Rabies is a well-documented virus dating back to the 4th century BC.¹ Observed in a Greek philosopher’s notes, it is no surprise that the rabies virus was named lyssavirus, after the Greek word for rabies “lyssa.”¹ Even then, they knew it was a death sentence. If, following a bite or scratch from a rabid dog, the virus reaches the brain and symptoms show, the illness is fatal 100% of the time. However, in 1885, a French scientist, Louis Pasteur, developed a vaccine¹ that, if administered quickly following exposure to the virus, prevents death.¹ Still, rabies lingers in the developing world, causing 55,000 deaths in Asia and Africa every year.² Symptoms can take anywhere from one week to one year to appear, and by then, it’s too late for the vaccine; however, in today’s study, they attempted to treat rabies-infected mice after clinical symptoms appeared.

Three takeaways to tell your friends:

• Rabies-infected mice had rabies virus in their spinal cord and brain four and five days following infection, respectively.³
• Rabies-infected mice showed physical symptoms like worsened motor skills and paralysis at seven and eight days following infection, respectively.³
• Proportions of rabies-infected mice provided with the treatment on days six, seven, or eight survived.³

We all know that rabies is treatable if caught before the arrival of symptoms: bit by a rabid coyote? Get rabies shots. However, in the developing world, this solution is less available, and more people end up with rabies silently spreading through their bodies until symptoms arise, then it’s too late. What if there were a treatment that could save someone once they noticed symptoms?

To test if rabies infection can be treated after the appearance of symptoms, researchers established a mouse model by first finding time points when symptoms arise (Table 1). The virus reaches the spinal cord four days following infection and the brain the following day.³ While physical symptoms emerge seven and eight days following infection; between days ten and thirteen, the mice succumb.³ Using this model, they began the treatment plan.

Days after rabies infection	Symptoms/Manifestations
4	•Virus reaches spinal cord
5	•Virus reaches brain
7	•Weight loss •Worsened motor skills
8	•Lethargy •Ataxia •Paralysis
10-13	•Death

The treatment in this study was a combination of two antibodies that bind to separate sites on the outer part of the virus.³ The thinking here is that the antibodies will seek out the virus, bind, and recruit immune cells to destroy the virus. To give the antibody treatment, the researchers injected it into the muscle where the rabies virus entered the body (similar to the location of a rabid bite)³; simultaneously, the same treatment was infused directly into the brain,³ a relatively safe method commonly used for chemotherapy.⁴ The brain infusions continued for 20 days, while the muscle injection occurred twice, once at the beginning of treatment and once after the brain infusions finished.³ The researchers began the treatments at different times to observe how well the mice responded (Table 2). The treatments started on days six, seven, or eight following infection.³ As seen in Table 1, symptoms arise around days seven and eight. Therefore, starting treatment on day seven or eight is equivalent to beginning treatment after symptoms arise. The results show that a percentage of mice survive, even when treated after symptoms are present.

Beginning of treatment (days after infection)	Percent survival of rabies-infected mice
6	100%
7	55.6%
8	33.3%

In summary, there is promising data for treating rabies following the arrival of symptoms. However, 20 days of constant brain infusions is less feasible in developing countries. A more recent publication by Mastraccio et al.⁵ found success with a single antibody injection to treat a rising rabies infection; their treatment started the day that the virus is seen in the spinal cord and around when symptoms arose. Taken together, there is hope for a future where rabies is not a death sentence, no matter where you live.

Note: During my research on the topic, I discovered a fascinating read. It is the history of rabies from the 4th century BC, compiled by Dr. Arthur A. King, a scintillating read about ancient philosophers’ healing methods for a disease they knew little about. The full text is available here. Enjoy!

REFERENCES

1.         King AA. Historical Perspective of Rabies in Europe and the Mediterranean Basin. 2004.

2.         Knobel DL, Cleaveland S, Coleman PG, Fevre EM, Meltzer MI, Miranda ME, et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ. 2005;83(5):360-8.

3.         de Melo GD, Sonthonnax F, Lepousez G, Jouvion G, Minola A, Zatta F, et al. A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO Mol Med. 2020;12(11):e12628.

4.         Cohen-Pfeffer JL, Gururangan S, Lester T, Lim DA, Shaywitz AJ, Westphal M, et al. Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration. Pediatr Neurol. 2017;67:23-35.

5.         Mastraccio KE, Huaman C, Coggins SA, Clouse C, Rader M, Yan L, et al. mAb therapy controls CNS-resident lyssavirus infection via a CD4 T cell-dependent mechanism. EMBO Mol Med. 2023;15(10):e16394.