"There's no gray 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 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.
Each year, more than 40,000 people worldwide die from rabies. It is one of the oldest and most feared human diseases, first described in 2300 B.C. Symptoms include agitation, convulsions, paralysis and delirium. Without prompt treatment, rabies almost inevitably ends in death.
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, raccoons, 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 $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.
"About three years ago," says Dr. Lodmell, "I became very interested in DNA vaccination, and thought it was a logical step for the rabies problem." DNA vaccines are inexpensive, stable and easy to make, and don't need refrigeration, qualities that make feasible the possible widespread use in developing countries.
A postdoctoral fellow in the lab at that time, Nancy B. Ray, Ph.D., made the vaccine from DNA encoding the surface glycoprotein of the rabies virus. After getting excellent immune responses and protection using this vaccine in mice, they decided to move into primates. "The vaccine worked beyond our wildest dreams," says Dr. Lodmell.
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. Neutralizing antibodies are known to be the primary source of protection for humans and animals.
Dr. Lodmell then had all the monkeys flown to Atlanta, where his collaborators tested the efficacy of the vaccine. At the CDC, Charles E. Rupprecht, D.V.M., Ph.D., chief of the rabies section, and his colleagues exposed the monkeys to lethal doses of rabies virus. By day 11, the two control monkeys had developed clinical signs of the disease. Yet six months after challenge, 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, as currently designed, 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.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH and CDC are agencies of the U.S. Department of Health and Human Services.
Reference: DL Lodmell, NB Ray, MJ Parnell, LC Ewalt, CA Hanlon, JH Shaddock, DS Sanderlin and CE Rupprecht. DNA immunization protects nonhuman primates against rabies virus. Nature Medicine 4(8):949-52 (1998).
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