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NCT Number: NCT03930017

Pregnancy, Arsenic and Immune Response

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.

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Key information

Conditions

Arsenic--Toxicology Immunologic Disorders Complicating Pregnancy Infections Influenza Influenza, Human Micronutrient Deficiency Orthomyxoviridae Infections RNA Virus Infections Respiratory Tract Diseases Respiratory Tract Infections Vaccine Response Impaired Virus Diseases

Age range

13 year–45 year

Sex eligibility

Female

Study type

Observational

Primary location

JiVitA Maternal and Child Health and Nutrition Research Program

Gaibandha, Bangladesh

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Seasonal influenza vaccine - VAXIGRIP TETRA influenza vaccine (quadrivalent, split virion, inactivated)

Biological

Influenza virus (quadrivalent, split virion, inactivated) of the strains that comply with the World Health Organization (WHO) recommendations (Northern Hemisphere) and European Union (EU) decision for the 2018/2019 season. The quadrivalent vaccine is propagated in fertilised hens' eggs from healthy chicken flocks.

Primary outcomes

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

Secondary outcomes

  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 outcomes

  1. Gestational age (GA) at birth

    Time frame: Within 72 hours of birth

    Calculated from known last menstrual period to the week of birth.

  2. Newborn anthropometry weight

    Time frame: Within 72 hours of birth

    Weight (grams)

  3. Newborn anthropometry length

    Time frame: Within 72 hours of birth

    Length (cm)

  4. Newborn anthropometry head, chest, middle-upper arm circumference

    Time frame: Within 72 hours of birth

    head, chest, and middle-upper arm circumference (cm)

  5. 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.

  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

Sponsors and collaborators

Lead sponsor

Johns Hopkins Bloomberg School of Public Health

Other

Collaborators

  • Columbia University
  • Institute of Epidemiology, Disease Control and Research
  • Johns Hopkins Bangladesh - The JiVitA Project Site
  • Sanofi Pasteur, a Sanofi Company
  • UNC Gillings School of Global Public Health
  • University of Graz

Registry information

Official study title

Arsenic and Immune Response to Influenza Vaccination in Pregnant Women and Newborns

Acronym: PAIR

Important dates

Study start
2018
Primary completion
2020
Study completion
2020
First posted
Apr 29, 2019
Registry last updated
Jan 5, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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