TRANSGENIC RODENT MALARIA PARASITES FOR THE EVALUATION OF PROTECTIVE IMMUNITY AGAINST PLASMODIUM FALCIPARUM
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Date
2015-08-27
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Johns Hopkins University
Abstract
Malaria is a global health emergency. Current estimates indicate that 3.3 billion people live at risk of infection and that more than half a million lives are lost to the disease annually, most of them from children under the age of 5. Despite extensive research and numerous clinical trials, the development of a fully efficient malaria vaccine remains an elusive goal. The RTS,S vaccine candidate has demonstrated significant potential to prevent clinical disease and severe malaria, but improvements in vaccine efficacy and duration of immunity are still needed. For decades, rodent Plasmodium parasites have been instrumental tools for addressing fundamental questions in malaria biology and immunology. However, their utility for the evaluation of vaccine candidates is limited due to significant differences in antigenic structure between murine and human parasite antigens. In recent years, transgenic rodent parasites expressing human malaria antigens have emerged as practical tools to overcome the limitations of the traditional rodent models. In this dissertation, I present a series of studies assessing protective immune responses against the P. falciparum Circumsporozoite Protein (CSP) using newly generated chimeric rodent malaria parasites. We demonstrate that a monoclonal antibody capable of inhibiting the proteolytic cleavage of CSP strongly inhibits in vivo infection of sporozoites expressing the N-terminus of P. falciparum CSP. In further chapters, we evaluated immune responses induced by full-length recombinant P. falciparum CSP in combination with different adjuvant systems and demonstrate that E. coli-derived recombinant protein is highly immunogenic and can induce considerable antibody and CD4+ T-cell responses that inhibit sporozoite infection. Also, we report the development of several epitope-focused virus-like particles (VLPs) incorporating different domains from the P. falciparum CSP. In this study, we found that a construct incorporating B- and T-cell CSP epitopes conferred sterilizing immunity to mice upon immunization with different adjuvant formulations. In more recent investigations, we assessed antibody and CD8+ T-cell responses, induced by immunizations with a novel cationic liposomal adjuvant, using new parasite chimeras expressing the entire P. falciparum CSP. Importantly, while antibodies against CSP can neutralize sporozoite infection, the induction of CD8+ T-cell responses against the P. falciparum CSP enhances the inhibitory capacity of humoral responses and induces long-lasting sterilizing immunity. Lastly, the studies here presented provide ample evidence supporting the usefulness of chimeric rodent parasites as platforms for the evaluation of malaria vaccine candidates.
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Keywords
malaria, vaccine