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Title: Molecular address tags for vaccines
Author: Winsbury, Rebecca
ISNI:       0000 0004 7962 7884
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2019
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Antibodies are neutralising proteins produced by plasma cells of the mammalian immune system to combat invading pathogens. The specificity of antibodies towards antigenic epitopes is paramount to successful vaccination therapies. This thesis set out to enhance antibody specificity by introduction of a 'molecular address tag' (MAT) to vaccines for targeting antigens to cells of the immune system. The aim was to produce antibodies more specific and more potent towards antigenic epitopes, eliminating the need for adjuvants. β-1,3-Glucan tags of 15 degrees of polymerisation were synthesised for use as address tags, along with laminarin, a commercially available storage polysaccharide of brown alga consisting of β-1,3-glucan backbone with β-1,6-glucan side chains. Following conjugation to BSA, MATs were studied for their ability to interact with Dectin-1, a C-type lectin receptor with an affinity for β-(1-3)-glucans, and to stimulate a Dectin-1-mediated signalling response, by utilising a Dectin-1-expressing reporter cell line. This study revealed a signalling response triggered by conjugated β-(1-3)-glucans with β-(1-6)-side chains, and particulate β-(1-3)-glucans of DP15 either free or unconjugated. The latter half of this thesis focused on antigen generation and immunisation trials. Fungal β-(1-2)-mannan antigens of DP3 and DP4 were synthesised enzymatically and isolated via gel permeation chromatography. However, conjugation efforts were unsuccessful and time did not allow for further optimisation. Two vaccines to protect against the causative agent of Q fever, Coxiella burnetii, were generated. Both vaccines comprised of a virus-like-particle core to which lamarin address tags were conjugated as well as a virenose antigen. The antigen comprise of either α-Vir(1-4)-α-Vir or β-Vir(1-4)-β-Vir, depending on the vaccine. Immunisation trials were performed in rabbits, and serum analysis performed by ELISA, revealing a specificity towards both α and β-virenose antigens when immunised with β-Vir(1-4)-β-Vir, but a specificity towards α-vir when immunised with α-Vir(1-4)-α-Vir.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available