Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.712101
Title: Optimizing a universal mosaic T cell vaccine for HIV-1
Author: Abduljawad, Sultan Khalid
ISNI:       0000 0004 6062 6697
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Abstract:
The development of an effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution to the global HIV-1 pandemic. This has proven difficult due to the high mutation rate and genetic diversity of the virus. One way to overcome this is for a T-cell vaccine to target highly functional conserved regions of HIV-1 across all clades, mutations would typically incur a cost on viral fitness. Our first conserved vaccine, HIVconsv, is a clade alternating consensus immunogen comprised of 14 conserved regions across the HIV-1 proteome. HIVconsv showed very promising results in mice and human clinical trials, inducing HIV-1 specific CD8+ T cells of high magnitude and breadth. In my work, four conserved mosaic immunogens were designed in-silico, to maximize the coverage of potential 9-mer T cell epitopes. The aim was to develop a new conserved mosaic vaccine to enhance the breadth and depth of the vaccine elicited responses. The first, tHIVcmo, designed to complement tHIVconsv and tConsv1, tConsv2 and tConsv3 were designed to complement each other in a trivalent vaccine. The immunogens were expressed from a plasmid DNA (D), ChAdV63 (C) and a MVA (M) vector, used in heterologous prime boost regimens DDDCM and CM. HHD transgenic mice, expressing a chimeric human HLA-A*02:01 were used to asses the breadth and depth of vaccine elicited T cells. I assessed whether or not combining tHIVcmo to tHIVconsv had any benefits, and compared this bivalent combination to the trivalent conserved mosaic vaccines. Over 70 known human HLA-A*02:01 epitopes of HIV-1 across major clades where used for analysis. The trivalent mosaic vaccines elicited T cell responses with greater breadth, depth, magnitude and killing efficacy compared to that of the bivalent or HIVconsv elicited responses. These are the first data on mosaic vaccines with regards to known human epitopes, using a model with a human HLA molecule and the first conserved mosaic vaccines tested. In a separate series of experiments, the effects of the tPA leader sequence were examined, comparing HIVconsv with and without tPA. Experiments in BALB/c mice have revealed that the addition of a tPA leader sequence had no added benefit on our T cell vaccine. Specificity, magnitude, breadth, depth and killing efficacy were all not affected by the addition of tPA to the vaccine.
Supervisor: Hanke, Tomas ; Dorrell, Lucy Sponsor: Saudi Arabia King Abdullah Scholarship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.712101  DOI: Not available
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