Iron and Immune Response to Vaccine (IRONMUM) (IRONMUM)

Iron Supplementation and Immune Responses to Maternal Vaccination in Pregnant Women

Iron deficiency causes anaemia and is common in pregnant women especially for those living in tropical regions where a high burden of infection and poor nutrition can compromise health. Low iron has been recognized as a cause of poor immune response because the group of cells that need to increase to make the immune response need iron to function. Vaccination is an important part of care during pregnancy because components of the immune response can cross the placenta and protect the young infant. More recently COVID-19 vaccination has also been recommended for pregnant women due to their higher risk of dying from this infection. Deeper investigation of whether low iron results in poor immune response is needed because the vaccines may not be providing as much protection as needed. The World Health Organization also recommends nutritional iron supplements in pregnancy and whether these improve immune response to vaccines is also not known. This study aims to test the body's immune response to recommended vaccines in pregnant women (tetanus and diphtheria (combination) and COVID-19 vaccine (if indicated)) who are anaemic and receiving iron supplements and compare their response to women who are not anaemic, who only receive a preventive, lower dose of supplement.

Study Overview

• Status: Enrolling by invitation
• Conditions: Pregnancy Related
• Intervention / Treatment: Dietary supplement: Sangobion and Thiamine Hydrochloride; Dietary supplement: Sangobion, Thiamine hydrochloride and Vitamin B12

Detailed Description

This is a prospective interventional open label cohort study with an exploratory framework. After assessment of gestation by routine ultrasound, women will be invited to participate if they have a viable, singleton pregnancy with a gestation < 28 weeks. Consenting pregnant women will be enrolled at first antenatal clinic [7] visit and receive tetanus and diphtheria immunisation after confirmation of vaccination history, and SARS-CoV-2 immunisation (first dose if indicated). All women will be classified as non-anaemic or anaemic based on haematocrit (Haematocrit<33% in first trimester (defined <14 weeks) and Haematocrit <30% in 2nd trimester (defined 14 to <28 weeks)). Women will be assigned to groups and receive prophylactic (non-anaemic) or treatment (anaemic) doses of nutritional supplements, respectively, as per routine practice. These supplements will be provided daily for 3 months (12 weeks) and women will be followed up at day 7, 1 month (day 28), 2 and 3 months. There after they will follow routine antenatal care until birth when a cord blood sample will be taken. Mother and infant blood samples will be taken at the 2 months post-partum visit when the newborn attends for routine vaccinations of the expanded program of immunisation. Immunological and haematological responses will be measured by venous blood sampling and finger-prick sampling (routine at the clinics) at study visits; as will adverse events in relation to nutritional supplements by monthly questions using a checklist of common reactions to oral iron. The Adherence Starts with Knowledge (ASK-12) instrument has been modified and used in this population and will be compared to the Haematocrit levels, the pill count and adverse events, as a measure of adherence.

IRONMUM study is funded by Procter and Gamble. The grant reference number is Thailand-UK-IRONMUM-2021-01.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Germana Bancone, Dr.; Phone Number: +66 (0) 84 921 3818; Email: germana@tropmedres.ac
• Study Contact Backup: Name: Rose McGready, Prof.; Phone Number: +66 (0) 81 785 3585; Email: rose@shoklo-unit.com

Study Locations

• Thailand
  • Tak
    • Mae Sot, Tak, Thailand, 63110
      • Shoklo Malaria Research Unit (SMRU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Viable singleton pregnancy<28 weeks confirmed by ultrasound
2. 18 years and older
3. Willingness and ability to comply with the study protocol for the duration of the study
4. Can understand information about the study and provide consent

Exclusion Criteria:

1. Any diphtheria-tetanus vaccine within the previous 2 years
2. History of allergic reaction to diphtheria-tetanus or COVID-19 vaccine
3. Haematocrit <21% or Haematocrit >50%

4. Known severe haemoglobinopathy (HbE/beta-thalassaemia syndrome, beta-thalassaemia major or HbH syndrome)* or G6PD deficiency

   * Iron supplementation is safe in pregnant women with haemoglobin E, alpha-thalassemia 1, or beta-thalassemia carriers.

5. HIV-positive
6. Slide confirmed presence of malaria
7. Fever (defined at >37.5°C)
8. Symptoms of COVID (these women will be PCR tested as routine in clinic)
9. Known severe medical or obstetric complication e.g. valvular heart disease, placenta praevia
10. Known or clinical vitB12 deficiency as indicated by megaloblastic anaemia (pernicious anaemia or clinical symptoms)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Non-anaemic pregnant women; 50 pregnant women who have normal haematocrit (not anaemic) at 12 weeks.	Dietary supplement: Sangobion and Thiamine Hydrochloride; Prophylactic dietary supplements: 1 capsule of Sangobion + separate Thiamine Hydrochloride tablet 100mg per day for 12 weeks. Then non-anaemic pregnant women will continue with prophylactic nutritional supplements until delivery.
Other: Anaemic pregnant women; 100 pregnant women who have haematocrit below 33% (equates to Hb 11g/dL) in first trimester (<14 weeks gestation) and below 30% (equates to Hb 10g/dL).	Dietary supplement: Sangobion, Thiamine hydrochloride and Vitamin B12; Treatment dietary supplements: 3 capsules of Sangobion + separate Thiamine Hydrochloride tablet 100mg, Vit B12 100mcg per day for 12 weeks. If experience a therapeutic increase of 3% Haematocrit within 28 days (responders), they will continue with prophylactic nutritional supplements until delivery. If no affect in Haematocrit level within 28 days (non-responders; defined by trimester of diagnosis), they will be investigated for their serum ferritin and if this is low (<15ng/mL) intravenous (iv) iron supplement (Venofer®) will be provided. The dose will be calculated for the individual concerned (required iron dose (mg) = (2.4 x (target Hb of 11g/dL (Ht 33%) x pre-pregnancy weight (kg) +1000mg for replenishment of stores). Doses will be administered by slow iv infusion 200 mg per dose (maximum of 3 doses per week). Following treatment they will continue with prophylactic nutritional supplements.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antibody responses to maternal vaccine	Antibody responses to diphtheria-tetanus and SARS-CoV-2 immunisation, measured by ELISA.	change from baseline before immunisation and at 7-days and 28-days after immunisation, and at 2 months post-partum in mother and infant.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular Immune response post-immunisation measured by Mass Cytometry (plasma cells and circulating T-follicular helper cells).		7-days after immunisation
Profile of the circulating immune system components over the course of pregnancy measured by CyTOF		change from before immunisation, 7-days and 28-days after immunization and until 2 months post-partum in mother and infant
Haematological, iron and inflammatory parameters including: Hb, MCV, haematocrit serum iron, ferritin, TSAT, hepcidin, CRP, G6PD, Hb typing.		change from before immunisation, 7-days and 28-days after immunization and at 2 months post-partum in mother and infant
Haematocrit from baseline if anaemic at baseline according to trimester of gestation		change from baseline and month 1,2 and 3, and delivery
Modified Adherence Starts with Knowledge (ASK-12) questionnaire including pill count.	ASK-12 scores can range from 12-60, with higher scores representing greater barriers to adherence]	Month 1,2 and 3
To monitor safety of iron supplements	Monitor adverse events in mother and neonate - gastrointestinal (e.g. constipation, diarrhea, infection)	change from baseline and month 1,2 and 3

Other Outcome Measures

Outcome Measure	Time Frame
To assess if the amount of betel nut consumption relates to Haematocrit response	change from baseline and month 1,2 and 3

Collaborators and Investigators

• Sponsor: University of Oxford
• Investigators: Principal Investigator: Hal Drakesmith, Dr., MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS UK

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2022
• Primary Completion (Estimated): March 31, 2024
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: March 24, 2022
• First Submitted That Met QC Criteria: May 17, 2022
• First Posted (Actual): May 23, 2022

Study Record Updates

• Last Update Posted (Estimated): January 15, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Iron supplementation; Immune responses; Maternal vaccination
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Vitamin B 12; Thiamine
• Other Study ID Numbers: HCR22001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All personal details of participants will be de-identified. These data including laboratory investigation results will be stored and may be shared to other researchers to apply in their research in accordance with the MORU data sharing policy.
• IPD Sharing Time Frame: After completion of trial activities. PI will upload results within 12 months of the end of the trial declaration.
• IPD Sharing Access Criteria: MORU Data Sharing Policy. The criteria for authorship will be consistent with the international guidelines (http://www.icmje.org/#author).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No