Year : 2004 | Volume
: 1 | Issue : 1 | Page : 10--16
From Australia antigen to eradication programs
Baruch S Blumberg
Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia PA 19111, USA
Baruch S Blumberg
Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia PA 19111
|How to cite this article:|
Blumberg BS. From Australia antigen to eradication programs.Hep B Annual 2004;1:10-16
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Blumberg BS. From Australia antigen to eradication programs. Hep B Annual [serial online] 2004 [cited 2023 Jan 31 ];1:10-16
Available from: https://www.hepatitisbannual.org/text.asp?2004/1/1/10/27916
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 that, at least initially, appeared to be remote from the discovery of infectious agents. In this chapter, I will briefly describe the process that resulted in the discovery of the virus, the invention of the vaccine, and, in time, the initiation of the control programs. I will include an account of our research in India and discuss the contribution this may have made to the current prevention program.
As a medical student at Columbia University in New York City (1947-1951), working in the wards of large city hospitals (1951-1955) 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 the 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 Surinam in South America (1949), 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 what appeared to be the same conditions of exposure. Some of these differences could be ascribed to chance and culture, but some could also be a consequence of inherited biochemical differences between individuals. (These studies can be found in references 1 and 2 below.)
POLYMORPHISMS AND DISEASE
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 in different populations and also discovered several polymorphic systems that were previously unknown.
In 1960 we introduced a new technique to identify inherited variants. 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 multiple 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 lipoprotein polymorphisms has revealed susceptibility genes for certain cardiovascular disease and for Alzheimer's disease.)
AUSTRALIA ANTIGEN AND HEPATITIS B VIRUS
Since this line of investigation 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, Harvey Alter, Sam Visnich, and I found an antibody in a transfused hemophilia patient that was quite different from that of 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 US 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's Syndrome are at a high risk for a form of childhood leukemia; when tested 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 - and studies showed this to be so too - and later, the hypothesis that Au was part of a hepatitis virus. Subsequent isolation, electron microscopy, transmission and other studies were consistent with this hypothesis.
As early as 1908, McDonald had proposed that a virus might be implicated in the causation of liver disease, although the virus had not been detected or seen. MacCallum, in 1947, posited the existence of two different viruses : hepatitis A, transmitted by the fecal oral route, and hepatitis B, by blood. The immunologic and other characteristics of these postulated viruses were further investigated by Krugman, Sherlock, Prince, and many others. It appeared that the virus associated with Australia antigen that we had discovered 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 bloods were routinely screened in many countries. This led to a dramatic drop in post transfusion hepatitis due to HBV. Subsequently, HCV an additional cause of post-transfusion hepatitis was identified and testing for this agent has further reduced the toll of post-transfusion hepatitis.
OUR RESEARCH IN INDIA
I will pause briefly in the account of our research to discuss my scientific visits to India. In the mid-1960s, as part of a worldwide investigation of Australia antigen in leprosy we conducted an extensive study at the Central Leprosy Teaching and Research Institute at Chingleput, Tamal Nadu. We found that there was a much higher frequency of Hepatitis B carriers ("Australia antigen positive") in patients with lepromatous leprosy than those with tuberculoid leprosy. This confirmed studies that we had done in the Philippines and elsewhere. This finding focused our attention on the relation of chronic HBV infection to immune differences that are known to characterize the two polar forms of leprosy. That is, that the propensity of a person to become a carrier rather than develop antibody against the virus was associated with differences in the immune system. It also generated a genetic hypothesis that postulated the existence of one or more human polymorphic locii related to infection with both HBV and Hansen's bacillus (the etiologic agent of Hansen's disease). Individuals with a specific allele would, when infected, be more likely to become carriers of HBV rather than develop antibody against the surface antigen. They would also be more likely to develop the lepromatous than the tuberculoid form of the disease when infected with Hansen's bacillus. Recently, several such polymorphic locii have been identified. The concept has been broadened to include a large number of susceptibility locii for infectious agents in addition to HBV and Hansen's bacillus.
I served as the Raman Professor at the Indian Institute of Science in Bangalore, Karnataka from January 14 to April 12, 1986. During my tenure I visited many parts of India and many institutions where I lectured and conferred with colleagues on their research and clinical experience with hepatitis and other diseases. It was a very illuminating experience. There was a great interest in hepatitis and its consequences including primary cancer of the liver. I spoke and had discussions with many colleagues in India I traveled to Agra, Bangalore, Bombay, Cochin, Delhi, Hyderabad, Lucknow, Madras, Vellore, and many other locations. Part of my mission was to evaluate the state of hepatitis research, treatment, and prevention. I met government officials in Delhi as well as in Karnataka and elsewhere. I spoke with the then Prime Minister late Rajiv Gandhi on 20 January 1986 and discussed the scientific and medical issues. His knowledge of and understanding of the problem were impressive. On March 31, 1987, I sent a report to him entitled "Comments on the prevention of hepatitis B infection in India" that was also circulated to The First Principal Secretary, the Minister of Science and Technology, The Science attache to the US Embassy, The American Ambassador, and to academic and health scientists whom I had met during my stay (see Appendix). In the document I discussed a vaccination program for HBV, but also addressed broader public health matters. A basic issue was the widespread concerns about the supply of clean water and the disposal of human waste in urban and rural areas. The other points included were the testing of donor blood, the indigenous manufacture of reagents for hepatitis diagnosis and of disposal needles and other medical equipment. Recognizing that education is of primary importance, I recommended the establishment of high standard Schools of Public Health at the University level, to be associated with elite Indian academic and research institutions. I received acknowledgement of the receipt of my report and believe that it may have been considered in some of the subsequent decisions concerning the hepatitis prevention programs.
THE HEPATITIS B VACCINE
In addition to the whole virus, the blood of HBV carriers contained quantities of particles made up only of the surface antigen of HBV. Irving Millman and I recognized that extracting these particles could produce a vaccine. The appropriate experimental studies were performed, a patent obtained, and in 1975, a large pharmaceutical company (Merck) was licensed to develop and produce the vaccine. Szmuness and his colleagues subjected the vaccine to a rigorous field trial. By the early 1980s, it had been approved by the USA Food and Drug Administration. Subsequently, the vaccine was manufactured by the recombinant method. As of May 2003 vaccination programs were in place in 151 of the 192 (79%) national members of the WHO; HBV vaccine is now one of the most commonly used in the world.
Results have been very impressive. Studies have shown a dramatic drop in the incidence of carriers in the vaccine-impacted group. For example, in a large epidemiological study in Taiwan, the prevalence of carriers in the 1-2 year age group dropped from 10.7% in 1984 (before the program) to 1.5% in 1989 (after the program was in place). The investigators predict that, with the continuation of the program, the prevalence will decrease to 0.1% by 2010. Population studies in many other locations have shown similar dramatic drops. In Japan, the prevalence has dropped from 3% to about 0.3%; in the younger age group in Gambia, West Africa, from 10.0% to 0.6%. In Native Americans in Alaska, USA, the incidence of acute hepatitis B dropped from 215 cases/100,000 population before the vaccination program, to no reported cases in 1995!
HBV is a major cause of hepatocellular carcinoma (HCC), one of the most common and deadly cancers in the world. Worldwide, it is the third most common cause of death from cancer in males and the 7th most common cause in females. The effects of the vaccination program have been impressive. Dr. M. H. Chang and her colleagues in Taiwan did an extensive study of HCC in the young before and after the vaccination program was in place. The average annual incidence of HCC dropped from 0.7 per 100,000 population, in children 6-14 years of age, between 1981-1986 (before), to 0.57 per 100,000 between 1986 and 1990 (after), and to 0.36 between 1990 and 1994. Studies in other age groups confirmed these findings.
The implication is that one of the most common cancers in the world can be controlled by the use of a vaccine; HBV vaccine can be considered the first cancer vaccine. It is likely that other cancer-virus relations will be found, for example, papilloma virus and cancer of the cervix and Epstein-Barr virus and nasopharyngeal cancer, and that in time, it may be possible to prevent many common cancers by the use of vaccines.
These impressive results suggest that, with a rigorous worldwide prevention program it may be possible to eradicate the virus. This was considered more than a decade ago at a meeting in Geneva Switzerland entitled, The International Conference on Prospects for Eradication of Hepatitis B Virus. Vaccination, testing of donor blood, strict use of disposable needles and other medical equipment, and treatment of active cases could all contribute to effective control and, conceivably, eradication. The HBV Eradication Day at S.C.B. Medical School, Cuttack can contribute greatly to this program. I am very pleased to be associated with this ongoing project.
|1||Blumberg BS. Australia antigen and the biology of hepatitis B. Science 1977;197:17-25.|
|2||Blumberg BS. Hepatitis B, The hunt for a killer virus. Princeton University Press, Princeton, 2002. |
|3||Blumberg BS, Melartin L. Australia antigen and lepromatous leprosy. Studies in South India and elsewhere. Int J Leprosy 1970;38:60-67. |
|4||Blumberg BS. Proc. International Conference on Prospects for Eradication of Hepatitis B Virus. Vaccine 1990;8: Introduction p.S5;Conclusion p.S139.|