Genetically Engineered Rabies Vaccine Is Released

Date August, 1990

A vaccinia virus, genetically engineered to contain rabies virus proteins, was released in Virginia to control rabies in raccoons.

Locale Parramore Island, off the coast of Virginia

Key Figures

• Charles E. Rupprecht (fl. late twentieth century), scientist who developed a live recombinant rabies vaccine
• David A. Espeseth (fl. late twentieth century), deputy director of veterinary biologics at the U.S. Department of Agriculture
• Edward P. Bruggemann (fl. late twentieth century), scientist with the National Audubon Society

Summary of Event

On July 5, 1989, the Virginia Department of Health approved the field testing of baits spiked with a genetically engineered rabies vaccine to control the spread of rabies in raccoons. The initial field test was conducted in 1990 on Parramore Island, off the coast of Virginia, after having been approved by the state and the Nature Conservancy, which owned the island. Both this test and one in Pennsylvania showed the recombinant vaccine to be effective in controlling the spread of rabies in raccoons. Additional tests, using a similar recombinant vaccine, were conducted in Europe to control rabies in foxes. Vaccination programs of this kind, although they undoubtedly helped control the spread of rabies in the wild, were found to be expensive, and it remained unclear whether the technique could be cost-effective when used on a large scale.

After 1977, the number of rabid raccoons reported in the mid-Atlantic states increased dramatically. The initial source of the epidemic was apparently the unknowing transport of rabid raccoons to the border between Virginia and West Virginia by hunting clubs. The epizootic (an epidemic within an animal population) spread slowly up the coast, reaching as far north as southern New Hampshire and parts of upstate New York by late summer, 1993. Although most wild mammals are susceptible to rabies, which is commonly found in many areas throughout the United States, the disease is carried most frequently by skunks, bats, foxes, and raccoons. Foxes, coyotes, and wolves are most susceptible to rabies, followed by raccoons, skunks, bats, and bobcats. Infected wildlife can carry the disease to humans directly or through dogs and cats with which humans come into contact. An effective vaccine to halt the spread of rabies in the wild would help prevent transmission of the disease to humans.

The incidence of rabies in humans in the United States declined considerably after the 1950’s, in large part as a result of extensive and successful programs for controlling rabies in pets; few human rabies deaths occur in the United States. In the early twenty-first century, most rabies deaths in humans take place in impoverished countries, where prevention and treatment programs are too expensive to be supported by the local governments. The fatal effects of exposure to known rabid animals can be prevented through cleansing of the wound and timely administration of gamma globulin and an antirabies vaccine.

By the early 1990’s, raccoons and animals infected by raccoons accounted for more than 60 percent of all diagnosed cases of rabies in the United States. Although the increased incidence of rabid raccoons after 1970 was not accompanied by an increase in the number of human rabies cases, it led to considerable anxiety.

In the mid-1980’s, Charles E. Rupprecht and a team of scientists from the Wistar Institute of Anatomy and Biology in Philadelphia, along with researchers at the Transgène Company in France, created a genetically engineered rabies vaccine that was later manufactured by the French veterinary pharmaceutical company Rhône Mérieux. The vaccine was derived from a weakened strain of vaccinia virus, the virus used for immunizations against smallpox, which causes a mild localized infection. Into that virus Rupprecht inserted the gene that produces the protein found on the surface of the bullet-shaped rabies virus, a sugar-containing protein (or glycoprotein) used by the virus to attach to host cells and against which the host’s immune system reacts. In the resultant recombinant, chimeric virus—part vaccinia virus and part rabies virus—the protein produced by the rabies gene finds its way to the surface of the vaccinia virus, where it would be positioned in the rabies virus; a host’s immune system would therefore react to the recombinant virus in much the same way as a rabies virus.

A genetically engineered vaccine of this kind has several advantages over traditional rabies vaccines. Unlike other vaccines, it can be administered orally, and it is effective in raccoons. Moreover, the recombinant vaccine cannot cause rabies because it contains only one of the rabies virus genes and lacks all the genes required to duplicate the virus and cause the disease.

Rupprecht and his team initially sought to test the vaccine in 1989 on Cedar and Murphy islands, off the coast of South Carolina. Island locations were desirable for testing because they would allow the researchers to prevent the possible spread of vaccinated animals to larger, mainland populations. South Carolina state health officials, concerned about the possible danger of the vaccinia virus to humans, suggested that the vaccine should be tested on nonhuman primates. When David A. Espeseth, deputy director of veterinary biologics at the U.S. Department of Agriculture (USDA), disagreed, South Carolina refused to allow the testing. One week later, however, on July 5, 1989, the Virginia Department of Health granted approval to Wistar Institute to carry out the tests on Parramore Island.

Field trials began in August, 1990, and continued for one year. The rabies vaccine was injected into fish that was distributed around the island as bait; uneaten bait was removed after two weeks. The bait, which contained a “marker” substance that allowed scientists to distinguish animals that had eaten it from ones that had not, attracted raccoons but usually not other species. The researchers found that raccoons that ate the vaccine-laced bait produced antibodies against rabies virus, whereas those that did not eat the bait did not produce antibodies.

Significance

Humans have feared rabies since antiquity. Left untreated, the rabies virus acquired from the bite of an infected animal proceeds along the host’s nerves at a rate of 8 to 20 millimeters per day until it reaches the spinal cord. The virus incubation period can be as short as five days or as long as many years, depending, at least in part, on the distance of the bite from the spinal cord. Once the virus has infected the spinal cord, it is no longer susceptible to the body’s immune system and cannot be stopped by immunization. Symptoms then progress rapidly within seven to fourteen days, beginning with spasms of the face and neck, body rigidity, extreme difficulty in swallowing—the disease is sometimes called hydrophobia because even the sight of water causes severe spasms of the throat—hallucinations, disorientation, and high fever. The illness ends with coma and death.

A number of attempts had been made previously to control the spread of rabies in wild mammals. In one method, called culling, the populations suspected of carrying the virus were killed, in the hope that reducing the population size would reduce the likelihood of animal-to-animal virus transmission; this method required the killing of very large numbers of animals to be effective. Another method involved capturing wild animals and vaccinating them with the same vaccine that protects domesticated animals; the percentage of animals captured was never high enough for this method to be effective, however. Several methods of self-vaccination had been tried in the 1960’s, but some of the techniques harmed the animals, and it was impossible to ensure that nontarget species were not immunized by mistake. In the mid-1970’s, William Winkler, then at the Centers for Disease Control, developed sausage baits containing a plastic drinking straw filled with vaccine to immunize foxes, but because the incidence of fox rabies declined in the United States through natural causes, that method was never field-tested.

Despite the successful results of the Parramore Island tests, a number of scientists believed that raccoon vaccination programs could have little long-term effect on the incidence of rabies. Edward P. Bruggemann, a scientist with the National Audubon Society, declared that rabies vaccination of raccoons would not protect public health because, according to a theoretical model designed by M. J. Coyne, raccoon vaccination reduces the fluctuations in population size that occur as a result of the disease; thus, as the level of vaccination increases, so does the population of raccoons. The percentage of rabid animals would not decrease significantly, however, unless nearly 95 percent of the raccoons were vaccinated. To maintain that level of vaccination, the immunizations would have to be done on a yearly basis. Bruggemann proposed vaccinating an animal species that requires lower rates of immunization to be effective in the population as a whole. Alternatively, a rabies-free area could be maintained through the immunization of animals whose populations are not yet affected.

Bruggemann also questioned the long-term effects of releasing a nonnative virus into the environment. Although vaccinia was used for many years to prevent smallpox, little was known about its host range or its ability to cause disease. The USDA concluded in a 1991 report, however, that laboratory and field tests had shown the genetically engineered rabies vaccine to have had no adverse effects on any species. In the same report, the department approved field testing on the grounds that such tests were safe and posed no significant environmental risk.

Some scientists questioned whether it was possible for large-scale rabies vaccination of wild mammals such as raccoons to be cost-effective. According to a review in the New England Journal of Medicine, 82 percent of expenditures for rabies prevention in the United States is accounted for by the vaccination of pets. Treatment of humans before and after exposure accounts for another 10 percent. The per-capita expense can double, however, when raccoon rabies infects a previously uninfected area, because the cost of oral vaccination of raccoons ranges from $325 to $1,000 per square kilometer of habitat. The cost for protecting an area the size of New Jersey, for example, would be between $6 million and $19 million each year. Expenses for treating humans would not decrease, because there is no way of deducing whether a raccoon that has bitten a human is rabid or not. Once a wild mammal population is known to be largely immune, however, the vaccination of pets would no longer be as imperative.

Although the recombinant rabies vaccine proved biologically successful, it was not successful from an economic point of view. It was thought, however, that the vaccine could eventually replace or become an alternative to the traditional rabies vaccines used in veterinary practice.

Bibliography

Anderson, Roy M. “Rabies: Immunization in the Field.” Nature 354 (December 26, 1991): 502-503. Describes the results of field tests in Europe of a recombinant vaccinia virus rabies vaccine. Suitable for general readers. Includes a list of references.

Avise, John C. The Hope, Hype, and Reality of Genetic Engineering: Remarkable Stories from Agriculture, Industry, Medicine, and the Environment. New York: Oxford University Press, 2004. Examines the potential of genetic engineering and provides examples of achievements and failures in the field. Includes discussion of the engineering of vaccines.

Bruggemann, Edward P. “Rabies in the Mid-Atlantic States: Should Raccoons Be Vaccinated?” BioScience 42 (October, 1992): 694-699. Discusses methods for controlling raccoon rabies in the wild and explains why raccoon vaccination may not be a practical strategy for controlling rabies. Includes illustrations, figures, and an extensive list of references.

Fishbein, Daniel B., and Laura E. Robinson. “Rabies.” New England Journal of Medicine 329 (November 25, 1993): 1632-1638. Scholarly article presents a thorough review of the biology of rabies and its spread in animals. Discusses the nature and cost of prevention. Includes tables, illustrations, and an extensive list of references.

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.

Sun, Marjorie. “South Carolina Blocks Test of Rabies Vaccine.” Science 244 (June 30, 1989): 1535. Discusses the reasons the first suggested field trial was prevented.

‗‗‗‗‗‗‗. “Virginia OKs Rabies Vaccine Test.” Science 245 (July 14, 1989): 126. Brief article reports approval for the first field study of the recombinant rabies vaccine in the United States.

Weintraub, Pamela. “Vaccines Go Wild: Once They’re Out, Can We Get Them Back?” Audubon 95 (January/February, 1993): 16-17. Short report examines the use of recombinant vaccines to prevent the spread of diseases in animals.

Winkler, William G., and Konrad Bögel. “Control of Rabies in Wildlife.” Scientific American 266 (June, 1992): 86-92. Discusses the methods used to control rabies in wild animals, the recombinant vaccine, and vaccination programs in Europe and the United States. Includes illustrations and references.