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Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial

BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c6495 (Published 30 November 2010) Cite this as: BMJ 2010;341:c6495
  1. Peter Aaby, professor12,
  2. Cesário L Martins, clinician1,
  3. May-Lill Garly, senior researcher12,
  4. Carlito Balé, clinician1,
  5. Andreas Andersen, statistician12,
  6. Amabelia Rodrigues, research director1,
  7. Henrik Ravn, senior statistician12,
  8. Ida M Lisse, senior registar3,
  9. Christine S Benn, senior researcher12,
  10. Hilton C Whittle, professor4
  1. 1Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau
  2. 2Bandim Health Project, Danish Epidemiology Science Centre, Statens Serum Institut, 2300 Copenhagen S, Denmark
  3. 3Department of Pathology, Herlev University Hospital, 2730 Herlev, Denmark
  4. 4MRC Laboratories, Fajara, POB 273, Gambia
  1. Correspondence to: P Aaby p.aaby{at}bandim.org
  • Accepted 20 September 2010

Abstract

Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy).

Design Randomised controlled trial.

Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area.

Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation.

Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C).

Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups.

Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99).

Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations.

Trial registration Clinical trials NCT00168558.

Footnotes

  • Contributors: MLG, CLM, HCW, IML, and PA designed the study. CLM, M-LG and PA initiated the study routines. CLM and CB treated the measles patients during the outbreak. AR supervised the routine registration system. CSB was principle investigator of the vitamin A trials and provided the data on these children. Data were analysed by PA, AA, and HR. AA and HR were responsible for the statistical analyses. PA wrote the first draft of the paper, and all authors contributed to the final version. PA is the guarantor.

  • Funding: The research on the decline in maternal antibodies that inspired this trial was funded by the Thrasher Foundation. This study was mostly funded by DANIDA and the Danish National Research Foundation. The project also received support from Fonden til Lægevidenskabens Fremme and Novo Nordisk Foundation. The Bandim Health Project received support from DANIDA. PA holds a research professorship grant from the Novo Nordisk Foundation. The funding agencies had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report.

  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The protocol was approved by the Danish Central Ethical Committee, the Gambia/MRC scientific and ethics committees, and the Guinean Ministry of Health’s Research Coordination Committee.

  • Data sharing: No additional data available.

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