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

Peter Aaby, Cesário L Martins, May-Lill Garly, Carlito Balé, Andreas Andersen, Amabelia Rodrigues, Henrik Ravn, Ida M Lisse, Christine S Benn, Hilton C Whittle, Peter Aaby, Cesário L Martins, May-Lill Garly, Carlito Balé, Andreas Andersen, Amabelia Rodrigues, Henrik Ravn, Ida M Lisse, Christine S Benn, Hilton C Whittle

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.

Conflict of interest statement

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.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787715/bin/aabp746123.f1_default.jpg
Fig 1 Trial diagram for early two dose measles vaccination trial. DTP3=third diphtheria-tetanus-pertussis vaccine; EZ=Edmonston-Zagreb vaccine; ITT=intention to treat analysis; MV=measles vaccine; PP=per protocol analysis; VAS=vitamin A supplementation. *Children in groups B and C were randomised to receive or not receive a booster dose of same measles vaccine at 18 months of age; deaths in parenthesis are number of deaths between randomisation at 18 months of age and end of the study; these deaths are included in total for group
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787715/bin/aabp746123.f2_default.jpg
Fig 2 Kaplan-Meier accumulated mortality curves according to vaccination group in intention to treat analysis. MRR=mortality rate ratio
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4787715/bin/aabp746123.f3_default.jpg
Fig 3 Kaplan-Meier accumulated mortality curves according to vaccination group and birth cohort in intention to treat analysis in children without vitamin A supplementation at birth. MRR=mortality rate ratio. 1365 children in cohort born before June 2004: 444 randomised to two dose group and 921 to one dose group. 2037 children in cohort born after June 2004: 663 randomised to two dose group and 1374 to one dose group

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