Clinical trial NCT01583972: Efficacy of Newborn Vitamin A Supplementation in Improving Immune Function
Official title: Efficacy of Newborn Vitamin A Supplementation in Improving Immune Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Vitamin A Deficiency
Keywords: Vitamin A deficiency
Vitamin A
retinyl palmitate
malnutrition
vaccine
vaccination
BCG
tuberculosis
polio virus
tetanus toxoid
hepatitis B virus
thymus
T lymphocyte
B lymphocyte
antibody
bacterial translocation
T-cell receptor excision circle
Lead sponsor: USDA, Western Human Nutrition Research Center
Sponsor class: FED
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
name: World Health Organization
First posted: 2012-04-24
Enrollment: 300
Sex: ALL
Maximum age (years): 48
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Vitamin A supplementation at birth may increase survival of infants through one year of age by reducing mortality from infectious diseases, though current studies are not conclusive on this point. The goal of our study is to determine if supplementation of newborn infants with 50,000 IU of vitamin A improves aspects of immune function that may be impaired by vitamin A deficiency. Our underlying assumption is that supplementation may thus decrease risk of death by improving immune function and the ability to survive infections. This project will be limited to the examination of the impact of vitamin A on immune function and will not aim to determine the impact on morbidity or mortality, which would require larger sample sizes. The hypotheses addressed by this study are as follows: Provision of vitamin A supplements to newborns at risk of vitamin A deficiency will (1) improve functioning of the thymus (the source of T lymphocytes, cells of the immune system that are important in response to infection and immunization); (2) enhance T lymphocyte-mediated responses to standard vaccines given at birth and early in infancy; and (3) improve gut barrier function (i.e., ability to prevent bacterial infection across the epithelial barrier), relative to provision of a placebo.

Detailed description: This project will examine the effect of vitamin A supplementation (50,000 IU) or placebo given with BCG and oral polio virus (OPV) immunization within 48 h of birth on immune function in 300 Bangladeshi infants (150 in each group) at risk of vitamin A deficiency recruited in a poor community of Dhaka, Bangladesh. Infants will be followed from birth through 15 wk of age. Current evidence from community-based mortality trials is not conclusive but suggests that such supplementation will decrease infant mortality from infectious disease through 6 m of age. The biological mechanism underlying this potential benefit is unclear but is presumed to include improving immune function. The investigators hypothesize that vitamin A supplementation at birth prevents vitamin A deficiency during a critical window of a few days to weeks when the immune system is first exposed to both normal, non-pathogenic organisms (e.g., commensal gut flora) and to potential pathogens. During this period the investigators propose that vitamin A supplementation will improve three aspects of immune function that will have sustained benefits throughout infancy: (1) normal thymus maturation and function; (2) development and mucosal targeting of adaptive immune responses, including regulatory T-cells (Treg), T-helper type 2 (Th2) cells, and IgA-secreting plasma cells and memory B-cells; and (3) mucosal barrier function. The three specific objectives of our project are: (1) Determine if vitamin A supplementation improves thymus maturation and function as indicated by ultrasonic analysis of thymus size and by analysis of thymic output of naïve T-cells using flow cytometric analysis of peripheral blood T-cells and by quantification of T-cell-receptor excision circles (TRECs) in peripheral blood. (2) Determine if vitamin A supplementation at birth alters (2.1) the T-cell response to BCG and OPV immunization assessed at 6 and 15 wk of age; (2.2) the T- and B-cell response to OPV immunization, assessed at 15 wk of age, and the secretory IgA response to OPV assessed at 6, 11 and 15 wk of age; and (2.3) the B-cell response to tetanus toxoid (TT) immunization, assessed at 15 wk of age. (3) Determine if vitamin A supplementation at birth will decrease bacterial lipopolysaccharide (LPS) concentrations in capillary blood, a marker of bacterial translocation.

Eligibility criteria: Inclusion Criteria:

* Infant receiving OPV and BCG within 48 hr of birth

Exclusion Criteria:

* Mother is less than 18 years of age
* Infant is part of a multiple birth
* Infant will likely not remain in the study area for the next 4 months
* Infant has a condition precluding vaccination
* Infant is unable to breastfeed or drink other fluids
* Birth weight is less than 1.5 kg

Primary outcomes:
measure: Thymus size measured by ultrasound
timeFrame: through 15 wk of age
measure: peripheral blood naive T-helper lymphocyte concentration
timeFrame: through 15 wk of age
measure: T-cell receptor excision circle (TREC) level in peripheral blood mononuclear cells (PBMC)
timeFrame: through 15 wk of age
measure: T-cell response to BCG (Bacillus Calmette-Guérin; to protect against tuberculosis) and oral polio virus (OPV) immunization
timeFrame: through 15 wk of age
measure: Antibody response to oral polio virus (OPV) immunization
timeFrame: through 15 wk of age
measure: T-cell and antibody response to tetanus toxoid (TT) and hepatitis B virus (HBV) vaccinations given at 6, 10 and 14 wk of age
timeFrame: through 15 wk of age
measure: bacterial translocation to blood
timeFrame: through 15 wk of age
Secondary outcomes:
measure: vitamin A status by modified, relative dose-response (MRDR) test
timeFrame: through 15 wk of age
measure: bulging fontanelle
timeFrame: 48 h after vitamin A dosing
Other outcomes:
Locations:
city: Dhaka
country: Bangladesh
facility: International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Study officials:
affiliation: USDA, Western Human Nutrition Research Center
name: Charles B. Stephensen, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ahmad SM, Huda MN, Raqib R, Qadri F, Alam MJ, Afsar MNA, Peerson JM, Tanumihardjo SA, Stephensen CB. High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age. J Nutr. 2020 Nov 19;150(11):3005-3012. doi: 10.1093/jn/nxaa260.
citation: Ahmad SM, Raqib R, Huda MN, Alam MJ, Monirujjaman M, Akhter T, Wagatsuma Y, Qadri F, Zerofsky MS, Stephensen CB. High-Dose Neonatal Vitamin A Supplementation Transiently Decreases Thymic Function in Early Infancy. J Nutr. 2020 Jan 1;150(1):176-183. doi: 10.1093/jn/nxz193.
citation: Huda MN, Ahmad SM, Alam MJ, Khanam A, Kalanetra KM, Taft DH, Raqib R, Underwood MA, Mills DA, Stephensen CB. Bifidobacterium Abundance in Early Infancy and Vaccine Response at 2 Years of Age. Pediatrics. 2019 Feb;143(2):e20181489. doi: 10.1542/peds.2018-1489.
citation: Ahmad SM, Raqib R, Qadri F, Stephensen CB. The effect of newborn vitamin A supplementation on infant immune functions: trial design, interventions, and baseline data. Contemp Clin Trials. 2014 Nov;39(2):269-79. doi: 10.1016/j.cct.2014.09.004. Epub 2014 Sep 28.