Iron Fortified Food to Improve Japanese Encephalitis and Typhoid Fever Vaccine Immunogenicity

Iron Fortified Food to Improve Japanese Encephalitis and Typhoid Fever Vaccine Immunogenicity: a Randomized Controlled Trial in Iron Deficient Thai Women

Iron deficiency (ID) anaemia (IDA) is a global public health problem, with the highest prevalence in Africa and in South-East Asia. While immunization programs have achieved high global coverage, vaccines often underperform in low- and middle-income countries (LMIC). The cause remains uncertain, but undernutrition, including ID, likely plays a role. Our recent in vitro and in vivo studies have shown the importance of iron status in adaptive immunity and vaccine response. Hypoferremia blunted T cell, B cell, and neutralizing antibody responses to influenza virus infection in mice, allowing the virus to persist. Iron deficient anaemic Kenyan women receiving intravenous iron at time of vaccination had a better immune response to the first dose of the ChAdOx Coronavirus 19 (COVID-19) vaccine and yellow fever vaccine. Japanese encephalitis and typhoid fever are endemic in Thailand. Vaccines are available but show variable efficacy. Whether ID impairs adult vaccine response to the live attenuated Japanese encephalitis (JE) and the Typhoid Vi polysaccharide (Vi-PS) vaccine and whether iron repletion via iron fortification improves vaccine response is uncertain.

The objective of this study is to assess whether IDA in Thai women impairs immune response to the JE and the Typhoid Vi-PS vaccine and whether fortification iron improves their response.

In this double-blind randomized controlled trial, IDA women will be assigned to two study groups: group 1 (fortification group) will receive iron-fortified biscuits (15mg iron as ferrous fumarate) for 56 days; group 2 (control group) will receive non-fortified biscuits for 56 days. All women will receive live attenuated JE and Typhoid Vi-PS vaccine on study day 28. Vaccine response will be measured 28 days after vaccination (on day 56) in both groups.

Study Overview

• Status: Recruiting
• Conditions: Iron Deficiency Anemia
• Intervention / Treatment: Other: Iron-fortified cookies; Biological: Japanese encephalitis (JE) vaccine; Biological: Typhoid Vi polysaccharide (Vi-PS) vaccine; Other: non-fortified cookies

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nicole Stoffel, PhD; Phone Number: +41 044 632 83 93; Email: nicole.stoffel@rdm.ox.ac.uk
• Study Contact Backup: Name: Pattanee Winichagoon, Prof; Phone Number: 66-2-800-2380; Email: pattanee.win@mahidol.ac.th

Study Locations

• Thailand
  • Roi Et, Thailand
    • Recruiting
    • Mahidol University
    • Contact: Sueppong Gowachirapant, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the trial.
• Female aged 18-49 years.
• Diagnosed with anaemia (i.e. hemoglobin (Hb) concentration <12 g/dl), but no severe anaemia (Hb <8 g/dl), and iron deficiency (ZnPP >40 µmol/mol)
• Anticipated residence in the area for the study duration

Exclusion Criteria:

• Pregnant (confirmed by rapid test during screening and at time of vaccination), lactating or planning pregnancy during the trial.
• Blood transfusion or intravenous iron treatment within 4 months of study start
• Major chronic infectious disease (e.g., tuberculosis, HIV+, hepatitis)
• Major chronic non-infectious disease (e.g., Type 1 or 2 diabetes, cancer)
• Treatment with supplemental iron two weeks prior to enrolment
• JE or typhoid vaccine within the past two years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Iron fortification group; Participants assigned to this group will receive iron-fortified cookies daily for the whole study duration	Other: Iron-fortified cookies; Study cookies fortified with ferrous fumarate, providing 15 mg of elemental iron in each portion.; Biological: Japanese encephalitis (JE) vaccine; All participants will be administered the live attenuated JE vaccine; Biological: Typhoid Vi polysaccharide (Vi-PS) vaccine; All participants will be administered the typhoid Vi-PS vaccine
Placebo Comparator: Control group; Participants assigned to this group will receive the same cookies containing no iron daily for the whole study duration	Biological: Japanese encephalitis (JE) vaccine; All participants will be administered the live attenuated JE vaccine; Biological: Typhoid Vi polysaccharide (Vi-PS) vaccine; All participants will be administered the typhoid Vi-PS vaccine; Other: non-fortified cookies; Study cookies containing no iron

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Immunoglobulin G (IgG) concentrations against Salmonella Typhi	day 28 (time of vaccination)
Immunoglobulin A (IgA) concentrations against Salmonella Typhi	day 28 (time of vaccination)
Immunoglobulin G (IgG) concentrations against Salmonella Typhi	day 56 (4 weeks after vaccination)
Immunoglobulin A (IgA) concentrations against Salmonella Typhi	day 56 (4 weeks after vaccination)
Neutralizing antibodies against Japanese encephalitis	day 28 (time of vaccination)
Neutralizing antibodies against Japanese encephalitis	day 56 (4 weeks after vaccination)

Secondary Outcome Measures

Outcome Measure	Time Frame
Hemoglobin concentration (g/dL)	day 0
Hemoglobin concentration (g/dL)	day 28
Hemoglobin concentration (g/dL)	day 56
zinc protoporphyrin (ZnPP) concentration (µmol/mol heme)	day 0
zinc protoporphyrin (ZnPP) concentration (µmol/mol heme)	day 28
zinc protoporphyrin (ZnPP) concentration (µmol/mol heme)	day 56
serum iron (SFe) concentration (ng/µl)	day 0
serum iron (SFe) concentration (ng/µl)	day 28
serum iron (SFe) concentration (ng/µl)	day 56
total iron binding capacity (µg/dL)	day 0
total iron binding capacity (µg/dL)	day 28
total iron binding capacity (µg/dL)	day 56
transferrin saturation (TSAT) (%)	day 0
transferrin saturation (TSAT) (%)	day 28
transferrin saturation (TSAT) (%)	day 56
plasma ferritin (PF) concentration (µg/L)	day 0
plasma ferritin (PF) concentration (µg/L)	day 28
plasma ferritin (PF) concentration (µg/L)	day 56
soluble transferrin receptor (sTfR) concentration (mg/L)	day 0
soluble transferrin receptor (sTfR) concentration (mg/L)	day 28
soluble transferrin receptor (sTfR) concentration (mg/L)	day 56
C-reactive protein (CRP) concentration (mg/L)	day 0
C-reactive protein (CRP) concentration (mg/L)	day 28
C-reactive protein (CRP) concentration (mg/L)	day 56
alpha-glycoprotein (AGP) concentration (g/L)	day 0
alpha-glycoprotein (AGP) concentration (g/L)	day 28
alpha-glycoprotein (AGP) concentration (g/L)	day 56
retinol-binding protein concentration (µmol/L)	day 0
retinol-binding protein concentration (µmol/L)	day 28
retinol-binding protein concentration (µmol/L)	day 56

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Mahidol University; Ministry of Health, Thailand

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2023
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: August 30, 2023
• First Submitted That Met QC Criteria: August 30, 2023
• First Posted (Actual): September 7, 2023

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; RNA Virus Infections; Virus Diseases; Infections; Hematologic Diseases; Encephalitis, Arbovirus; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infectious Encephalitis; Arbovirus Infections; Vector Borne Diseases; Flavivirus Infections; Flaviviridae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Anemia, Hypochromic; Anemia; Iron Metabolism Disorders; Enterobacteriaceae Infections; Salmonella Infections; Neuroinflammatory Diseases; Encephalitis, Japanese; Encephalitis; Anemia, Iron-Deficiency; Typhoid Fever; Iron Deficiencies; Physiological Effects of Drugs; Immunologic Factors; Vaccines
• Other Study ID Numbers: Vest

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