Development and application of viral whole genome sequencing for Severe Acute Respiratory Syndrome Coronavirus 2 and Hepatitis B virus

During my DPhil, I set out to develop and apply sequencing techniques to Hepatitis B Virus (HBV), a pathogen which causes over a million deaths a year and for which molecular epidemiology is poorly resolved. However, this work was eclipsed by the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which rapidly became the world’s biggest viral killer. I rapidly applied the tools and approaches planned for endemic HBV to tackle pandemic SARS-CoV, implementing whole genome sequencing (WGS) techniques as a translational tool. I established SARS-CoV-2 WGS in my local hospital and explored how sequencing can help track the spread of SARS-CoV-2 in healthcare settings. By combining WGS with epidemiological data, I showed that most hospital-acquired infections result from superspreading events, providing insights to inform infection prevention control (IPC) practice. Returning to work on HBV, I optimised WGS tools, developing methods for HBV WGS, including the easy to use, open-access HEP-TILE protocol. To explore the clinical need for sequencing, I conducted a systematic review and meta-analysis to determine the epidemiology of drug resistance, demonstrating the high genetic barrier for tenofovir resistance compared to entecavir. Using HEP-TILE, I generated HBV genomes from adults with CHB in Uganda, Kenya, South Africa and the Democratic Republic of Congo. I described new HBV strains including recombinants and established the prevalence of resistance associated mutations (RAMs). I also discovered a potential link between a specific HBV polymorphism (S13T) and liver disease (fibrosis/cirrhosis). To further develop insights into HBV treatment, I explored the application of HBV treatment guidelines in Uganda, highlighting the limitations of current non-invasive tests. My thesis demonstrates how viral WGS can be applied to different viruses to enhance public health management. Globally, sequencing expertise and infrastructure gained during the COVID-19 pandemic can be applied to HBV, to support progress towards 2030 elimination targets for viral hepatitis.