Functional Immuno-genetic Correlates of Immunity to Malaria

Project summary

This project will define immune-genetic correlates of malaria immunity and strengthen research capacity through:

1. Identification of immuno-genetic determinants of immunity to malaria: Malaria immunity has been associated with antibody titres and infection outcome often ignoring polymorphisms in host genes crucial for antibody function. Here, interactions between polymorphisms in (ITGB2, FCGR2A, FCGR2B, FCGR3A, FCGR3B, IGHG3) genes, quality and quantity of malarial antibodies in relation to risk of malaria will be assessed.

2. Dynamics of Plasmodium falciparum (Pf) genetic variations underlying acquisition of immunity to malaria: The high variability of Pf infection outcome is inadequately explained by host related factors alone. Here, sequences and expression profiles of genes encoding proteins crucial for parasite invasion, transmission and cytoadherence will be evaluated from parasite strains during one malaria season.

3. Functional assessment of naturally acquired malarial antibodies: Growth Inhibition Assay (GIA), Antibody Dependent Cellular Inhibition (ADCI) and Antibody Dependent Respiratory Burst (ADRB) assays will be established. Genetic and phenotypic factors for effector cell function in ADCI and ADRB will be ascertained.

4. Functional assessment of vaccine boosted malarial antibodies: GMZ2 Phase 2b trial samples will be assessed for functional antibodies by the GIA, ADCI and ADRB assays. Polymorphisms in relevant host genes will be assessed. Statistical models for analyzing preclinical and clinical data incorporating host and parasite genetic factors will be proposed.

Outputs

Midterm report:

The field work has been completed and prevalence of asymptomatic malaria parasitaemia among children (aged 0.5-12 yrs) in the study community was 7% during the dry season. After the 50-week longitudinal follow up, with both active and passive case detections, 227 (26.7%) out of the 849 children who completed the follow up were infected with Plasmodium falciparum at least once. Of those infected, 129 (56.8%) experienced febrile malaria episodes while 98 (43.2%) did not. After adjusting for age and ABO blood group, immunoglobulin (Ig) G antibodies against merozoite surface protein (MSP) 3 and N-MSP3 were significantly associated with reduced incidence of febrile malaria. Opsonic phagocytosis (OP) was also significantly associated with protection against malaria in the children. In the GMZ2 vaccine trial samples, we found higher vaccine specific IgG in vaccinated children than controls indicating immune boosting by the vaccine and OP was associated with protection against malaria. However, efficacy seemed to have been delayed.