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Rabies on the Rise

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.

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.

Forms

There are two forms of rabies. "Furious" rabies largely affects the brain and causes an infected animal to be aggressive or excitable (the very picture of the foaming-at-the-mouth, "mad dog" image people have of rabies). "Paralytic" or "dumb" rabies, mainly affects the spinal cord, causing the animal to be weak-limbed, lethargic, and unable to raise its head or make sounds because neck and throat muscles are paralyzed. In the beginning phase of paralytic rabies, an animal may also appear to be choking.

A wild animal acting unusually tame can also be an early warning sign for rabies. Both types of rabies are the result of the virus multiplying as it moves to the central nervous system and, finally, to all body organs and tissues.

Because rabies may be contagious before any clinical signs appear, a healthy-looking animal can transmit the disease. Rabies' incubation period, the time between infection and the appearance of symptoms, can range from a few weeks to a year or longer in humans, although 30 to 50 days is average. Animals usually develop symptoms between 20 and 60 days after exposure. The incubation period depends on bite location and the dose of virus received.

In humans, a string of worsening symptoms appears: itching or burning at the bite site, fever, headache, and appetite loss. The rabies sufferer grows restless, may experience hydrophobia (a fear of water, because of difficulty swallowing), have convulsions, or hallucinate. Signs of nervous system damage, such as paralysis or disorientation, follow; the only treatment is sedatives and painkillers. The person may slip into a coma, or die suddenly of respiratory or cardiac arrest.

Control in Animals

Experts agree that preventing rabies in people depends on controlling rabies in animals. Animal rabies vaccines are available for domesticated animals like dogs, cats, sheep, cattle, horses, and even ferrets. But controlling rabies in wildlife populations is a more challenging problem.

The sharp rise in animal rabies, particularly among raccoons, the most common animal carrier, led to a 1995 conditional license approval for an oral rabies vaccine for raccoons. The conditional license was issued by the Animal and Plant Health Inspection Service (APHIS), an arm of the U.S. Department of Agriculture, which regulates animal vaccines. The conditional license allows the vaccine to be dropped to wildlife habitats in vaccine-laced bait. Such conditional licenses are issued to meet emergency situations or "special circumstances," limited markets, or local situations, in this case defined by APHIS as a raccoon rabies "epizootic," or outbreak, stretching from Maine to Florida.

The oral raccoon vaccine is unique because it was created using genetic engineering.

"Scientists took a gene from the rabies virus and inserted it into a vaccinia virus using recombinant DNA technology, or technology where the genetic material in a cell is manipulated," explains Robert B. Miller, D.V.M., chief of virology in Veterinary Biologics with APHIS. "When the modified vaccinia virus, a member of the pox virus family, infects a cell, it produces a protein normally produced by the rabies virus. The animal's body recognizes the protein as foreign, and the animal develops an active immunity."

Preliminary studies showed that if the vaccine went directly to the stomach, it would be killed by stomach acids, so the vaccine is placed inside a tube of fish meal and is absorbed by the animal's tonsils, prompting the immune response. Although aimed at raccoons, Miller says the recombinant virus was tested for safety in over 50 different animal species before the conditional license was issued.

Because of how the vaccine is distributed, Miller says few humans are expected to be exposed. APHIS advised that local public health authorities in the areas where the vaccine is to be distributed be notified before bait distribution, and said authorizing state or federal agencies should be notified of any reports of human contact with vaccine-laden baits.

Nevertheless, Miller is concerned about the vaccine's use.

"One of my concerns is that we license its use but we don't control how it's used. I think a lot of art will be required in the use of this vaccine, because not only does it have to be effective, but [bait] placement requires special knowledge," he explains. "Baits are attractive to animals other than raccoons, so you need the proper timing of application and the appropriate number of baits so you get the most benefit."

CDC's Rupprecht says he is "encouraged" so far by the vaccine's use.

"We are encouraged with the use of the vaccine and the results we have seen in the Northeast to date. It took from 1983 to 1995 to get a conditional license because we don't have all the bugs worked out yet, but by the next decade we should be generating enough data to come to grips with that," he notes. "The United States has the most complex rabies problem in the world because of the size of the country, the affected area, the diversities of reservoirs [host animals], and the viruses adapted to them. Socioeconomic philosophies here have also not [traditionally] supported the concept of oral vaccination."

The four human deaths that occurred in 1995 in the United States were due to bites from bats or from animals bitten by rabid bats. In that sense, the four human fatalities were not related to the current raccoon epizootic. (Rabid bats have been associated with at least 21 human deaths since 1951 in the United States.) Although most animal cases involve raccoons, there has never been a reported human rabies death directly or indirectly connected to a raccoon.

CDC has provided the 1995 compendium of animal rabies control recommendations to veterinarians, public health officials, and others concerned with rabies control. The recommendations included immunization procedures with detailed vaccine information; information on human rabies prevention and rabies in domestic animals and wildlife; preexposure animal vaccination and management; and postexposure management directives.

CDC's Rupprecht emphasizes that despite the advent of oral vaccines for wildlife and advances in human rabies vaccines, the key to rabies control remains education.

"We need to keep nature in perspective; the world is not all bright and beautiful. That's the reason why we perceive wildlife as wild," he says. "The same old things that worked 50 years ago still work: Vaccinate your pets, and have a healthy attitude toward wildlife. To paraphrase a common rabies control idiom: Love your own, leave others alone."

He adds, "But the dynamics of rabies have changed, and will continue to change. The dynamics have changed both in shifts of rabies from domestic to wild animals, within domestic animals from dogs to cats, and shifts in the number of important wildlife species annually and geographically that are affected by rabies. This will continue to press us to come up with novel ways to control the disease in wildlife."

FDA's Fitzgerald agrees with the concept of change in terms of human rabies vaccine.

"I've seen an awful lot change over the years. Rabies vaccines were much cruder, such as those made from duck embryos. We are now into a whole new level of purification and potency," Fitzgerald says. "We have good vaccines for humans with few side effects. You only have to look at other countries where people by the thousands die of rabies to know how lucky we are here."

Audrey T. Hingley is a writer in Mechanicsville, Va.

Justified Fear

The fear caused by rabies begins with its very transmission. A viral infection affecting the brain and spinal cord, rabies is transmitted through the saliva of an infected animal, usually by a bite. It can also be transmitted when infected saliva comes in contact with a cut or skin break. Infected bat droppings are suspected of transmitting the disease, and at least two people are believed to have been exposed to rabies by breathing the air in caves where rabid bats live. Other rare deaths have occurred in people who have received corneal eye transplants from donors with undiagnosed rabies.

Bite transmissions can be difficult to detect, as illustrated by the death of a 4-year-old girl last year who was exposed to rabies from a bat that flew in her room while she was sleeping. The bat was killed and buried, and no signs of a bite were found on the girl. When she died a month later of rabies, health authorities recovered the bat carcass, tested it, and found the bat and the child both had the same variant of rabies.

--A.T.H.

Rabies Prevention

• Keep pet shots up-to-date and observe leash laws. Don't leave your dog chained alone in the yard: If attacked by a rabid animal, it can't escape.
• Don't make your house or yard attractive to wildlife; feed your pet indoors, and keep garbage cans closed tightly.
• Seal basement, porch, and attic openings, and cap chimneys with screens.
• No matter how cute, avoid contact with wild or unfamiliar animals. Don't touch a wild animal even if it's dead.
• Report strays or animals acting strangely or sick to local authorities.

--A.T.H.