Rabies virus: can we treat the untreatable?

Posted on June 25, 2019   by Laura Cox

Every year, an estimated 59,000 people die from rabies. Usually contracted following a bite from an infected animal, rabies is almost always fatal in people who have not been vaccinated. Once symptoms of appear, there is little-to-no hope for the infected individual, with no treatment options currently available.

Rabies is a viral disease that spreads to humans from animals and infects the nerves and brain. The disease is caused by lyssaviruses; a genus of viruses in the Rhabdoviridae family. The lyssavirus most important to human health is Rabies virus (RABV), which is still a major concern to human health around the world. Only six people are known to have survived from rabies infection after symptoms appear, making it one of the world’s deadliest viruses.

The virus is spread through saliva and is usually contracted following a bite or scratch from an infected dog. Other animal carriers include bats, wild canines and cats. The virus moves through the nervous system, travelling from the peripheral nerves, up the spinal cord and to the brain. Within 3-12 weeks of exposure, symptoms develop including fever, headache and anxiety. Within days, these symptoms develop to more severe signs, including aggressive behaviour, frothing at the mouth, hallucinations and paralysis. Once the virus reaches the brain, it causes overstimulation of nerve receptors – known as excitotoxicity – killing brain cells at an alarming rate.

Of course, the virus does not immediately enter a nerve following a bite or scratch from an infected animal and must replicate in other cell types until it can come into contact with, and infect, a nerve cell. During this time, there are no symptoms and the virus is at its most vulnerable to clearance by the immune system. It is during this time that the post-exposure vaccine can be administered with an excellent success rate.

Protection and prevention:

Vaccines to protect against rabies infection have been around for a long time, with the first rabies vaccine developed by Louis Pasteur. In 1885, after five years of work developing a vaccine to protect dogs from the disease, Pasteur administered his vaccine on a nine-year-old boy who had been bitten by a rabid dog. The vaccine worked, and rapidly became a life-saving post-exposure treatment for the disease.

Over the following years, research into the vaccine continues, and in 1908 an inactivated vaccine was developed and approved. Rabies vaccines are now given around the world, and the World Health Organization estimates that the vaccine prevents over 270,000 deaths each year. Unfortunately, the vaccine can only provide protect against the disease before symptoms emerge, meaning people who are unknowingly infected have little chance of survival.

 

The Milwaukee Protocol:

In 2004, a fifteen-year-old girl called Jeanna was bitten on the finger by a bat. Just over a month later, Jeanna started showing symptoms of infection, including slurred speech, fever and vomiting. Luckily for Jeanna, doctors at the Children’s Hospital of Wisconsin had an idea of how to protect the brain before the virus can enter it: a coma. To give her immune system time to fight off the virus, they induced a coma and provided a number of antiviral drugs and ketamine, a procedure they named as The Milwaukee Protocol. Within days they found antibodies against the virus in the spinal fluid – the infection cleared and Jeanna began to recover. Finally, there was hope for a cure!

The procedure that showed so much promise, with overwhelming success on the first attempt unfortunately did not live up to expectations. The Protocol has been tried over 50 times around the world, but only a handful of patients have survived, meaning this treatment is not recommended and remains highly controversial.

The challenges:

So why is rabies so difficult to treat? Viral infections can usually be treated using anti-viral drugs, which inhibit virus development. Rabies virus uses a myriad of strategies to avoid the immune system and hide from antiviral drugs, even using the blood brain barrier to protect itself once it has entered the brain. The blood brain barrier is a membrane that prevents cells and large molecules from entering the brain. During infection of the brain, the permeability of the barrier can increase, allowing immune cells and antibodies through to help clear the infection. However, during infection with rabies virus, the blood brain barrier locks down, meaning nothing can get through, even antiviral drugs.

The virus goes even further to continue infection and manipulates the immune system to destroy itself instead of targeting infected nerve cells. This manipulation of host responses has made finding strategies to treat rabies following infection difficult for researchers, with many potential antivirals showing promising results in in vitro, laboratory tests being unsuccessful in more complex, in vivo systems.  

Looking forward:

A recent review published in the Journal of General Virology, authored by researchers from the Animal and Plant Health Agency (APHA), St George’s, University of London and the University of West Sussex discusses the ongoing research into finding treatment for the virus and the efforts being made to develop new vaccines.