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Vitamin A, Stool Microbiota and Vaccine Response in Bangladeshi Infants

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by USDA, Western Human Nutrition Research Center
Sponsor:
Collaborators:
International Centre for Diarrhoeal Disease Research, Bangladesh
University of California, Davis
Thrasher Research Fund
Information provided by (Responsible Party):
USDA, Western Human Nutrition Research Center
ClinicalTrials.gov Identifier:
NCT02027610
First received: December 23, 2013
Last updated: August 1, 2014
Last verified: August 2014
  Purpose

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.


Condition
Vitamin A Deficiency

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Newborn Vitamin A Supplementation, Gut Microbiota and Vaccine Response During the Second Year of Life in Bangladeshi Infants

Resource links provided by NLM:


Further study details as provided by USDA, Western Human Nutrition Research Center:

Primary Outcome Measures:
  • Naïve T-cells in peripheral blood [ Time Frame: measured once at 52 - 104 weeks of age ] [ Designated as safety issue: No ]
    The concentration of naïve T-cells in peripheral blood will be measured once at 52 - 104 wk of age by flow cytometric analysis.


Secondary Outcome Measures:
  • Thymic output of naïve T cells [ Time Frame: measured once at 52 - 104 weeks of age ] [ Designated as safety issue: No ]
    The thymic output of naïve T cells will be measured once at 52 - 104 wk of age by T-cell receptor excision circle (TREC) levels in DNA purified from peripheral blood mononuclear cells (PBMC).

  • Immune response to vaccines [ Time Frame: Measured once at 52 - 104 weeks of age ] [ Designated as safety issue: No ]
    The immune responses to vaccines, measured at 52 - 104 wk of age, include: (A) Serum immunoglobulin G (IgG) and immunoglobulin A (IgA) responses to oral polio virus vaccine (OPV; given at birth, 6 wk, 10 wk, 14 wk); (B) serum IgG response to tetanus toxoid vaccine (TT; given at 6, 10 and 14 wk) and (C) Hepatitis B virus vaccine (HBV; given at 6, 10 and 14 wk); (D) the IgA response to OPV in stool; the (E) proliferative and (F) cytokine response of peripheral blood cluster of differentiation 4 (CD4) T-cells to OPV, TT, HBV vaccines and to the tuberculosis vaccine (BCG; given at birth). Antibody responses will be measured by ELISA, T-cell proliferation by flow cytometric analysis after 6 days of culture with corresponding vaccine antigens, and cytokines will be measured in supernatant after 3 and 6 d of culture with the same antigens.

  • Change in the relative abundance of stool bacteria [ Time Frame: 6, 10, 14 and 52-104 weeks of age ] [ Designated as safety issue: No ]
    The relative abundance of stool bacteria will be measured using DNA extracts at four time points (6, 10 and 14 wk, and at one point between 52 and 104 wk) using culture-independent, next generation sequencing (NGS) of bacterial populations, followed by quantitative PCR (QPCR) and Bifidobacterium-specific terminal restriction-fragment-length polymorphism (TRFLP.)

  • Serum Vitamin A status [ Time Frame: measured once at 52-104 weeks of age ] [ Designated as safety issue: No ]
    Vitamin A status will be assessed by serum retinol or retinol binding protein (RBP4) at 52 - 104 wk of age.

  • Secretor status of the study infant's mother. [ Time Frame: measured once when infant is 52 - 104 weeks of age ] [ Designated as safety issue: No ]
    The "secretor status" of the mother is determined by the FUT2 genotype. FUT2 is related to FUT1, the gene encoding fucosyltransferase 1, which determines the composition of specific glycans on erythrocytes that determine the ABO (or ABH) and Lewis blood group antigens. The activity of fucosyltransferase 2 (encoded by FUT2) causes the synthesis and secretion of these same glycans into breast milk and other secretions (e.g., saliva and other intestinal secretions).


Biospecimen Retention:   Samples With DNA

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.


Estimated Enrollment: 306
Study Start Date: October 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
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

Ages Eligible for Study:   12 Months to 24 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

  • none
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02027610

Contacts
Contact: Shaikh M. Ahmad, PhD (+88 02) 9827001-10
Contact: Charles B Stephensen, PhD 530-754-9266 Charles.Stephensen@ars.usda.gov

Locations
United States, California
University of California, Davis Not yet recruiting
Davis, California, United States, 95616
Sub-Investigator: David A Mills, PhD         
Sub-Investigator: Mark Underwood, MD         
USDA Western Human Nutrition Research Center Not yet recruiting
Davis, California, United States, 95616
Sub-Investigator: Gertrud Schuster, PhD         
Principal Investigator: Charles B Stephensen, PhD         
Bangladesh
International Centre for Diarrhoeal Disease Research, Bangladesh Not yet recruiting
Dhaka, Bangladesh, 1212
Contact: Shaikh M Ahmad, PhD    (+88 02) 9827001-10      
Sub-Investigator: Rubhana Raqib, PhD         
Sub-Investigator: Shaikh M Ahmad, PhD         
Sponsors and Collaborators
USDA, Western Human Nutrition Research Center
International Centre for Diarrhoeal Disease Research, Bangladesh
University of California, Davis
Thrasher Research Fund
Investigators
Principal Investigator: Charles B Stephensen, PhD USDA, Western Human Nutrition Research Center
  More Information

Additional Information:
No publications provided

Responsible Party: USDA, Western Human Nutrition Research Center
ClinicalTrials.gov Identifier: NCT02027610     History of Changes
Other Study ID Numbers: PR-13068
Study First Received: December 23, 2013
Last Updated: August 1, 2014
Health Authority: United States: Federal Government

Keywords provided by USDA, Western Human Nutrition Research Center:
Infant
Bangladesh
vitamin A
microbiota
vaccine
immunity

Additional relevant MeSH terms:
Malnutrition
Nutrition Disorders
Night Blindness
Vitamin A Deficiency
Avitaminosis
Deficiency Diseases
Eye Diseases
Vision Disorders
Vitamin A
Vitamins
Growth Substances
Micronutrients
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 27, 2014