Pregnancy, Arsenic and Immune Response

Influenza Clinical Trial

— PAIR  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03930017
• Other study ID #: R01ES026973
• Status: Completed
• Start date: October 14, 2018
• Est. completion date: January 6, 2020

Study information

• Verified date: January 2023
• Source: Johns Hopkins Bloomberg School of Public Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 784
• Est. completion date: January 6, 2020
• Est. primary completion date: January 6, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 13 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Arsenic--Toxicology
• Immune System Diseases
• Immunologic Disorders Complicating Pregnancy
• Influenza
• Influenza, Human
• Micronutrient Deficiency
• Pregnancy Complications
• Vaccine Response Impaired

Intervention

Biological:
• Seasonal influenza vaccine - VAXIGRIP TETRA influenza vaccine (quadrivalent, split virion, inactivated)
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.

Locations

Country	Name	City	State
Bangladesh	JiVitA Maternal and Child Health and Nutrition Research Program	Gaibandha

Sponsors (7)

Lead Sponsor	Collaborator
Johns Hopkins Bloomberg School of Public Health	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

Country where clinical trial is conducted

Bangladesh, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Gestational age (GA) at birth	Calculated from known last menstrual period to the week of birth.	Within 72 hours of birth
Other	Newborn anthropometry weight	Weight (grams)	Within 72 hours of birth
Other	Newborn anthropometry length	Length (cm)	Within 72 hours of birth
Other	Newborn anthropometry head, chest, middle-upper arm circumference	head, chest, and middle-upper arm circumference (cm)	Within 72 hours of birth
Other	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
Other	Change in cytokines	Cytokines and chemokines will be measured in plasma or serum, including interleukin 1 beta (IL-1ß), interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-a), interferon gamma (IFN-?).	Comparing baseline to 28 days post vaccination, birth, and 3 months post-partum
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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
Primary	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.
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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

External Links

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