37]). For BCG-Japan, there were 185 admissions vs 161 admissions for BCG-Russia (IRR, 1.15 [95% CI, .93-1.43]). The 6-week mortality did not differ: BCG-Denmark/BCG-Russia (MRR, 1.15 [95% CI, .74-1.80]); BCG-Japan/BCG-Russia (MRR, 0.71 [95% CI, .43-1.19]). BCG-Denmark and BCG-Japan induced more BCG scars and PPD reactions than BCG-Russia.

CONCLUSIONS

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.

CLINICAL TRIALS REGISTRATION

NCT02447536.

Address: Institute of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark.; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.; Research Center for Vitamins and Vaccines, Statens Serum Institut, Copenhagen, Denmark.; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.; Research Center for Vitamins and Vaccines, Statens Serum Institut, Copenhagen, Denmark.; Research Center for Vitamins and Vaccines, Statens Serum Institut, Copenhagen, Denmark.; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.; Institute of Clinical Research, University of Southern Denmark and Odense University Hospital, Odense, Denmark.; Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau.; Research Center for Vitamins and Vaccines, Statens Serum Institut, Copenhagen, Denmark.; Danish Institute of Advanced Science, University of Southern Denmark, Odense, Denmark.

DOI: 10.1093/cid/ciz1080

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MeSH Terms: BCG Vaccine, Denmark, Guinea-Bissau, Humans, Infant, Infant, Newborn, Japan, Russia, Vaccination