Kinetics of anti-malarial antibodies in Children with common Haemoglobinopathies in a Tanzanian population

Alphaxard Manjurano^1,2,3,4*Nuno Sepulveda^3,5Sixbert Mkumbaye⁶Taane Gregory Clark³Anorld Ndaro⁶Christian Wang⁷Louise Turner⁷Thor G Theander⁷Kevin K A Tetteh³Eleanor Riley³Franklin Mosha⁴Chris Drakeley^3,4

• ¹National Institute of Medical Research (Tanzania), Dar es Salaam, Tanzania
• ²National Institute for Medical Research Mwanza Research Centre, Mwanza, Tanzania
• ³London School of Hygiene & Tropical Medicine Faculty of Infectious and Tropical Diseases, London, United Kingdom
• ⁴Kilimanjaro Christian Medical Centre, Moshi Urban, Tanzania
• ⁵Universidade de Lisboa Centro de Estatistica e Aplicacoes, Lisbon, Portugal
• ⁶Kilimanjaro Clinical Research Institute, Moshi Urban, Tanzania
• ⁷Rigshospitalet, Copenhagen, Denmark

Haemoglobin gene mutations have long been associated with protection against malaria, as evidenced by the concordant geographic distribution of these mutations with malaria parasite prevalence and by the reduced risk of severe disease among individuals carrying thalassaemia or sickle cell trait alleles. However, the mechanisms underlying this protection remain poorly understood. Although the precise correlates of immunity to malaria are still debated, antibody-mediated responses are widely considered to play a critical role. In this study, we investigated changes in putatively protective anti-malarial antibody titres in relation to age, malaria infection, and protection in Tanzanian children with and without α⁺-thalassaemia. Antibody responses were quantified using a multiplex assay targeting sporozoite antigens (CSP), merozoite antigens (AMA1, MSP1₁₉, MSP3, GLURP R0 and R2), and infected red blood cell surface antigens (PfEMP1 groups A, B, and E). A linear mixed-effects modelling framework, assuming a multivariate normal distribution of residuals, was applied to determine whether antibody responses to specific antigens or antigen groups differed by haemoglobinopathy status or were associated with protection from malaria. In age-adjusted analyses, antibody levels to MSP3 and Group B PfEMP1 exhibited opposing associations with inherited red blood cell disorders: responses were negatively associated with α⁺-thalassaemia and positively associated with sickle cell trait, respectively. These findings suggest that sickle cell trait may modulate PfEMP1 expression, thereby weakening the adhesion of Plasmodium falciparum– infected red blood cells to microvascular endothelial cells, while α⁺-thalassaemia may interfere with the shedding of parasite surface proteins involved in 3 erythrocyte invasion. Collectively, these results provide further insight into the immunological and cellular mechanisms by which haemoglobinopathies confer protection against malaria.