Conference Agenda

Human infection with malaria begins with the injection of sporozoites by a feeding mosquito. The sporozoite surface has a dense layer of one, immunodominant protein, called circumsporozoite protein (CSP). This protein contains 38 NANP amino acid tandem repeats which are highly immunogenic. The current licensed malaria vaccines being rolled out in Africa (RTS,S and R21) both target CSP, however they require multiple boosters to maintain high antibody titre, with vaccine efficacy waning overtime. Given CSP’s immunodominance and prevalence, could it be acting as an immunological decoy, evolved to evade an immune response from other critical cell surface proteins on the parasite? Here, we have used a CSP-tolerant mouse model, immunising mice with human infective Plasmodium falciparum sporozoites to induce an immune response towards non-CSP antigens on the surface of the sporozoite. We then performed 10x single-cell sequencing of the expanded B cell clones from immunized mice and generated a panel of monoclonal antibodies. Using these monoclonals alongside, polyclonal sera we have identified non-CSP sporozoite surface antigens as potential targets for next generation malaria vaccines.

Plasmodium vivax is the most widespread Plasmodium species causing human malaria, remains a major global health risk. Effective interventions against P. vivax remain challenging due to its distinct biology. Although vaccines exist for Plasmodium falciparum, P. vivax lacks a licensed vaccine and has few candidates in clinical trials. Naturally acquired clinical immunity to malaria, driven by antibody responses that develop through repeated exposure in endemic areas, provides promising insights for vaccine development. This study evaluated whether IgG and IgM responses to P. vivax antigens are associated with protection against clinical malaria across transmission settings. Antibody responses to 61 antigens were simultaneously measured using the Luminex INTELLIFLEX platform in longitudinal cohorts from low transmission settings (Brazil, n = 258; Thailand n = 70) and a high transmission setting (Papua New Guinea, n = 184), where participants were followed over time for clinical malaria episodes used in the data analysis. The study shows that high IgG levels against RBP2b, EBPII, MSP3a, MSP5, RBP2a, CyRPA, RIPR, Pv-fam-a (PVX_090265), MSP7, RAMA, RBP2c-non-binding region and stAR related lipid transfer protein are strongly associated with protection from clinical malaria across all three cohorts. Overall, this study has identified both well-studied vaccine candidates and underexplored candidates.

Plasmodium falciparum malaria remains a major global health burden. Co-infection with HIV, common among adults in malaria endemic regions, increases susceptibility to malaria and disease severity. However, the impact of HIV on vaccine induced and naturally acquired malaria immunity remains poorly understood. We evaluated a cohort of Kenyan adults naturally exposed to malaria who were vaccinated with the RTS,S malaria vaccine as part of a phase-IIb clinical trial. Individuals were either HIV-negative (n=204) or HIV-positive (n=45) at baseline. Using a multi-antigen multi-functional assay platform, we quantified antibody responses (IgG, Fc-receptor binding and complement fixation) to 35 malaria antigens, including the RTS,S vaccine antigen CSP, in plasma samples collected 28 days after vaccination. There was no difference in CSP IgG responses, including functional activities between HIV-negative and HIV-positive individuals. However, IgG and functional antibody responses to a majority of the non-vaccine malaria antigens were significantly higher in HIV-negative compared to HIV-positive individuals. HIV infection was associated with widespread impairment in the acquisition of naturally acquired malaria immunity, but did not substantially impact RTS,S vaccine induced immunity. Our findings suggest that malaria vaccines could provide benefit to HIV-positive people who have impaired acquired immunity and are at a higher risk of malaria.