Short communicationBacille Calmette-Guérin vaccination at birth and differential white blood cell count in infancy. A randomised clinical trial
Introduction
The Bacille Calmette-Guérin (BCG) vaccine against tuberculosis (TB) is part of the childhood immunisation programme in TB-endemic countries. Recent studies have suggested that the vaccine may reduce all-cause child mortality more than can be explained by protection against TB due to so-called non-specific effects (NSEs) [1]. Furthermore the BCG vaccination has been associated with reduced morbidity, specifically infections [2] and atopic disease [3]. Recently WHO reviewed the epidemiological evidence and suggested that the BCG vaccine reduces overall mortality more than expected, and have therefore recommended further research [4], [5].
Emerging immunological evidence suggests that the NSEs of BCG may be at least partially explained by trained innate immunity [6], [7], [8]. Effects of BCG could also be mediated via changes in the proportion of different white blood cells (WBCs): In Guinea-Bissau, BCG at birth may have been associated with increased production of cytokines upon heterologous challenge 4 weeks post-vaccination, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. In parallel, BCG was potentially associated with increased total leucocytes, monocytes and basophil granulocyte counts 4 weeks post vaccination in females [9].
Given the possible effect of BCG on mortality and morbidity and the potential observed effect on WBCs in Guinean newborns, we investigated the effect of BCG at birth on differential WBC counts in healthy, Danish infants. Nested within a clinical trial testing the effect of BCG at birth on infant morbidity [10], a sub-group of infants had blood samples collected at three time points during the first year of life; 4 days after randomisation, and at ages 3 and 13 months.
Section snippets
Study design
The study was nested within The Danish Calmette Study [10]; a randomised, controlled, clinical multicentre trial conducted at three Danish University Hospitals, investigating the effect of BCG at birth on infant morbidity. Between October 2012 and November 2013, 4262 newborn infants were randomised within 7 days of birth with a 1:1 allocation to either BCG vaccination or no BCG vaccination. Infants randomised to BCG received an intradermal BCG vaccine (Danish strain 1331, Statens Serum
Study population
A total of 320 infants (BCG = 184, control = 136) were included in the study; 161 infants at 4 days (BCG = 82, control = 79), two infants at 3 months of age (BCG = 2, control = 0), and 157 infants at 13 months of age (BCG = 100, control = 57), respectively (Fig. 1). Two infants allocated to the control group were BCG vaccinated outside the study and were therefore excluded from all analyses.
At 4 days, 3 months, and 13 months of age, a total of 152 infants (BCG = 74, control = 78), 152 infants (
Main findings and comparison with previous studies
We found no significant effect of BCG at birth on WBC differential counts in healthy, term infants during the first year of life.
Jensen et al.[9] did not find an overall effect of BCG on WBCs – in accordance with our findings – but in sub-analyses observed a potential sex-differential association between BCG vaccination and WBC counts in low birth weight Guinean infants 4 weeks after immunization; this tendency was not found in our study and we were not able to corroborate the findings by
Conclusion
In this explorative investigation of the effect of BCG on differential WBC count within a large randomised clinical trial we found no overall effect of BCG at birth on differential WBC count during the first year of life in a high-income setting in Danish, healthy infants.
Authors’ contributions:
CSB, LGS, OP, DLJ, NMB, KJJ and TNN conceived the idea and designed the experiments. OP and DLJ supervised the collection of data. SKJ, TMJ, NMB, and TNN participated in the data collection. SKJ carried out data management and analysed the data with help from TNN, DLJ, NMB, LGS, KJJ and CSB. TNN supervised the statistical analyses. SKJ drafted the manuscript. All authors read and approved the final manuscript.
Funding
The study was funded by Copenhagen University Hospital, Hvidovre, and the Danish National Research Foundation (DNRF108).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We gratefully acknowledge the participation of the children and their parents. Special thanks to Birgit Peitersen, Linda Billetorp, Arild Ejsing, and Andreas Andersen for invaluable assistance.
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