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Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

BMJ 2016; 355 doi: (Published 13 October 2016) Cite this as: BMJ 2016;355:i5170

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Bacillus Calmette Guerin (BCG) vaccine. Is the association to childhood mortality a specific effect?

Dear Editor,

I read the review by Higgins et al with great interest, and have a comment concerning the association between the Bacillus Calmette Guerin (BCG) vaccine and childhood mortality.1

BCG has been observed to maybe reduce childhood mortality more than what may be explained by the specific protection against tuberculosis. In 2011, a trial in Guinea-Bissau among low birth weight (LBW) infants found BCG was associated with reduced neonatal mortality. We interpreted the finding as being in line with the hypothesis of vaccines having “non-specific” effects on childhood mortality caused by other conditions than the vaccine target disease.2

Thus, we tested the hypothesis of BCG having non-specific effects on early childhood morbidity in a high-income setting with low childhood mortality. During 2012-2015, we carried out a large-scale randomised controlled trial in Denmark, where routine BCG vaccination at school start was discontinued from 1979 due to low prevalence of tuberculosis. We randomised 4262 children to BCG within 7 days after birth and followed the children for the primary outcome of early childhood hospitalisations. However, no non-specific effect was observed in main analyses of the primary outcome, or secondary outcomes.3

There may be several explanations of the discrepancy between the observations in low-income settings of a beneficial “non-specific” effect, and the observation of no non-specific effect of BCG in the high-income setting of Denmark.3 One explanation, which to my knowledge has not been discussed before, is that the “non-specific” effect of BCG on childhood mortality may be at least partly specific. The strongest beneficial “non-specific” effect of BCG on childhood mortality has been observed in studies from settings where tuberculosis was prevalent. For example, the prevalence of tuberculosis is very high in Guinea Bissau, where family contact with a tuberculosis case has been found to be a significant risk factor for child mortality.4 Information on causes of death is based on verbal autopsy, and it is not possible to know if the cause of death was related to tuberculosis. Low birth weight is a risk factor for tuberculosis.5 Interestingly, the “non-specific” beneficial effect of BCG on neonatal mortality in the trial among from Guinea-Bissau was mainly due to fewer cases of neonatal sepsis, respiratory infections, and fever; 2 i.e. potential early mycobacterial infection.

In the light of the importance of vaccines in global health, it seems relevant to further scrutinize the nature of the effects of the BCG vaccine. Specific as well as non-specific.

Reference List

(1) Higgins JP, Soares-Weiser K, Lopez-Lopez JA, Kakourou A, Chaplin K, Christensen H et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016; 355:i5170.
(2) Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011; 204(2):245-252.
(3) Stensballe LG, Sorup S, Aaby P, Benn CS, Greisen G, Jeppesen DL et al. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial. Arch Dis Child 2016.
(4) Gomes VF, Andersen A, Wejse C, Oliveira I, Vieira FJ, Joaquim LC et al. Impact of tuberculosis exposure at home on mortality in children under 5 years of age in Guinea-Bissau. Thorax 2011; 66(2):163-167.
(5) Ramachandran R, Indu PS, Anish TS, Nair S, Lawrence T, Rajasi RS. Determinants of childhood tuberculosis--a case control study among children registered under revised National Tuberculosis Control Programme in a district of South India. Indian J Tuberc 2011; 58(4):204-207.

Competing interests: No competing interests

10 January 2017
Lone G. Stensballe
Research leader, paediatrician, ph.d.
The Child and Adolescent Clinic 4072, Juliane Marie Centret, Rigshospitalet, Copenhagen University Hospital
Blegdamsvej 9, DK-2100 Copenhagen East, Denmark