Clinical trial NCT02027610: Vitamin A, Stool Microbiota and Vaccine Response in Bangladeshi Infants
Official title: Newborn Vitamin A Supplementation, Gut Microbiota and Vaccine Response During the Second Year of Life in Bangladeshi Infants
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Vitamin A Deficiency
Keywords: Infant
Bangladesh
vitamin A
microbiota
vaccine
immunity
Lead sponsor: USDA, Western Human Nutrition Research Center
Sponsor class: FED
Collaborators: name: International Centre for Diarrhoeal Disease Research, Bangladesh
name: University of California, Davis
name: Thrasher Research Fund
First posted: 2014-01-06
Enrollment: 258
Sex: ALL
Minimum age (years): 12
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The present study will recruit infants who completed NCT01583972 when they are from 12 to 24 months of age. Mothers of these infants will also be recruited for collection of DNA from a cheek swab.

Brief summary: Vitamin A deficiency (VAD) increases the risk of death from infections in infants and young children. The World Health Organization (WHO) recommends high-dose vitamin A supplementation (VAS) from 6-59 months of age to reduce the risk of death in countries where VAD is common. Such countries include Bangladesh, where this study is being conducted. While providing VAS at 6 months is recommended, providing VAS at birth may also decrease the risk of death since newborn infants are also at risk of VAD. VAS presumably reduces infant mortality by improving the immune response to infection and immunization. Vitamin A particularly affects the development and function of T cells, which develop in the thymus and are a key component of the memory response to infection and immunization. Vitamin A is important for development of an important class of T cells, regulatory T-cells, in the intestine. Regulatory T-cells prevent over-reaction of the immune system to substances the immune system might otherwise treat as harmful such as food or the healthy bacteria in the intestine. VAD could disrupt the normal colonization of the infant's intestinal tract and cause a condition called "dysbiosis" where abnormal bacteria flourish and adversely affect the infant's immune system. Dysbiosis may disrupt the immune response to injectable and oral vaccines. VAS at birth may prevent dysbiosis and thus improve immune function, response to vaccines, and child survival. The investigators recently completed an intervention trial in Bangladeshi infants (NCT01583972) examining the effect of VAS at birth on immune function and response to vaccines administered from birth to 14 wk of age. The present study will recruit infants who completed NCT01583972 when they are from 12 to 24 m of age to determine if VAS at birth affects the responses to these same vaccines when they are measured during the second year of life. The investigators will examine the effect of VAS at birth on gut microbiota measured early in infancy and during the second year of life, and explore the association of the gut microbiota with vaccine response. Mothers of study infants will participate in the study because the breast milk oligosaccharide content strongly affects gut microbiota composition and the "secretor status" of the mother, which can be determined from maternal FUT2 genotype, strongly affects breast milk oligosaccharide content.

Detailed description: Hypotheses and Specific Aims The investigators will test the hypotheses that VAS at birth will (1) improve production of new T cells at 1-2 yr of age; (2) improve T-cell memory responses at 1-2 yr of age to vaccines given early in infancy (birth - 14 wk); and (3) alter intestinal colonization early in infancy (6, 11 and 15 wk) and at 1-2 yr of age to increase Bifidobacterium and other healthy bacteria and decrease Proteobacteria and other harmful bacteria. Because the "secretor status" of the mother affects the carbohydrate content of the breastmilk, which can in turn affect Bifidobacterium growth in the infant gut, the "secretor status" of the mother will be determined. Furthermore these differences in composition of the intestinal bacteria will be associated with greater immunologic responses to oral and systemic vaccines.

Specific Aim 1: Determine if VAS or placebo at birth affect the blood concentration and thymic output of naïve T-cells at 1-2 yr of age. Specific Aim 2: Determine if VAS or placebo at birth affect T-cell mediated responses at 1-2 yr of age to vaccines given early in infancy, including serum and intestinal antibody levels, vaccine-specific proliferative responses by T cells and cytokine production by T cells. Specific Aim 3: Determine if VAS or placebo at birth affect the relative abundance of healthy intestinal bacteria and common harmful bacteria in the feces at 6, 11, and 15 wk of age and at 1-2 yr of age and determine if relative abundance of these bacteria correlates with vaccine responses shortly after vaccination (6, 11, 15 wk) and later in infancy (1-2 yr). As part of Aim 3 the "secretor status" genotype (FUT2 gene) of the mother will be determined from a cheek swab DNA sample.

Eligibility criteria: Inclusion Criteria:

* for infant: completion of NCT01583972
* for mother: mother of study infant

Exclusion Criteria:

* none

Primary outcomes:
measure: Naïve T-cells in peripheral blood
timeFrame: measured once at 52 - 104 weeks of age
Secondary outcomes:
measure: Thymic output of naïve T cells
timeFrame: measured once at 52 - 104 weeks of age
measure: Immune response to vaccines
timeFrame: Measured once at 52 - 104 weeks of age
measure: Change in the relative abundance of stool bacteria
timeFrame: 6, 10, 14 and 52-104 weeks of age
measure: Serum Vitamin A status
timeFrame: measured once at 52-104 weeks of age
measure: Secretor status of the study infant's mother.
timeFrame: measured once when infant is 52 - 104 weeks of age
Other outcomes:
Locations:
city: Davis
country: United States
facility: University of California, Davis
state: California
city: Davis
country: United States
facility: USDA Western Human Nutrition Research Center
state: California
city: Dhaka
country: Bangladesh
facility: International Centre for Diarrhoeal Disease Research, Bangladesh
Study officials:
affiliation: USDA, Western Human Nutrition Research Center
name: Charles B Stephensen, PhD
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, Kalanetra KM, Taft DH, Alam MJ, Khanam A, Raqib R, Underwood MA, Mills DA, Stephensen CB. Neonatal Vitamin A Supplementation and Vitamin A Status Are Associated with Gut Microbiome Composition in Bangladeshi Infants in Early Infancy and at 2 Years of Age. J Nutr. 2019 Jun 1;149(6):1075-1088. doi: 10.1093/jn/nxz034.
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.