The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination

doi:10.1016/j.vaccine.2009.02.080

Vaccine

Volume 27, Issue 21, 11 May 2009, Pages 2891-2898

https://doi.org/10.1016/j.vaccine.2009.02.080 Get rights and content

Abstract

Unexpectedly, we found no overall beneficial effect on mortality in a randomised trial of vitamin A supplementation (VAS) or placebo administered with BCG vaccine at birth in Guinea-Bissau. We conducted an explorative analysis to examine whether subsequent diphtheria–tetanus–pertussis (DTP) vaccinations had modified the effect of VAS at birth. VAS was associated with a weak tendency for decreased mortality as long as BCG was the most recent vaccination, the mortality rate ratio being 0.86 (0.48–1.54); 0.82 (0.32–2.08) in girls and 0.89 (0.43–1.88) in boys. However, after DTP vaccination VAS at birth was associated with increased mortality in girls (2.19 (1.09–4.38)), whereas no difference was seen for boys (0.90 (0.44–1.82)) (p = 0.08 for equal effect of VAS in the two sexes if DTP is the last vaccine). The explanation for the lack of beneficial effect in our setting may have been that VAS at birth interacted negatively with subsequent DTP vaccinations in girls.

Introduction

Three randomised trials from Asia have reported a beneficial effect on mortality of vitamin A supplementation (VAS) at birth [1], [2], [3]. One of the studies followed children to 12 months of age [1]. The beneficial effect was only apparent in the first 4 months of life. The two other studies followed children to 6 months of age [2], [3]. The largest effect was observed in the first 3–4 months of life. There was a tendency for a more beneficial effect in boys in two of the studies [1], [2], but not in the third study [3]. In contrast, a recent trial from Zimbabwe randomised both mothers and neonates to VAS in a two-by-two factorial design, and found no beneficial effect of VAS at birth on mortality at 12 months of age [4], [5]. The survival curves indicated that during the first 2 months of life mortality was highest in the group in which mother as well as child received placebo (Fig. 2 in Ref. [4]). However, after the first months, mortality was higher in the two groups in which the children received VAS and this tendency remained until 12 months of age. The data were not reported by sex [6].

We have conducted a randomised trial of the effect on mortality of 50,000 IU vitamin A administered simultaneously with BCG at birth in Guinea-Bissau. The main results were reported elsewhere [7]. In brief, among 4345 participating infants we found no overall beneficial effect of VAS, the mortality rate ratio being 1.07 (0.79–1.44) [7]. However, the effect of VAS tended to differ between boys and girls, especially after the first months of life. From 4 to 12 months of age; the mortality rate ratio in boys was 0.74 (0.41–1.34) compared with 1.67 (0.94–2.97) in girls (p for equal effect of VAS in the two sexes = 0.05) [7].

The overall results from the three Asian studies and the two African studies are conflicting, since the Asian studies found a beneficial effect of VAS [1], [2], [3] whereas the African studies did not [4], [5], [7]. Nonetheless there are some similarities between the studies. All studies suggest that the effect of VAS at birth is not constant over time. It may be beneficial during the first 2–4 months of life but this effect disappears and may even be counteracted by a negative effect later in infancy. Furthermore, three of the four studies that published results by sex found that VAS tended to benefit boys more than girls [1], [2], [7].

It would seem important to explain these contrasts and similarities. Understanding the mechanisms might have consequences for how and to whom VAS should be distributed to optimise its beneficial effect on child survival. Particularly, it would seem important to understand the apparent later increase in mortality in the African trials.

We have previously proposed the hypothesis that VAS amplifies the non-specific effects of routine childhood vaccines, being beneficial when given in the time-window of the live vaccines such as BCG vaccine (recommended at birth) or measles vaccine (9 months of age), but potentially harmful when given when the inactivated DTP vaccine is the predominant vaccine (1–5 months of age) [8]. Accordingly, we expected VAS given with BCG at birth would be beneficial. However, the contradictory results made us speculate that the potential beneficial effect of VAS with BCG at birth may have been counteracted by a negative interaction between VAS and the subsequent DTP vaccinations.

Hence, within the Guinea-Bissau trial we conducted a post hoc explorative analysis comparing the effect of VAS while BCG was the last vaccine received with the effect of VAS once the children received DTP vaccine. Due to the observed sex-differences in response to VAS [1], [2], [6], [7], [9], [10], and due to consistent observations of sex-differential non-specific effects of routine vaccinations [11], [12], [13], we analysed all data by sex.

Section snippets

Setting and population

The Bandim Health Project (BHP) has a demographic surveillance system (DSS) in six districts of the capital of Guinea-Bissau, covering approximately 90,000 inhabitants. The study area is poor. Most people live in multi-family mud-brick houses with zinc or straw roofs. More than 60% have no electricity in the house. Around 30% of the mothers in the present trial had no education. All houses in the study area are visited monthly to register new pregnancies and births. Once a newborn is

Results

A total of 4345 children were enrolled in the study and received VAS or placebo with a BCG vaccine. Of these, 70 (2%) were never found after enrolment, and 186 other children (4%) received a DTP before or at the same time as the BCG vaccine. These children were not considered in the subsequent analyses. Of the remaining 4089 children, 3708 (91%) changed status to DTP vaccinated before they were censored. Among these children 3295 (89%) changed status at the exact date of vaccination; the rest

Principal findings

Routine vaccines have been associated with non-specific and sex-differential effects. The live BCG and measles vaccines have beneficial effects on overall mortality. However, inactivated vaccines including DTP have been associated with increased mortality. The non-specific effects have been strongest in girls [11], [12], [13]. We have previously hypothesised that VAS amplifies these non-specific effects of vaccines [8]. We conducted a randomised trial of VAS with BCG and expected the effect to

Acknowledgements

Contributors: CB was the chief investigator and guarantor and responsible for the scientific papers. CB, AR, MY, HW, and PA designed the original study. CB, AR, AF, and PA developed the study hypothesis. HR contributed to the statistical analysis. CB wrote the first draft of the paper. All authors contributed to and approved the final version of the paper. Funding: The study was funded by the EU (ICA4-CT-2002-10053), The Danish Medical Research Council, University of Copenhagen, March of Dimes,

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Cited by (48)

Effect of national immunisation campaigns with oral polio vaccine on all-cause mortality in children in rural northern Ghana: 20 years of demographic surveillance cohort data
2023, eClinicalMedicine
Studies from Guinea-Bissau and Bangladesh have shown that campaigns with oral polio vaccine (C-OPV) may be associated with 25–31% lower child mortality. Between 1996 and 2015, Ghana had 50 national C-OPVs and numerous campaigns with vitamin A supplementation (VAS), and measles vaccine (MV). We investigated whether C-OPVs had beneficial non-specific effects (NSEs) on child survival in northern Ghana.
We used data from a health and demographic surveillance system in the Navrongo Health Research Centre in rural northern Ghana to examine mortality from day 1–5 years of age. We used Cox models with age as underlying time scale to calculate hazard ratios (HR) for the time-varying covariate “after-campaign” mortality versus “before-campaign” mortality, adjusted for temporal change in mortality, other campaign interventions and stratified for season at risk.
From 1996 to 2015, 75,610 children were followed for 280,156 person-years between day 1 and 5 years of age. In initial analysis, assuming a common effect across all ages, we did not find that OPV-only campaigns significantly reduced all-cause mortality, the HR being 0.96 (95% CI: 0.88–1.05). However, we subsequently found the HR differed strongly by age group, being 0.92 (0.75–1.13), 1.29 (1.10–1.51), 0.79 (0.66–0.94), 0.67 (0.53–0.86) and 1.03 (0.78–1.36) respectively for children aged 0–2, 3–5, 6–8, 9–11 and above 12 months of age (p < 0.001). Triangulation of the evidence from this and previous studies suggested that increased frequency of C-OPVs and a different historical period could explain these results.
In Ghana, C-OPVs had limited effects on overall child survival. However, triangulating the evidence suggested that NSEs of C-OPVs depend on age of first exposure and routine vaccination programs. C-OPVs had beneficial effects for children that were not exposed before 6 months of age. These non-specific effects of OPV should be exploited to further reduce child mortality.
DANIDA; Else og Mogens Wedell Wedellsborgs Fond.
Non-specific effects of BCG and DTP vaccination on infant mortality: An analysis of birth cohorts in Ghana and Tanzania
2022, Vaccine
Citation Excerpt :
The evidence regarding the interaction between vitamin A and DTP vaccination on child mortality is less clear, since there have been no randomized trials investigating this interaction. One observational analysis of a vitamin A supplementation trial in Guinea-Bissau found that vitamin A supplementation was associated with increased mortality (hazard ratio (HR): 2.19, 95% CI: 1.09–4.38) only within the subgroup of female infants who had received DTP [17]. However, a similar study in Tamil Nadu found no interaction [18].
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.
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.
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.
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)
Vaccinology: time to change the paradigm?
2020, The Lancet Infectious Diseases
The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.
Contrasting female-male mortality ratios after routine vaccinations with pentavalent vaccine versus measles and yellow fever vaccine. A cohort study from urban Guinea-Bissau
2016, Vaccine
In addition to protection against the target diseases, vaccines may have non-specific effects (NSEs). Measles vaccine (MV) has beneficial NSEs, providing protection against non-measles deaths, most so for girls. By contrast, though protecting against diphtheria, tetanus and pertussis, DTP vaccine is associated with increased female mortality relative to male mortality. In 2008, Guinea-Bissau replaced DTP with the DTP-containing pentavalent vaccine (Penta; DTP-H. influenza type B-Hepatitis B) at 6, 10 and 14 weeks and yellow fever vaccine (YF) was to be given with MV. We investigated possible sex-differential mortality rates following Penta and MV+YF vaccination.
Bandim Health Project (BHP) registers vaccines given by the three government health centres in the study area and vital status through demographic surveillance. We assessed the association between sex and mortality by vaccination status in Cox proportional hazards models with age as underlying timescale. Follow-up was censored at a subsequent vaccination contact or after 6 months of follow-up.
Between September 2008 and April 2011, we registered 23,448 vaccination contacts for children aged 42–365 days; 17,313 were for Penta and 3028 for MV (2907 co-administered with YF). During follow-up 112 children died. The female/male mortality rate ratio was 1.73 (1.11–2.70) following Penta and 0.38 (0.12–1.19) after MV (p = 0.02 for same effect). Adjusting for maternal education or weight-for-age at the time of vaccination did not change the estimates.
Penta appears to have the same negative effects on mortality as those seen for DTP. Assessing post-vaccination mortality for boys and girls is necessary to improve the vaccination programme.
Interaction between neonatal vitamin A supplementation and timing of measles vaccination: A retrospective analysis of three randomized trials from Guinea-Bissau
2014, Vaccine
Citation Excerpt :
A third trial randomized normal birth weight neonates 1:1:1 to 50,000 IU vitamin A, 25,000 IU vitamin A or placebo (VITA III, 2004–2007) [3]. We observed that NVAS interacted with subsequent routine vaccinations in a sex-differential manner; the effect of NVAS tended to be negative in females once they started receiving the diphtheria–tetanus–pertussis vaccine (DTP) recommended at 6 weeks of age [2,4]. From 2003 to 2007 a trial randomizing children to early measles vaccine (MV) at 4.5 months of age or no early MV in addition to the usual MV at 9 months of age was also conducted [5,6].
In Guinea-Bissau we conducted three trials of neonatal vitamin A supplementation (NVAS) from 2002 to 2008. None of the trials found a beneficial effect on mortality. From 2003 to 2007, an early measles vaccine (MV) trial was ongoing, randomizing children 1:2 to early MV at 4.5 months or no early MV, in addition to the usual MV at 9 months. We have previously found interactions between vitamin A and vaccines.
We investigated whether there were interactions between NVAS and early MV.
We compared the mortality of NVAS and placebo recipients: first, from 4.5 to 8 months for children randomized to early MV or no early MV; and second, from 9 to 17 months in children who had received two MV or one MV. Mortality rates (MR) were compared in Cox models producing mortality rate ratios (MRR).
A total of 5141 children were randomized to NVAS (N = 3015) or placebo (N = 2126) and were later randomized to early MV (N = 1700) or no early MV (N = 3441). Between 4.5 and 8 months, NVAS compared with placebo was associated with higher mortality in early MV recipients (MR = 30 versus MR = 0, p = 0.01), but not in children who did not receive early MV (p for interaction between NVAS and early MV = 0.03). From 9 to 17 months NVAS was not associated with mortality. Overall, from 4.5 to 17 months NVAS was associated with increased mortality in early MV recipients (Mortality rate ratio = 5.39 (95% confidence interval: 1.62, 17.99)).
These observations indicate that NVAS may interact with vaccines given several months later. This may have implications for the planning of future child intervention programs.
High-dose vitamin A supplementation administered with vaccinations after 6 months of age: Sex-differential adverse reactions and morbidity
2013, Vaccine
WHO recommends vitamin A supplementation (VAS) at vaccination contacts after six months of age. The effect of this recommendation on mortality has not been evaluated.
We tested the effect of VAS at vaccination contacts on mortality in a randomised trial in Guinea-Bissau. In a subgroup within this trial we studied adverse reactions to VAS and whether VAS modified known adverse reactions to live and inactivated vaccines and general morbidity during the first month after supplementation overall and by sex. Children aged 6–17 months were randomised to VAS or placebo at the day of vaccination (day 0). We interviewed the caretaker, assessed the fontanel and measured temperature and local reaction at the injection site at home visits on day 1, 2, 3, 7, 14, 21, and 31. We defined systemic adverse reactions to inactivated and live vaccines as fever on day 1 and 2 and on 4–14 respectively. Clinical symptoms associated with increased intracranial pressure (ICP) on day 1 were considered possible adverse reactions to VAS.
In 1673 children VAS had no overall effect on clinical symptoms associated with increased ICP (Relative Risk(RR) = 1.07 (95%CI: 0.85–1.35)). However, VAS was associated with such clinical symptoms in boys RR = 1.38 (1.00–1.91)) but not in girls (p = 0.03 for interaction between VAS and sex). VAS had no effect on fever after inactivated vaccines. VAS had no overall effect on fever after live vaccines (RR = 0.86 (0.53–1.39)), but tended to reduce the prevalence of fever in boys (RR = 0.58 (0.30–1.14)), but not in girls (RR = 1.37 (0.66–2.84)) (p = 0.09 for interaction between VAS and sex). VAS was associated with increased local reactions to measles vaccine in both sexes (RR = 3.65 (1.20–11.12)).
Adverse reactions were rare, mild and transient and may not in their own right cause concern. However, VAS caused sex-differential adverse reactions and may have sex-differential effects on adverse reactions to vaccines.

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^☆: Trial registration: The study was registered under clinicaltrials.gov, number NCT00168597.

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The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination☆

Abstract

Introduction

Section snippets

Setting and population

Results

Principal findings

Acknowledgements

J Pediatr

Am J Clin Nutr

Lancet

Vaccine

Vaccine

Vaccine

AJCN

J Nutr

AJCN

Vaccine

Lancet

Vaccine

Lancet

Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomised trial in southern India

BMJ

Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh

Pediatrics

Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality

J Infect Dis

Sex-differential effect of neonatal vitamin A supplementation on mortality?

J Infect Dis