The discovery of the hepatitis B virus and the invention of the vaccine: A scientific memoir

The hypothesis had been supported and had resulted in interesting findings; we continued to look for additional antibodies in transfused patients to reveal other polymorphisms.We were not disappointed. In 1963, Dr Harvey Alter, Sam Visnich, and I found an antibody in a transfused hemophilia patient that was quite different than the low density lipoprotein polymorphism. Since it initially reacted with the serum of an Australian we named it the ‘Australia’ antigen (Au) and set about to determine what it was. Population studies showed that the antigen was rare in normal USA populations, but common in patients with leukemia. (It was also common in populations in Asia and Africa.) We hypothesized that it might also be common in patients at risk of developing leukemia. Patients with Down syndrome are at high risk for a form of childhood leukemia; they also had a high prevalence of Au. We followed these patients over time and found that one of them who initially had been scored as negative subsequently developed Au coincident with the onset of asymptomatic hepatitis. This observation generated the hypothesis that Au was associated with clinical hepatitis—studies showed this to be so—and later, the hypothesis that Au was part of a hepatitis virus. Subsequent isolation, electron microscopy (EM), transmission, and other studies were consistent with this hypothesis. The whole virus was later identified by EM by Dane et al. As early as 1908, McDonald had proposed that a virus might be implicated in the causation of liver disease. MacCullum, in 1947, posited the existence of two different viruses; hepatitis A, transmitted by the fecal oral route, and hepatitis B, by blood.The immunological and other characteristics of these viruses was further investigated by Krugman, Sherlock, Prince, and others. It appeared that the virus associated with the Australia antigen was most similar to the previously hypothesized hepatitis B virus and it has been called HBV since the 1970s. The discovery of the virus and the methods for its detection which resulted from our research led to the testing of donor blood for the detection of occult carriers of HBV. By the late 1970s, sensitive tests had been developed and donor bloods were routinely screened in most industrialized countries. This led to a dramatic drop in post transfusion hepatitis due to HBV, although hepatitis due to other viruses still persisted. The discovery of the hepatitis B virus and the subsequent invention of the vaccine came about as a result of basic scientific studies in an area of research which, at least initially, appeared to be remote from the discovery of an infectious agent. As a medical student working in the wards of a large city hospital and, later, while providing clinical care and doing epidemiological research in the tropics, I had been impressed with the selective nature of disease risk. There were striking differences in response among individuals who were at apparently equal exposure to disease-causing agents. For example, many were exposed to Tuberculosis bacillus, but only a few succumbed to the disease and of those who became ill, some recovered rapidly and others did not. Or, as I observed in Suriname in South America, there was a striking difference in the prevalence of the parasite Wuchereria bancrofti (the cause of elephantiasis) between populations of different geographic origin living under the same conditions of exposure. Some of these differences could be ascribed to chance, but some could also be a consequence of inherited differences between individuals. The opportunity to study inherited biochemical differences in populations arose in 1957. While I was at Oxford University my colleague, Anthony Allison, and I began to study common inherited differences in human and animal serum proteins—protein polymorphisms—as revealed by small differences in mobility in the newly-invented starch gel electrophoresis. We studied the distribution of polymorphic variants and also discovered several that were previously unknown. In 1960 we introduced a new technique.We reasoned that if there were many serum protein polymorphisms then some might be antigenic and patients who received many blood transfusions could develop antibodies against variants that they themselves had not inherited or acquired. We soon found an antibody in a multiply transfused patient—Mr C de B—that reacted with the serum of some individuals in the population, but not others. This trait was inherited as a simple autosomal dominant; it was a consequence of a genetic polymorphism of the serum low density lipoproteins. (Subsequent work, by others, on the lipoprotein polymorphism has revealed susceptibility genes for certain cardiovascular disease and for Alzheimer’s Disease). The discovery of the hepatitis B virus and the invention of the vaccine: A scientific memoir