A UNSW researcher studying the history of hepatitis B treatment uncovers the prehistory of COVID-19's famous RAT and PCR tests – and an Australian connection.
As the coronavirus unfolded in 2020, and citizens around the world took RAT tests to detect infection and PCR tests were used to quickly identify viral variants, Dr Michelle Bootcov realised her PhD on the history of hepatitis B was also a history of the medical discoveries underlying the world's ability to respond to the pandemic.
Bootcov's research provides a unique window into the transformation of virology in the late 20th century.
"Both the rapid antigen tests (RAT tests) and the variant sequence analysis (PCR tests) that became common knowledge to the general public during COVID, had historical antecedents in hepatitis B research of the 1960s to 1990s," says Dr Bootcov.
Hepatitis B was a medical emergency in the 1960s, because the increasing use of blood transfusion was accompanied by an increasing incidence of post-transfusion hepatitis.
"And although the incidence was low in Australia, elsewhere it was as high as 20 to 50%, particularly for multi-unit transfusions from paid donors" she says.
Hepatitis B infection was frequently asymptomatic, and at that time there was no way to prevent transmission through rapid detection of the virus in donor blood.
"In fact, there was no way to rapidly diagnose any viral infection. Laboratory diagnosis took so long that the saying was the patients were dead or discharged from hospital before the results came back," says Dr Bootcov.
Without a detection test for the virus, the extent of hepatitis B infection was unknown, and only identified in asymptomatic donors when their blood recipients developed post-transfusion hepatitis.
The precursor to the RAT test
After decades of futile research by virologists and haematologists, in the late 1960s there was a breakthrough – a test that could detect an antigen associated with the virus. The presence of that antigen in blood indicated hepatitis B infection.
Improvements to those antigen testing techniques soon reduced the time-frame of results to mere hours, an essential requirement for the use of donor blood products.
These were the first rapid antigen tests for mass screening of a virus in the world.
"This discovery transformed blood transfusion services' management of donor blood, and the high demand for those tests fuelled the establishment of the viral diagnostics industry," says Dr Bootcov.
Reliable testing also revealed the true extent of hepatitis B infection (in some countries it was hyper-endemic.
The improvements in blood donor testing paved the way for blood management when HIV/AIDS emerged in the 1980s.
A serendipitous link to Australia
Those first rapid antigen tests for hepatitis detected a protein on the surface of the hepatitis B virus. Initially it was called the Australia antigen because the blood in which it was discovered came from an Indigenous community in Central Australia. It was sent as an experimental sample from Perth-based geneticist Robert Kirk to Baruch Blumberg, a geneticist on the east coast of the US, where the novel antigen was identified and at first thought to be a human protein.
"At that time geneticists across the globe were seeking novel blood protein variants for use in the understanding of human inheritance, difference and migration patterns. Genes (which code for proteins) could not be interrogated directly for that purpose, because DNA sequencing techniques did not yet exist," says Dr Bootcov.
"The Australia antigen was serendipitously identified in the mid-1960s through genetics enquiry. Within a few years, following a series of research twists and turns and two hepatitis B transmission events that caught the attention of alert scientists, it became clear that the Australia antigen was not the product of a human gene, it was a viral protein," says Dr Bootcov.
The method used in genetics to identify the Australia antigen became the method by which hepatitis B infection could be detected rapidly in donor blood.
Hepatitis B was also amongst the first viruses to be fully sequenced and its variants analysed. A type of analysis that became familiar across the world during the COVID-19 pandemic when Delta, Omicron, and other variants were surveilled, traced and tracked.
The COVID-19 connection
"Looking back to December 2019 and the emergence of an unfamiliar pneumonia in Wuhan, China, it is amazing to recall the speed with which the coronavirus was isolated, and its genome fully sequenced and published," says Dr Bootcov.
Not long after that, widespread, accurate and fast pathology screening tests were implemented to proactively identify cases of SARS-CoV-2. Rapid antigen tests could be conducted at home within 15 minutes, PCR and sequencing was so fast that a result could be texted within hours, and viral variant transmission tracked in real time.
"Few paused to marvel at the magnitude of that scientific possibility," says Dr Bootcov.
"It had come to be expected. And much of it was thanks to the technologies that emerged through research that began with the hepatitis B virus and its Australia antigen."
