Update on Rabies
Rabies has been mostly eradicated in the U.S.; however, it still occurs, and when suspected or known to be contracted, treatment must be immediate with hyperimmune globulin and vaccines.
- By Jim Trageser
RABIES IS A fatal disease — one in which patients will almost assuredly die if treatment is not started immediately after exposure. Fortunately, due to advances in rabies treatment, only approximately 10 people die of it each year in the United States out of some 60,000 who receive treatment for potential exposure — typically from an animal bite or scratch.1 However, this is not true in nations with less developed medical and veterinary systems, where rabies remains a deadly scourge, with some 30,000 to 70,000 human fatalities a year.2 In these parts of the world, the disease is almost always acquired from a bite by an infected dog.
Rabies has been known and described in both humans and dogs since ancient times, with the Mesopotamian Codex of Eshnunna (roughly 2000 BC) describing the legal obligations of owners of infected dogs.3 The common name itself is derived from the Latin verb rabere, which translates as “to rage” in reference to the manic delusions that patients of rabies may exhibit, particularly if exposed to water.4 Even the scientific name of the genus of viruses that cause rabies, Lyssavirus, is taken from the Greek lyssa, for frenzy or madness.
In 1885, Louis Pasteur successfully tested a rabies vaccine using an attenuated virus. It was used to save a boy’s life that same year after he was bitten by a rabid dog.5 Dogs have historically been and remain the primary vector of rabies in humans in wide swaths of Africa and Asia. However, thanks to widespread veterinary immunization that began in 1908, rabies in domesticated dogs in the United States, Canada and Western Europe is practically eradicated today.6 Instead, bats are the leading source of rabies infections today in the United States, Canada and Western Europe, although nearly all mammals can be infected by and spread rabies.7
What Is Rabies?
Rabies is a viral disease that causes encephalitis in humans. It is almost always fatal once the infection takes hold, with reports of fewer than two dozen people in history surviving a documented case of rabies.8 (And, of those who did survive, only one has shown much in the way of recovery; the others all suffered from significant damage to the brain.)
The viruses that cause rabies are part of the Lyssavirus genus. While most human cases of rabies are caused by the Rabies lyssavirus (RABV), there are some two dozen species of virus in the Lyssavirus genus, and it is believed all of them can lead to the rabies disease.9 In Australia, for instance, rabies is caused by Australian bat lyssavirus (ABLV); however, ABLV is very rare, with only three recorded human cases in history.10
While rabies is widespread in wild animal populations in the continental United States, including Alaska, it does not exist in Hawaii.11 But even where it is common, biologists are trying to reduce the natural reservoir of the virus by spreading oral vaccines onto food left for wildlife.
As mentioned, nearly all cases of rabies in the United States are spread by bats, although rabies has been found in wild skunks, raccoons and foxes.1 It is also thought that an infected human could spread rabies to other humans, but no such case has ever been documented. It’s possible to acquire rabies while traveling, particularly to areas of the world where dogs are not routinely vaccinated and remain the primary vector. In fact, some 80 Americans have contracted rabies in this way since 1990.1
After the viral infection enters the body through a wound in the skin, typically a bite or a scratch, it then spreads through the peripheral nervous system toward the central nervous system, including the brain stem and brain. Once the virus reaches the brain stem and brain, encephalitis occurs, causing the symptoms usually associated with rabies: hydrophobia and agitation, or conversely, a state near catatonia. Death usually occurs fairly rapidly after encephalitis begins.2
Symptoms and Progression of Rabies
The most significant symptom of a potential rabies infection is a bite or scratch from a wild or unknown domesticated animal. Most recent cases of rabies in the United States have occurred after individuals handled a bat, often when trying to remove it from a home or outbuilding.12
If the animal that bit or scratched is not captured to be tested for rabies, or if the animal is caught and tests positive, treatment needs to begin immediately. By the time symptoms other than the bite or scratch appear, the disease is untreatable and fatal. Untreated rabies is clinically diagnosed based on presentation of symptoms; there is currently no blood or other test for rabies. A postmortem laboratory test to confirm rabies generally involves examining brain tissue for the antigen associated with the rabies virus.13
As mentioned above, there are two manifestations of rabies: furious rabies and paralytic rabies.14 Most patients with untreated rabies will develop furious rabies, which is marked by heightened aggression, seizures and delirium. Dogs that develop this form may froth at the mouth, which is where popular culture imagery of rabid dogs comes from. Paralytic rabies leads to weakness and paralysis.
Both of these forms will show up only toward the end of the disease progression, in the third of four stages:
- Incubation phase: This is the period in the days or weeks after infection, before the virus makes its way into the peripheral nervous system. This can last from just over a week to up to two years, although in most cases it is between one and three months.15 There are no symptoms during this phase.
- Prodromal phase: Once the virus enters the peripheral nervous system, the prodromal phase begins. Tingling or numbness at the wound and flulike symptoms may be reported.14 This period usually lasts from two to 10 days.
- Acute neurologic phase: In this phase, the virus has entered the central nervous system, encephalitis has begun and the patient begins to show symptoms of neurological dysfunction. This is when the patient will either exhibit furious or paralytic symptoms. Both may include fever, and toward the end of this phase, breathing may become irregular. Paralytic patients may experience a longer duration of the acute neurologic phase, sometimes up to a month. Furious patients may only last a few days to a week before progression.14
- Coma phase. In this phase, the patient will lose consciousness, breathing will grow more irregular and full paralysis may occur. This phase usually lasts only a few days before death.
Preventing Rabies
Due to the low risk of exposure in the United States (60,000 potential exposures per year out of a population of 335 million, or less than two one-hundredths of a percent chance), rabies vaccines are not part of the normal childhood vaccination regimen.16 However, preventive vaccine exceptions are made for high-risk individuals, including veterinary staff, and those who work with or come in close proximity to wild animals (zoo workers, park rangers, wildlife biologists, etc.). They may also be considered for patients traveling to a part of the world with a high incidence of rabies.
One such vaccine is the purified chick embryo cell vaccine (PCECV), which may be marketed under the brand name RabAvert.
Treating Rabies
Treatment for rabies must begin before a formal diagnosis can take place; the mere possibility of exposure to rabies is enough to begin treatment. And, treatment must be started early in the incubation phase before the virus has entered the nervous system.
The treatment regimen itself hasn’t changed much since Pasteur’s day: Rabies vaccine is still applied in a series of injections over the course of a few weeks. One advancement (beyond the obvious improvements in quality control and a wider network of trained professionals to administer the treatments) is the addition of human rabies immune globulin (HRIG) to the tool chest available to physicians.
If individuals are bitten or scratched by an untreated or unknown animal, the bite or scratch should immediately be thoroughly washed with soap and water. This can reduce the risk of general bacterial infections, as well as remove virus-carrying saliva, reducing the viral load entering the body.17
There is no antiviral treatment for rabies. Rather, rabies treatment is a post-exposure prophylaxis (PEP). When exposure is even suspected, and the patient has not previously received the RabAvert vaccine, treatment will begin on the first medical visit with:
- A single dose of human rabies immune globulin (HRIG) (brand names Kedrab and HyperRAB) administered near the wound to provide an immediate boost to the immune response; and
- The first dose of a rabies vaccine (which should not be administered near the HRIG injection site) to start a longerterm buildup of the immune system.
Follow-up medical visits are then required on days three, seven and 14 and will include the second, third and fourth doses of the rabies vaccine. These subsequent doses can and should be administered near the wound, unlike the first dose. Patients with a compromised immune system should receive a fifth dose of the vaccine on the 28th day after the initial treatment.17
For patients who have been vaccinated previously, treatment will consist of a vaccine dose on days zero and three in the deltoid area in adults or in the thigh in children. HRIG should be avoided in those already vaccinated as it may interfere with the vaccine boosters.
The Centers for Disease Control and Prevention recommends two vaccine types for PEP treatment: the human diploid cell rabies vaccine (HDCV) produced by the Merieux Institute and the PCECV vaccine.
One area of potential worry is that current rabies vaccines may not work against emergent Lyssavirus strains being identified in Europe.18 However, given that these new strains have only accounted for a few dozen human cases, and that the vaccines seem to offer at least some crossover protection, the risk seems to be low.
Looking Ahead
Various international and national health agencies have set a goal for global eradication of dog-mediated rabies by the year 2030. With poor nations in Africa and Asia incurring the highest incidence of rabies, the goal is to bring assistance to these nations by:19
- Increasing access to human rabies vaccines
- Inoculating domestic animals, especially dogs
- Controlling the population of wild dogs
- Equipping and training medical facilities to be able to provide timely PEP
In addition, research continues to find more effective treatments of rabies. There are currently more than 100 recent and ongoing clinical studies about rabies listed on the U.S. Food and Drug Administration’s clinicalstudies.gov website. Among them are studies in Asia looking at the efficacy of preventive rabies vaccines in young children in areas where rabies is widespread. Most of the studies listed, however, are investigating improvements to existing vaccines and HRIG versions, modifying dosage schedules and other fine-tuning.
With no apparent leads on a rabies treatment that would be effective after the virus gains access to the nervous system, it seems likely that for the foreseeable future, the only viable treatment for those potentially exposed to rabies will be the current PEP.
References
- Centers for Disease Control and Prevention. About Rabies. Accessed atwww.cdc.gov/rabies/about/index.html.
- Koury, R, and Warrington, S. Rabies. StatPearls, Oct. 31, 2022. Accessed at www.ncbi.nlm.nih.gov/books/NBK448076.
- Dunlop, RH, and Williams, DJ. Veterinary Medicine: An Illustrated History.MarylandHeights,Mo.,Mosby, 1996.
- Etymologia: Rabies. Emerging Infectious Diseases, July 2012. Accessed at www.nc.cdc.gov/eid/article/18/7/et-1807_article#;.
- Institut Pasteur. The History of the First Rabies Vaccination in 1885. Accessed at www.pasteur.fr/en/research-journal/news/history-firstrabies-vaccination-1885.
- Miller, K. A Journey Through Time: TheHistory of Rabies Vaccine and Pet Vaccination. BSMPartners, Oct. 2, 2023. Accessed at bsmpartners.net/insights/a-journey-through-time-the-history-of-rabies-vaccineand-pet-vaccination.
- Centers for Disease Control and Prevention Yellow Book 2024. Rabies. Accessed at wwwnc.cdc.gov/travel/yellowbook/2024/infectionsdiseases/rabies.
- Mani, R, Damodar, T, Domala, S, et al. Case Reports: Survival from Rabies: Case Series from India. The American Journal of Tropical Medicine and Hygiene, Nov. 5, 2018. Accessed at pmc.ncbi.nlm.nih.gov/articles/PMC6335910.
- Eggerbauer, E, Troupin, C, Passior, K, et al. Chapter Eight — The Recently Discovered Bokeloh Bat Lyssavirus: Insights into Its Genetic Heterogeneity and Spatial Distribution in Europe and the Population Genetics of Its Primary Host. Advances in Virus Research, 2017. Accessed at www.sciencedirect.com/science/article/abs/pii/ S0065352717300167.
- NSW Health. Rabies and Australian Bat Lyssavirus Infection Fact Sheet, Jan. 15, 2025. Accessed at www.health.nsw.gov.au/Infectious/factsheets/Pages/rabies-australian-bat-lyssavirus-infection.aspx.
- National Park Service. Rabies. Accessed at www.nps.gov/articles/000/rabies.htm.
- Centers for Disease Control and Prevention. CDC Reports Increase in Human Rabies Cases Linked to Bats in the U.S., Jan. 6, 2022. Accessed at www.cdc.gov/media/releases/2022/p0106-human-rabies.html.
- World Health Organization. Diagnosis: Rabies. Accessed at www.who.int/teams/control-of-neglected-tropical-diseases/rabies/diagnosis.
- Cleveland Clinic. Rabies. Accessed at my.clevelandclinic.org/health/diseases/13848-rabies.
- Rupprecht, C. Chapter 61: Rhabdoviruses: Rabies Virus. Medical Microbiology (4th edition), 1996. Accessed at www.ncbi.nlm.nih.gov/books/NBK8618.
- Children’s Hospital of Philadelphia. Rabies: The Disease & Vaccines. Accessed at www.chop.edu/vaccine-education-center/vaccinedetails/rabies-vaccine.
- Centers for Disease Control and Prevention. Rabies Post-Exposure Prophylaxis, June 20, 2024. Accessed at www.cdc.gov/rabies/hcp/prevention-recommendations/post-exposure-prophylaxis.html.
- Echevarría, J, Banyard, A, Fooks, A, et al. Current Rabies Vaccines Do Not Confer Protective Immunity against Divergent Lyssaviruses Circulating in Europe. Viruses, Sept. 24, 2019. Accessed at pmc.ncbi.nlm.nih.gov/articles/PMC6832729.
- World Health Organization. Zero by 30: The Global Strategic Plan to End Human Deaths from Dog-Mediated Rabies by 2030, June 3, 2018. Accessed at www.who.int/publications/i/item/9789241513838.