Epstein-Barr Virus and Hepatitis B Virus

Epstein-Barr Virus

While the early discoveries of Ellerman and Bang and Rous might have predicted that retroviruses would be found associated with human cancers, in fact it was a herpesvirus that was the first viral agent implicated in a human cancer.  This was what was called the Epstein-Barr virus – now Human herpesvirus 4 – that was discovered in 1964 by Michael Epstein, Bert Achong and Yvonne Barr in specimens from a  Burkitt lymphoma patient sent from Uganda by the surgeon Denis Burkitt.  The virus was later implicated in infectious mononucleosis or glandular fever, also known as the “kissing disease” or because it tends to get spread around by intimate contact between college students.

A human herpesvirus. Copyright Linda M Stannard

The virus is carried by up to 95% of adults worldwide, after mainly asymptomatic infections as children.  It is implicated in causing over 95% of nasopharyngeal carcinomas, nearly 50% of Hodgkin lymphoma, and about 10% of gastric carcinomas – for a total of nearly 200 000 cancers worldwide per year.  There is still no vaccine, although candidates are in clinical trial.

Hepatitis B virus

The next virus to be definitively linked to a human cancer was Hepatitis B virus (HBV), that had been discovered more or less accidentally during serological studies in the 1960s by Baruch Blumberg and colleagues.  However, a transmissible agent had been implicated in “serum hepatitis” as early as 1885, when A Lurman showed that contaminated lymph (serum) was to blame for an outbreak in a shipyard in Bremen after a smallpox prevention exercise.  Subsequently, reuse of hypodermic needles first introduced in 1909 was shown to be responsible for spreading the disease.

Blumberg’s “initial discoveries were based primarily on epidemiologic, clinical, and serological observations”; however, by 1968 the “Australia antigen” was seen to consist of 22 nm empty particles, now known to be composed of capsid protein or “surface antigen”, and by 1970 a 42 nm DNA-containing “Dane particle” was found which is now known to be the virion.  Blumberg had by 1972 patented a vaccine derived by purification of 22 nm particles composed of HBV surface antigen (HBsAg) from donor blood, a process pioneered by Maurice Hilleman.  By 1975 Blumberg and others had also implicated HBV in the causation of primary hepatic carcinoma, now known as hepatocellular carcinoma (HCC) and a serious complication of chronic infection with HBV, especially if acquired in early life.  The vaccine was licenced for use in 1982, meaning it was the first anti-cancer vaccine, and the first viral subunit vaccine.  Blumberg shared the 1976 Nobel Prize in Physiology or Medicine with D Carleton Gajdusek – who described the first prion-caused diseases – for “…their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases”.

By 1979 the whole HBV genome had been cloned and sequenced, and molecular biology studies could start in earnest. A recombinant HBsAg produced in yeast was subsequently licenced in 1986, and has supplanted the earlier one.  It is being used in a many countries as part of the EPI (Extended Programme of Immunisation) bundle given to infants, as there is more risk of chronic infection the younger the person is that is infected.  Given that upwards of 2 billion people have been infected, and the over 300 million people that are chronically infected with HBV have a 15-25% risk of dying prematurely from HBV-related causes, there is the potential to make a very significant impact on liver disease.

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Tags: Epstein-Barr, hepatitis B, herpesvirus