Medical Biology - Theses
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ItemDevelopment of antibody therapeutics for deadly infectious diseases: malaria and COVID-19( 2021)Monoclonal antibodies are one of the most powerful drugs used in the treatment of human diseases, particularly for autoimmune diseases and cancer. The development of therapeutic antibodies to combat infectious diseases is expanding, with successful treatments available against viral diseases such as COVID-19, Ebola virus, HIV and RSV. The use of monoclonal antibodies complements vaccines by providing immediate protection, preventing disease in immunocompromised people and in containing emerging disease outbreaks. In this thesis, I aimed to characterise neutralizing antibodies against two of the deadliest infectious diseases that affect global populations, malaria and COVID-19. The growth and replication of both these pathogens are critically dependent on their entry into host cells. Neutralizing antibodies that block pathogen entry into host cells can prevent infection and reduce severe disease. Plasmodium vivax is the most widespread relapsing human malaria, which invades reticulocytes through the critical interaction between P. vivax reticulocyte binding protein 2b (PvRBP2b) and human Transferrin receptor 1 (TfR1). I identified TfR1 residues that are critical for complex formation with PvRBP2b. In addition, I characterised naturally acquired human monoclonal antibodies to PvRBP2b, and using structural biology, revealed the epitopes of eight high affinity inhibitory antibodies that block complex formation through different mechanisms. The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which utilizes its spike protein to engage human angiotensin-converting enzyme 2 (ACE2) for host cell entry. I performed deep mutational scanning on a lead neutralising nanobody against SARS-CoV-2 to improve its potency, stability and affinity. These structural studies increase our understanding of host-pathogen interactions and the antibodies that block them, which can inform the development of antibody therapeutics or vaccines.
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ItemPlasmodium vivax naturally acquired immunity: patterns and influences( 2020)Malaria is caused by Plasmodium parasites and Plasmodium vivax is the dominant Plasmodium spp. in low-transmission regions outside of Africa. Due to the unique biological characteristics of this parasite, such regions often feature asymptomatic patients with sub-microscopic parasitaemia and relapses. Naturally acquired antibody responses are induced after Plasmodium infection, providing partial protection against high parasitaemia and clinical episodes. Serology is a promising tool for monitoring transmission levels, estimating past and recent exposure and identifying populations at risk of infections. However, due to key gaps in our knowledge of naturally acquired antibody responses to P. vivax, the full potential of serology has not yet been reached. This thesis aimed to establish antibody kinetics against a large panel of P. vivax antigens following infections in western Thailand, and investigate the factors potentially associated with the acquisition and development of antibody responses. A multiplexed bead-based assay was first established and antibody measurements against more than 50 antigens were taken in P. vivax-infected individuals from western Thailand following symptomatic and asymptomatic infections. I found that most P. vivax antigens followed a highly similar post-infection kinetic pattern in the absence of any boosting infections. The magnitude and longevity of antibody responses varied between antigens, antibody subclasses and subtypes. An assay quantifying the antigen-specific memory B cell responses was established and verified to determine the role of memory B cells on antibody kinetics for future experiments. Lastly, I reported that the genetic diversity of an antigen sequence had a significant impact on antigen-specific antibody responses, and such impact increased in individuals with more past exposure and mature immunity. The findings presented in this thesis provide novel insights into naturally acquired immunity development to P. vivax and support the decision of taking genetic diversity of antigen sequences into consideration for the development of highly efficacious sero-surveillance tools and vaccines.
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ItemNaturally acquired humoral responses to Plasmodium vivax and Plasmodium falciparum: identification of antigenic targets to inform rational biomarker and vaccine development( 2016)Malaria is an infectious disease caused by Plasmodium spp. parasites, transmitted by the bite of infected Anopheles mosquitoes. Among the five species that can cause disease in humans, P. falciparum and P. vivax are responsible for the majority of the cases and deaths. Due to increased political commitment and funding, the last decades have experienced a dramatic reduction in the burden of malaria, with several countries now attempting to permanently eliminate this disease. Achieving the goal of malaria elimination would be greatly facilitated by the development of biomarkers that can identify the remaining populations at-risk, as well as an effective vaccine. However, while it is clear that individuals living in endemic areas become gradually protected against malaria disease, the targets and mechanisms underlying the acquisition of natural immunity are complex and still poorly understood, hindering the development of such tools. This thesis aimed to investigate comprehensive panel of P. vivax and P. falciparum proteins as targets of natural immunity in Asia Pacific populations, and how this information can be used to inform rational vaccine and biomarker development. Strong associations of antibody responses to both novel and known P. vivax antigens with protection against clinical malaria were identified, as well as optimal antigenic combinations with predicted protective efficacy above 90%. By comparing humoral responses to P. vivax and P. falciparum, this thesis shows that early immune responses are markers of exposure and thus increased risk, whereas prolonged exposure and higher antibody titers are required to achieved clinical protection. The findings of this study support the development of a highly efficacious multicomponent malaria vaccine, and the use of serology as a surveillance tool.