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

Study Overview
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Brief Summary
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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.

Official Title
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Effects of Oral Iron Supplementation Before vs at Time of Vaccination on Immune Response in Iron Deficient Kenyan Women

Conditions
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Iron Deficiency Anemia

Intervention / Treatment
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* Dietary Supplement: Iron supplementation
* Biological: MenACWY vaccine
* Biological: COVID-19 vaccine
* Other: Placebo
* Biological: Typhim Vi vaccine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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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 28 - baseline antibody titer | 
| 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 28 - baseline antibody titer | 
| 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 28 - baseline antibody titer | 
| 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 | 
| Plasma zinc | Zinc status | Day 28 | 
| Plasma zinc | Zinc status | Day 56 | 
| 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 |