The world's first genetically engineered vaccine against a human disease--Hepatitis B--is considered one of biotechnology's greatest triumphs. The achievement stands on the shoulders of pioneering work by UW genetics professor Benjamin Hall and then-postdoctoral researcher Gustav Ammerer to develop genetic engineering techniques using yeast cultures to produce proteins of interest.
Hepatitis B is one of the world's most common blood-borne viruses. It infects some 200,000 people per year in the U.S. alone. The virus is one hundred times more contagious than the HIV virus; like HIV, it is transmitted through blood and sexual contact and can be transmitted from mother to child at birth. The virus can exist in the bloodstream of a carrier for an entire lifetime. It is estimated that about 300 million people worldwide are carriers, of whom about 25% will die from cirrhosis or cancer of the liver brought on by the disease. (see Epidemiology of Hepatitis B: Form Carrier to Cancer)
Conventional hepatitis vaccines made from the blood of people infected with the virus were beset by two major disadvantages. Although steps to process the blood were believed to inactivate any live hepatitis virus present, there still was a possibility that the derived blood product might contain new and undetected viruses. Secondly, it was impossible to get enough blood plasma to satisfy the demand for vaccine. Genetic engineering techniques held promise, but early attempts to make the bacterium Escherichia coli produce a suitable vaccine were unsuccessful--the E. coli carrying the key viral gene just wouldn't grow.
Ironically, Hall and colleagues did not set out to develop a Hepatitis B vaccine. In the late 1970s and early 80s, they were studying the basic mechanisms by which yeast cells read and act upon the genetic instructions encoded in their own DNA. Genetically engineered production of certain human proteins had been achieved in E. coli, but at that time no one had yet been able to express a foreign protein in yeast. There were reasons to want to do so besides intellectual curiosity.
First of all, yeast culture techniques were very well-known; humans have used yeast to produce bread, beer, and wine by fermentation for some 10,000 years. That tradition and the practical knowledge of yeast culture techniques would be very useful in coaxing genetically engineered yeast organisms to grow. Furthermore, since yeasts, like humans, are advanced organisms with an organized cell nucleus and an extensive system of cytoplasmic membranes and specialty organelles, they might be expected not only to decode mammalian genes more easily than E. coli and to synthesize and activate proteins the way mammals do; they might also be more likely than E. coli to survive the process and grow under those conditions. That feature would be important in producing human proteins with therapeutic value such as insulin or growth hormones.
Together with scientists from Genentech, Hall and Ammerer announced in February, 1981 their successful experiments on production of human interferon in yeast. At that time, interferon was considered to have great potential as an anti-cancer drug. Although that promise has not been borne out, excellent assays for interferon were available at Genentech, enabling the UW researchers to verify that their system had made a human protein in yeast.
Within one week of that public announcement, Hall was approached by groups wanting to express the surface antigen protein of hepatitis B virus. These strange and harmless protein particles form an empty shell, a virus "overcoat." These "overcoats" inadvertently produced by the virus in enormous quantities cannot infect cells because they lack DNA, yet the body perceives them as dangerous and mounts an immune response to them. The strategy was to get yeast to express these surface antigens, the major constituent of the overcoats, thereby producing a vaccine for Hepatitis B. With support from the Virology Research Laboratories of Merck & Co., Hall and Ammerer began a collaborative project with William Rutter and Pablo Valenzuela of the University of California to produce in yeast a vaccine against Hepatitis B.
Hall and Ammerer fused a segment of viral DNA specifying the surface antigen to the control elements of a yeast gene. When they transferred these hybrid genes into yeast cells, the resulting cultures produced Hepatitis B surface antigen. Serendipitously, these protein building blocks were found to clump together into the immunity-producing overcoat particles. With that observation, the key to a safe and effective vaccine was in hand.
After appropriate testing, the Merck group received a commercial license for the product: the world's first genetically engineered vaccine against a human disease, the first vaccine against a sexually transmitted disease, and the first vaccine against a virus that leads to human cancer. The vaccine has since been used to immunize medical and dental personnel against Hepatitis B. Immunization programs are now being extended to pre-teens and infants to forestall sexual or intravenous drug transmission of the virus in teenagers and young adults.
As of early 1996, Hall's technology has been licensed by the Washington Research Foundation on behalf of the UW to 16 firms, which include, in addition to Merck, Smith Kline Beecham Biologicals, Genentech, Immunex, and American Cyanamid, among others.