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Title: Towards an effective vaccine against Plasmodium vivax malaria
Author: Rawlinson, Thomas
ISNI:       0000 0004 7971 6190
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Over seventy vaccines are now licensed against more than thirty pathogens, but despite a century of effort, the malaria parasite is not among them. In the meantime, effective drugs and anti-mosquito measures notwithstanding, millions still suffer and die from of a disease which belongs in the history books. The reasons are largely political and economic, malaria is a neglected disease of the poor, but also scientific; a parasite as protean as Plasmodium is not easy to pin down with a vaccine. It has been known for over a hundred years that almost a billion people on the world's most malarial continent are 'naturally immune' to Plasmodium vivax (P. vivax) malaria. I can think of no other human pathogen with such an ancient and continental-scale natural experiment to inspire research. The source of this immunity was discovered, over forty years ago, to be due to the lack of the Duffy antigen on the surface of red blood cells. The parasite must bind to this Duffy antigen, using its 'Duffy-binding protein' (DBP), in order to invade the erythrocyte. Despite this 'Achilles heel' of P. vivax being known about for decades, it was not until 2014 that it was first targeted in a human vaccine trial. This long overdue trial of a P. vivax DBP (PvDBP) vaccine provided the source material for, and the starting point of, this DPhil Thesis. The extreme polymorphism of malaria antigens, such as PvDBP, poses a great challenge to vaccine design, but new approaches are emerging to tackle this and it is one of these, known as 'epitope-focused vaccinology', that I pursue in this Thesis. I report the production of the first panel of vaccine-induced human monoclonal antibodies (mAb) against PvDBP and, through testing in functional assays using both P. vivax and a transgenic Plasmodium knowlesi line, the discovery of a broadly-neutralising mAb. X-ray crystallographic studies have identified its epitope on PvDBP and the process of re-engineering the PvDBP vaccine to place this conserved and critical epitope in the immune system's spotlight has begun.
Supervisor: Draper, Simon ; Higgins, Matt Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available