FDA Approves a Genetically Engineered Vaccine for Hepatitis B Summary

  • Last updated on November 10, 2022

The U.S. Food and Drug Administration’s approval allowed the widespread use of the first vaccine produced through genetic engineering, an artificial vaccine for hepatitis B that had been produced in yeast.

Summary of Event

Hepatitis B is a viral disease that causes liver damage, jaundice, sometimes death, and possibly liver cell cancer. It is present in about two million chronically infected carriers worldwide, mostly in the poorer countries of Africa, Asia, and Latin America. The disease generally is passed from these carriers to others through body fluids or close contact or through food and water under unsanitary conditions. Specific smaller populations in North American and Western European countries are also at high risk, such as health care workers, drug abusers, promiscuous homosexuals and heterosexuals, and persons undergoing dialysis. The best way to prevent continued spread of hepatitis B is to vaccinate those at risk for the disease to produce natural immunity to the virus in each individual. Hepatitis B vaccine Genetic engineering;hepatitis B vaccine Vaccines;hepatitis B Recombivax-HB[Recombivax HB] Diseases;hepatitis B [kw]FDA Approves a Genetically Engineered Vaccine for Hepatitis B (July, 1986) [kw]Genetically Engineered Vaccine for Hepatitis B, FDA Approves a (July, 1986) [kw]Vaccine for Hepatitis B, FDA Approves a Genetically Engineered (July, 1986) [kw]Hepatitis B, FDA Approves a Genetically Engineered Vaccine for (July, 1986) Hepatitis B vaccine Genetic engineering;hepatitis B vaccine Vaccines;hepatitis B Recombivax-HB[Recombivax HB] Diseases;hepatitis B [g]North America;July, 1986: FDA Approves a Genetically Engineered Vaccine for Hepatitis B[06120] [g]United States;July, 1986: FDA Approves a Genetically Engineered Vaccine for Hepatitis B[06120] [c]Health and medicine;July, 1986: FDA Approves a Genetically Engineered Vaccine for Hepatitis B[06120] [c]Genetics;July, 1986: FDA Approves a Genetically Engineered Vaccine for Hepatitis B[06120] [c]Science and technology;July, 1986: FDA Approves a Genetically Engineered Vaccine for Hepatitis B[06120] Valenzuela, Pablo Hilleman, Maurice R. Zuckerman, Arie J. Smith, Geoffrey L.

In July, 1986, the U.S. Food and Drug Administration (FDA) licensed Merck & Company (also known as Merck Sharp & Dohme), Merck a major pharmaceutical corporation, to market a new vaccine against infection with the hepatitis B virus (HBV). The use of this vaccine—called Recombivax-HB—marked a milestone in medical history because it was the first vaccine produced by genetic engineering. After approximately four years of research and testing (led by Maurice R. Hilleman), the new product was to be placed in general use.

Recombivax-HB became an alternative to another vaccine made by Merck, Heptavax-B, Heptavax-B[Heptavax B] which was produced from the plasma of humans who had recovered from hepatitis B. The Heptavax-B vaccine had been licensed in 1981 and had proved to be both effective and safe, with three levels of treatment during processing to inactivate any viruses, living cells, or harmful chemicals in the plasma. Unfortunately, many of the plasma donors for production of Heptavax-B were homosexuals, and male homosexuals as a group are at high risk for infection with the human immunodeficiency virus (HIV) as well as the virus that causes hepatitis B. Thus, beginning about 1983, there was widespread apprehension about the possibility of HIV contamination of the pooled plasma-derived HBV vaccine.

The concern about possible contamination of Heptavax-B, as well as other considerations, led to the development of so-called second- and third-generation hepatitis B vaccines. Both second- and third-generation vaccines are based on recombinant DNA (genetic engineering) technology, Recombinant DNA technology in which the genetic information for a protein, called an antigen, on the hepatitis virus is clipped out chemically and inserted into another virus’s deoxyribonucleic acid (DNA) or into a cell’s DNA. As the host virus replicates, or as the host cell functions, the hepatitis antigen is produced. Because no hepatitis DNA is present, however, no complete infectious hepatitis virus can be constructed, and the vaccine is considered safe for use in humans.

A physician’s assistant administers a Hepatitis B vaccination to an infant.

(Centers for Disease Control and Prevention)

The technique used for production of Recombivax-HB was one of several being developed using genetic engineering. All such experimental vaccines depend on antigens (chemicals that cause antibody formation against them in an immunized person) that are found in or on the virus. The most commonly used antigen in the vaccines is on the surface of the HBV, called HBsAg. Other antigens are also found inside the virus; these are called HBcAg (for core antigen) or HBeAg (for an enzyme antigen). The antigens in the virus are produced according to genetic information carried in viral DNA. That viral DNA had been taken apart in the laboratory, and the piece that coded for the HBsAg was separated from all the other viral DNA. The piece of DNA specific for HBsAg was then spliced into a kind of carrier DNA molecule—a plasmid Plasmids —and then moved into a cell or another large virus. Pablo Valenzuela, a biochemist, led the team that developed the vaccine that was finally marketed, which was produced in yeast cells, single cells of a fungus with the scientific name Saccharomyces cerevisiae, commonly used in baking bread.

In addition to the antigens grown in yeast cells, other second-generation vaccine experiments were being performed in other kinds of cells. At the National Institutes of Health in Bethesda, Maryland, a group led by Geoffrey L. Smith joined the HBV gene for HBsAg to the DNA of the vaccinia virus. This is the virus that causes cowpox and was used as the vaccine to eradicate smallpox. The reason for joining the genetic information of these two viruses was to allow formation of an infectious virus, the vaccinia virus, that could infect people naturally and cause them to produce antibodies against hepatitis B as well. It was considered somewhat dangerous, however, because nonvirulent viruses can mutate to cause serious disease.

The HBsAg DNA had also been inserted into live cells of Escherichia coli, Escherichia coli the bacterium that is the most studied and most well-understood organism on Earth. It was believed that E. coli infections might arise as a result of the use of this vaccine, but work continued on it. Human cells of a continuously growing cell line derived from a liver cell cancer were also used as the host for the gene for hepatitis B surface antigens. The antigens produced by this cell line were excellent, but the cell line was thought to be less safe for vaccine production than yeast because of the possible presence of genes or chemicals in the cells that might cause cancer.

A third-generation vaccine was developed in the laboratory as well, with protein antigens produced by direct, cell-free chemical synthesis. Arie J. Zuckerman in London was involved in this work, which seemed likely to lead to a possible source of a vaccine to be marketed in the future.

In the development of Recombivax-B, the viral DNA that coded for HBsAg was inserted into the yeast DNA in such a manner that the antigen, a protein, could be produced within the yeast cell. Large numbers of yeast cells were grown easily in the laboratory and induced to produce the surface antigens of the hepatitis B virus, which the researchers then collected by breaking apart the yeast cells and separating out the specific molecules of antigen. These were purified, treated to kill any contaminants, and combined with other chemicals to form the vaccine.

Tests of the resultant vaccine were conducted in mice, rabbits, chimpanzees, and finally humans. The testing took place over a period of about two years, involving thousands of volunteers in Africa, China, Greece, England, the United States, and other areas of the world. All types of people were tested, from homosexuals and drug abusers at high risk to the “average American” with low risk for exposure to the hepatitis B virus. Infants of infected mothers, health care workers, and immunosuppressed patients such as those on hemodialysis for kidney failure were tested also. In most cases, the vaccine provided immunity to the virus, with the least immunity seen in the immunosuppressed patients. The results of this widespread testing showed that the new yeast-derived vaccine was essentially similar in its properties to the previous plasma-derived vaccine. It produced no damaging side effects and caused no injury to those who were vaccinated. The FDA therefore gave Merck & Company approval to market the vaccine.


The development of this genetically engineered, yeast-grown vaccine against hepatitis B was of worldwide importance in that it made possible the production of much larger quantities of a vaccine of consistently high quality. The vaccine produced by this method was also free of any possible contaminants from human plasma. Licensing of the vaccine for widespread utilization was a major advance in the new technology of genetic engineering through the use of recombinant DNA technology.

The first hepatitis B vaccine, Heptavax-B, was shown by extensive testing to be safe and effective at producing immunity to the disease in chimpanzees and humans, the only species in which the virus produces disease. Heptavax-B could be produced only in limited quantities, however, because of the requirement for human plasma from individuals who had recovered from the disease. The vaccine required extensive treatment and testing to ensure that no other viral contaminants were present; this caused it to be quite expensive to produce. As a result of the cost and the reluctance of some potential recipients to trust that they would not be exposed to HIV with the use of the vaccine, Heptavax-B had a limited impact in the United States and Europe on infection levels of hepatitis B. Also, it had almost no effect on the rate of infection and illness in other parts of the world because it could not be widely used.

The development and release of Recombivax-HB removed the need for concern about possible HIV infection, but the cost of treatment did not decrease. In fact, because the new dosage was half of that required with the plasma-derived vaccine, at the same price to the patient, it could be considered to have increased. Discussion in medical and scientific journals in 1986 and 1987 suggested that the price might be reduced eventually as more vaccine was produced, as the cost of development and testing would be recovered early, but that did not occur. Because of continuing high cost, the vaccine has had little impact on the Third World nations, where hepatitis B infection frequencies are highest.

The acceptance of the genetically engineered vaccine led to further work on other forms of hepatitis B vaccines as well as on other potential vaccines that will allow immunization against viral diseases for which there currently are no vaccines. In the twenty-first century, work continues to develop genetically engineered vaccines against herpes, hemorrhagic fever, viruses associated with cancers, and others. In addition, studies are being conducted on alternative forms of genetically engineered viral vaccines that will be more easily produced, leading to wider distribution and greatly reduced cost. The ultimate goal is to immunize every possible victim and eradicate not only the hepatitis B virus but also all other disease viruses from all natural populations, as was done in the 1970’s with the smallpox virus. The general use of Recombivax-HB, a vaccine produced through the use of recombinant DNA technology, represents an important step toward that goal. Hepatitis B vaccine Genetic engineering;hepatitis B vaccine Vaccines;hepatitis B Recombivax-HB[Recombivax HB] Diseases;hepatitis B

Further Reading
  • citation-type="booksimple"

    xlink:type="simple">Brown, Fred, Robert M. Chanock, Harold S. Ginsberg, and Richard A. Lerner, eds. Vaccines 90: Modern Approaches to New Vaccines Including Prevention of AIDS. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 1990. Collection of papers presented at a conference held in September, 1989, includes several that refer to the hepatitis B vaccines, including two on the core antigens, one on recombinant HBV with vaccinia virus, and one on the production of HBV vaccine in yeast.
  • citation-type="booksimple"

    xlink:type="simple">Ginsberg, Harold S., Fred Brown, Richard A. Lerner, and Robert M. Chanock, eds. Vaccines 88: New Chemical and Genetic Approaches to Vaccination. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 1988. Collection of papers presented at a conference in September, 1987, includes one on a synthetic vaccine for hepatitis B and another that discusses the core antigens as vaccine sources.
  • citation-type="booksimple"

    xlink:type="simple">Hollinger, F. Blaine. “Hepatitis B Vaccines: To Switch or Not to Switch?” Journal of the American Medical Association 257 (May 15, 1987): 2634-2636. An editorial written for the physician in practice, to give both sides of the issue of whether patients should be given the recombinant DNA vaccine produced in yeast or the older vaccine from human blood plasma. Presents the dilemma very well and argues that a higher dose of the newer vaccine may be required.
  • citation-type="booksimple"

    xlink:type="simple">McAleer, William J., et al. “Human Hepatitis B Vaccine from Recombinant Yeast.” Nature 307 (January 12, 1984): 178-180. Article by the research group at Merck that brought the vaccine to the market covers the science background for the vaccine’s development and testing. Includes a photograph of the antigen particles produced by the yeast.
  • citation-type="booksimple"

    xlink:type="simple">Petersen, Alan, and Robin Bunton. The New Genetics and the Public’s Health. New York: Routledge, 2002. Examines the implications of genetic research in general for the public health arena. Includes discussion of the potential impacts of genetically engineered vaccines.
  • citation-type="booksimple"

    xlink:type="simple">Valenzuela, Pablo, et al. “Synthesis and Assembly of Hepatitis B Virus Surface Antigen Particles in Yeast.” Nature 298 (July 22, 1982): 347-350. Discussion of the process used by the team that placed the genetic information for the surface antigen of hepatitis B virus into yeast cells and produced the surface antigen protein. Compares protein particles made by yeast and those produced by human cells with viral infection.
  • citation-type="booksimple"

    xlink:type="simple">Zuckerman, Arie J. “New Hepatitis B Vaccines.” British Medical Journal 290 (February 16, 1985): 492-496. A major investigator in this field discusses polypeptide vaccines, recombinant DNA vaccines, and chemically synthesized vaccines as well as the properties and uses of each in preventing hepatitis B.

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