P. falciparum Transmission Intensity and the Quality of Antimalarial Antibodies

Immunity to malaria, where antibodies play a critical role, is acquired slowly, rarely sterile, and poorly maintained. The quality than just the quantity of antibodies may provide more insight into the slow acquisition and poor maintenance of immunity to malaria. I hypothesized that frequent P. falciparum infections interrupt avidity maturation and IgG subclass composition, which affects the acquisition and maintenance of immunity to malaria. In the first aim, the avidity index to AMA-1 and MSP1-19 was compared across three crosssectional malaria transmission intensity sites. In the second and third aims, avidity index, total IgG, and IgG1 – 4 against 18 P. falciparum blood-stage antigens were measured in a longitudinal cohort at 4-time-points; 2 before and 2 after interruption of malaria transmission by IRS. Results showed that avidity to both AMA-1 and MSP1-19 was significantly lower at the site of highest P. falciparum transmission in children above 5 years and adults. In all 18 malaria blood-stage antigens, the avidity index was positively associated with days since the last infection independent of age and heterogeneous across antigens. There was heterogeneity in antibody half-life estimation across antigens and IgG subclasses. IgG3 had the shortest half-life of the IgG subclasses. The predominance of IgG subclass in the absence of infection shifted from IgG1 to IgG3 with age. IgG3 improved the specificity of antigens as a marker of recent infection compared to total IgG. 3 P. Results provide supporting evidence to our hypothesis by demonstrating (i) preferential expansion of non-avid antibody pool that rapidly wane in the absence of infection (ii) slow acquisition of the avid antibody pool that persists in the absence of infection. (iii) slow acquisition of IgG3 memory. The thesis provides the rationale for further investigation of malaria-specific MBC phenotypes, class switching, somatic hypermutation, the avidity of antibodies, and the antibody in vitro function. These further studies will provide more knowledge in the acquisition and maintenance of effective antibody memory.