Conference Agenda

Antibody Fc regions have important roles in clearance of Plasmodium falciparum infected erythrocytes. One such role is engagement with Fcg receptors on host leukocytes. In the case of FcgRIIIa and b, this interaction is greatly enhanced when the IgG glycan is afucosylated. In this study, we used a fucose-sensitive enzyme-linked immunosorbent assay, FEASI, to assess afucosylation in IgG specific for placental malaria protein VAR2CSA from n=139 malaria-exposed pregnant Malawian women, correlating these data with mass spectrometry-based analysis. Furthermore, we measured the effect of afucosylation on Fc-mediated leukocyte functions, using both plasma and a monoclonal antibody, PAM2.8, with varying levels of afucosylation.

Results showed significantly higher levels of VAR2CSA-specific IgG afucosylation in women with no placental malaria measured by FEASI (p < 0.0001), which correlated strongly with mass spectrometry analysis (R = 0.8, p < 0.0001). In addition, highly afucosylated IgG mediated significantly greater neutrophil phagocytosis of antigen coated beads and induction of NK cell degranulation by IEs.

Afucosylated IgG to VAR2CSA, measured by FEASI or mass spectrometry, was a correlate of protection from placental malaria, and afucosylated IgG activated NK cells and neutrophils. Naturally acquired or therapeutic afucosylated IgG antibody could have a role in protection from malaria infection.

Helminth infections, whether experimental or naturally acquired, are increasingly recognised as potent modulators of human immunity, with protective effects across a range of inflammatory diseases. Much of this activity is driven by excretory/secretory proteins (ESPs), complex mixtures of bioactive molecules that act at the host–parasite interface to reshape immune responses and suppress inflammation. Despite this, the therapeutic use of live helminths remains limited due to safety concerns, complex life cycles, and variable host responses. Consequently, focus has shifted toward isolating individual ESPs as more tractable, drug-like candidates. To address this, we generated a recombinant library spanning the secretomes of both larval and adult stages of the human hookworm Necator americanus. This enabled systematic screening across in vitro and in vivo assays to identify proteins with immunoregulatory activity. To date, two distinct protease inhibitors have emerged, each displaying pronounced anti-inflammatory effects. Their independent identification via separate screening strategies underscores the library's versatility as a discovery platform. Their protease inhibitory activity has been confirmed in vitro, consistent with established roles for helminth-derived inhibitors in modulating host inflammatory pathways. Work is now focused on defining their mechanisms of action in vivo and assessing their potential as pre-clinical therapeutic candidates.

Effective malaria interventions are essential to reduce disease burden in children. Combining RTS,S vaccination with seasonal antimalarial chemoprevention was shown to enhance efficacy against clinical malaria among children by ~72% over the first year compared to either intervention alone. However, over four years, efficacy of this combination steadily decreased despite annual boosters. Protective antibodies were shown to peak following primary vaccination but became progressively lower with each annual booster. It is unknown what drives poor antibody responses to boosters, which likely vary between different antibody isotypes and antigenic targets, and if host factors such as viral co-infections and micronutrient deficiencies are implicated in this suboptimal response.

To address these knowledge gaps, we evaluated plasma samples from young children (n=1,929) in West Africa who received RTS,S and subsequent boosters with or without seasonal chemoprevention over four years as part of a phase-III clinical trial. We found that repeated vaccine doses had differential effects on antibody responses, which varied by the antigenic region of the vaccine. We also investigated the impact of host factors on these responses. By improving our understanding of the immune response to repeated booster doses, this work informs optimal RTS,S implementation strategies to improve vaccine efficacy and longevity.