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

Abstract

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]

Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection

“…Consistent with this finding, we have observed that laboratory animals with both VAD and VDD had weaker immune responses toward respiratory virus antigens than animals with either VAD or VDD alone; supplementation with vitamins A and D corrected these responses (39). …”

Prevnar-13 vaccine failure in a mouse model for vitamin A deficiency

“…The situation may be worsening, as low income families gain better access to ‘fast’ foods rather than unprocessed and fortified foods. Our study in Memphis showed that low vitamin A levels associated with low serum IgA as well as poor influenza virus-specific neutralizing antibodies [6]. A placebo controlled, randomized, blinded, clinical study is now in progress to determine if vitamin supplements can be partnered with the administration of influenza virus vaccines to increase vaccine-induced immune responses in vitamin-deficient or vitamin-insufficient children in Memphis (Clinicaltrials.gov, CTG ID# NCT02649192, FLUVIT ).…”

“…Vitamin A deficiencies (VAD) and insufficiencies are present in both developed and developing countries [6–9] and have been associated with poor immune responses toward respiratory tract pathogens [10, 11], as well as an increased incidence of and morbidity from respiratory disease in school age children. Knowing that prevention of infection is critical in these highly susceptible populations, we employed a murine model of VAD to determine if PCV-13 was efficacious in the context of VAD.…”

Recent Approaches for Solid Dose Vaccine Delivery

“…A proprietary FDT formulation, Zydis ® for olanzapine, an antipsychotic drug, has been produced by Catalent Pharma Solutions using their patented freeze-drying technology [34], but none is still available for vaccines [17]. Besides, to overcome the vitamin-A deficiency it is recommended to give vitamin-A supplements during the vaccination process, though the actual dose needs to be determined in human studies [35].…”