Development of a rubella- hepatitis C virus-like particle vaccine platform
Publication Date
July 18, 2023
Creator
Abstract
The Hepatitis C virus (HCV) currently infects 1% of the global population and is attributed to 400,000 deaths annually, thus presenting a major public health threat. Persistent infection results in extensive liver damage and is associated with the development of hepatocellular carcinoma. Current treatments rely on highly effective therapeutic direct acting antiviral compounds. However, these do not prevent reinfection. The current WHO target for HCV elimination by 2030 is unlikely to be met in the absence of a prophylactic vaccine. Approximately 25 % of acute infections spontaneously resolve and several studies have associated this outcome with the rapid production of broadly neutralising antibodies that target the HCV envelope glycoproteins, providing a goal for HCV vaccine candidates.
Virus-like particles (VLPs) offer a highly immunogenic and safe vaccination approach. VLPs can induce greater titres of antibodies compared to subunit vaccines due to the presence of multiple copies of epitopes present in these structures. In addition to this, chimeric VLPs allow the presentation of foreign viral epitopes to the immune system. The Rubella virus (RV) induces long-lasting humoral responses upon exposure following natural infection or vaccination. Recombinant expression of the three RV structural proteins, capsid-E2-E1, leads to the assembly of RV-LPs that are similar to infectious RV in both morphology and immunogenicity.
This project explored the use of RVLPs as a vaccine platform for the presentation of HCV envelope glycoproteins. First an in-house system for the expression of RVLPs was established and validated. Following this, a panel of Rubella-Hepatitis C virus (RH) chimeras were designed and constructed using homologous recombination cloning methods. Five RH constructs were generated and validated for VLP formation and secretion. Of these constructs, one chimera, RH5, was found to produce chimeric VLPs that incorporated the HCV envelope glycoproteins. Furthermore, the RH5 chimeric VLPs reacted with conformation sensitive anti-HCV antibodies. Finally, immunisation of bovines with RH5 elicited autologous neutralising antibodies. This project described the development and early validation of a novel chimeric vaccine platform for HCV.
Item Type
ethesis
Thesis Type
PhD
Supervisors
Keywords
Subjects (LC)
Associated Schools / Departments
School of Life Sciences
eprints ID
72893
UoN Repository URI
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J_Duncan PhD Corrected Thesis Submission 2023.pdf
Type
Full-text
Description
Examined. Corrected thesis
Size
4.1 MB
Format
Adobe PDF
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