Pregnancy, Arsenic and Immune Response (PAIR)

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

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.

Study Overview

• Status: Completed
• Conditions: Influenza; Vaccine Response Impaired; Micronutrient Deficiency; Arsenic--Toxicology; Immunologic Disorders Complicating Pregnancy
• Intervention / Treatment: Biological: Seasonal influenza vaccine - VAXIGRIP TETRA influenza vaccine (quadrivalent, split virion, inactivated)

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 Type: Observational
• Enrollment (Actual): 784

Contacts and Locations

Study Locations

• Bangladesh
  • Gaibandha, Bangladesh
    • JiVitA Maternal and Child Health and Nutrition Research Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in influenza hemagglutination-inhibition (HI) antibody titer	Influenza hemagglutination-inhibition (HI) antibody titer will be measured in participant's serum.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Mean percent influenza virus antibody avidity	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.	Measured at baseline, 28 days post vaccination, birth, and 3 months post-partum
Seroconversion rate	The proportion of pregnant women demonstrating seroconversion	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.
Change in geometric mean HI antibody titer (GMT)	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.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Geometric mean ratio of infant:mother HI titer	Ratio of infant to mother HI titer as a measure of transplacental transfer of influenza antibody.	Birth and 3 months post-partum
Change in influenza virus neutralizing antibody titer	Virus neutralization is measured as a titer calculated based on the highest serum dilution that eliminates virus.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Change in anti-influenza virus total immunoglobulin G (IgG) enzyme immunoassay	Total IgG antibodies to influenza virus as measured in serum or plasma by enzyme immunoassay	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal influenza-like illness (ILI)	Defined as at least one symptom-free day prior to onset of fever >37.8°C and cough or sore throat.	From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals
Infant influenza-like illness (ILI)	Defined as at least one symptom-free day prior to onset of fever >37.8°C and cough.	From date of birth visit until date of 3 months postpartum visit, assessed at weekly intervals
Laboratory-confirmed influenza (LCI)	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.	From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals
Acute respiratory illness (ARI)	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).	From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gestational age (GA) at birth	Calculated from known last menstrual period to the week of birth.	Within 72 hours of birth
Newborn anthropometry weight	Weight (grams)	Within 72 hours of birth
Newborn anthropometry length	Length (cm)	Within 72 hours of birth
Newborn anthropometry head, chest, middle-upper arm circumference	head, chest, and middle-upper arm circumference (cm)	Within 72 hours of birth
Change in micronutrient deficiency status	Micronutrient deficiency status will be assessed for micronutrients critical for one-carbon metabolism (folate, vitamin B12 [cobalamin]) and vitamin D and zinc.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Change in cytokines	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).	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Change in peripheral blood lymphocyte numbers	Peripheral blood lymphocytes cluster of differentiation (CD) 4+ (CD4+) T cell and cluster of differentiation (CD) (CD8+) T cell will be measured.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Change in peripheral blood lymphocyte function	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.	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Change in total circulating immunoglobulin (Ig) levels, including IgG (IgG 1-4 subclasses), IgA, IgM, IgE	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	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Occurrence of WHO Definition of Diarrhea	Occurrence of participant self-report of watery stools, 3 or more times a day within previous 7 days	From date of enrollment visit until date of 3 months postpartum visit, assessed at weekly intervals

Collaborators and Investigators

• Sponsor: Johns Hopkins Bloomberg School of Public Health
• Collaborators: Columbia University; Sanofi Pasteur, a Sanofi Company; Institute of Epidemiology, Disease Control and Research; University of Graz; Johns Hopkins Bangladesh - The JiVitA Project Site; UNC Gillings School of Global Public Health
• Investigators: Principal Investigator: Christopher D Heaney, PhD, Johns Hopkins Bloomberg School of Public Health

Publications and helpful links

General Publications

• Attreed SE, Navas-Acien A, Heaney CD. Arsenic and Immune Response to Infection During Pregnancy and Early Life. Curr Environ Health Rep. 2017 Jun;4(2):229-243. doi: 10.1007/s40572-017-0141-4.
• Heaney CD, Kmush B, Navas-Acien A, Francesconi K, Gossler W, Schulze K, Fairweather D, Mehra S, Nelson KE, Klein SL, Li W, Ali H, Shaikh S, Merrill RD, Wu L, West KP Jr, Christian P, Labrique AB. Arsenic exposure and hepatitis E virus infection during pregnancy. Environ Res. 2015 Oct;142:273-80. doi: 10.1016/j.envres.2015.07.004. Epub 2015 Jul 15.

Helpful Links

• JiVitA Maternal and Child Health and Nutrition Research Project Site in Bangladesh
• Institute of Epidemiology and Disease Control Research (IEDCR) collaborator
• Johns Hopkins University (JHU) Center for Human Nutrition
• Johns Hopkins Environmental Health Microbiology and Immunology Laboratory

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2018
• Primary Completion (Actual): January 6, 2020
• Study Completion (Actual): January 6, 2020

Study Registration Dates

• First Submitted: August 16, 2017
• First Submitted That Met QC Criteria: April 24, 2019
• First Posted (Actual): April 29, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2023
• Last Update Submitted That Met QC Criteria: January 4, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Immunology; Influenza; Observational; Arsenic; Vaccine immunogenicity
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human; Pregnancy Complications; Immune System Diseases; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: R01ES026973 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No