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.