Vitamin A, Stool Microbiota and Vaccine Response in Bangladeshi Infants
Condition: Vitamin A Deficiency
MeSH terms: Night Blindness; Vitamin A Deficiency
Study type: Observational

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.
    

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.
      
Biospecimen description: 
      Infant specimens containing DNA isolated from periferal blood mononuclear cells (PBMC) will
      be retained for future analyses. Maternal specimens containing DNA from cheek swabs will be
      retained for future analyses.
    
Keywords: Infant; Bangladesh; vitamin A; microbiota; vaccine; immunity