Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

Abstract

Objectives: To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A.

Design: Systematic review, including assessment of risk of bias, and meta-analyses of similar studies.

Study eligibility criteria: Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5.

Data sources: Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified.

Results: Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV.

Conclusions: Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Fig 1 Flow diagram summarising study selection process. *34 further full text articles contained additional relevant information

Fig 2 Forest plot for BCG and all cause mortality. c=event was censored in analysis; FE=fixed effect meta-analysis method; HR=hazard ratio; MRR=mortality rate ratio; OR=odds ratio; OS=often received simultaneously with DTP; RE=random effects meta-analysis method; RR=relative risk; SS=sometimes received simultaneously with DTP. *(BCG deaths+non-BCG deaths)/total children or total deaths/total children. †Proportion of children likely to receive DTP during period of observation. ‡Proportion of children likely to receive MCV during period of observation. §Period of observation applicable to result presented in forest plot, aiming to capture effect of BCG with minimal impact of subsequent vaccinations; full study may have had longer follow-up. ¶Computed as (1−RR)×100%; non-negative number describes proportion of deaths prevented by vaccine; negative number reflects higher death rate among vaccinated children (for example, if vaccine efficacy is −100%, then an additional 100% of deaths that would have occurred without vaccine would occur with vaccine). **Early phase of trial stopped prematurely because of faulty randomisation procedure in one centre. ††(Subsequent) main trial phase with larger sample size (both phases in low birthweight infants only). In two cohort studies with “none” as adjustment for confounding, unadjusted rate ratios were computed from rates presented in article. Reference numbers correspond to those in appendix 3

Fig 3 Forest plot for DTP and all cause mortality. c=event was censored in analysis; FE=fixed effect meta-analysis method; HR=hazard ratio; MRR=mortality rate ratio; OR=odds ratio; OS=often received simultaneously with DTP; RE=random effects meta-analysis method; RR=relative risk; SS=sometimes received simultaneously with DTP. *(DTP deaths+non-DTP deaths)/total children or total deaths/total children. †Whether children studied had received BCG. ‡Proportion of children likely to receive MCV during period of observation; §Period of observation applicable to result presented in forest plot, aiming to capture effect of DTP with minimal impact of subsequent vaccinations; full study may have had longer follow-up. ¶Computed as (1−RR)×100%; non-negative number describes proportion of deaths prevented by vaccine; negative number reflects higher death rate among vaccinated children (for example, if vaccine efficacy is −100%, then an additional 100% of deaths that would have occurred without vaccine would occur with vaccine). In two cohort studies with “none” as adjustment for confounding, unadjusted rate ratios were computed from rates presented in article. Reference numbers correspond to those in appendix 3

Fig 4 Forest plot for measles containing vaccine (MCV) and all cause mortality. c=censored in analysis; FE=fixed effect meta-analysis method; HR=hazard ratio; MRR=mortality rate ratio; OR=odds ratio; OS=often received simultaneously with DTP; RE=random effects meta-analysis method; RR=relative risk. *(MCV deaths+non-MCV deaths)/total children or total deaths/total children. †Whether children studied had received BCG. ‡Whether children studied had received DTP. §Period of observation applicable to result presented in forest plot, aiming to capture effect of MCV with minimal impact of subsequent vaccinations; study may have had longer follow-up. ¶Computed as (1−effect size)×100%; non-negative number describes proportion of deaths prevented by vaccine; negative number reflects higher death rate among vaccinated children (for example, if vaccine efficacy is −100%, then an additional 100% of deaths that would have occurred without vaccine would occur with vaccine). (a) and (b) for Guinea-Bissau 1989-99 and Guinea-Bissau 1978-83 each reflect two results from same birth cohort in non-overlapping groups of children. In most observational studies with “none” as adjustment for confounding, unadjusted rate ratios were computed from rates presented in article. Reference numbers correspond to those in appendix 3

Fig 5 Forest plot for comparisons of different sequences of vaccines and all cause mortality. FE=fixed effect meta-analysis method; HR=hazard ratio; OR=odds ratio; RE=random effects meta-analysis method; RR=relative risk. *(MCV deaths+non-MCV deaths)/total children or total deaths/total children. †Period of observation applicable to result presented in forest plot, aiming to capture effect with minimal impact of subsequent vaccinations; full study may have had longer period of follow-up. ‡Meta-analysis excludes one Papua New Guinea result (1-5 months) to avoid double counting. In most observational studies with “none” as adjustment for confounding, unadjusted rate ratios were computed from rates presented in article. Results from Senegal 1996-99 were computed from full sample, rather than sample aged 9-24 months also reported. Reference numbers correspond to those in appendix 3

Fig 6 Differential vaccine effects by sex: meta-analyses of within study estimates of interaction. FE=fixed effect meta-analysis method; R=randomised trial; RE=random effects meta-analysis method; RR=relative risk. *Risk of bias assessments for main effects of the vaccine (from fig 2 to fig 4). Reference numbers correspond to those in appendix 3

Fig 7 Differential vaccine effects by age at vaccination. CC=case-control study; RR=relative risk. Reference numbers correspond to those in appendix 3

Fig 8 Summary of results from studies examining all three vaccines. CC=case-control study; HR=hazard ratio; OR=odds ratio; RR=relative risk. Reference numbers correspond to those in appendix 3