Hepatitis B core (HBc) virus like particle (VLP) as a platform for innovation of chimeric adjuvant-free VLP vaccines targeting oncoviruses

Immunotherapy is an advanced technology for treatment of oncoviruses leading cancers. However, lack of effective and safe vaccines against the oncoviruses has limited the development. This thesis aims to apply Hepatitis B core (HBc) virus like particle (VLP) as a platform for innovation of chimeric adjuvant-free VLP vaccines targeting oncoviruses. Two chimeric HBc VLP-based vaccines presenting Epstein–Barr virus nuclear antigen 1 (EBNA1) epitope (short and non-structural epitope) and Hepatitis C virus (HCV) core epitope (long and structural epitope) were successfully expressed and purified in the Escherichia coli (E. coli) expression system with high production yields, 62.1 mg/g and 40.3 mg/g of wet cell weight, respectively. To further understand and evaluate the influence of insertion of different epitopes to HBc VLP, the stability of chimeric HBc VLP vaccines under different stresses were analysed in comparison with non-chimeric HBc VLP. Computational protein modelling was employed to assist the understanding of the possible cause for the differences. Results indicate that the stability of chimeric HBc VLP vaccines was related to the hydrophobicity of chimeric HBc monomers. The stability of chimeric HBc VLP decreased with the decrease of hydrophobicity of its monomer. This finding would help and improve the efficiency in the development and design of chimeric HBc VLP-based vaccines. In the immunogenicity evaluation, both adjuvant-free EBNA1-HBc VLP and HCV core-HBc VLP induced strong epitope-specific immune response in mice compared with other reported vaccine candidates of EBV and HCV. The achieved immune responses of adjuvant-free EBNA1-HBc VLP and HCV core-HBc VLP groups were comparable to the groups with aluminium adjuvant. No side effect and death of mice were detected during the examination. This confirms that adjuvant-free HBc VLP can present either short non-structured epitope or long structured epitope and can induce strong epitope-specific immune response with low safety risks. Chimeric EBNA1-HBc VLP tended to elicit predominated humoral immune response, while chimeric HCV core-HBc VLP induced predominated cellular immune response. This indicates that the nature of antigens presented by HBc VLP has an impact on the immune response performance, which should be considered in the design of chimeric HBc VLP vaccines in the future. The thesis also found that the addition of aluminium adjuvant would improve the humoral immune response while supressing the cellular immune response of chimeric HBc VLP vaccines. EBNA1-HBc VLP was less affected by the adjuvant on the immune response tendency compared with HCV core-HBc VLP. At last, long-term immunogenicity of two chimeric HBc VLPs were examined by evaluated the epitope specific memory T cells. Both HCV core-HBc VLP and EBAN1-HBc VLP showed good potential for long-term protection. With all above findings, chimeric adjuvant-free HBc VLP-based vaccine is promising to present different types of oncoviruses epitopes with high epitope-specific immune response and low risks. More epitopes targeting different oncoviruses could be presented by chimeric adjuvant-free HBc VLP platform for cancer treatment, and further computational protein modelling is helpful in the design and investigation of these novel chimeric HBc VLP-based vaccines.

Author dc:creator

• Zhang, Bingyang

Advisors dc:contributor.advisor

• Bi, Jingxiu
• Jiao, Yan
• Su, Zhigou

• Hepatitis B cor
• virus like particle
• protein purification
• protein characterization
• adjuvant-free
• molecular dynamic simulation

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/2440/130894

OAI identifier oai:identifier

oai:digital.library.adelaide.edu.au:2440/130894