Conference Agenda

Despite major progress over the past 25 years, malaria remains a significant global health burden, and protection from current vaccines is limited. Pre-erythrocytic vaccines targeting the liver stage of infection are therefore promising. Immunisation with genetically attenuated Plasmodium parasites, such as P. falciparum GA2, can induce strong, even sterile, protection in humans. Liver-resident memory CD8⁺ T cells play a key role in this protection, yet their antigenic targets remain poorly defined.

To address this, we isolated reactive T cells following immunisation with a protective dose of P. berghei GA2. Antigen-responsive clones were identified using the “Timer of Cell Kinetics and Activity” (Tocky) mouse model, which detects recently activated T cells via Nr4a3-driven fluorescent protein expression and enables analysis of signalling dynamics. These cells underwent single-cell RNA and TCR sequencing to define transcriptional profiles and clonal expansion as compared to mock-immunised controls.

A subset of expanded TCRs was expressed in murine CD8⁺ Jurkat cells and used to screen ~200,000 predicted epitopes via a chimeric SABR platform. This system presents pMHC complexes linked to signalling domains, enabling antigen discovery. This pipeline will identify targets for validation and inform next-generation malaria vaccine design.

Malaria vaccine development is heavily challenged by the extensive genetic diversity of Plasmodium falciparum antigens. The full-length merozoite surface protein 1 (MSP1) is a promising blood-stage vaccine candidate, but its global diversity remains a critical hurdle for broad efficacy. To inform rational vaccine design, we evaluated the population genetic diversity and patterns of selection across MSP1 domains, followed by serological analysis of one highly polymorphic region.

Using 10,974 P. falciparum genomes from 26 countries globally, our population genomic analyses identified Block 4 as a putative target of immune selection, with high levels of polymorphism and strong signatures of balancing selection. We synthesised a peptide representing the most common variant of the MSP1 Block 4 domain and measured IgG antibody reactivity against it using Enzyme-Linked Immunosorbent Assays (ELISAs), utilising sera from Papua New Guinean children exposed to natural infection.

Despite the extensive polymorphism and balancing selection, we found antibody reactivity to the MSP1 Block 4 peptide in children developing immunity. Further work will include testing additional circulating variants individually and in combination using competition ELISAs to identify antigenically distinct variants, defining their relevance for multivalent vaccine design.

While platelets are known for their clotting function, they have immune functions as well. A recent discovery that platelets preferentially bind to senescent erythrocytes and aid in their clearance suggests that platelets are involved in erythrophagocytosis. This preferential binding is also observed in blood diseases including malaria. This project aims to explore the immune protective role of platelets in the clearance of infected erythrocytes during blood stage malarial infection.

We first determine whether platelets aid in the clearance of infected erythrocytes by infecting platelet-depleted mice with Plasmodium berghei. We observed a decrease in phagocytosed infected erythrocytes in the spleens of platelet-depleted mice compared to controls.

Next, we investigate whether it is platelets directly affect splenic macrophage function or is binding to erythrocyte an essential first step. We co-incubate murine splenic macrophages with erythrocytes in the presence of platelets. We observed increased erythrophagocytosis in the presence of platelets ex vivo. We will compare the expression level of functional markers of splenic macrophages in platelet-depleted mice to controls.

Finally, we will look at a cohort of spleen-intact and splenectomised malaria patients to determine whether our findings can also be observed in humans.