5 August 1998

Putting The Bite On Rabies

Each year, more than 40 000 people world-wide die from rabies. First described in 2300 BC, symptoms include agitation, convulsions, paralysis and delirium. Without prompt treatment, rabies almost inevitably ends in death.

In what could be a major step forward for the prevention of rabies in humans, scientists at the Rocky Mountain Laboratories (RML), part of the National Institute of Allergy and Infectious Diseases (NIAID), have developed a DNA vaccine against rabies that protected eight of eight vaccinated monkeys from the disease. It is the first DNA vaccine to show complete protection in non-human primates against a virus that attacks the central nervous system (CNS). Their report describing the successful experiment appears in the August 1998 issue of Nature Medicine.

"There's no grey area in this experiment. That's what's so beautiful about it," comments lead author Donald L. Lodmell, Ph.D., an expert in NIAID's Laboratory of Persistent Viral Diseases located in Hamilton, Mont. In addition to the apparently perfect protection afforded by the vaccine, anti-rabies antibodies elicited by the vaccine neutralized a global range of rabies viruses. These results suggest, says Dr. Lodmell, that the DNA vaccine could be effective anywhere in the world.

In the United States, few people die from rabies because of widespread immunization of domestic animals: since 1994, only eight deaths have been reported to the Centers for Disease Control and Prevention (CDC).

However, the CDC estimates that another 30 000 to 40 000 people each year receive shots to fend off the disease after possible exposure. Rabid bats, racoons, skunks or other wild animals are the primary sources of human infection in the United States. Most deaths occur in developing countries where rabies is endemic and resources are inadequate to provide optimal post-exposure treatment. Such treatment, which consists of injections of rabies virus grown in human cells and then inactivated, and human anti-rabies serum, costs about US$ 2 000. Cruder concoctions used in developing countries, derived in animal brains, often cause severe neurological side effects such as allergic encephalitis, which can lead to paralytic reactions as well as death.

DNA vaccines are inexpensive, stable, easy to make, and don't need refrigeration, qualities that make feasible their widespread use in developing countries.

A postdoctoral fellow in the lab, Nancy B. Ray, Ph.D., made the vaccine from DNA encoding the surface glycoprotein of the rabies virus. After getting encouraging immune responses and protection using this vaccine in mice, they decided to move into primates. They vaccinated eight monkeys with the DNA vaccine, two monkeys with a current human diploid cell vaccine (HDCV) and two control monkeys with the DNA vector alone. All animals received at least one booster shot at 190 days. In all but the two control animals, the researchers could measure high levels of anti-rabies antibodies.

All the monkeys were then flown to Atlanta where they were exposed to lethal doses of the rabies virus. By day 11, the two control monkeys had developed clinical signs of the disease. Yet six months after exposure, the investigators still could detect no evidence of rabies virus in the eight monkeys that received the DNA vaccine and the two that received the HDCV vaccine.

The only drawback of the DNA vaccine, says Dr. Lodmell, is that the antibody response cannot be detected before 30 days. Hence, the vaccine would not be suitable for post-exposure prevention of disease. However, he believes researchers will be able to overcome this problem in the future. On the other hand, DNA vaccines typically provide long-lasting immunity, so they could be used prophylactically to protect people at high risk, such as veterinarians and individuals who live in developing countries. Currently, Dr. Lodmell and his colleagues are assessing the durability of the antibody response following just one immunization to investigate the requirement for booster vaccinations, as well as other issues related to protection.

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