Rabies primary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

There is no known cure for symptomatic rabies, but it can be prevented by vaccination, both in humans and other animals. Virtually every infection with rabies was a death sentence, until Louis Pasteur and Emile Roux developed the first rabies vaccination in 1885. This vaccine was first used on a human on July 6, 1885 – nine-year old boy Joseph Meister (1876–1940) had been mauled by a rabid dog.[2] [3]

Their vaccine consisted of a sample of the virus harvested from infected (and necessarily dead) rabbits, which was weakened by allowing it to dry. Similar nerve tissue-derived vaccines are still used now in some countries, and while they are much cheaper than modern cell culture vaccines, they are not as effective and carry a certain risk of neurological complications.

The human diploid cell rabies vaccine (H.D.C.V.) was started in 1967. Human diploid cell rabies vaccines are made using the attenuated Pitman-Moore L503 strain of the virus. Human diploid cell rabies vaccines have been given to more than 1.5 million humans as of 2006. Newer and less expensive purified chicken embryo cell vaccine, and purified Vero cell rabies vaccine are now available. The purified Vero cell rabies vaccine uses the attenuated Wistar strain of the rabies virus, and uses the Vero cell line as its host.

Primary Prevention

Be a Responsible Pet Owner

• Keep vaccinations up to date for all dogs, cats, and ferrets. This requirement is important not only to keep your pets from getting rabies, but also to provide a barrier of protection for you, if your animal is bitten by a rabid wild animal.
• Keep your pets under direct supervision so they do not come in contact with wild animals. If your pet is bitten by a wild animal, seek veterinary assistance for the animal immediately.
• Call your local animal control agency to remove any stray animals from your neighborhood. They may be unvaccinated and could be infected by the disease.
• Spay or neuter your pets to help reduce the number of unwanted pets that may not be properly cared for or regularly vaccinated.

Avoid Direct Contact with Unfamiliar Animals

• Enjoy wild animals (raccoons, skunks, foxes) from afar. Do not handle, feed, or unintentionally attract wild animals with open garbage cans or litter.
• Never adopt wild animals or bring them into your home. Do not try to nurse sick animals to health. Call animal control or an animal rescue agency for assistance.
• Teach children never to handle unfamiliar animals, wild or domestic, even if they appear friendly. "Love your own, leave other animals alone" is a good principle for children to learn.
• Prevent bats from entering living quarters or occupied spaces in homes, churches, schools, and other similar areas, where they might come in contact with people and pets.
• When traveling abroad, avoid direct contact with wild animals and be especially careful around dogs in developing countries.
• Rabies is common in developing countries in Asia, Africa, and Latin America where dogs are the major reservoir of rabies.
• Tens of thousands of people die of rabies each year in these countries. Before traveling abroad, consult with a health care provider, travel clinic, or your health department about the risk of exposure to rabies, preexposure prophylaxis, and how you should handle an exposure, should it arise.

Pre-Exposure Prophylaxis

Currently pre-exposure immunization has been used on domesticated and normal non-human populations. In many jurisdictions, domestic dogs, cats, and ferrets are required to be vaccinated. A pre-exposure vaccination is also available for humans, most commonly given to veterinarians and those traveling to regions where the disease is common, such as India. Most tourists do not need such a vaccination, just those doing substantial non-urban activities. However, should a vaccinated human be bitten by a carrier, failure to receive subsequent post-exposure treatment could be fatal, although post-exposure treatment for a vaccinated human is far less extensive than which would normally be required by one with no pre-exposure vaccination.

In 1984 researchers at the Wistar Institute developed a recombinant vaccine called V-RG by inserting the glycoprotein gene from rabies into a vaccinia virus. The V-RG vaccine has since been commercialised by Merial under the trademark Raboral. It is harmless to humans and has been shown to be safe for various species of animals that might accidentally encounter it in the wild, including birds (gulls, hawks, and owls).

V-RG has been successfully used in the field in Belgium, France, and the United States to prevent outbreaks of rabies in wildlife. The virus is stable under relatively high temperatures and can be delivered orally, making mass vaccination of wildlife possible by putting it in tasty baits. The plan for immunization of normal populations involves dropping bait containing food wrapped around a small dose of the live virus. The bait would be dropped by helicopter concentrating on areas that have not been infected yet. Just such a strategy of oral immunization of foxes in Europe has already achieved substantial reductions in the incidence of human rabies. A strategy of vaccinating "neighborhood dogs" in Jaipur, India, (combined with a sterilization program) has also resulted in a large reduction in the number of human cases.

Risk for travellers

• The risk to travellers in areas where rabies occurs is proportional to the probability of contact with rabid mammals. In most developing countries, the estimated ratio of dogs, both owned and ownerless, to human beings is 1:10 and an average 100 suspected rabid dog bites per 100 000 inhabitants are reported annually. As rabies is a lethal disease, medical advice should be sought immediately at a competent medical centre – ideally, the rabies treatment centre of a major city hospital. First-aid measures should also be started immediately.

• Travellers should avoid contact with free-roaming animals, especially dogs and cats, and with wild, free-ranging or captive animals. For travellers who participate in caving or spelunking, casual exposure to cave air is not a concern, but cavers should be warned not to handle bats. In most countries of the world, suspected contact with bats should be followed by post-exposure prophylaxis.

• The following map shows WHO’s categories of risk, from no risk (rabies-free) countries or areas, to countries or areas of low, medium and high risk. Categorization is based primarily on the animal host species in which the rabies virus is maintained, e.g. bats and/or other wildlife and/or dogs, and on the availability of reliable laboratory-based surveillance data on these reservoir species. Access to proper medical care and the availability of modern rabies vaccines have also been taken into consideration on a country basis. In countries or areas with even low risk of rabies, pre-exposure immunization against rabies is recommended for travellers with certain characteristics:

No risk areas Low and medium risk areas: In these countries the following groups should receive pre-exposure prophylaxis: Travellers involved in any activities that might bring them into direct contact with bats and other wild animals (for example, wildlife professionals, researchers, veterinarians and travellers visiting areas where bats and wildlife are commonly found) High risk areas: In these countries the following groups should receive pre-exposure prophylaxis: Travellers spending considerable periods of time in rural areas Travelers involved in activities such as running, bicycling, camping or hiking Significant occupational risks, such as veterinarians, and expatriates living in areas with a significant risk of exposure to domestic animals, particularly dogs, and wild carnivores Children, as they are at higher risk through playing with animals, particularly dogs and cats; they may receive more severe bites and are less likely to report contact with animals suspected of having rabies

Courtesy dedicated to WHO
http://www.who.int/rabies/epidemiology/en/

Vaccine

Vaccination against rabies is used in two distinct situations:

• To protect those who are at risk of exposure to rabies, in other words pre-exposure vaccination.
• To prevent the development of clinical rabies after exposure has occurred, usually following the bite of an animal suspected of having rabies, in other words post-exposure prophylaxis.

The vaccines used for pre-exposure and post-exposure vaccination are the same, but the immunization schedule differs. Rabies immunoglobulin is used only for post-exposure prophylaxis. Modern vaccines of cell-culture or embryonated-egg origin are safer and more effective than the older vaccines, which were produced in mouse brain tissue. These modern rabies vaccines are now available in major urban centers of most countries of the developing world. Rabies immunoglobulin, on the other hand, is in short supply worldwide and may not be available, even in major urban centres, in many countries where canine rabies is prevalent.

Pre-exposure vaccination

• Pre-exposure immunization is recommended for all individuals living in or traveling to areas where rabies is highly enzootic, and for those exposed to rabies by nature of their occupation, including laboratory staff, veterinarians, animal handlers and wildlife officers. However, according to age-stratified studies of incidence, those at greatest risk are children living in rabies-enzootic regions of the developing world. Pre-exposure vaccination is therefore advisable for children living in or visiting areas with a high risk of rabies. Pre-exposure vaccination is also recommended for individuals travelling to isolated areas or to areas where immediate access to appropriate medical care is limited or to countries where modern rabies vaccines are in short supply and locally available rabies vaccines might be unsafe and/or ineffective.

• Pre-exposure rabies vaccination consists of three full intramuscular (IM) doses of cell-culture- or embryonated-egg-based vaccine given on days 0, 7 and 21 (or day 28, if more convenient); a few days’ variation in the timing is not important. For adults and children aged ≥2 years, the vaccine should always be administered in the deltoid area of the arm; for children aged <2 years, the anterolateral area of the thigh is recommended. Rabies vaccine should never be administered in the gluteal area: administration in this manner results in lower neutralizing antibody titres.
• To reduce the cost of cell-derived vaccines for pre-exposure rabies vaccination, intradermal vaccination in doses of 0.1 ml on days 0, 7 and either 21 or 28 may be considered. This method of administration is an acceptable alternative to the standard intramuscular administration, but it is technically more demanding and requires appropriately trained staff and qualified medical supervision. Concurrent use of chloroquine can reduce the antibody response to intradermal application of cell-culture rabies vaccines. People who are currently receiving malaria prophylaxis or who are unable to complete the entire three-dose pre-exposure series before starting malarial prophylaxis should therefore receive pre-exposure vaccination by the intramuscular route.
• Periodic booster injections are not recommended for general travellers. However, in the event of exposure through the bite or scratch of an animal known or suspected to be rabid, individuals who have previously received a complete series of pre- or post-exposure rabies vaccine (with cell-culture or embryonated-egg-derived vaccine) should receive two booster doses of vaccine. Ideally, the first dose should be administered on the day of exposure and the second 3 days later. This should be combined with thorough wound treatment (see Post-exposure prophylaxis, below). Rabies immunoglobulin is not required for patients who have previously received a complete vaccination series.

Precautions and contraindications

Modern rabies vaccines are well tolerated. The frequency of minor adverse reactions (local pain, erythema, swelling and pruritus) varies widely from one report to another. Occasional systemic reactions (malaise, generalized aches and headaches) have been noted after intramuscular or intradermal injections.

Post-exposure prophylaxis

In countries or areas at risk of rabies, the circumstances of an animal bite or other contact with an animal suspected to be rabid may require post-exposure prophylaxis. In such situations, medical advice should be obtained immediately. Strict adherence to the WHO-recommended guidelines for optimal post-exposure rabies prophylaxis virtually guarantees protection from the disease. The administration of vaccine, and of immunoglobulin if required, must be conducted by, or under the direct supervision of, a physician.

Category	Type of contact with a suspected or confirmed rabid domestic or wild(a) animal or animal unavailable for testing	Type of exposure	Recommended post-exposure prophylaxis
I	Touching or feeding of animals Licks on intact skin	None	None, if reliable case history is available
II	Nibbling of uncovered skin Minor scratches or abrasions without bleeding	Minor	Administer vaccine immediately(b). Stop treatment if animal remains healthy throughout an observation period of 10 days(c) or is proved to be negative for rabies by a reliable laboratory using appropriate diagnostic techniques.
III	Single or multiple transdermal bites or scratches, licks on broken skin Contamination of mucous membrane with saliva (i.e. licks) Exposures to bats(d)	Severe	Administer rabies immunoglobulin and vaccine immediately. Stop treatment if animal remains healthy throughout an observation period of 10 days(c) or is proved to be negative for rabies by a reliable laboratory using appropriate diagnostic techniques.

a)Exposure to rodents, rabbits and hares seldom, if ever, requires specific anti-rabies post-exposure prophylaxis.

b)If an apparently healthy dog or cat in or from a low-risk country or area is placed under observation, the situation may warrant delaying initiation of treatment.

c)This observation period applies only to dogs and cats. Except in the case of threatened or endangered species, other domestic and wild animals suspected to be rabid should be humanely killed and their tissues examined for the presence of rabies virus antigen using appropriate laboratory techniques.

d)Post-exposure prophylaxis should be considered for individuals who have been in close contact with bats, particularly following bites or scratches or exposure to mucous membranes.

• Wound treatment : Thorough washing of the wound with soap/detergent and water, followed by the application of ethanol or an aqueous solution of iodine or povidone.
• Passive immunization : Human rabies immunoglobulin or equine rabies immunoglobulin should be used for category III exposures as well as for some category II exposures (see Table 6.2). Passive immunization should be administered just before or shortly after administration of the first dose of vaccine given in the post-exposure prophylaxis regimen. If it is not immediately available, passive immunization can be administered up until the seventh day after initiation of the primary series of post-exposure prophylaxis (with cell-culture or embryonated-egg rabies vaccine).
  • Dosage and administration: The dose for human rabies immunoglobulin is 20 IU/kg body weight and for equine rabies immunoglobulin and F(ab)2 products 40 IU/kg body weight. The full dose of rabies immunoglobulin, or as much as is anatomically feasible, should be administered into and around the wound site. Any remainder should be injected intramuscularly at a site distant from the site of active vaccine administration. Multiple needle injections into the wound should be avoided. If the correct dose of rabies immunoglobulin is too small to infiltrate all wounds, as might be true of a severely bitten individual, it can be diluted in physiological buffered saline to ensure greater wound coverage.
• Active immunization: Cell-culture- or embryonated-egg-based rabies vaccines should always be used for post-exposure prophylaxis. They can be administered either intramuscularly or intradermally. Intramuscular regimens: Both a five-dose and a four-dose IM regimen are recommended for post-exposure vaccination; the fivedose regimen is the more commonly used.
  • The five-dose regimen is administered on days 0, 3, 7, 14 and 28 into the deltoid muscle.
  • The four-dose regimen is administered as two doses on day 0 (one dose in the right and one in the left arm (deltoid muscles), and then one dose on each of days 7 and 21 into the deltoid muscle.
• An alternative post-exposure regimen for healthy, fully immunocompetent exposed people who receive wound care plus high-quality rabies immunoglobulin plus WHO-prequalified rabies vaccines consists of four doses administered intramuscular on days 0, 3, 7 and 14.
• Intradermal regimens: Intradermal administration of cell-culture- and embryonated-egg-based rabies vaccines has been successfully used in many developing countries that cannot afford the five- or four-dose i.m. schedules.
  • The two-site intradermal method: one intradermal injection at two sites on days 0, 3, 7 and 28.
• The volume per intradermal injection should be 0.1 ml with both purified Vero cell rabies vaccine and purified chick embryo rabies vaccine.

Summary of vaccine data

	Considerations for travellers for Rabies vaccination
Type of vaccine	Modern cell-culture or embryonated-egg vaccine
Number of doses	Three, one on each of days 0, 7 and 21 or 28, given IM (1.0 or 0.5 ml/dose depending on the vaccine) or i.d. (0.1 ml/inoculation site).
Boosters	Not routinely needed for general travellers
Contraindications	Severe allergy to components of the vaccine
Adverse reactions	Minor local or systemic reactions.
Before departure	Pre-exposure prophylaxis for those planning a visit to a country or area at risk, especially if the area to be visited is far from urban centres and appropriate care, including the availability of postexposure rabies prophylaxis, cannot be assured.
Indication	Those planning to visit a country or an area of high risk for rabies.
Special precautions	Travellers should avoid contact with free-roaming animals, especially dogs and cats, and with wild, free-ranging or captive animals. For travellers who participate in caving or spelunking, casual exposure to cave air is not a concern, but cavers should be warned not to handle bats.

Preexposure Vaccinations

People who work with rabies in laboratory settings and animal control and wildlife officers are just a few of the people who should consider rabies preexposure vaccinations.

If you are traveling to a country where rabies is widespread, you should consult your doctor about the possibility of receiving preexposure vaccination against rabies.

Consider preexposure vaccination in:

• The patient stay longer than 1 month in an area where rabies is common.
• The patient will be visiting remote areas where medical care is difficult to obtain or may be delayed.
• Rabies research laboratory workers and rabies biologics production workers.
• Veterinarians and terrestrial animal-control workers in areas where rabies is uncommon to rare.
• All persons who frequently handle rabies vector animals.

Although preexposure vaccination does not eliminate the need for additional therapy after a rabies exposure, it simplifies management by eliminating the need for rabies immune globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk for exposure to rabies in areas where immunizing products might not be available or where lesser quality biologics might be used which would place the exposed person at increased risk for adverse events.

Preexposure prophylaxis may also protect people whose postexposure therapy is delayed and provide protection to people who are at risk for unapparent exposures to rabies.

Rabies Preexposure Prophylaxis Guide

Risk Category	Nature of Risk	Typical Population	Preexposure Recommendations
Continuous	Virus present continuously, often in high concentrations. Specific exposures likely to go unrecognized. Bite, nonbite, or aerosol exposure.	Rabies research laboratory workers; rabies biologics production workers.	Primary course. Serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level.
Frequent	Exposure usually episodic, with source recognized, but exposure also might be unrecognized. Bite, nonbite, or aerosol exposure.	Rabies diagnostic lab workers, spelunkers, veterinarians and staff, and animal-control and wildlife workers in rabies-enzootic areas. All persons who frequently handle bats.	Primary course. Serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level.
Infrequent	Exposure nearly always episodic with source recognized. Bite or nonbite exposure.	Veterinarians and terrestrial animal-control workers in areas where rabies is uncommon to rare. Veterinary students. Travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care including biologics is limited.	Primary course. No serologic testing or booster vaccination.
Rare (population at large)	Exposure always episodic with source recognized. Bite or nonbite exposure.	U.S. population at large, including persons in rabies-epizootic areas.	No vaccination necessary.

Primary vaccination

Three 1.0-mL injections of HDCV or PCEC vaccine should be administered intramuscularly (deltoid area) — one injection per day on days 0, 7, and 21 or 28. Vaccine preparations for intradermal administration are no longer available in the United States.

Booster doses

Continuous risk

People who work with rabies virus in research laboratories or vaccine production facilities are at the highest risk for unapparent exposures. Such persons should have a serum sample tested for rabies antibody every six months. Intramuscular booster doses of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT.

Frequent risk

This group includes other laboratory workers such as those performing rabies diagnostic testing, spelunkers, veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic. The frequent-risk category also includes persons who frequently handle bats, regardless of location in the Unites States. Persons in the frequent risk group should have a serum sample tested for rabies antibody every 2 years; if the titer is less than complete neutralization at a 1:5 serum dilution by the RFFIT, the person also should receive a single booster dose of vaccine.

Infrequent risk

Veterinarians, veterinary students, and terrestrial animal-control and wildlife officers working in areas where rabies is uncommon to rare (infrequent exposure group) and at-risk international travelers fall into this category and do not routine preexposure booster doses of vaccine after completion of primary preexposure vaccination.

Rabies vaccines and immunoglobulin available in the United States

Type	Name	Route	Indications
Human Diploid Cell Vaccine (HDCV)	Imovax® Rabies	Intramuscular	Preexposure or Postexposure
Purified Chick Embryo Cell Vaccine (PCEC)	RabAvert®	Intramuscular	Preexposure or Postexposure