High-dose vitamin A supplementation administered with vaccinations after 6 months of age: Sex-differential adverse reactions and morbidity

Fisker, Ane Bærent; Balé, Carlitos; Jørgensen, Morten; Balde, Ibriama; Hornshøj, Linda; Bibby, Bo Martin; Aaby, Péter; Benn, Christine Stabell

doi:10.1016/j.vaccine.2013.04.072

Cited by 15 publications

(11 citation statements)

References 19 publications

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“…We have recently discovered hot spots for vitamin receptor DNA binding motifs in the switch (S) regions of murine and human immunoglobulin heavy chain genes (particularly S, Sε, and S␣, but rarely S␥), which suggests that there may be direct and indirect influences of vitamins on class switch recombinations (CSR) and on B cell antibody isotype expression patterns (47). Hot spots for DNA binding motifs of related nuclear receptors (e.g., estrogen receptors) are also found in S regions, perhaps explaining, in part, the complexity of vitamin influences on their target genes (e.g., males and females respond differently to vitamin supplementation [48]). …”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have exhibited benefits of vitamin supplementation in the context of other vaccination programs, but results have been inconsistent (30,51,52). This may be because (i) previous clinical studies have focused largely on vitamin A or vitamin D without consideration of cross-regulatory capacities, and (ii) vitamin supplementation studies were often conducted without measurement of incoming vitamin levels; some participants may have been vitamin replete and negatively impacted by high vitamin doses (48,53). With these caveats in mind, our results and previous literature encourage careful clinical tests of vitamin A and D supplements in vitamin insufficient and deficient recipients of i.n.…”

Section: Discussionmentioning

confidence: 99%

“…Benefits and risks must be contemplated upon clinical trial design (48,54), as an overzealous immune response in the respiratory tract, particularly if comprising T cell responses in the absence of neutralizing antibodies, can lead to a cytokine storm and obstructed airways (55). It is unlikely that the doses described in mice can be directly translated to humans, in part because a normal mouse diet (as was received by control animals in our experiments) contains more than 10 times the recommended daily allowance in humans by weight (41).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Surman

Penkert

Jones

et al. 2016

Clin Vaccine Immunol

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V itamin A deficiencies (VAD) and vitamin D deficiencies (VDD) have long been considered maladies in the developing world, but recent research demonstrates that children and adults of developed countries also suffer from vitamin deficits (1-4). Individuals with low vitamin levels are particularly vulnerable to infections of the gastrointestinal and respiratory tracts (5-8), the latter of which are responsible for one-fifth of all deaths among children under the age of five (1, 9).Vitamin A is ingested in the form of retinyl esters or betacarotene. It is stored in the liver as an ester and is transported through the circulatory system as retinol bound to the retinol binding protein (RBP) (10). Upon cellular uptake, retinol is converted to retinal by ubiquitous alcohol dehydrogenases, but further conversion to retinoic acid (RA), an active metabolite of vitamin A, requires specialized aldehyde dehydrogenases (ALDH1A). ALDH1A enzymes are expressed by a subset of cells, including gut dendritic cells and epithelial cells lining the upper and lower respiratory tracts (URT and LRT) (5, 8). Once converted from retinal, RA in the form of all-trans-RA can be spontaneously isomerized to 9-cis-RA. The two metabolites function as high-affinity ligands, respectively, for the retinoic acid receptor (RAR) and retinoid X receptor (RXR) proteins (11, 12). RAR and RXR are members of the nuclear receptor superfamily. These exist as monomers, homodimers, and heterodimers. DNA motifs for RAR-RXR binding (known as retinoic acid response elements [RARE]) are typically direct repeats of half sites puG(G/T)TCA separated by 2 or 5 nucleotides. RA binding to RAR-RXR (and related heterodimeric receptors) can have profound effects on immune cell development, activation, homing, and function (5,(12)(13)(14).Vitamin D can be synthesized by the body in addition to being obtained through dietary sources. Cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) are acquired through the diet, but cholecalciferol is also produced photochemically from 7-dehydrocholesterol in the skin. Cholecalciferol is con- Vitamin A and D metabolites are highly interactive. Calcitriol binds the vitamin D receptor (VDR), which like RAR can heterodimerize with RXR (17). The same DNA binding motifs described for RAR-RXR [puG(G/T)TCA] can be recognized by the VDR-RXR complex, but half sites are often separated by 3 nucleotides (17) rather than 2 or 5. Receptor proteins can bind promiscuously to ligands and to noncanonical DNA motifs. In some instances, vitamin receptors (and related members of the nuclear receptor superfamily) behave synergistically, but in other instances, they antagonize one another (e.g., vitamin D exerts a negative effect on the vitamin A-dependent commitment of bone marrow cells to the granulocytic lineage [13,[17][18][19][20]

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Surman

Penkert

Jones

et al. 2016

Clin Vaccine Immunol

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“…As specified in the protocol, secondary outcomes are reported elsewhere. 26,27 The follow-up for mortality ended at whichever came first: subsequent VAS, 12 months of follow-up, first visit after February 24, 2011 (when another trial was initiated), or at latest July 21, 2011 when the code was broken. When a death was registered, an interview was conducted on the circumstances leading to the death.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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WHAT'S KNOWN ON THIS SUBJECT:The World Health Organization recommends using vaccination contacts to deliver high-dose vitamin A supplementation (VAS) to children aged 6 to 59 months. The effect of this policy on overall child mortality has not been assessed. WHAT THIS STUDY ADDS:In this first randomized controlled trial of VAS at routine vaccination contacts after 6 months, VAS had no overall effect on mortality but was associated with reduced mortality in girls and increased mortality in boys.abstract BACKGROUND: The World Health Organization recommends vitamin A supplementation (VAS) at routine vaccination contacts after 6 months of age based on the assumption that it reduces mortality by 24%. The policy has never been evaluated in randomized controlled trials for its effect on overall mortality. We conducted a randomized double-blind trial to evaluate the effect of VAS with vaccines. METHODS:We randomized children aged 6 to 23 months 1:1 to VAS (100 000 IU if aged 6-11 months, 200 000 IU if aged 12-23 months) or placebo at vaccination contacts in Guinea-Bissau. Mortality rates were compared in Cox proportional-hazards models overall, and by gender and vaccine. CONCLUSIONS: This is the first randomized controlled trial to assess the effect of the policy on overall mortality. VAS had no overall effect, but the effect differed significantly by gender. More trials to ensure an optimal evidence-based vitamin A policy are warranted.

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“…We expected that children randomly assigned to the intervention group would have a higher incidence of adverse events in the first 14 days after enrollment in the study [12]. Hence, the potential NSEs of early MV receipt were assessed from day 15 after enrollment to 9 months of age.…”

Section: Methodsmentioning

confidence: 99%

Effect of an Early Dose of Measles Vaccine on Morbidity Between 18 Weeks and 9 Months of Age: A Randomized, Controlled Trial in Guinea-Bissau

Biering-Sørensen

Fisker

et al. 2017

J Infect Dis.

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BackgroundChildren in Guinea-Bissau receive measles vaccine (MV) at 9 months of age, but studies have shown that an additional dose before 9 months of age might have beneficial nonspecific effects. Within a randomized trial designed to examine nonspecific effects of early MV receipt on mortality, we conducted a substudy to investigate the effect of early MV receipt on morbidity.MethodsChildren were randomly assigned at a ratio of 2:1 to receive 2 doses of MV at 18 weeks and age 9 months (intervention group) or 1 dose of MV at age 9 months, in accordance with current practice (control group). Children were visited weekly from enrollment to age 9 months; the mother reported morbidity, and the field assistants examined the children. Using Cox and binomial regression models, we compared the 2 randomization groups.ResultsAmong the 1592 children, early measles vaccination was not associated with a higher risk of the well-known adverse events of fever, rash, and convulsions within the first 14 days. From 15 days after randomization to age 9 months, early measles vaccination was associated with reductions in maternally reported diarrhea (hazard ratio [HR], 0.89; 95% confidence interval [CI], .82–.97), vomiting (HR, 0.86; 95% CI, .75–.98), and fever (HR, 0.93; 95% CI, .87–1.00).ConclusionEarly MV receipt was associated with reduced general morbidity in the following months, supporting that early MV receipt may improve the general health of children.

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High-dose vitamin A supplementation administered with vaccinations after 6 months of age: Sex-differential adverse reactions and morbidity

Cited by 15 publications

References 19 publications

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

Vitamin Supplementation at the Time of Immunization with a Cold-Adapted Influenza Virus Vaccine Corrects Poor Mucosal Antibody Responses in Mice Deficient for Vitamins A and D

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

Effect of an Early Dose of Measles Vaccine on Morbidity Between 18 Weeks and 9 Months of Age: A Randomized, Controlled Trial in Guinea-Bissau

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