Effects of Oral Iron Supplementation Before vs at Time of Vaccination on Immune Response in Iron Deficient Kenyan Women (DIVA_II)

Iron deficiency (ID) anemia (IDA) is a global public health problem, with the highest prevalence in Africa. Vaccines often underperform in low- and middle-income countries (LMIC), and undernutrition, including ID, likely plays a role. Recent studies have shown the importance of iron status in vaccine response. Intravenous iron given at time of vaccination improved response to yellow fever and COVID-19 vaccines in IDA Kenyan women. Whether oral iron treatment would have a similar beneficial effect on vaccine response is uncertain. Also, timing of oral iron treatment needs further investigation.

The co-primary objectives of this study are to assess 1) whether IDA in Kenyan women impairs vaccine response, and whether oral iron treatment improves their response; 2) the timing of oral iron treatment to improve vaccine response (prior to vaccination vs at time of vaccination).

We will conduct a double-blind randomized controlled trial in southern Kenya to assess the effects of iron supplementation on response to three single-shot vaccines: Johnson & Johnson COVID- 19 (JJ COVID-19), the quadrivalent meningococcal vaccine (MenACWY) and the typhoid Vi polysaccharide vaccine (Typhim Vi). Women with IDA will be recruited and randomly assigned to three study groups: group 1 (pre- treatment) will receive 100 mg oral iron as ferrous sulfate (FeSO4) daily on days 1-56; group 2 (simultaneous treatment) will receive matching placebo daily on days 1-28, and 200 mg oral iron as FeSO4 daily on days 29-56; and group 3 (control) will receive matching placebo daily on days 1-56. Women in all groups will receive the JJ COVID-19 vaccine, the MenACWY and the Typhim Vi vaccine on day 28. Cellular immune response and serology will be measured at 28 days after vaccination in all groups.

Study Overview

• Status: Recruiting
• Conditions: Iron Deficiency Anemia
• Intervention / Treatment: Biological: COVID-19 vaccine; Biological: MenACWY vaccine; Dietary supplement: Iron supplementation; Biological: Typhim Vi vaccine; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Giulia Pironaci, MSc; Phone Number: +41 44 632 93 29; Email: giulia.pironaci@hest.ethz.ch
• Study Contact Backup: Name: Nicole Stoffel, PhD; Phone Number: +41 44 632 83 93; Email: nicole.stoffel@hest.ethz.ch

Study Locations

• Kenya
  • Nairobi, Kenya, 00200
    • Recruiting
    • Jomo Kenyatta University of Agriculture and Technology
    • Contact: Simon Karanja, PhD; Phone Number: +254726424669; Email: skaranja@jkuat.ac.ke

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Willing and able to give informed consent for participation in the trial
• Female aged 18-49 years
• Moderate anemia (Hb <110 g/L, but not severely anemic with Hb <80 g/L)
• Iron deficient (ZnPP >40 mmol/mol haem)
• Anticipated residence in the study area for the study duration

Exclusion Criteria:

• Major chronic infecious disease (e.g., HIV infection);
• Major chronic non-infecious disease (e.g., Type 2 diabetes, cancer);
• Chronic medications;
• Use of iron-containing mineral and vitamin supplementation 2 weeks prior to study start;
• COVID-19 vaccine or confirmed COVID-19 infection within the past 2 years
• MenACWY vaccine in the past
• Typhim Vi vaccine in the past
• Pregnant (confirmed by rapid test during screening)
• Malaria (confirmed by rapid test) à study start will be postponed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pre-treatment group; Participants assigned to this group will receive 100 mg oral iron daily on study days 1-56.	Biological: COVID-19 vaccine; Johnson & Johnson COVID- 19 (JJ COVID-19) vaccination given on day 28 to all participants; Biological: MenACWY vaccine; MenACWY vaccination given on day 28 to all participants; Dietary supplement: Iron supplementation; Iron supplements as 100 mg oral iron as FeSO4 given daily; Biological: Typhim Vi vaccine; Typhim Vi vaccination given on day 28 to all participants
Experimental: Simultaneous treatment group; Participants assigned to this group will receive placebo daily on study days 1-28 and 100 mg oral iron daily on study days 29-56.	Biological: COVID-19 vaccine; Johnson & Johnson COVID- 19 (JJ COVID-19) vaccination given on day 28 to all participants; Biological: MenACWY vaccine; MenACWY vaccination given on day 28 to all participants; Dietary supplement: Iron supplementation; Iron supplements as 100 mg oral iron as FeSO4 given daily; Biological: Typhim Vi vaccine; Typhim Vi vaccination given on day 28 to all participants; Other: Placebo; matching placebo capsules given daily
Placebo Comparator: Control group; Participants assigned to this group will receive placebo daily on study days 1-56.	Biological: COVID-19 vaccine; Johnson & Johnson COVID- 19 (JJ COVID-19) vaccination given on day 28 to all participants; Biological: MenACWY vaccine; MenACWY vaccination given on day 28 to all participants; Dietary supplement: Iron supplementation; Iron supplements as 100 mg oral iron as FeSO4 given daily; Biological: Typhim Vi vaccine; Typhim Vi vaccination given on day 28 to all participants; Other: Placebo; matching placebo capsules given daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
JJ COVID-19 vaccine response	Anti-spike (S1) IgG and anti-receptor-binding domain (RBD) IgG against SARS-COV-2	Day 56
MenACWY vaccine response	Measurement of antibody response against serogroups A, C, W, and Y.	Day 56
Typhoid vaccine response	Measurement of antibody response against Typhoid	Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin	iron status	Day 1
Hemoglobin	iron status	Day 28
Hemoglobin	iron status	Day 56
Serum ferritin	iron status	Day 1
Serum ferritin	iron status	Day 28
Serum ferritin	iron status	Day 56
soluble transferrin receptor	iron status	Day 1
soluble transferrin receptor	iron status	Day 28
soluble transferrin receptor	iron status	Day 56
Plasma iron	iron status	Day 1
Plasma iron	iron status	Day 28
Plasma iron	iron status	Day 56
Total iron binding capacity	iron status	Day 1
Total iron binding capacity	iron status	Day 28
Total iron binding capacity	iron status	Day 56
Transferrin saturation	iron status	Day 1
Transferrin saturation	iron status	Day 28
Transferrin saturation	iron status	Day 56
C- reactive protein	inflammation status	Day 1
C- reactive protein	inflammation status	Day 28
C- reactive protein	inflammation status	Day 56
alpha- 1- glycoprotein	inflammation status	Day 1
alpha- 1- glycoprotein	inflammation status	Day 28
alpha- 1- glycoprotein	inflammation status	Day 56
Retinol binding protein	Vitamin A status	Day 1
Retinol binding protein	Vitamin A status	Day 28
Retinol binding protein	Vitamin A status	Day 56
Plasma zinc	Zinc status	Day 1
COVID-19 specific T cell response	QuantiFERON SARS-CoV-2 whole blood assay - detection of IFN-gamma	Day 28
COVID-19 specific T cell response	QuantiFERON SARS-CoV-2 whole blood assay - detection of IFN-gamma	Day 56
COVID-19 specific T cell response	ELISpot assay on isolated peripheral blood mononuclear cells	Day 28
COVID-19 specific T cell response	ELISpot assay on isolated peripheral blood mononuclear cells	Day 56
Typhim Vi specific B-cell response	ELISpot assay on isolated peripheral blood mononuclear cells	Day 28
Typhim Vi specific B-cell response	ELISpot assay on isolated peripheral blood mononuclear cells	Day 56

Collaborators and Investigators

• Sponsor: Swiss Federal Institute of Technology
• Collaborators: University of Oxford; Jomo Kenyatta University of Agriculture and Technology

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2023
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: October 30, 2023
• First Submitted That Met QC Criteria: October 30, 2023
• First Posted (Actual): November 3, 2023

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Iron Deficiencies; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: DIVA_II

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