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.

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