Andersson Group - Occult hepatitis B virus infection (OBI) in people who donate blood: virology, immunology and liver health (OPAL)

ABOUT THE RESEARCH

Occult hepatitis B virus infection (OBI) is an important and challenging health problem because of its association with transfusion-transmitted infection and an elevated risk of hepatocellular carcinoma (HCC). OBI is defined as the presence of replication competent hepatitis B virus (HBV) DNA in the liver or blood of individuals who have tested negative for hepatitis B surface antigen (HBsAg). For the purposes of blood donor screening and this research proposal, the definition is narrowed to those individuals who have serological evidence of past HBV infection (anti-HBc positivity) with detectable levels of HBV DNA in their peripheral blood in the absence of detectable HBsAg. Individuals with OBI may transmit their infection by transfusion. An estimated 8-29% of recipients of blood from donors with OBI, become infected with HBV. Current evidence indicates that OBI prevalence in blood donors worldwide varies from 0.06% to 12.0%. The real-world figure may be higher than this, considering the limited sensitivity of most assays for HBV DNA.

The natural history of OBI is not well understood. HBsAg may become negative following HBV infection resolution (where viral load is typically less than 200 IU/mL), or there may be variants of HBsAg (S-escape mutations) or pre-S1/S2 variants that preclude HBsAg recognition.

OBI is challenging to diagnose; while cases are anti-HBc positive, detection of often extremely low levels of virus requires highly sensitive PCR assays for detection;  observations of several transfusion transmitted infections of HBV from the OBI donors that were missed on standard HBV screening prompted the UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) to advise including anti-HBc screening for all donors. This has been implemented by all UK blood services since April 2022. Whilst this is an important strategy to identify potentially infectious donations that were previously missed, it has highlighted major deficits in our understanding of this condition and uncertainty in clinical management. 

The UK blood services now exclude all anti-HBc positive donors, irrespective of the presence/absence of HBV DNA or other HBV markers, which has led to considerable donor loss - the majority of whom are not infectious. An additional problem with this approach is that since the risk of past exposure to HBV infection is more common in ethnic minority groups, this results in exclusion of highly valuable donors with rarer blood types.  

OBI donors are known to reactivate with detectable HBV DNA in blood sporadically, which often remains below the cut-off used to detect HBV DNA in blood donation screening. It is not currently possible to identify which anti-HBc positive donors may be at greater risk of transmission. The identification of specific biomarkers that may be predictive of those at risk would be extremely valuable as a means to selectively exclude high risk donors without excluding those who pose no transmission risk. 

Another major uncertainty highlighted by the donor screening programme is how to advise and clinically manage those with an OBI diagnosis; for example, there is now increasing evidence for its association with risk of HCC. Screening donors without any evidence-based guidance on whether or how to follow these cases is problematic. Therefore, data are urgently needed to address questions related to liver health and risk of HCC in this group of donors. 

This study will be based at NDCLS with close collaboration with the University of Oxford Blood Transfusion and Transplantation Transmitted Infections Research Unit which is part of the ‘Genomics to Enhance Microbiology Screening’ (GEMS) project (https://www.medsci.ox.ac.uk/about-us/who-we-are/departments-networks-clinical-trial-units/networks/blood-and-transplant-research-units/genomics-to-enhance-microbiology-screening) and colleagues at the Peter Medawar Building for Pathogen Research.

Additional supervision may be provided by Professor Michael Pavlides, Dr Azim Ansari and Dr Heli Harvala.

TRAINING OPPORTUNITIES

This project will give the successful candidate opportunity to develop expertise in techniques to interrogate virus structure, molecular diversity and diagnostic methods. There will be opportunity to develop expertise in techniques to better understand the interplay between the virus and the host – using exome sequencing, epigenetics, transcriptomics and proteomics. High throughput single-cell RNA sequencing technologies will be used to enable genome wide transcriptomic profiling of single cells within complex cellular mixtures allowing direct investigation of local immune responses.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

 As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

PUBLICATIONS