Hepatitis B – epidemics to vaccination

Tragedy to biotech, 1965-76

Hepatitis B virion model.  medicalgraphics.de

The first cases of dialysis-associated hepatitis were reported in 1965, killing a nurse, porter, and patient, and infecting several others in Manchester. The ‘Australia antigen’ was identified in Philadelphia in the same year, and the following year associated with hepatitis. A key observation was the new positivity of a lab worker at the same time as she developed hepatitis – presumably from the samples she was working with. The discovery and follow-up work (Blumberg 1977) led to a Nobel prize.

Hepatitis was soon identified in many renal units, peaking around 1970 with a devastating epidemic in Edinburgh that killed several members of staff. Not surprisingly this had a profound impact on renal units, and on attitudes to dialysis, which in the eyes of many was still in its uncertain early days as a treatment for end stage renal failure.

As tests for Australia Antigen (Hepatitis B Surface antigen, HBsAg) became available, hepatitis transmission by blood and blood products, sexual contact, and in childbirth, were discovered. Also its association with liver cancer. However vaccines were not perceived by pharmaceutical companies to be profitable at the time, and Hepatitis B was thought to be of only niche interest.

Vaccines from virus, 1981
Nevertheless, in addition to establishing tests, Blumberg himself working with Merck Pharmaceuticals began to purify nucleic-acid-free particles from the plasma of patients with hepatitis B, in order to make a vaccine. This was complex and expensive, but finally marketed in 1981 as Heptavax B. Its very high cost, and concerns about safety as it was made from human blood, led to low take-up. A similar vaccine, Hevac-B, was released in France by the Institut Pasteur, also in 1981.

Recombinant proteins become thinkable
Meanwhile the 1970s had seen the birth and astonishing development of the new science of recombinant DNA technology. This raised the possibility of synthesizing vaccine components as recombinant proteins. University research groups in San Francisco, Edinburgh, and Paris, and another initiative by Merck, made substantial progress.

Cloning and the birth of biotech
Researchers in San Francisco and Edinburgh sped their research by setting up joint biotechnology companies, a new concept, bringing in funding from external investors. Genentech was the first, in California in 1976. Biogen, in 1978, was a European collaboration in which Edinburgh’s Kenneth Murray was a key contributor, working with microbiologists with personal experience of the local hepatitis outbreak.

In 1979 the cloning and sequencing of large parts of Hepatitis B Virus DNA, and expression of its proteins in bacteria, were reported in Nature from Edinburgh, San Francisco and Paris. Turning this into an effective vaccine required a move from bacteria to fungal (San Francisco, Edinburgh) or mammalian (Paris) cells, and complex collaboration with established pharmaceutical companies.

First recombinant vaccines, 1986
Two vaccines produced in yeast were marketed in 1986. Recombivax by Merck, developed with a second San Francisco biotech, Chiron; and Engerix B by Smith Kline with Biogen. They were unexpectedly a runaway commercial success. These were only the third recombinant proteins to be marketed after Human Insulin and Growth Hormone. However the risks of hepatitis B were increasingly recognised, and the recombinant vaccines were perceived to be very safe as they did not depend on purification from infected patients.

Everyone a winner
Vaccination soon became standard for staff and then patients on dialysis units. We now almost never hear of hepatitis B contracted on renal units, despite treating infectious patients. The originating biotech companies did extraordinarily well. Kenneth Murray gave millions of pounds of his personal profit back to the University of Edinburgh, underwriting facilities and future research.

The illustration of the hepatitis virion is from medicalgraphics.de (CC-BY)
This article would not have been possible without the research work of Farah Huzair and Steve Sturdy (University of Edinburgh) – or the original work of Kenneth Murray in Edinburgh in the early days of modern molecular biology.
A version of this post appears in the Journal of Kidney Care

Blumberg BS, 2003 . Australia antigen and the biology of hepatitis B. Science 197:17-25. A fascinating read. Link is to the Nobel lecture, as the Science version is behind a paywall.
Huzair F, Sturdy S, 2017. Biotechnology and the transformation of vaccine innovation: the case of the hepatitis B vaccines 1968-2000. Studies in history and philosophy of biological and biomedical sciences 64:11-21 (open access)

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