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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/14/2021.

Pregnancy, Arsenic and Immune Response

Clinicaltrials.gov identifier NCT03930017

Recruitment Status Enrolling by invitation

First Posted April 29, 2019

Last update posted May 6, 2019

Study Description

Brief summary:

As the global availability of vaccines increases, and reaches areas disproportionately affected by arsenic and malnutrition, resolving questions about potential environmental and biologic barriers to maternal immunization has become increasingly urgent. It is not known whether arsenic, a known developmental toxicant, can alter maternal immune responses to vaccination and whether exposure to arsenic during pregnancy can impair the transfer of maternal vaccine-induced antibody to the newborn. Moreover, factors known to affect arsenic metabolism and toxicity outcomes, particularly micronutrients critical in one-carbon metabolism, have not been evaluated in studies of arsenic immunotoxicity and vaccine-induced protection in mothers and their newborns. The objective in this study is to investigate whether maternal arsenic exposure and one-carbon metabolism micronutrient deficiencies alter maternal and newborn measures of vaccine-induced protection, respiratory morbidity, and systemic immune function following influenza vaccination during pregnancy.

  • Condition or Disease:Immunologic Disorders Complicating Pregnancy
    Vaccine Response Impaired
    Micronutrient Deficiency
    Influenza
    Arsenic--Toxicology
  • Intervention/Treatment: Biological: Seasonal influenza vaccine - VAXIGRIP TETRA influenza vaccine (quadrivalent, split virion, inactivated)
  • Phase: N/A
Detailed Description

The objective in this study is to investigate whether maternal arsenic exposure and one-carbon metabolism micronutrient deficiencies alter maternal and newborn measures of vaccine-induced protection, respiratory morbidity, and systemic immune function following influenza vaccination during pregnancy. The hypothesis is that maternal arsenic exposure and one-carbon metabolism micronutrient deficiencies alter maternal and newborn influenza antibody titer and avidity, respiratory infection morbidity, and markers of systemic immune function following maternal influenza vaccination during pregnancy. This study leverages a comprehensive pregnancy surveillance system at the JiVitA Maternal and Child Health and Nutrition Research Project site in Bangladesh (hereafter JiVitA) to pursue the following three aims: Aim 1. Establish whether arsenic exposure during pregnancy alters maternal and newborn influenza antibody titer and avidity following maternal influenza vaccination. Aim 2. Determine whether markers of systemic immune function mediate the association between arsenic exposure and respiratory illness in pregnant women and their newborns. Aim 3. Assess whether arsenic exposure and one-carbon metabolism micronutrient deficiencies during pregnancy have a joint effect on markers of systemic immune function and respiratory illness in mothers and their newborns. This study will yield three expected outcomes. First, it will fill critical knowledge gaps about whether arsenic exposure and one-carbon metabolism micronutrient deficiencies alter immune responses to a vaccination with known benefits for mothers and their newborns. Second, it will increase understanding of arsenic-associated respiratory morbidity and specific immune function pathways between arsenic exposure and respiratory morbidity in mothers and their newborns. Finally, as the global availability of vaccines increases, improving knowledge of potential environmental and biologic barriers to maternal and newborn vaccine-induced protection could lead to improved vaccine regimens (targeted vaccination campaigns, higher vaccine doses, and/or additional booster immunizations) to restore vaccine-induced protection in arsenic-exposed and malnutrition-affected populations of pregnant women and newborns worldwide.

Study Design
  • Study Type: Observational
  • Estimated Enrollment: 800 participants
  • Observational Model: Cohort
  • Time Perspective: Prospective
  • Official Title: Arsenic and Immune Response to Influenza Vaccination in Pregnant Women and Newborns
  • Actual Study Start Date: October 2018
  • Estimated Primary Completion Date: February 2020
  • Estimated Study Completion Date: February 2020
Outcome Measures
  • Primary Outcome Measures: 1. Change in anti-influenza virus total immunoglobulin G (IgG) enzyme immunoassay [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Total IgG antibodies to influenza virus as measured in serum or plasma by enzyme immunoassay
  • 2. Change in influenza virus neutralizing antibody titer [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Virus neutralization is measured as a titer calculated based on the highest serum dilution that eliminates virus.
  • 3. Change in influenza hemagglutination-inhibition (HI) antibody titer [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Influenza hemagglutination-inhibition (HI) antibody titer will be measured in participant's serum.
  • 4. Mean percent influenza virus antibody avidity [ Time Frame: Measured at baseline, 28 days post vaccination, birth, and 3 months post-partum ]
    The accumulated strength of multiple affinities of individual non-covalent binding interactions of influenza-specific antibodies, including avidity of antibodies to seasonal inactivated influenza virus (IIV) strains included in the formulation in Sanofi Pasteur's 2018-2019 seasonal VAXIGRIP® TETRA vaccine.
  • 5. Seroconversion rate [ Time Frame: Defined as a post-vaccination HI titer of ≥40 given a pre-vaccination titer ≤10 or, alternatively, a ≥4-fold increase in HI titer between pre-vaccination and post-vaccination sera if the pre-vaccination titer was >10. ]
    The proportion of pregnant women demonstrating seroconversion
  • 6. Change in geometric mean HI antibody titer (GMT) [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    GMT HI antibody titers will be transformed to binary logarithms, and original values will be divided by 4 (undetectable titer) to set the starting point of the log scale to zero prior to transformation. We will calculate average log2 GMT antibody titers.
  • 7. Geometric mean ratio of infant:mother HI titer [ Time Frame: Birth and 3 months post-partum ]
    Ratio of infant to mother HI titer as a measure of transplacental transfer of influenza antibody.
  • Secondary Outcome Measures: 1. Maternal influenza-like illness (ILI) [ Time Frame: From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals ]
    Defined as at least one symptom-free day prior to onset of fever >37.8°C and cough or sore throat.
  • 2. Infant influenza-like illness (ILI) [ Time Frame: From date of birth visit until date of 3 months postpartum visit, assessed at weekly intervals ]
    Defined as at least one symptom-free day prior to onset of fever >37.8°C and cough.
  • 3. Laboratory-confirmed influenza (LCI) [ Time Frame: From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals ]
    Influenza A and/or B virus real-time (RT)-quantitative polymerase chain reaction (qPCR) positive nasal swab from a participant reporting ILI at a weekly mobile phone positive follow-up.
  • 4. Acute respiratory illness (ARI) [ Time Frame: From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals ]
    Defined as: cough; rapid breathing or grunting or wheezing, excluding asthma; blood in sputum; ear discharge; low fever; and/or headache. A stand-alone outcome of ARI plus fever will be defined as the above symptoms plus high fever >37.8°celsius (C).
  • Other Outcome Measures: 1. Change in micronutrient deficiency status [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Micronutrient deficiency status will be assessed for micronutrients critical for one-carbon metabolism (folate, vitamin B12 [cobalamin]) and vitamin D and zinc.
  • 2. Gestational age (GA) at birth [ Time Frame: Within 72 hours of birth ]
    Calculated from known last menstrual period to the week of birth.
  • 3. Newborn anthropometry weight [ Time Frame: Within 72 hours of birth ]
    Weight (grams)
  • 4. Newborn anthropometry length [ Time Frame: Within 72 hours of birth ]
    Length (cm)
  • 5. Newborn anthropometry head, chest, middle-upper arm circumference [ Time Frame: Within 72 hours of birth ]
    head, chest, and middle-upper arm circumference (cm)
  • 6. Change in cytokines [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Cytokines and chemokines will be measured in plasma or serum, including interleukin 1 beta (IL-1β), interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ).
  • 7. Change in peripheral blood lymphocyte numbers [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Peripheral blood lymphocytes cluster of differentiation (CD) 4+ (CD4+) T cell and cluster of differentiation (CD) (CD8+) T cell will be measured.
  • 8. Change in peripheral blood lymphocyte function [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Functional responses of peripheral blood lymphocytes cluster of differentiation (CD) 4+ (CD4+) T cell and cluster of differentiation (CD) (CD8+) T cell will be measured.
  • 9. Change in total circulating immunoglobulin (Ig) levels, including IgG (IgG 1-4 subclasses), IgA, IgM, IgE [ Time Frame: Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum ]
    Total circulating immunoglobulin (Ig) levels, including immunoglobulin G (IgG) 1-4 subclasses, immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin E (IgE) will be measured in plasma or serum
  • 10. Occurrence of WHO Definition of Diarrhea [ Time Frame: From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals ]
    Occurrence of participant self-report of watery stools, 3 or more times a day within previous 7 days
  • Biospecimen Retention: Samples With DNA

    Venous blood will be collected at a volume of ~24 milliliter (mL) / visit from mothers and ~1.5 mL / visit from newborns. Urine will be collected from mother and baby in whatever volume is provided at the time. Saliva will be collected in whatever volume is provided using the Oracol sampler sponge collection device (Malvern Medical Developments Ldt, Worcester, UK). Samples will be transported to the nearest JiVitA field office in a temperature monitored cooler on ice within 1hr of collection and processed within 4hrs thereafter.

Eligibility Criteria
  • Ages Eligible for Study: 13 to 45 Years (Child, Adult)
  • Sexes Eligible for Study: Female
  • Accepts Healthy Volunteers: Yes
  • Sampling Method: Non-Probability Sample
  • Study Population: The study will be conducted at the Johns Hopkins JiVitA project site, in the rural Gaibandha district, Bangladesh, one of the largest project sites in South Asia, covering more than 650,000 people in an area of more than 500 sq. km. Over 150,000 married women of reproductive age have been enlisted through thirteen years of previous studies in the area with approximately 12% of registered women becoming pregnant each year.
Criteria

Inclusion Criteria:

Women who:

- are within 13-16 weeks of gestational age (GA) of pregnancy;

- are between 13 and 45 years of age;

- are married;

- provide informed consent for herself and assent for her unborn child;

- agree to receive the seasonal influenza vaccine (VAXIGRIP® TETRA seasonal quadrivalent
inactivated influenza vaccine, Sanofi Pasteur) upon study enrollment.

Exclusion Criteria:

Women who:

- have pre-existing immune-related health condition (e.g., immunodeficiency, lupus,
chronic infection, or cancer);

- previous or current use of immune-altering drug/therapy (e.g., steroids);

- have already received influenza vaccination for the current season.

Contacts and Locations
Contacts
Locations

Bangladesh
JiVitA Maternal and Child Health and Nutrition Research Program
Gaibandha

Sponsors and Collaborators

Johns Hopkins Bloomberg School of Public Health

Sanofi Pasteur, a Sanofi Company

Institute of Epidemiology, Disease Control and Research

Johns Hopkins Bangladesh - The JiVitA Project Site

University of Graz

Columbia University

UNC Gillings School of Global Public Health

Investigators

Principal Investigator: Christopher D Heaney, PhD Johns Hopkins Bloomberg School of Public Health

More Information