Q&A: Global eradication of rabies possible with vaccination

Photo Arnon Shimshony
Arnon Shimshony
Photo of Boris Yakobson
Boris A. Yakobson

Rabies, an infectious viral disease that can be fatal without vaccination, causes tens of thousands of deaths every year globally, according to WHO.

Dogs are the main source of human rabies deaths and contribute up to 99% of all rabies transmissions to humans; however, rabies eradication is possible through vaccination of dogs and the prevention of dog bites, according to the health agency. Vaccinating dogs and eliminating canine rabies offers the most cost-effective strategy for preventing rabies in people.

According to the World Organization for Animal Health, nearly 100% of human rabies cases are preventable.

Sept. 28 is World Rabies Day. To promote awareness of this disease and provide clinicians with information to improve the prevention and treatment of rabies, Infectious Disease News spoke with its Editorial Board member Arnon Shimshony, DVM, associate professor at the Koret School of Veterinary Medicine at Hebrew University of Jerusalem, and Boris A. Yakobson DVM, PhD, head of the National & OIE Reference Rabies Laboratory at the Kimron Veterinary Institute in Israel. – by Savannah Demko

How big of a threat is rabies globally, and how can clinicians best advise their patients to prevent infection?

Shimshony: Human rabies is present in 150 countries and territories and on all continents. Endemic human rabies has become rare or has been eliminated in Western Europe, the United States and Canada and in dog rabies-free countries in Asia (Japan, Singapore, and Republic of Korea). The number of human rabies cases globally is estimated to be around 59,000, affecting mostly children in developing countries. Over 95% of human cases of rabies are due to dog bites, with the vast majority in Africa (36.4%) and Asia (59.6%). Less than 0.05% of estimated deaths occurred in the Americas, of which over 70% occurred in Haiti. India, with 35% of human rabies deaths, accounted for more deaths than any other country.

Human rabies cases in the U.S. are rare, with one to three cases reported annually, of which one, on average, contracted the virus outside of the U.S. The rabies reservoir in the U.S. is wildlife (bats, raccoons, skunks).

Owners of dogs and cats should vaccinate their animals annually or according to their vet’s advice. In rabies-endemic countries, avoid contact with wild or stray animals; never attempt to pick up an unusually tame animal, unowned puppies or animals that appear to be unwell. Following a possible rabies exposure, immediately wash the wound with detergent or soap for several minutes, apply a disinfectant and seek medical advice as early as possible.

Before traveling to rabies-endemic areas, it is advised to refer to CDC’s “Yellow Book for international travel. In some cases, it is advised to get a preventive rabies vaccination.

What improvements, if any, can be made in controlling, tracking and preventing rabies?

Yakobson: All improvements in the application of the well-known guidelines — such as vaccination of owned dogs and cats, vaccination and management of stray dog populations through the use of contraceptives and sterilants, along with oral vaccination of wild carnivores, public education and full implementation of prevailing legislation (eg, tie-up orders, individual animal identification and registry) — are beneficial.

Novel approaches for the treatment of clinical human cases by ribavirin and interferon-alpha deserve to be further explored, addressing their ability to cross the blood-brain barrier. The possible application of deliberate hypothermia requires further studies and clinical trials.

Equine anti-rabies serum (ERIG) and human rabies immunoglobulin (HRIG), currently used for rabies post-exposure serotherapy, are either associated with adverse effects (ERIG) or are extremely expensive (HRIG). Recent studies have shown that passive immunization of rodents with murine or human monoclonal antibodies (mAbs) specific for the G protein of rabies virus offers protection from the disease in a post-exposure situation. Research efforts are required to study and advance the great potential of antiviral mAbs as effective therapy against rabies in humans; such treatment can also abrogate a lethal rabies virus infection after the virus has entered the central nervous system. Recombinant DNA technology can be used to humanize murine mAbs, increasing the biological half-life and minimizing the possibility of adverse effects.

Can you discuss the importance of prompt treatment for rabies?

Yakobson: Following the exposure, usually a bite, the rabies virus first incubates in the site of inoculation, usually in muscle cells, and then travels through the peripheral nerves by retrograde axonal flow to the central nervous system. The length of time until development of clinical signs is related in part to the distance the virus must travel. A bite to a distal periphery has a longer incubation period than a bite to the face. This provides time for post-exposure vaccination to work, even in the absence of prior vaccination. Such post-exposure protocol should start with immediate local treatment of the wound (flushing and washing for a minimum of 15 minutes with soap and water, then disinfecting the wound), followed by administration of the vaccine (with or without rabies immune globulin [RIG] depending upon the type of exposure).

Appropriate wound cleansing and disinfection can prevent one-third of rabies infections. Modern cell culture vaccines used in combination with RIG are nearly 100% effective in preventing human deaths if inoculated promptly to rabies virus-exposed victims following appropriate wound management. Any delay in implementation may cause a failure of the treatment.

What is the controversy surrounding the Milwaukee protocol?

Yakobson: In 2004, a young patient from Wisconsin who was infected by a bat survived rabies. She was treated by the induction of therapeutic coma and the use of N-methyl D-aspartate (NMDA) receptor antagonist therapy. This treatment suppressed her neuronal activity and delayed the progression of rabies symptoms, effectively allowing time for her adaptive immune system to produce enough antibodies to attack the virus and neutralize the infection. Her therapy was dubbed the Milwaukee protocol.

Out of 41 patients who have so far been treated according to the protocol, six have survived. It is uncertain whether these successes can be attributed to the protocol itself or to exposure of the patient to a low-pathogenic variant of the rabies virus, coupled with the patient’s robust immune response.

A study done in Peru found that seven out of the 63 people infected by bats tested positive for rabies antibodies. Of those people, only one had previously received the rabies vaccine. This meant that the other six had produced antibodies on their own after being exposed to the bat virus and survived. According to alternative explanations, a rabies-related virus with low pathogenicity induced cross-reactive antibodies, or a large enough dose of rabies elicited an immune response but viral replication did not occur.

The Milwaukee protocol has been recently criticized and remains controversial.

What is the take-home message for clinicians on World Rabies Day?

Yakobson: Dog-borne rabies, the most common and devastating form of this fatal zoonotic disease in the past, has been practically eradicated from all developed countries. In some of them, sylvatic rabies has been similarly eradicated. This should not lead to total negligence. The continued circulation of the virus in bats in various countries and the possibility of rabies cases in those returning from visiting rabies-stricken parts of the world should not be forgotten.

Clinicians in developed countries should inform patients traveling to dog-borne rabies-affected countries about the rabies hazard, indicating the need to avoid contact with animals and to seek immediate medical help when exposure is suspected. Those returning from recent travels should be questioned about suspected exposures, and measures should be undertaken immediately if they were bitten or scratched. In view of the availability, safety and efficacy of post-exposure prophylaxis (PEP), such inquiries might be life-saving. Contacts with bats, even in a rabies-free country, should be considered as a potential exposure to rabies. Those dealing directly with bats should receive PEP.

In rabies-endemic countries, clinicians should advise or perform PEP in any suspected exposures without delay, applying biologicals obtained from certified, state-controlled manufacturers.

References:

WHO. WHO Guide for Rabies Pre- and Post-Exposure Prophylaxis in Humans.http://www.who.int/rabies/PEP_Prophylaxis_guideline_15_12_2014.pdf. Accessed on Sept. 25, 2017.

WHO. Rabies Fact Sheet. http://www.who.int/mediacentre/factsheets/fs099/en. Accessed on Sept. 25, 2017.

World Organization for Animal Health. No more Deaths from Rabies. http://www.oie.int/infographic/rabies/index.html. Accessed on Sept. 25, 2017.

Disclosures: Shimshony and Yakobson report no relevant financial disclosures.

Photo Arnon Shimshony
Arnon Shimshony
Photo of Boris Yakobson
Boris A. Yakobson

Rabies, an infectious viral disease that can be fatal without vaccination, causes tens of thousands of deaths every year globally, according to WHO.

Dogs are the main source of human rabies deaths and contribute up to 99% of all rabies transmissions to humans; however, rabies eradication is possible through vaccination of dogs and the prevention of dog bites, according to the health agency. Vaccinating dogs and eliminating canine rabies offers the most cost-effective strategy for preventing rabies in people.

According to the World Organization for Animal Health, nearly 100% of human rabies cases are preventable.

Sept. 28 is World Rabies Day. To promote awareness of this disease and provide clinicians with information to improve the prevention and treatment of rabies, Infectious Disease News spoke with its Editorial Board member Arnon Shimshony, DVM, associate professor at the Koret School of Veterinary Medicine at Hebrew University of Jerusalem, and Boris A. Yakobson DVM, PhD, head of the National & OIE Reference Rabies Laboratory at the Kimron Veterinary Institute in Israel. – by Savannah Demko

How big of a threat is rabies globally, and how can clinicians best advise their patients to prevent infection?

Shimshony: Human rabies is present in 150 countries and territories and on all continents. Endemic human rabies has become rare or has been eliminated in Western Europe, the United States and Canada and in dog rabies-free countries in Asia (Japan, Singapore, and Republic of Korea). The number of human rabies cases globally is estimated to be around 59,000, affecting mostly children in developing countries. Over 95% of human cases of rabies are due to dog bites, with the vast majority in Africa (36.4%) and Asia (59.6%). Less than 0.05% of estimated deaths occurred in the Americas, of which over 70% occurred in Haiti. India, with 35% of human rabies deaths, accounted for more deaths than any other country.

Human rabies cases in the U.S. are rare, with one to three cases reported annually, of which one, on average, contracted the virus outside of the U.S. The rabies reservoir in the U.S. is wildlife (bats, raccoons, skunks).

Owners of dogs and cats should vaccinate their animals annually or according to their vet’s advice. In rabies-endemic countries, avoid contact with wild or stray animals; never attempt to pick up an unusually tame animal, unowned puppies or animals that appear to be unwell. Following a possible rabies exposure, immediately wash the wound with detergent or soap for several minutes, apply a disinfectant and seek medical advice as early as possible.

Before traveling to rabies-endemic areas, it is advised to refer to CDC’s “Yellow Book for international travel. In some cases, it is advised to get a preventive rabies vaccination.

PAGE BREAK

What improvements, if any, can be made in controlling, tracking and preventing rabies?

Yakobson: All improvements in the application of the well-known guidelines — such as vaccination of owned dogs and cats, vaccination and management of stray dog populations through the use of contraceptives and sterilants, along with oral vaccination of wild carnivores, public education and full implementation of prevailing legislation (eg, tie-up orders, individual animal identification and registry) — are beneficial.

Novel approaches for the treatment of clinical human cases by ribavirin and interferon-alpha deserve to be further explored, addressing their ability to cross the blood-brain barrier. The possible application of deliberate hypothermia requires further studies and clinical trials.

Equine anti-rabies serum (ERIG) and human rabies immunoglobulin (HRIG), currently used for rabies post-exposure serotherapy, are either associated with adverse effects (ERIG) or are extremely expensive (HRIG). Recent studies have shown that passive immunization of rodents with murine or human monoclonal antibodies (mAbs) specific for the G protein of rabies virus offers protection from the disease in a post-exposure situation. Research efforts are required to study and advance the great potential of antiviral mAbs as effective therapy against rabies in humans; such treatment can also abrogate a lethal rabies virus infection after the virus has entered the central nervous system. Recombinant DNA technology can be used to humanize murine mAbs, increasing the biological half-life and minimizing the possibility of adverse effects.

Can you discuss the importance of prompt treatment for rabies?

Yakobson: Following the exposure, usually a bite, the rabies virus first incubates in the site of inoculation, usually in muscle cells, and then travels through the peripheral nerves by retrograde axonal flow to the central nervous system. The length of time until development of clinical signs is related in part to the distance the virus must travel. A bite to a distal periphery has a longer incubation period than a bite to the face. This provides time for post-exposure vaccination to work, even in the absence of prior vaccination. Such post-exposure protocol should start with immediate local treatment of the wound (flushing and washing for a minimum of 15 minutes with soap and water, then disinfecting the wound), followed by administration of the vaccine (with or without rabies immune globulin [RIG] depending upon the type of exposure).

Appropriate wound cleansing and disinfection can prevent one-third of rabies infections. Modern cell culture vaccines used in combination with RIG are nearly 100% effective in preventing human deaths if inoculated promptly to rabies virus-exposed victims following appropriate wound management. Any delay in implementation may cause a failure of the treatment.

PAGE BREAK

What is the controversy surrounding the Milwaukee protocol?

Yakobson: In 2004, a young patient from Wisconsin who was infected by a bat survived rabies. She was treated by the induction of therapeutic coma and the use of N-methyl D-aspartate (NMDA) receptor antagonist therapy. This treatment suppressed her neuronal activity and delayed the progression of rabies symptoms, effectively allowing time for her adaptive immune system to produce enough antibodies to attack the virus and neutralize the infection. Her therapy was dubbed the Milwaukee protocol.

Out of 41 patients who have so far been treated according to the protocol, six have survived. It is uncertain whether these successes can be attributed to the protocol itself or to exposure of the patient to a low-pathogenic variant of the rabies virus, coupled with the patient’s robust immune response.

A study done in Peru found that seven out of the 63 people infected by bats tested positive for rabies antibodies. Of those people, only one had previously received the rabies vaccine. This meant that the other six had produced antibodies on their own after being exposed to the bat virus and survived. According to alternative explanations, a rabies-related virus with low pathogenicity induced cross-reactive antibodies, or a large enough dose of rabies elicited an immune response but viral replication did not occur.

The Milwaukee protocol has been recently criticized and remains controversial.

What is the take-home message for clinicians on World Rabies Day?

Yakobson: Dog-borne rabies, the most common and devastating form of this fatal zoonotic disease in the past, has been practically eradicated from all developed countries. In some of them, sylvatic rabies has been similarly eradicated. This should not lead to total negligence. The continued circulation of the virus in bats in various countries and the possibility of rabies cases in those returning from visiting rabies-stricken parts of the world should not be forgotten.

Clinicians in developed countries should inform patients traveling to dog-borne rabies-affected countries about the rabies hazard, indicating the need to avoid contact with animals and to seek immediate medical help when exposure is suspected. Those returning from recent travels should be questioned about suspected exposures, and measures should be undertaken immediately if they were bitten or scratched. In view of the availability, safety and efficacy of post-exposure prophylaxis (PEP), such inquiries might be life-saving. Contacts with bats, even in a rabies-free country, should be considered as a potential exposure to rabies. Those dealing directly with bats should receive PEP.

In rabies-endemic countries, clinicians should advise or perform PEP in any suspected exposures without delay, applying biologicals obtained from certified, state-controlled manufacturers.

References:

WHO. WHO Guide for Rabies Pre- and Post-Exposure Prophylaxis in Humans.http://www.who.int/rabies/PEP_Prophylaxis_guideline_15_12_2014.pdf. Accessed on Sept. 25, 2017.

WHO. Rabies Fact Sheet. http://www.who.int/mediacentre/factsheets/fs099/en. Accessed on Sept. 25, 2017.

World Organization for Animal Health. No more Deaths from Rabies. http://www.oie.int/infographic/rabies/index.html. Accessed on Sept. 25, 2017.

Disclosures: Shimshony and Yakobson report no relevant financial disclosures.

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