Severe Malaria: Identifying Immune Targets and Mechanisms Associated With Protection in Kenyan Children

Murungi, Linda Muthoni (2014). Severe Malaria: Identifying Immune Targets and Mechanisms Associated With Protection in Kenyan Children. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000efe6

Abstract

Naturally-acquired immunity (NAI) to malaria develops first to the most severe form of disease followed by uncomplicated malaria episodes. NAI is never completely achieved therefore asymptomatic P. falciparum infections are often detected in adults living in malaria endemic areas. The timing and sequential acquisition of immunity to the three distinct manifestations of an infection suggests that different targets and mechanisms of protection are involved. Immunity is thought to be partly mediated by antibodies directed to blood-stage antigens. This thesis explores the potential merozoite targets and mechanisms of immunity to severe malaria and to uncomplicated malaria episodes in Kenyan children. First, using a well-studied cohort of children aged 1-12 years recruited during a period of high malaria transmission (Chonyi), IgG responses to five merozoite antigens were quantified using a standard reference reagent. Thereafter, protective threshold concentrations were derived using a statistical approach and applied to a separate age-matched cohort (Junju) in which antibodies to the same antigens were not associated with protection using a conventional cutoff of seropositivity. Children who achieved antibody concentrations above the proposed thresholds had a reduced risk of developing clinical episodes of malaria during the subsequent 6-months of follow-up. Second, using a matched case-control design nested within a birth cohort of children followed up every three months for the first two years of life, I examined the targets and mechanisms of protection against severe malaria. Children admitted to Kilifi County hospital with well-defined severe malaria were identified and matched to controls who were never admitted to hospital with severe malaria. Antibody responses to five merozoite antigens were measured in all the three-monthly samples from the cases and controls and prospectively associated with the odds of developing severe malaria. The ability of antibodies to inhibit parasite growth in the Growth Inhibition Activity (GIA) assay and mediate antibody dependent respiratory burst (ADRB) by neutrophils was also investigated and prospectively associated with the odds of developing severe malaria. Dynamic antibody patterns were observed with transient peaks in antibody titres occurring during asymptomatic infections in some children. Overall, antibody levels were similar in the cases and controls and were not associated with a reduced odds of developing severe malaria with the exception of anti-AMAl antibodies. Interestingly, children who had a combination of antibodies that mediated both GIA and ADRB, had a significantly reduced odds of developing severe malaria. This thesis provides direct evidence of an association between achieving specific antibody thresholds and protection against uncomplicated episodes of malaria. My findings also highlight the possible involvement of multiple antibody-mediated effector functions in protection against severe malaria in young children. These findings enhance our knowledge of the acquisition of immunity to malaria and provide insights that may be valuable for advancing malaria vaccine development and testing.

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