Effect of Iron Deficiency and Iron Deficiency Anemia on Natural Immunity to Malaria Infections and Malaria Vaccine Response in Kilifi Children

Abstract

In Kenya, the prevalence of iron deficiency (ID) has been reported to be as high as 35%. ID has been associated with impaired immunity thus increasing susceptibility to infectious diseases. In addition, it has been shown to lower vaccine responses to some childhood vaccines such as measles, diptheria-pertussis and influenza. On the other hand, malaria infection caused by Plasmodium falciparum remains a public health problem causing about half a million deaths annually However, little is known about how ID might affect acquisition of natural immunity to malaria and malaria vaccine responses. The objective of this study was to determine the effects of iron deficiency on acquisition of antibodies to malaria and malaria vaccine responses. To achieve these malaria antibodies, iron and inflammatory biomarkers from community-based children were assayed. ID was defined using two definitions a) low ferritin (WHO definition) and b) low transferrin saturation (TSAT) < 10%. Malaria antibodies were measured using enzyme-linked immunosorbent assay (ELISA), including apical merozoite antigen1 (AMA1), merozoite surface antigens 1 and 2 (MSP1 & 2) and schizont in community-based children (n=1,160) and anti-circumsporozoite (CSP) antibodies in RTSS-vaccinated children (n=115). For ME-TRAP-vaccinated children (n=91), interferon gamma (IFN ᵧ) producing peripheral blood mononuclear cells (PBMCs) were assayed by enzyme-linked immunosorbent spots (ELISPOTs). Student's t-tests, univariate and adjusted multivariate linear regression models were used to determine the effect of ID on natural immunity. The overall prevalence of ID was 33% using the WHO definition and 48% using the low TSAT definition. Using unadjusted linear regression models, there was a significant association between ID (as defined by low ferritin) and AMA1 (β -1.16, 95% CI -1.16; -0.97, p < 0.001) and MSP1 (β -0.83, 95% CI -1.02; -0.64, p < 0.001). Low TSAT was associated with lower AMA1 (β -0.81, 95% CI -0.99; -0.62, p < 0.001) and MSP1 (β -0.45, 95% CI -0.63; -0.28, p < 0.001) antibodies in children with TSAT <10% compared to children with TSAT>10%. In the adjusted model antibody levels to AMA1 (β -0.42, 95% CI -0.59; -0.25, p < 0.001) and MSP1 (β -0.40, 95% CI -0.60; -0.20, p < 0.001) were significantly lower in ID compared to iron replete (IR) children. However, with the low TSAT definition, only antibodies to AMA1 (β -0.21, 95% CI -0.36; -0.05, p = 0.008) remained significantly lower in ID children compared to IR children. were obtained. ID using both definitions was also associated with non-significantly lower antibody responses to the RTSS,S’ vaccine at 3, 6 and 14 months after vaccination. However, iron deficient (low TSAT definition) children had higher IFNᵧ concentrations at 6 months after the ME-TRAP vaccine (β 0.38, 95% CI 0.10; 0.65 p = 0.01). In conclusion, ID decreases malaria antibodies acquisition in children, which may decrease their protection and recovery from malaria. Vaccine responses were not significantly affected by ID in children receiving the RTSS,S’ vaccine. However, ID children had higher IFNᵧ responses to the ME-TRAP malaria vaccine. Strategies to prevent and treat iron deficiency may improve natural immunity to malaria for children living in Kenya.