Clinical trial NCT05385042: Iron and Immune Response to Vaccine (IRONMUM)
Official title: Iron Supplementation and Immune Responses to Maternal Vaccination in Pregnant Women
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Pregnancy Related
Keywords: Iron supplementation
Immune responses
Maternal vaccination
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2022-05-23
Enrollment: 150
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Antibody responses to maternal vaccine
timeFrame: 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 outcomes:
measure: Cellular Immune response post-immunisation measured by Mass Cytometry (plasma cells and circulating T-follicular helper cells).
timeFrame: 7-days after immunisation
measure: Profile of the circulating immune system components over the course of pregnancy measured by CyTOF
timeFrame: change from before immunisation, 7-days and 28-days after immunization and until 2 months post-partum in mother and infant
measure: Haematological, iron and inflammatory parameters including: Hb, MCV, haematocrit serum iron, ferritin, TSAT, hepcidin, CRP, G6PD, Hb typing.
timeFrame: change from before immunisation, 7-days and 28-days after immunization and at 2 months post-partum in mother and infant
measure: Haematocrit from baseline if anaemic at baseline according to trimester of gestation
timeFrame: change from baseline and month 1,2 and 3, and delivery
measure: Modified Adherence Starts with Knowledge (ASK-12) questionnaire including pill count.
timeFrame: Month 1,2 and 3
measure: To monitor safety of iron supplements
timeFrame: change from baseline and month 1,2 and 3
Other outcomes:
measure: To assess if the amount of betel nut consumption relates to Haematocrit response
timeFrame: change from baseline and month 1,2 and 3
Locations:
city: Mae Sot
country: Thailand
facility: Shoklo Malaria Research Unit (SMRU)
state: Tak
Study officials:
affiliation: MRC Human Immunology Unit, John Radcliffe Hospital, University of Oxford, OX3 9DS UK
name: Hal Drakesmith, Dr.
role: PRINCIPAL_INVESTIGATOR
References: