Peter Aaby and colleagues present again highly controversial data in the Archives, namely that vaccines have non-specific effects on infant survival depending on the timing and sequence of vaccines and on sex.[1] The same research group has already published many articles on this topic which have generated much debate [2-4] without reaching a final conclusion whether their claims are correct or not (for a full publication list of the research group see http://www.bandim.org/index.php?publications and http://www.ncbi.nlm.nih.gov/pubmed?term=aaby%20p). Despite the authors' own conclusions, this current paper may not be as convincing as supposed.

My first argument relates to the small numbers of deaths in the different categories on which their conclusions are based (see table 3).[1] In 3 sub-groups, only 2 or 3 deaths occurred during the 4 months of study. If just 1 death less or more had occurred in the opposite sub- groups, leaving total numbers of deaths and sex-related deaths the same, then BCG at birth followed by DTP would increase the deaths rate ratios (DRR) to 2.04 for girls and boys (not only for girls as claimed by Aaby and colleagues), whereas in the late BCG group there would be an advantage for boys (DRR 0.40), but no effect at all on girls (DRR 1.20) (for these hypothetical recalculations the table can be supplied by email as it was not possible to include it here for technical reasons).

My second argument relates to the high attrition rates and hence incomplete reporting. When looking at figure 1, out of the initial cohort of 2320 neonates 490 infants were not included in the follow-up after 2 months because either they had died, moved, travelled, refused to participate or had no vaccination card.[1] This equals an attrition rate of 21% at this point of the trial. Out of the remaining 1830 infants, only 1501 (including the 50 deaths) could be assessed in the final analysis at 6 months, a loss of another 14% of the original cohort. The authors do not provide further data about this group of infants lost to follow-up whether any additional deaths occurred and if so in which sub-group. But in 2011, the same group published results of the same trial with exactly the same cohort covering the first 12 months of life in another journal where they examined the non-specific effect of early versus late BCG vaccination on survival.[5] In that paper, they reported 8 more deaths between the age of 2 and 6 months, 3 in the early and 5 in the late BCG vaccination sub- group. Thus there must be some more information on the outcome of infants between the age of 2 and 6 months which is not reported in this publication (for details compare the trial profiles in this (figure 1) and the earlier publication (figure 1)).[1,5] It would be most welcome if the authors could explain why they did not report on these 8 additional deaths here and what the results would be with these additional deaths.

These observations demonstrate that the question of beneficial or harmful non-specific effects of vaccines on infants has not been settled yet. As the expanded program on immunization is so central to the health and survival of infants all over the world, I fully agree with the authors that randomised controlled trials are needed to answer this extremely important, but still controversial issue.

References

1. Aaby P, Ravn H, Roth A, Rodrigues A, Lisse IM, Diness BR, Lausch KR, Lund N, Rasmussen J, Biering-Sorensen S, Whittle H, Benn CS. Early diphtheria-tetanus-pertussis vaccination associated with higher female mortality and no difference in male mortality in a cohort of low birthweight children: an observational study within a randomised trial. Arch Dis Child. 2012 Feb 13. [Epub ahead of print]

2. Fine PE, Smith PG, Evans SJ. Non-specific effects of BCG? J Infect Dis. 2012 Feb;205(3):515.

3. Aaby P, Roth A, Biering-Sorensen S, Ravn H, Rodrigues A, Whittle H, Benn CS. No evidence of bias in trial showing BCG reduces neonatal mortality. J Infect Dis. 2012 Feb;205(3):515-7.

4. Shann F. The nonspecific effects of vaccines and the expanded program on immunization. J Infect Dis. 2011 Jul 15;204(2):182-4.

5. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, Stensballe L, Diness BR, Lausch KR, Lund N, Biering-Sorensen S, Whittle H, Benn CS. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis. 2011 Jul 15;204(2):245-52.

Conflict of Interest:

None declared