Non-specific effects of BCG and DTP vaccination on infant mortality: An analysis of birth cohorts in Ghana and Tanzania

Abstract

Background: Vaccines may induce non-specific effects on survival and health outcomes, in addition to protection against targeted pathogens or disease. Observational evidence suggests that infant Baccillus Calmette-Guérin (BCG) vaccination may provide non-specific survival benefits, while diphtheria-tetanus-pertussis (DTP) vaccination may increase the risk of mortality. Non-specific vaccine effects have been hypothesized to modify the effect of neonatal vitamin A supplementation (NVAS) on mortality.

Methods: 22,955 newborns in Ghana and 31,999 newborns in Tanzania were enrolled in two parallel, randomized, double-blind, placebo-controlled trials of neonatal vitamin A supplementation from 2010 to 2014 and followed until 1-year of age. Cox proportional hazard models were used to estimate associations of BCG and DTP vaccination with infant survival.

Results: BCG vaccination was associated with a decreased risk of infant mortality after controlling for confounders in both countries (Ghana adjusted hazard ratio (aHR): 0.51, 95% CI: 0.38-0.68; Tanzania aHR: 0.08, 95% CI: 0.07-0.10). Receiving a DTP vaccination was associated with a decreased risk of death (Ghana aHR: 0.39, 95% CI: 0.26-0.59; Tanzania aHR: 0.19, 95% CI: 0.16-0.22). There was no evidence of interaction between BCG or DTP vaccination status and infant sex or NVAS.

Conclusion: We demonstrated that BCG and DTP vaccination were associated with decreased risk of infant mortality in Ghana and Tanzania with no evidence of interaction between DTP or BCG vaccination, NVAS, and infant sex. Our study supports global recommendations on BCG and DTP vaccination and programmatic efforts to ensure all children have access to timely vaccination.

Clinical trials registration: Ghana (Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12610000582055) and Tanzania (ANZCTR: ACTRN12610000636055).

Keywords: BCG Vaccine; DTP Vaccine; Infant mortality; Vitamin A.

Fig. 1

Combined forest plot of the adjusted effect of vitamin A supplementation on infant mortality, stratified by DTP vaccination statusFig. 1Description: These estimates correspond with estimates presented in Table 3 of the main paper. Hazard Ratios were combined by through a fixed-effect metanalysis of the adjusted estimates from Tanzania and Ghana. All hazard ratios are calculated using Cox proportional hazards models allowing for time-varying vaccination status and are controlled for continuous birthweight (with spline knots at 1.5, 2, 2.5, and 3.5 kg), head of household (mother, father, grandmother, grandfather, other), household religion (Christian, Muslim, None, Traditional African), maternal age (<20, 20–24, 25–29, 30–34, 35–39, ≥40), maternal education (None, Primary, Secondary for Tanzania, and additionally Post-secondary for Ghana), multiple or singleton birth, number of living children in household (0, 1, 2, 3 + ), number of children in household who have died (0, 1, 2, 3 + ), place of birth (Home, Facility, Other), site ID (1–4 for Ghana and 1–2 for Tanzania), wealth quintile, delivery type (vaginal or caesarean), and maternal megadose of vitamin A. See supplemental table S13.

Fig. 2

Combined forest plot of the adjusted effect of vitamin A supplementation on infant mortality, stratified by DTP vaccination status and sexFig. 2Description: These estimates correspond with estimates presented in Table 3 of the main paper. Hazard Ratios were combined by through a fixed-effect metanalysis of the adjusted estimates from Tanzania and Ghana. All hazard ratios are calculated using Cox proportional hazards models allowing for time-varying vaccination status and are controlled for continuous birthweight (with spline knots at 1.5, 2, 2.5, and 3.5 kg), head of household (mother, father, grandmother, grandfather, other), household religion (Christian, Muslim, None, Traditional African), maternal age (<20, 20–24, 25–29, 30–34, 35–39, ≥40), maternal education (None, Primary, Secondary for Tanzania, and additionally Post-secondary for Ghana), multiple or singleton birth, number of living children in household (0, 1, 2, 3 + ), number of children in household who have died (0, 1, 2, 3 + ), place of birth (Home, Facility, Other), site ID (1–4 for Ghana and 1–2 for Tanzania), wealth quintile, delivery type (vaginal or caesarean), and maternal megadose of vitamin A. See supplemental table S13.

Fig. 3

Adjusted Survival Curves among Female and Male Infants by Vitamin A and DTP Vaccination Beginning at 30 DaysFig. 3Description: Cox proportional hazards models were used to predict survival curves, accounting for covariates using weighted averages to get an overall estimate for each vitamin A supplementation and vaccination subgroup. Covariates included continuous birthweight (with spline knots at 1.5, 2, 2.5, and 3.5 kg), head of household (mother, father, grandmother, grandfather, other), household religion (Christian, Muslim, None, Traditional African), maternal age (<20, 20–24, 25–29, 30–34, 35–39, ≥40), maternal education (None, Primary, Secondary for Tanzania, and additionally Post-secondary for Ghana), multiple or singleton birth, number of living children in household (0, 1, 2, 3 + ), number of children in household who have died (0, 1, 2, 3 + ), place of birth (Home, Facility, Other), site ID (1–4 for Ghana and 1–2 for Tanzania), wealth quintile, delivery type (vaginal or caesarean), and maternal megadose of vitamin A.