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Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine
  1. Peter Aaby1,2,
  2. Andreas Andersen2,
  3. Cesário L Martins1,
  4. Ane B Fisker1,2,
  5. Amabelia Rodrigues1,
  6. Hilton C Whittle3,
  7. Christine S Benn1,2
  1. 1Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau
  2. 2Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark
  3. 3The London School of Hygiene and Tropical Medicine, London, UK
  1. Correspondence to Dr Peter Aaby; p.aaby{at}


Background BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral polio vaccine (OPV).

Methods During an RCT of 2 doses of MV at 4.5 and 9 months versus 1 dose of MV at 9 months of age, we experienced 2 natural experiments with OPV. We assessed whether these OPV experiments modified the effect of 2-dose MV in the MV trial.

Setting MV RCT conducted in urban Guinea-Bissau 2003–2009.

Interventions Natural experiments with OPV due to missing vaccine and the implementation of OPV campaigns.

Main outcome measure Changes in the mortality rate ratio (MRR) for 2-dose MV versus 1-dose MV.

Results First, the MRR (2-dose/1-dose MV) overall was 0.70 (0.52 to 0.94), but the MRR was 1.04 (0.53 to 2.04) when OPV at birth (OPV0) was not given, suggesting that early priming with OPV was important for the effect of 2-dose MV. The effect of OPV0 depended on age of administration; the MRR (2-dose/1-dose MV) was 0.45 (0.29 to 0.71) for children receiving OPV0 in the first week of life, but 3.63 (0.87 to 15.2) for those receiving OPV0 after the first month of life (p=0.007, test of no interaction). Second, campaign-OPV may have reduced the difference between the randomisation groups since the MRR (2-dose/1-dose MV) was 0.60 (0.42 to 0.85) for children who had not received campaign-OPV before RCT-enrolment versus 0.72 (0.23 to 2.31) and 1.42 (0.70 to 2.90) for children who had received 1 or 2 doses of campaign-OPV-before-enrolment, respectively.

Conclusions Bissau had no polio infection during this trial, so OPV0 and campaign-OPV may have NSEs since they modified the effect of 2-dose MV in an RCT. Different interventions may interact to a much larger effect than usually assumed.

  • age of administration,
  • measles vaccine,
  • natural experiment,
  • OPV,
  • oral polio vaccine,
  • non-specific effect of vaccines

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  • Contributors PA and CSB planned the analysis. AA conducted the statistical analyses. CLM, AR, HCW, CSB and PA organised the trial of early MV. CSB and ABF organised data collection in connection with the campaigns. The first draft was written by PA; all authors contributed to the final version of the paper. PA and AA will act as guarantors of the study.

  • Funding The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark (grant number 104.Dan.8.f.), Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant number Health-F3-2011-261375). CSB held a starting grant from the ERC (ERC-2009-StG-243149). CVIVA is supported by a grant from the Danish National Research Foundation (DNRF108). PA held a research professorship grant from the Novo Nordisk Foundation.

  • Disclaimer The funding agencies had no role in the study design, data collection, data analysis, data interpretation or the writing of the report.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The protocol for the original trial8 was approved by the Guinean Ministry of Health's Research Coordination Committee, the Danish Central Ethical Committee, and the Gambia/MRC Scientific and Ethics Committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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