| Autor: |
Elias, Sean C. |
| Rok vydání: |
2014 |
| Předmět: |
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| Druh dokumentu: |
Electronic Thesis or Dissertation |
| Popis: |
The apicomplexan parasite Plasmodium falciparum is the causative agent of the most severe and deadly form of human malaria. The production of an efficacious malaria vaccine is seen as one of the key steps towards the eradication of the disease, however to date only one candidate has progressed to application for licensure. Candidate malaria vaccines target the different stages of the P. falciparum lifecycle through induction of a functional immune response. Vaccines targeting the blood-stage parasite require induction of high titre neutralising antibodies. To achieve this, vaccine regimens have been designed specifically to maximise antibody induction and maintenance in humans. The ultimate test of any candidate vaccine is clinical efficacy and controlled human malaria infection (CHMI) is a powerful tool for measuring this. This model can also be used to study how vaccine induced antigen-specific components of the immune system respond to native antigen exposure in the context of parasitic infection In this Thesis I describe the induction and maintenance of B cell responses, including memory B cells (mBC) and antibody secreting cells (ASC) to the candidate blood-stage malaria antigens MSP1 and AMA1 following vaccination with a variety of regimens and CHMI. These B cell populations along with peripheral blood T follicular helper (Tfh) cells correlate strongly with antibody induction. Within these populations I have identified a number of phenotypically distinct subsets which contribute to a functional response to vaccine and/or parasite antigen. From single cell sorting of ASC at day seven post-boost I have managed to produce the first fully human monoclonal antibodies (hmAbs) specific for AMA1, one of which shows significant growth inhibitory activity (GIA). Despite promise the vaccine candidates MSP1 and AMA1 have been disappointing in terms of human efficacy. In this Thesis I have attempted to provide explanations on a cellular level as to why there is such disparity between pre-clinical and human data and ultimately why these candidates may have failed to provide efficacy. Such work will provide a strong basis for analysing future clinical trials of alternative candidate blood-stage vaccines and allow accurate characterisation of immune correlates and clinical efficacy when it is achieved. |
| Databáze: |
Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
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