Elsevier

Vaccine

Volume 21, Issues 21–22, 20 June 2003, Pages 2782-2790
Vaccine

BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa: A non-specific beneficial effect of BCG?

https://doi.org/10.1016/S0264-410X(03)00181-6Get rights and content

Abstract

Previous studies have suggested that the bacille Calmette–Guérin (BCG) vaccine may have a non-specific beneficial effect on childhood survival in areas with high mortality. We examined whether BCG-vaccinated children with a BCG scar or a positive tuberculin reaction had better survival than children without such reactions. As part of an ongoing two-dose measles vaccine trial for which children were recruited at 6 months of age, we examined 1813 children for BCG scar at 6 months of age and 813 BCG-vaccinated children were skin-tested for delayed hypersensitivity to tuberculin, tetanus and diphtheria. We found that BCG-vaccinated children with a BCG scar had significantly lower mortality compared with BCG scar-negative children, the mortality ratio in the first 12 months of follow-up being 0.41 (0.25–0.67). BCG-vaccinated children with a positive tuberculin test had a mortality ratio of 0.45 (0.24–0.85) compared with tuberculin negative children. These results were unchanged by control for potential confounders or using different cut-off points for a tuberculin-positive response. Exclusion of dead children who had HIV antibodies did not modify the estimate (mortality rate (MR)=0.46 (0.23–0.94)). After censoring for tuberculosis (TB) exposure at home, the mortality ratios for having a scar and being tuberculin-positive were 0.46 (0.27–0.79) or 0.42 (0.21–0.84), respectively. Children positive to tetanus or diphtheria in the skin test had the same mortality as children not responding to these vaccine-related antigens. Thus, BCG scar and a positive tuberculin reaction were associated with better survival in early childhood in an area with high mortality. Since nothing similar was found for responders to diphtheria–tetanus–pertussis (DTP) vaccine, and the effect could not be explained by protection against tuberculosis, the effect of BCG vaccination could be due to non-specific immune-stimulation protecting against other infections.

Introduction

The bacille Calmette–Guérin (BCG) vaccine was first given to humans in 1921 [1], and came into common use in many countries during the 1930s [2], [3]. The vaccine protects against tuberculosis (TB) [4] and leprosy [5], but the efficacy against TB varies a lot between countries [6]. Recent research has provided support for the hypothesis that the variation in BCG vaccine efficacy can be ascribed to prior sensitisation with environmental mycobacteriae [7].

BCG vaccination is known to stimulate cell-mediated immunity, and BCG immunotherapy has for many decades been used in the treatment of bladder cancer resulting in improved survival [8]. Several studies investigated the effect of BCG vaccination on other cancer forms, but results in terms of survival have been contradictory [9]. In West Africa we found BCG vaccination of infants to be associated with a Th1-biased immune response [10], increased antibody response to unrelated antigen [11], less atopy [12], less anergy [13] and a reduction in childhood mortality [14]. Cutaneous anergy to tuberculin and panels of antigens has been associated with decreased survival in adults [15], [16].

If the difference in mortality between BCG-vaccinated and BCG-unvaccinated children [14] is due to the vaccine and not a result of selection bias between vaccinated and unvaccinated children, we hypothesise that the strongest beneficial effect should be found among children with a BCG scar or a positive tuberculin reaction. In connection with a vaccine trial in Guinea-Bissau, we obtained data on BCG scar status and tuberculin reaction in BCG-vaccinated infants and their subsequent childhood mortality. Since TB is also studied in this community, we examined whether the effect of BCG was related to better protection against household exposure to TB.

Section snippets

Routine vaccination programme in Guinea-Bissau

BCG and the first oral polio vaccine (OPV) are given at birth. OPV and the diphtheria–tetanus–pertussis (DTP) vaccine are given at 6, 10 and 14 weeks, and sometimes a booster dose at 18 months of age. The measles vaccine is routinely given at 9 months of age. The Bandim Health Project gave the measles vaccinations, the other vaccines were administered by the Expanded Programme on Immunisations (EPI) in Bissau.

BCG vaccination

Vaccination status was obtained via the routine surveillance system and double-checked

Study individuals

Fifty-nine percent (479/813) had a positive reaction to old tuberculin, 33% (268/813) to diphtheria, and 47% (384/813) to tetanus. The median diameter (mm) of positive reactions (range) was 4.0 (2.0–11.0) for tuberculin, 3.5 (2.0–6.5) for diphtheria, and 4.0 (2.0–12.5) for tetanus [13]. Among measles vaccinated children there was no difference in tuberculin positivity whether the child had received measles vaccine less than, 56% (73/130), or more than 6 weeks before skin-testing, 60% (168/282),

Discussion

We found BCG scar and a positive tuberculin reaction to be associated with better survival in BCG-vaccinated children. BCG vaccination has recently been associated with reduction in mortality [14]. To our knowledge, this is the first report to link BCG scar and a positive tuberculin response after BCG vaccination with better survival in childhood. Our study provides evidence that this effect is unlikely to be due to improved protection against TB as exclusion of children exposed to TB had no

Contributors

The study was planned by PA, MLG, IML, and HW. CLM, CB, MAB and MLG managed the two-dose trial and carried out the child examinations for the present study. PG managed the community study of TB. IML carried out the T-cell analyses. KLH carried out the statistical analyses. PA suggested the first analyses, MLG wrote the first draft of the paper and all authors contributed to the final version of the paper.

Acknowledgements

We are grateful to the following for logistic or financial support: Ministry of Public Health, Guinea-Bissau; Danish Council for Development Research; Danish Medical Research Council (SSVF 9700716); and the Science and Technology for Development Programme of the European Community (TS3CT910002 and ERBIC 18 CT950011). We thank Professor Per Kragh Andersen for his assistance with the statistical analyses, and Ms. Ramu Sarge-Njee and Mrs. Elishia Roberts for the HIV-testing.

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