Imagine the sense of accomplishment one would feel for preventing the death of millions of people by discovering something completely unprecedented. Imagine decreasing the incidence of a potentially debilitating disease from 15% to 1%, as was done in Taiwan, and practically eliminating it in others, as in the entire state of Alaska. Impossible right? Well, these are the exact noble deeds of Dr. Baruch Blumberg, the 1976 Noble Prize winner for the discovery of the hepatitis B vaccine. After receiving a doctorate in biochemistry at Oxford University, Blumberg began his worldwide quest to understand the phenomena of genetic polymorphisms; the occurence in a population of more than one form of a gene at a frequency greater than mutation rate (1%). A perfect example of a polymorphism is that of sickle-cell anemia; Blumberg was interested in why or how certain selective pressures influenced the existence of the heterozygote (HbS/HbA) versus the dominant (HbA/HbA) and recessive (HbS/ HbS) phenotypes. He discovered the immense diverity of antigenic variants in the blood through isolation of the proteins by starch-gel electrophoresis and double diffusion in agar gel. One of the most fantastic of his findings was that of an antibody, in a hemophiliac who had received many blood transfusions, that reacted with the serum of an Australian Aborigine. This antigen in the Aborigine (Au) was found in a rather indirect fashion through electron microscopy and epidemiological studies to be the surface antigen of the hepatitis B virus (HBsAg). Because of the rapid association made between hepatitis and Au, the government instigated a mandatory testing of blood banks with Blumberg's Au test, and the incidence of post-trasfusion hepatitis declined from 18% to 6%. Blumberg continued the studies regarding the association between Au and hepatitis while at the National Institutes of Health and later the Fox Chase Cancer Center in Philadelphia.
In 1969, Blumberg and his colleagues realized the potential uses of the multitude of HBsAg particles in individuals who were carriers of the virus. It turned out that noninfectious HBsAg (without the core antigen which contains the infectious nucleic acid) could be isolated from the serum of these asymptomatic carriers. These antigens were subsequently injected into millions of people to provide pre-prophylaxis against the hepatitis B virus as the vaccinees developed protective anti-HbsAg antibodies. This method of serum isolation of the actual noninfectious antigen for vaccine usage was a novel one; prior to this date, vaccines were created using a live attenuated or killed form of the virus.
As creators of this web page, we decided that an interview with such a prominant figure in the scientific community would be more than well warranted. Baruch Blumberg is currently a visiting Professor in the Human Biology department at Stanford University and this interview was conducted on the Stanford campus on March 1998. The questions asked delved into the most intellectually stimulating and profound implications of Dr. Blumberg's discovery and in turn, his responses, like all in science, raise even more questions that merit further inquiry by future researchers.
Note: The responses are not varbatim but simply a paraphrased summary of Dr. Blumberg's main ideas. More background information has also been added when necessary.
Questions 1: How and where is your vaccine being used currently?
Answer: Dr. Blumberg relayed that soon after the date of the widespread availability of his vaccine in 1982, various laboratories in the U.S. and Europe created recombinant forms that became mainstream. However, his vaccine is still being used in China, Korea and Italy where commercially produced recombinant vaccines are not readily available and where carriers of the virus are numerous.
Question 2. Do you believe that universal vaccination and/or eradication of hepatitis B is feasible and practical?
Answer: Dr. Blumberg indicated that 80 countries with a high prevalence of HBV already have universal compulsory childhood vaccination programs. In Japan, the identification of "carrier" pregnant women is carried out so that the neonate can be vaccinated. Dr. Blumberg attended an International Conference in Geneva in 1989, where the Feasability of Eradication of hepatitis B was the main topic of discussion. They consolidated much data from each country, such as the total number of carriers of the virus. The members of the conference left believing that the eradication of the hepatitis B virus was surely theoretically possible, however, the lack of funding from the government coupled with the low motivation of countries with the finances to carry out the project (US and Europe; where the prevalence and severity of HBV is much less) proved to be insurmountable barriers.
Question 3. Why do you think the efforts to eradicate HIV are much greater than those for HBV?
Answer: Blumberg showed his frustration with the response to this question since he believes that more should be done to help the 350 million people still infected with HBV worldwide, especially since; the mutation rate for HBV is much less than for HIV making it a much easier target for therapy and vaccination; hepatitis B has killed more people worldwide than AIDS and continues to be one of the top killers; and HBV is much more infectious than HIV even though it is transmitted through the same routes. Blumberg postulates that the reason for the AIDS hysteria is because when HIV was first encountered in the early 80's, it was immediately associated with a probability of death, if infected, near 100%. Hepatitis B, however, is manifested often in its acute form, that has a roughly 90% recovery rate (the other 10% reach a state of chronic hepatitis from the acute infection and this can result in death--often known as "Fulminant" hepatitis). Additionally, the symptoms and diseases of chronic hepatitis, such as liver cancer, usually develop many years after infection and initially they were not associated with hepatitis B infection. There is also very little public awareness about the hepatitis B virus due to the lack of funding for education (which is a small fraction of the funding for AIDS).
Question 4. Do you think that the prevention of Hepatitis B related Hepatocellular carcinoma is a strong enough incentive for universal vaccination or eradication?
Answer: Dr. Blumberg relayed that the association between liver cancer and hepatitis is without a doubt increasing eradication efforts in China where the Chinese Medical Association understands the direct link between the two in their country. Blumberg believes that if publicity were to get across that the hepatitis B vaccine was, in fact, the only known cancer vaccine , that eyes and ears would open to eradication efforts. He stated that the incidence of Hepatocellular carcinoma due to hepatitis B was second only to the incidence of lung cancer due to cigarette smoking.
Question 5. What are the current treatments that are widely used for Hepatitis B infection?
Answer: Blumberg indicated his hopes for a new anti-viral that may prevent the spread of HBV infection from cell to cell. The drug inhibits the terminal glycosylation at one of the three glyosylation sites on the M protein on the hepatitis B surface antigen. This in turn inhibits the folding of the protein and the change in tertiary structure disturbs the assembly of the virus. Thus, the virus is still allowed to replicate but can not be exported from the hepatocyte. The drug was tested in woodchucks afflicted with woodchuck hepatitis virus that has >70% homology with the hepatitis B virus and it was observed that there was a significant decrease in viral load.
Other options for treatment he mentioned include nucleoside analogs, protease inhibitors, interferon, and post-prophylaxis vaccination.
Question 6. Why is it that certain individuals respond differently to infection/exposure with Hepatitis B; i.e. acute vs. chronic vs. asymptomatic carrier cases?
Answer: The answer to this question stems back to Blumberg's polymorphism studies that eventually led him to the discovery of the vaccine. He explained that six different polymorphic loci have been identified that are associated with an inherited susceptibility to becoming an asymptomatic carrier after exposure. (The Au or Australian antigen was hypothesized by Blumberg as a gene that increased one's susceptibility to becoming an aymptomatic carrier, however, the actual gene has not been elucidated). For example, studies postulate that if an individual has the specific MHCII haplotype DRB1*1302, then he/she is less likely to become a chronic carrier with symptoms; or if the individual has the G308 type of the TNF gene, then he/she is more likely to develop the diseases associated with chronic hepatitis. Other loci include the VDR (Vitamin Receptor Gene) and the IL-10 promoter genes. An interesting implication of these findings serves to complicate hopes of gene therapy for any disease. If medicine were to act and eliminate any of these loci that serve to increase risk of chronic carrier state then one or another beneficial aspect of the gene will also go with it. For example, the recessive form of the Vitamin D receptor gene that makes one less susceptible for HBV and cerebral malaria also makes one more susceptible for osteoperosis. The point is that pleiotropy, the effect of one gene on many traits, is a powerful phenomena that can not be overlooked or underestimated. Also, just because one gene may slightly increase risk, does not warrant the identification of that gene as deleterious. "Biology is not destiny" says Blumberg.
Question 7. What are the cofactors that can increase one's risk for developing chronic diseases vs. the carrier state?
Answer: Blumberg explains that there are many environmental cofactors that increase one's susceptiibility to the development of cancer from hepatitis B. These include Aflatoxin and Arsenic. Other extremely interesting physiological and possibly genetic cofactors are high body iron levels and gender. Surprisingly enough, Blumberg relayed to us that the sex ratio (male/female) is effected by the HBV state of the parents. In a study conducted in Greece, if either parent was a carrier then the ratio was significantly higher. When parents have anti-HBsAg antibodies then the ratio actually decreases (that is, the parents actually have fewer male offspring). Males have also been found to be carriers moreso than female in general. This holds an interesting irony in countries like China where there is a cultural pressure to have males and there is also a high prevalence of the carrier state; if one parent is a carrier then the chance of having a girl decreases and thus, they are more likely to have a boy. It is almost as if biology is facilitating their desired sociology.
Question 8. Do you believe that insects can transmit hepatitis B?
Answer: Blumberg stated that there have been scientifically sound studies that support a high infection rate in mosquitos and bedbugs. In one study in Uganda and Ethiopia, greater than 50% of bedbugs were infected. There have been no reported cases of these insects ever infecting humans, however. One researcher did a follow up study in Gambia and did not find a difference in transmission between those areas with a high prevalence of infected insects and areas with hardly any infected insects at all. However, Blumberg stated that the researcher never published these results. As a side note Blumberg stated that, "Often times, unpublished results are just as important as published". Many will still wonder whether arthropod transmission of hepatitis B has ever been studied since there is barely anything in the literature about the negative association between the two. Blumberg is still keeping an open-mind about the possibility of insect transmission, however, due to the fact that there are many unknown causes of hepatitis B transmission today.
We would like to thank Dr. Baruch Blumberg for his kindness, assistance and cooperation in making this interview a more than pleasurable as well as memorable experience.
We would also like to thank Professor Robert Siegel for giving us the unique opportunity to construct this web page; which has been a wonderful and forever useful learning experience.