Medicine (RMH) - Theses
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ItemUnderstanding mechanisms enabling long-lasting immunity to malaria( 2023-07)An efficacious vaccine that generates long-lasting immunity is critically needed to reduce the global burden of malaria and protect young children in high transmission areas, who are most at risk of severe disease and death. However, despite four decades of development, the most advanced malaria vaccine induces only moderate and short-lived protection and other candidate vaccines are yet to demonstrate more sustained efficacy. Advancement in malaria vaccine design is impeded by an absence of established correlates of immunity, limiting targets for directed vaccine improvements. Host-specific factors, such as age, previous malaria infection and nutritional status, may modulate immune function and impair vaccine responsiveness, highlighting the need for an extensive characterisation of immune function in children in malaria endemic regions. In this thesis, we explored correlates and determinants of sustained immunity to malaria and examined how vaccine modification may improve long-lasting protection. We first considered immune and host factors associated with antibody-mediated protection and antibody maintenance in clinical samples. We investigated the value of antibody avidity, previously reported as a marker of robust and high-quality immune induction, as a possible correlate of long-lasting malaria immunity following vaccination in children and adults. Our findings suggest that avidity is an unreliable marker of antibody maintenance and antibody functional properties. In malaria, monocytes may be key effector cells of antibody-mediated functions which have shown protective associations in vaccine trials. We found that monocytes in children with malaria infection expressed high levels of cell surface receptors relevant to functions in malaria immunity. Given the importance of potent antibody responses to generate protective and sustained immunity, we also explored the role of undernutrition in IgG responses to routine vaccinations in children living in regions of endemic malaria transmission and found that underweight and wasting were associated with reduced vaccine-induced antibody levels. Finally, we used mouse models to investigate vaccine strategies and dietary modifications that may alter the magnitude and longevity of antibodies induced by malaria vaccines. We demonstrated differences in antibody maintenance generated by different vaccine approaches, including varying adjuvants and antigens, and that deficiencies in critical micronutrients, such as zinc, may impair the antibody response to vaccination, an effect modulated by adjuvant selection. The work in this thesis supports the role of monocytes in immunity, shows that nutritional factors impact vaccine antibody levels, and demonstrates that vaccine formulation – including adjuvant and antigen selection – and host factors, such as zinc deficiency, interact to modulate the induction and maintenance of antibody responses to vaccination. In summary, we illustrate the challenges and complexity of inducing sustained immunity with malaria vaccines, providing foundations for future work characterising the interplay of host factors, the immune system and vaccine features to support vaccine-induced immunity to malaria.
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ItemIdentifying Antibody Responses Associated with Protection from Severe Malaria in Children( 2023-04)Malaria is a major global public health burden that affects individuals in 87 countries and causes 600,000 deaths annually. The majority of cases of severe malaria and malaria related deaths occur in children under the age of five, who lack protective immunity that is acquired by adulthood in endemic regions. Antibodies are a key component of protective immunity, however, the target antigens of antibodies and the functions of antibodies that confer protection are unclear. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the surface of parasite infected erythrocytes is a highly variant, multi-domain protein that mediates adhesion to a range of vascular endothelial cell receptors including Intercellular Adhesion Molecule-1 (ICAM-1) and Endothelial Protein C Receptor (EPCR). PfEMP1 is an important virulence factor and is a strong candidate target of protective antibodies against severe malaria. Therefore, the overall objective of this thesis was to understand the antibody response to PfEMP1 antigens that may confer protection from severe malaria in children. This thesis aimed to: 1) characterize the antibody response to PfEMP1 antigens that are associated with protection from cerebral malaria (the most severe form of malaria) in a cohort of Malawian children; 2) characterize the antibody response to PfEMP1 antigens that are associated with protection from severe malaria in a cohort of Papua New Guinean children; 3) assess the association of disease severity with antibody dependent neutrophil and monocyte phagocytosis of infected erythrocytes expressing important PfEMP1 variants. For aims 1 and 2 we applied systems serology, which involves measuring multiple features of antibodies targeting multiple recombinant antigens and using machine learning with statistical methods to identify the best correlates of protection. For aim 3, we selected parasite-infected erythrocytes expressing two PfEMP1 variants (that bind to ICAM-1) and measured antibody dependent neutrophil phagocytosis (ADNP) and antibody dependent cell phagocytosis (ADCP) of opsonized infected erythrocytes by flow cytometry. The important findings of this thesis were: 1) in both Malawian children and Papua New Guinean children, a combination of a small subset of PfEMP1 specific antibody responses could be used to differentiate between children with severe and uncomplicated malaria with high accuracy; 2) in both cohorts, DBL-beta3 domains that bind to ICAM-1 receptor were targets of antibodies associated with protection from severe malaria. We also affirmed that 3) in addition to measuring the quantity of antigen specific antibodies, the biophysical properties and Fc interactions (or ‘Fc features’) of PfEMP1 specific antibodies are useful correlates of protection from severe malaria. A range of antibody Fc features were associated with protection, suggesting there are multiple pathways to protection from severe malaria. The antibody responses associated with protection included Fc-gamma-RIIIb binding to antibodies targeting DBL-beta3 domains that bind to ICAM-1, suggesting that antibodies to ICAM-1 binding PfEMP1 may induce killing mechanisms by neutrophils. In the final chapter, we found that 4) ADNP of ICAM-1+EPCR binding infected erythrocytes was associated with protection from cerebral malaria in Malawian children but was not associated with protection from severe malaria in Papua New Guinean children. Additionally, 5) ADCP of ICAM-1 binding infected erythrocytes was not associated with protection from severe malaria in either cohort of children. In considering the different methodological approaches used in this thesis, we concluded that systems serology is an effective approach to identify correlates of protective immunity to PfEMP1 but currently cannot replace more complex cell-based assays like ANDP and ADCP. Overall, this thesis highlights the important role of functional antibodies to PfEMP1 in protection from severe malaria in children from diverse geographic regions and supports the development of a DBL-beta domain based therapeutic.