Viewpoint articles represent the opinions of the authors and do not represent AVMA endorsement of such statements.
Introduction
Ask most Americans what they know about rabies, and they will likely answer with a puzzled expression or complain about taking their dog or cat to the “vet” for a shot. Here is what most Americans don’t know and what veterinarians should tell their clients about rabies.
Question: Why do dogs and cats need rabies shots?
Answer: During the first 30 years of the 20th century, rabies killed more than 10,000 domestic animals (mostly dogs) and 50 Americans every year (Figure 1) in the US.1,2 Twenty years after rabies vaccination of dogs became mandatory in 1947, rabies was transformed from an American public health emergency to a problem nearly solved.1 Eradication of dog-transmitted rabies was the first spectacular vaccination victory over human lethal infections in 20th-century America, followed by the eradication of smallpox in 1952 and poliomyelitis in 1994.3 While mass vaccination of dogs and cats is responsible for near elimination of dog- and cat-transmitted rabies and human fatalities in America today, rabies transmitted from and between wild and domestic animals remains a constant threat to reintroducing endemic rabies in companion animals, particularly dogs. Sustained high-compliance rabies immunization of companion animals is the most effective way to keep Americans safe from reemergence of this deadly threat. If Americans ever become complacent and stop vaccinating dogs and cats, our public health efforts will once again face a great challenge in protecting the country from rabies. Annual vaccination of companion animals for rabies is a small price to pay for their health and our peace of mind.
Human and animal rabies in the US from 1938 to 2018. (Adapted from Pieracci EG, Pearson CM, Wallace RM, et al. Vital signs: trends in human rabies deaths and exposures—United States, 1938–2018. MMWR Morb Mortal Wkly Rep. 2019;68(23):524–528. doi:10.15585/mmwr.mm6823e1)
Citation: Journal of the American Veterinary Medical Association 261, 4; 10.2460/javma.22.09.0420
Human and animal rabies in the US from 1938 to 2018. (Adapted from Pieracci EG, Pearson CM, Wallace RM, et al. Vital signs: trends in human rabies deaths and exposures—United States, 1938–2018. MMWR Morb Mortal Wkly Rep. 2019;68(23):524–528. doi:10.15585/mmwr.mm6823e1)
Citation: Journal of the American Veterinary Medical Association 261, 4; 10.2460/javma.22.09.0420
Human and animal rabies in the US from 1938 to 2018. (Adapted from Pieracci EG, Pearson CM, Wallace RM, et al. Vital signs: trends in human rabies deaths and exposures—United States, 1938–2018. MMWR Morb Mortal Wkly Rep. 2019;68(23):524–528. doi:10.15585/mmwr.mm6823e1)
Citation: Journal of the American Veterinary Medical Association 261, 4; 10.2460/javma.22.09.0420
Question: Is rabies a problem in the US?
Answer: Rabies was described by Aristotle circa 380 BC, and it continues to kill 60,000 to 125,000 (95% confidence limits) people each year, mostly children living in 122 nations where dog rabies is endemic.4 Almost a century of success in controlling rabies transmitted by dogs in the US gives Americans a false sense of security, but rabies remains endemic in wild animals in North America. Transmission of rabies from wild animals to people, pets, farm stock, and other wild animals continues to threaten Americans’ health. In 2020, of approximately 88,000 animal samples tested for rabies in North America, 1,400 bats were positive, along with 1,403 raccoons, 846 skunks, 338 foxes, 228 cats, and 37 dogs.5 Every year > 50,000 Americans who are exposed to suspected rabid animals receive postexposure rabies prevention treatment.1 There are 3 to 5 human rabies fatalities in the US each year, mostly transmitted by rabid bats6 or contracted while the victim was visiting countries where dog rabies is endemic. There were 25 Americans killed by rabies from 2002 through 2018,7 and 5 cases of human rabies were reported in 2021, including 4 contracted from bats and 1 contracted from a dog during a visit to the Philippines.5,7 Individuals who undergo postexposure prevention for rabies and experience the intensive treatment and associated anxiety will testify that rabies is a very real American problem. The families of patients killed by rabies know sadly that rabies remains a lethal menace.
Question: Isn’t rabies only a problem in poor countries?
Answer: Human rabies is contracted primarily from dogs (> 95%) in India, China, and countries in Africa where dog rabies is endemic.8,9 Immunizing dogs is the most cost-effective way to combat rabies, but lack of government commitment to eradicate dog-transmitted rabies is the greatest reason that rabies still kills so many people.9 India is an industrial nation with an established health-care system that has a population of 1.4 billion humans and 35 to 40 million dogs. More than half of these dogs are unowned and free roaming and are euphemistically called “community” dogs, of which < 15% are vaccinated for rabies. Euthanasia of unowned dogs is prohibited, so the size of this population of dogs is estimated to increase at an astonishing rate of 75% every 5 years.10 Every year, 20,000 citizens of India reportedly die of rabies, but that number grossly underestimates the actual case frequency because until 2021 rabies was not a reportable disease; 17 million Indians are bitten by dogs each year, yet many of those living in rural and poor communities do not have access to rabies prevention and die at home.10,11 There are several reasons that so many people continue to die of rabies, the most important of which are ignorance, poverty, and government neglect and policies that prevent effective control.9
Question: Is there a vaccine that can conquer rabies worldwide like polio and smallpox?
Answer: Louis Pasteur developed the first vaccine for rabies in 1881, making rabies the second disease preventable by vaccines (the cowpox vaccine to prevent smallpox was invented in 1798 by Edward Jenner, who named the lifesaving procedure “vaccinae” after vacca, the Latin word for cow3). By 1885, Pasteur had immunized 50 dogs against rabies, and that year he treated the first human patient, Joseph Meister, a 9-year-old boy from Alsace who was bitten savagely by a rabid dog and would have died but was saved by Pasteur’s vaccine. By 1886, Pasteur vaccinated 350 more patients exposed to rabid dogs.12 The safety and reliability of rabies vaccines progressed steadily, and in 1935 a rabies virus isolated from a rabid dog was attenuated by passage in mice and made into a dog vaccine at the Communicable Disease Center (CDC, now the Centers for Disease Control and Prevention) Virus & Rickettsia Laboratory in Montgomery, Alabama. That vaccine, called Street Alabama Dufferin (SAD-B19), was used for the first mandatory mass immunization of dogs, marking the beginning of the end of dog-transmitted rabies in the US.1,13 Today, rabies vaccines are very safe and reliable, they induce long-lived protective immunity, and they are inexpensive and widely available. Yes, vaccines could conquer dog-transmitted rabies worldwide, but unless they are used diligently and widely, animals and people will continue to die of rabies. New vaccines based on molecular technology are being developed that are more protective for longer periods,14 but industry satisfaction with current profitable products and the exorbitant cost of regulatory approval inhibit their development and use. There is a serious international effort called Zero by 30 that attempts to immunize all dogs and end human rabies by 2030.15,16 Is that possible or realistic? There are approximately 650 million dogs worldwide, and only 10% to 15% are immunized against rabies. Approved vaccines must be readministered every 1 to 3 years. Most dogs that pose the greatest risk for human exposure to rabies are free roaming and difficult to trap or handle, and unless their reproduction is controlled, their populations increase every year. The admirable Zero by 30 initiative does not emphasize controlling the growth of dog populations. Therefore, if all 650 million dogs were immunized today, next year there will be several million more dogs to be vaccinated, and that will be repeated every year thereafter. Unless dog populations are controlled, mass immunization may never conquer dog-transmitted rabies. The technology needed to curtail dog reproduction and simultaneously immunize against rabies in a single vaccine is ready to be developed, if there is a commitment and adequate resources are dedicated to this worthy goal.17–21
Question: What are the chances of dying from rabies after being bitten by a rabid animal?
Answer: Preventive treatment after exposure to a rabid animal is very effective and has saved millions of lives (approx 15 million a year, worldwide).22 However, it must be administered urgently and is medically intensive, expensive, and not available to most people living in dog rabies–endemic countries. It is extremely important to determine whether an animal that bites is rabid, because most are not.5 If possible, a suspect companion animal should be taken alive and quarantined, but the time needed to exclude rabies by laboratory tests does not eliminate the need for a person at risk to be given preventive treatment. A dead animal’s head must be preserved for a veterinary pathologist to examine brain tissue for diagnosis of rabies. There is no approved diagnostic method that can diagnose rabies antemortem, but a reliable rapid test is within the capability of modern technology and could help to initiate prophylactic care promptly or prevent unnecessary anxiety and needless prophylaxis.23 Prevention after exposure to rabies includes wound care, injection of bite sites with antirabies immune serum followed by 4 doses of a human rabies vaccine given over 4 weeks.22,24 The antirabies human immunoglobulin and vaccine alone cost as much as $6,500, not including expenses for wound treatment and physician and hospital care or lost productivity and wages.1,25 Unfortunately, current human rabies vaccines used for postexposure treatment require multiple treatments given over weeks, which burdens impoverished communities with limited health care, resulting in poor compliance and needless mortality.26,27 Bat bite wounds are so small that they can be undetected or not considered significant, but they can be just as lethal as a rabid dog bite if preventive therapy is not given promptly.28 In fact, bats are the leading cause of human rabies deaths in the US (70%) and other countries where dog-transmitted rabies is controlled.6,29 Veterinarians, public health officials, and physicians faced with the decision to recommend postexposure treatment should refer to the latest recommendations of the CDC Committee on Immunization Practices for Human Rabies Prevention in the United States.22,30
Question: Can rabies be treated?
Answer: It is important to distinguish between prevention and treatment. As described above, postexposure prevention if given quickly and properly saves lives, but there is no reliable treatment for rabies once symptoms occur.31 Weeks or months after being bitten by a rabid animal, patients can develop progressively severe and ultimately lethal encephalitis. Differential diagnosis of rabies from other viral diseases is difficult without the patient recalling a bite wound and exhibiting symptoms of encephalitis, which may include thirst and fear of water (hydrophobia); this symptom is not definitive but is historically associated with rabies. Relentlessly advancing neurological degeneration usually ends in coma and death within weeks. Very few people recover from confirmed rabies, and survivors may be left with profound neurological deficits and a shortened life span.32 Can “untreatable” rabies encephalitis be treated to save lives and prevent crippling neurological deficits? With advanced technology, an appropriate priority, and sufficient support, treatment may be possible. Details of an approach to therapy are summarized below.
Question: If cancer, heart disease, and COVID-19 can be treated, why not rabies?
Answer: The instant the diagnosis of rabies is made, the virus has already infected the nervous system widely. The virus evades normal body defenses and keeps brain cells alive but crippled to serve as factories propagating more virus.33 The virus travels along nerves to infect salivary glands that facilitate transmission of the infection to the next animal or person bitten, completing the virus life cycle. The rabies virus is clever and deadly, but not invincible. Given appropriate commitment and funding, existing and promising technology are poised to treat rabies encephalitis.
The first and immediate therapy must be suppression of viral proliferation. The recent discovery of molecular methods that interfere with the viral genome provides hope for an effective way to block viral proliferation.34,35 Rabies viral inhibitory nucleotides have been discovered36 but can be effective clinically only if delivered through the blood-brain barrier to the brain and into neurons where rabies virus proliferates. The Nobel Prize was awarded for the discovery of a system of normal intercellular exchange called extracellular vesicles.37 These micron-sized spheres can be created and engineered to carry therapeutics across the blood-brain barrier, including antiviral nucleic acids against rabies.38,39
After proliferation is slowed, the virus must be neutralized. Systemic antibodies are excluded from the nervous system by the blood-brain barrier, requiring a method to deliver neutralizing antibodies directly to the brain. Adeno-associated viral vectors expressing recombinant antirabies antibodies can achieve astonishingly high rabies-neutralizing antibody titers in the serum and brain of mice and lower, but protective, levels in cats.40–42 This method complements suppression of viral production, and together they may achieve two of the most important missing elements of lifesaving therapy for rabies and possibly other viral encephalitides.
Rabies virus has evolved over millennia to evade host defenses and hijack cellular machinery to propagate itself while brain function diminishes progressively and ultimately fails. Since the metabolic pathways that enable rabies virus to inhibit neuronal function are being discovered, methods to defeat this crippling action are being revealed that may provide a way to preserve neurons while virus replication is blocked and antibodies neutralize the viral load.43,44
Louis Pasteur admonished, “to solve the problem of rabies would be a blessing for humanity.”38 On the 200th anniversary of Pasteur’s birth (December 27, 1822) we can celebrate remarkable progress in solving “the problem of rabies,” but the final solution has yet to be achieved. Worldwide eradication of dog-transmitted rabies is possible. Postexposure prevention is lifesaving if used promptly and properly. That leaves a cure as one of the last of Pasteur’s wishes for humanity to be achieved. Rabies is untreatable—only if it’s allowed to be untreatable!
Acknowledgments
Some of the research cited was supported in part by the Scott-Ritchey Research Center, the Auburn University Research Support Program, and an Edward Via College of Osteopathic Medicine One Health Research Grant.
Drs. Henry Baker, Douglas Martin, and Kent Van Kampen are inventors of the US Patent “Antibody Gene Therapy for Treatment and Prevention of Infection by Rabies Lyssavirus,” US Patent Office #PCT/US2020/051284, WO/2021/055614, filed March 25, 2021.
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