Rabies: Vaccines

by Food and Drug Administration (FDA)

After years of decline in America, a form of viral encephalitis transmitted through infected animal saliva is on the rise.

The life-threatening disease is rabies. According to John Krebs, a public health scientist with the Centers for Disease Control and Prevention, rabies cases in animals increased dramatically between 1990 and 1993. In 1990 there were 4,880 reported animal deaths from rabies; that figure jumped to 9,495 three years later.

With treatment, human deaths from rabies are rare in the United States. One death in 1990, three deaths in 1991, one death in 1992, and three deaths in 1993 were recorded, with six people dying in 1994 and four in 1995 from the disease.

Charles Rupprecht, V.M.D., Ph.D., chief of CDC's rabies section, says education is the key to preventing the disease. Rupprecht says only one inadequately treated person is known to have recovered completely from rabies and escaped death.

"In 1970 Matthew Winkler was exposed [to rabies], treated [with postexposure vaccine], and because vaccines were not as good then, experienced a vaccine failure. He recovered despite the vaccine failure, which is a far different thing than catching the disease, [not being treated,] and recovering," he points out. "Some people question to this day whether that case meets all the criteria [of a human known to survive rabies without treatment]."

Over the years, scientists have improved both the effectiveness and safety of human rabies vaccines, regulated by the Food and Drug Administration as biologics. Today's vaccines are highly effective and produce few side effects. They work by causing the immune system to produce antibodies that neutralize the rabies virus before it causes the disease. Unlike most vaccines, which are given before disease exposure occurs, rabies vaccine is usually administered after someone has been exposed to the disease. A preexposure vaccine series designed for people considered high-risk for exposure to rabies — such as veterinarians, researchers, forest rangers, animal control officers, cave explorers, animal handlers, or those who spend time in countries where rabies is prevalent — is also available.

But whether pre- or postexposure, rabies vaccines and rabies immune globulin are the first — and only — line of defense for humans exposed to rabies. There are no tests that can detect rabies in humans at the time of a bite, and by the time symptoms appear, it's too late for treatment. The disease is a swift, deadly killer, and there's no cure.

Vaccines

Three human rabies vaccines are currently licensed by FDA for U.S. use:

Human diploid cell vaccine (HDCV), or Imovax, is the most widely used vaccine. It is produced in cultures of normal human diploid cells by Pasteur Merieux, a French company. Pasteur Merieux's pre- and postexposure intramuscular HDCV vaccines were approved in 1980, while an intradermal preexposure HDCV vaccine was approved for use in 1988.

A vaccine made by a Michigan state agency, Michigan Biologic Products Institute, uses fetal rhesus monkey cell cultures. It was approved for use in 1988 and is distributed outside of Michigan by Smith Kline Beecham.

Inactivated diploid cell origin (DCO), a dried vaccine made by Connaught Laboratories in Toronto, Canada, was approved for use in 1991.

"Virtually all vaccines are made from living systems, whether you are talking about the oral polio vaccine or DTP shots that your kids get or rabies [vaccines]," explains Edward A. Fitzgerald, Ph.D., director of the division of product quality control in FDA's Center for Biologics Evaluation and Research. "Any viral vaccine has to be made in a living cell system."

All three human rabies vaccines are made in a similar fashion: Cells are grown in a monolayer, or single-cell layer, in an artificial medium that bathes the cells much as blood bathes human cells. The virus is added, replicates, and is released into the cell medium as the cells die. The medium is then harvested to produce the vaccine. Since the harvested medium contains live virus, a chemical is used to kill the virus; the chemical is then removed via a purification process, resulting in a final vaccine.

Human diploid cell vaccine is made by allowing the rabies virus to multiply in human diploid cells, normal cells that contain two complete sets of human chromosomes, grown in glass or plastic bottles. Like HDCV, DCO vaccines are made with human diploid cells, but use a different purification process. The Michigan-produced vaccine uses fetal rhesus monkey diploid cells. At first, live rhesus monkey fetuses were used to establish a cell line. But today, live monkey fetuses are no longer needed; only the cell line, frozen in liquid nitrogen, is used.

Shot Schedule

"The preexposure series for all human rabies vaccines is given in three shots: on day 0, day 7, and on day 21 or day 28 for the third shot. How often booster shots are taken depends on how good you are at producing antibody," Fitzgerald says.

People who have received the preexposure series need only two booster shots if they are later exposed to rabies. People in high-risk jobs are encouraged to have their blood tested at regular intervals so boosters can be given if antibody levels fall below a baseline value. Fitzgerald says the average high-risk worker usually needs boosters only about once every two years.

"Postexposure rabies vaccine consists of five shots, given on day 0, day 3, day 7, day 14, and day 28 [after exposure]. On day zero rabies immune globulin is also given because the vaccine takes, depending on the individual, seven to fourteen days to provide an active antibody response," Fitzgerald says.

Rabies immune globulin, which consists of antibodies from blood donors given rabies vaccine, acts as a kind of safety net, providing passive immunity, interim protection until active antibodies are produced from the vaccination.

Many people shudder at the mention of human rabies vaccines because they are recalling an older form of human vaccine, made from duck embryos and requiring 21 shots, many of which were given in the abdomen. Today most shots are given intramuscularly, usually in the shoulder muscle. (It's important that the vaccine be injected into muscle, since studies have shown that vaccine injected into fatty tissue may induce a lower response.) The preexposure intradermal vaccine normally is given in the forearm or shoulder, and rabies immune globulin is injected both at the bite site and in the buttocks.

About the Author

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