"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
"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.
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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