Identifying epitopes associated with reduced vaccine efficacy
The HBV surface antigen (HBsAg) contains the major virus neutralisation domain and forms the basis of the HBV vaccine. HBsAg is a conformationally dynamic protein, and the HBsAg profile is vulnerable to structural alterations applied by divergent strains or variants (potential escape variants), and therapeutic or immune pressure. Stephen’s group has developed a novel immunoassay to map HBsAg fingerprint using monoclonal antibody panels targeting HBsAg epitope domains. The clinical and diagnostic application of this novel HBsAg fingerprinting assay aims to define and report HBV vaccine efficacy and escape, and to identify novel epitopes targets for therapeutic vaccine development.
Identifying predictive biomarkers of treatment response in the setting of antiviral therapy
HBsAg clearance and seroconversion to anti-HBs antibody is rarely achieved naturally or on-treatment, but represents a functional cure for chronic HBV infection. Few biomarkers reliably predict this outcome. Stephen’s group has developed novel assay that determines the HBsAg profile or fingerprint, which is influenced by immune (or antibody) recovery during treatment, to identify and report an HBsAg clearance profile (CP) predictive of surface protein clearance on antiviral therapy. In addition, they have developed a range of virological, serological, and biochemical assays to isolate and identify potent clearance anti-HBs antibodies and characterise the anti-HBs response, target specificity and mechanism of viral clearance.
Identifying mechanisms by which HBV causes liver cancer as well as novel biomarkers
Infection of liver cells with HBV can ultimately lead to liver cancer. The vast majority of HBV related liver cancers also harbour abnormally active Wnt signalling. However, our understanding of the interplay between these two oncogenic drivers of liver cancer is not well-understood. This is primarily because HBV only infects normal human liver cells (hepatocytes). Thus, the study of HBV entry into, and natural infection of, human hepatocytes has been hampered by a lack of suitable models. Elizabeth’s group recently established an in vitro mini-liver organoid culture system that supports HBV infection and investigates the oncogenic interplay with Wnt.
Characterising novel strains of HBV in culturally and linguistically diverse populations (CALD)
Stephen’s group have been characterising novel strains of HBV isolated from culturally and linguistically diverse populations including Indigenous Australians and African immigrants. The HBV isolated from Indigenous Australians from the Northern Territory is a rare genotype unique to Australia’s Indigenous population, which has been associated with vaccine escape and advanced liver disease. Stephen’s group is expanding these studies to Northern Queensland and the Torres Strait Islands. In Melbourne, they are also studying chronic HBV infection in African immigrants. A major strength of these studies is the collaborations they have with clinicians working in the communities, resulting in ethically and effectively engaged communities.
Targeting different stages of the HBV life cycle to develop HBV cure strategies
Hepatitis B Virus (HBV) exists as nine major genotypes and over 40 subtypes globally, with natural history, disease progression and treatment response varying markedly for many genotypes and subtypes. The HBeAg is critical for establishment of chronic infection and the HBx protein is required for transcription of viral cccDNA, a major impediment to HBV cure as it is not targeted by current antiviral therapies. Peter’s team is interrogating the role of the HBeAg and HBx proteins in HBV infection, replication and cccDNA expression, to assess their feasibility as a novel therapeutic targets that may lead to HBV cure across genotypes.
Professor Stephen Locarnini
(03) 9342 9637 | [email protected]
Professor Stephen Locarnini is a medical virologist whose interest is the molecular pathogenesis of the hepatitis viruses. He is Divisional Head, Research and Molecular Development at the Victorian Infectious Diseases Reference Laboratory (VIDRL) where he has worked since 1989. He was Director of Laboratory Services from 1990 to 1993 and the Founding Director of VIDRL in 1993. He is also Director of the World Health Organization (WHO) Regional Reference Laboratory for Hepatitis B.