Published online 6 July 2009 | Nature | doi:10.1038/news.2009.627

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Single injection cures infected mice — and it can protect those who haven't yet caught the disease.

The study could be a shot in the arm for the treatment of rabies. WHO

A rabies vaccine that reverses the disease in mice after just one injection may pave the way to cheap, effective prevention of the fatal illness.

Once a person is exposed to rabies — which is most often transmitted by a dog bite — he or she must quickly begin a month-long series of five vaccination shots to prevent the onset of disease. The procedure is effective, but the expense and logistics of multiple shots makes it inaccessible to much of the developing world, where more than 99% of the 55,000 rabies deaths each year occur1.

Now, a team of virologists and immunologists in the United States have engineered a new strain of the rabies virus that induces a far more potent immune response than current vaccines. In mice already infected with a virulent rabies strain, a single administration of the new vaccine was enough to clear the virus from the body, even after early symptoms had appeared2.

Conventional post-exposure rabies vaccines consist of inactivated viruses that can't grow or cause infection, and require several injections to produce an appropriate immune response. Live viruses that are 'attenuated' — weakened — induce a much stronger immune response than inactivated virus but are problematic because they may themselves cause disease.

Sounding the alarm

Virologist Bernhard Dietzschold and his team at Thomas Jefferson University in Philadelphia, Pennsylvania, wanted to make the new virus strain as safe as an inactivated virus, yet able to rouse the immune response to expunge the infecting virus as quickly as possible.

“It's a lot safer than other live attenuated vaccines that are out there.” Craig Hooper

Thomas Jefferson University

Dietzschold realized he could accomplish both goals by tinkering with a protein on the virus's surface. This protein — called the rabies virus glycoprotein (G) — sets off an alarm within the body's immune system but is normally produced at such low levels that the body's defences barely pick it up. Dietzschold's team found that they could ramp up the immune response by inserting three copies of the gene encoding the protein into the viral genome. The researchers were also able to abolish the toxicity of the strain by changing two amino acids in the protein's sequence.

"When you express a lot of glycoprotein, it makes it a better target because they're the target for the immune system," says co-author Craig Hooper, also at Thomas Jefferson. "But it's also more toxic. For the immune system that's a good thing: If the first cells you infect are going to die, that means you bump up immune response very quickly, so you prevent the virus from spreading."

To make sure the viral strain they developed didn't cause disease, they injected it directly into the brains of healthy, but very young, mice. Pups as young as five days old did not show any signs of rabies. "This means it's a lot safer than other live attenuated vaccines that are out there," Hooper says.

Later treatment?

Dietzschold and his co-workers then infected adult mice with a virulent strain of rabies virus, injecting the pathogen either into muscle or directly into the brain, and found that their new vaccine could prevent onset of the disease if it was administered within three days of exposure.

"[At present] for humans, we must initiate treatment within 20 hours," says Dietzschold. "We showed we might be able to administer the vaccine later because we can clear the virus even after the onset of early symptoms."

Finally, the group demonstrated the vaccine's efficacy as a pre-exposure treatment — which is how rabies vaccines are currently used in wild animals and dogs. Mice given the vaccine up to three weeks before being infected with the virus did not develop rabies. "If this proves as safe as we think it is, it could be contemplated as a vaccine where one shot may protect for life," Hooper says.

In the nearer term, Dietzschold hopes further testing may reveal the vaccine's potential for eradicating the disease in dogs and provide a cheaper and easier alternative to current vaccines for humans.

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Clinician Rodney Willoughby of the Medical College of Wisconsin in Milwaukee, who treats people with rabies and was not involved in the study, is cautious about the new vaccine's potential for treating the disease once symptoms begin. "As far as treatment is concerned, this doesn't bring anything new to the table," he says. That's because if the person is already infected the vaccine could elicit an aggressive immune response in the central nervous system, Willoughby says, which can be harmful and even fatal.

Willoughby is more optimistic about the usefulness of the vaccine if it is administered before exposure, however. He hopes it paves the way for routine immunization of children before they're exposed to rabies in regions where the disease is widespread, such as parts of Asia and Africa — places where the World Health Organization already recommends pre-exposure vaccinations for travellers. The vaccine's apparent safety and need for just a single administration "allows the economics of vaccination to take a giant step forward", he says.