Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries
- Peter Aaby1,2,
- Christine Benn1,2,
- Jens Nielsen1,2,
- Ida Maria Lisse1,2,
- Amabelia Rodrigues1,2,
- Henrik Ravn1,2
- 1Bandim Health Project, INDEPTH Network, Statens Serum Institut, Bissau, Guinea-Bissau
- 2Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark
- Correspondence to Dr Peter Aaby;
- Received 30 November 2011
- Accepted 12 April 2012
- Published 22 May 2012
Background Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection.
Objective The authors examined whether whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and non-specific effects.
Data sources and eligibility Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status.
Setting High-mortality countries in Africa and Asia.
Methods The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP.
Main outcome Consistency between studies.
Results In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two ‘natural experiments’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female–male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality.
Conclusions These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
To cite: Aaby P, Benn C, Nielsen J, et al. Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries. BMJ Open 2012;2:e000707. doi:10.1136/bmjopen-2011-000707
Contributors The first draft was written by PA. All authors contributed to the papers which form the basis for this hypothesis and to the final version of the present paper. PA will act as guarantors of the study.
Funding The Bandim Health Project received support from DANIDA and the Danish National Research Foundation. PA holds a research professorship grant from the Novo Nordisk Foundation. CB is funded by the European Research Council (ERC-2009-StG, grant agreement number 243149). The Research Center for Vitamins and Vaccines (CVIVA) is supported by the Danish National Research Foundation.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data available. The authors' own data sets are available through data sharing agreements (see http://www.bandim.org/).
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