Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau

Adam Edvin Roth, Christine Stabell Benn, Henrik Ravn, Amabelia Rodrigues, Ida Maria Lisse, Maria Yazdanbakhsh, Hilton Whittle, Peter Aaby, Adam Edvin Roth, Christine Stabell Benn, Henrik Ravn, Amabelia Rodrigues, Ida Maria Lisse, Maria Yazdanbakhsh, Hilton Whittle, Peter Aaby

Abstract

Objective: To determine whether BCG revaccination at 19 months of age reduces overall child mortality.

Design: Randomised trial, with follow-up to age 5.

Setting: A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants.

Participants: 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrollment.

Intervention: BCG vaccination or no vaccination (control).

Main outcome measure: Hazard ratios for mortality.

Results: 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrollment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrollment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrollment (1.78, 1.04 to 3.04).

Conclusions: There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions. Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.

Conflict of interest statement

Competing interests: None declared.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787910/bin/rota622704.f1_default.jpg
Fig 1 BCG revaccination trial profile. PPD=tuberculin purified protein derivative
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787910/bin/rota622704.f2_default.jpg
Fig 2 Number of deaths by month, July 2002 to May 2006 (numbers should be interpreted with caution as number of enrolled children and their average age changed over time). Sequence of events: recruitment to trial started in July 2002; oral polio vaccine and vitamin A supplementation campaign (high coverage) occurred in October and November 2002; malaria survey and iron supplementation in August and November 2003; measles epidemic in November 2003-May 2004; missed vaccines and vitamin A supplementation campaign (low coverage) in November 2003; recruitment stopped in April 2004; oral polio vaccine and vitamin A supplementation campaign (high coverage) took place in October and November 2004, and October and November 2005; measles vaccine for all aged <15 and vitamin A supplementation campaign (high coverage) and end of follow-up was in May 2006
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787910/bin/rota622704.f3_default.jpg
Fig 3 Cumulative mortality curves for BCG revaccinated children and controls
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787910/bin/rota622704.f4_default.jpg
Fig 4 Mortality according to total-time-on-test analysis. Boundaries (dashed lines) corresponding to total-time-on-test (see text). Under assumption of constant mortality intensity, plot should approximate straight line with unit slope. If curve crosses any of boundaries hypothesis of constant mortality intensity can be rejected

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