Does vitamin A supplementation interact with routine vaccinations? An analysis of the Ghana Vitamin A Supplementation Trial

Abstract

Background: The World Health Organization recommends vitamin A supplementation (VAS) at vaccination contacts after 6 mo of age to reduce mortality. However, it is unknown whether the effect of VAS is independent of vaccinations. One of the original VAS trials from Ghana had collected vaccination information. Objective: We reanalyzed the data to explore the hypothesis that VAS reduces mortality in children who had bacille Calmette-Guérin or measles vaccine as their most recent vaccine but increased mortality when diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccine. On the basis of previous studies, we expected the effects to be strongest in girls. Design: At enrollment, children aged 6-90 mo were randomly assigned to receive VAS or placebo every 4 mo for 2 y. Vaccination status was assessed at enrollment and after 1 and 2 y by reviewing the children's health cards. Lack of a health card was presumed to mean that the child had not been vaccinated. Results: VAS had a beneficial effect only in children with no record of vaccination at enrollment (n = 5066); the mortality rate ratio (MRR) was 0.64 (95% CI: 0.47, 0.88) compared with 0.95 (95% CI: 0.72, 1.26) in children with one or more vaccinations (n = 6656). Among vaccinated children, the effect of VAS differed between boys (MRR: 0.74; 95% CI: 0.51, 1.08) and girls (MRR: 1.18; 95% CI: 0.84, 1.67) (P = 0.046 for interaction). VAS had a negative effect in measles-vaccinated girls who were missing one or more doses of DTP at enrollment, a group who often received DTP during follow-up (MRR: 2.60; 95% CI: 1.41, 4.80). Conclusions: The effect of VAS differed by vaccination status. This is potentially problematic because VAS is provided at vaccination contacts.

Non-specific and sex-differential effects of routine vaccines: What evidence is needed to take these effects into consideration in low-income countries?

“…41 That has turned out to fit the data perfectly including trials of VAS showing that VAS was associated with increased mortality for girls who had received DTP as their most recent vaccine. 32,42,43 Such consistencies in observational studies and corroboration of unexpected deductions are not found unless biological causality when measles vaccine was introduced in general campaigns in Senegal in the late 1980s, female-male mortality, which had not been different before the MV campaigns, in two demographic surveillance areas dropped much more for girls than boys such that girls had 35% lower mortality than boys after the campaigns. 13,14 This differential effect has been consistent in subsequent studies.…”

“…36 Third, we have shown repeatedly that girls have higher mortality than boy after DTP vaccination as the most recent vaccine. 34,36,38,39,42,44 Fourth, given the sexdifferential effect of DTP, we tested the hypothesis that the problem of increased female mortality after HTMV was due to a change in the sequence of vaccinations. HTMV was given early at 4-5 months of age and most children received DTP after HTMV.…”

High-dose Vitamin A With Vaccination After 6 Months of Age: A Randomized Trial

“…29,30 In a reanalysis of one of the trials that reported a beneficial effect, 31 we found no effect among vaccinated children. 32 In more recent studies, we observed negative effects of VAS when provided to neonate girls who subsequently received DTP 33,34 and when provided to children who had received BCG revaccination. 35 The original trials documenting beneficial effects before the full implementation of the vaccination program 1 may therefore not reflect the effect of VAS today in the context of much higher vaccination coverage and repeated doses of VAS.…”

High dose vitamin A capsules – Rusty bullets?

“…However, as has been seen in other studies (Benn, et al, 2005;Benn, et al, 2008;Benn, et al, 2009;Benn, et al, 2010), opposing effects were seen in boys and girls; boys had a 92% (-2-275%) increase in mortality while mortality in girls was lowered by 55% (13-76%). Hence, the assumption that providing HDVAC to children with vaccinations after 6 months of age can never have a negative effect on child mortality may not be correct.…”