3. Electronic Theses and Dissertations (ETDs) - All submissions

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Author: search.filters.author.Lamb, CamillaSubject: search.filters.subject.Carcinoma, Hepatocellular

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    Development of an mRNA vaccination strategy for the prevention and treatment of HBV infection
    (2017) Lamb, Camilla
    Persistent HBV infection carries an elevated risk of developing cirrhosis and hepatocellular carcinoma (HCC). Infection is preventable by immunisation with a recombinant protein vaccine encompassing the major surface antigen (HBsAg) of Hepatitis B virus (HBV). The vaccine is globally administered resulting in a notable decrease in global carrier rates. However, some recipients (5-10%) remain as hypo- or non-responders associated with minimal to no protective antibody levels. HBV-specific DNA-vaccines have demonstrated potential for induction of potent antibody responses and target-specific activation of cellular immunity with purported application in chronic HBV infection (CHB) treatment. Furthermore, in situ production of HBsAg allows for inclusion of neutralising and cross-specific preS epitopes absent from the current vaccine. Immunisation with mRNA accompanies a superior safety profile and offers several other advantages over DNA, but no such vaccine targeting HBV exists. To develop an anti-HBV mRNA-based vaccine, vectors engineered for mRNA production were constructed. From the production vectors, LHBs (large HBsAg) and SHBs (small or major HBsAg) mRNA was synthesised by in vitro transcription using phage T7 polymerase, and translated in transfected cells to produce detectable LHBs and SHBs. SHBs was readily secreted while LHBs was retained intracellularly. This investigation constitutes a preliminary step towards the preclinical development of an anti-HBV mRNA-based prophylactic and therapeutic vaccine formulation and has provided proof-of-principle that LHBs encompassing preS epitopes is expressible in situ from synthetic mRNA transcripts. Further developments will include modification of the mRNA synthesis protocol to comply with GMP regulations and functional testing of the vaccine candidate in appropriate animal models. Keywords: HBV, HCC, HBsAg, preS, DNA-vaccines, CHB, mRNA-based vaccine
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