Rabies

KEY FACTS

Rabies is widely distributed across the globe. More than 55 000 people die of rabies each year.
About 95% of human deaths occur in Asia and Africa.

Most human deaths follow a bite from an infected dog. Between 30% to 60% of the victims of dog
bites are children under the age of 15.

Wound cleansing and immunizations, done as soon as possible after suspect contact with an animal
and following WHO recommendations, can prevent the onset of rabies in virtually 100% of
exposures.

Once the signs and symptoms of rabies start to appear, there is no treatment and the disease is
almost always fatal.

Globally, the most cost-effective strategy for preventing rabies in people is by eliminating rabies in
dogs through animal vaccinations.

Rabies is a zoonotic disease (a disease that is transmitted to humans from animals) that is caused by
a virus. Rabies infects domestic and wild animals, and is spread to people through close contact with
infected saliva (via bites or scratches). The disease is present on nearly every continent of the world
but most human deaths occur in Asia and Africa (more than 95%). Once symptoms of the disease
develop, rabies is fatal.

Symptoms

The first symptoms of rabies are flu-like, including fever, headache and fatigue, and then progress to
involve the respiratory, gastrointestinal and/or central nervous systems. In the critical stage, signs of
hyperactivity (furious rabies) or paralysis (dumb rabies) dominate. In both furious and dumb rabies,
some paralysis eventually progresses to complete paralysis, followed by coma and death in all cases,
usually due to breathing failure. Without intensive care, death occurs during the first seven days of
illness.

Transmission

Dogs continue to be the main carrier of rabies in Africa and Asia and are responsible for most of the
human rabies deaths worldwide. Humans most often become infected with rabies through the bite
or scratch of an infected dog or cat.

In developed countries rabies continues mainly in wild animals. The disease is transmitted to
domestic animals and humans through exposure to infected saliva. In the past few years, bat rabies
has emerged as a public health problem in the Americas and Europe. For the first time in 2003, more
people in South America died from rabies following exposure to wildlife, particularly bats, than from
dogs.
Human rabies deaths following exposure to wild foxes, raccoons, skunks, jackals and wolves are very
rare. Livestock, horses and deer can become infected with rabies, but although they could transmit
the virus to other animals or people, this rarely occurs.

Who is most at risk?

People most at risk of rabies live in rural areas of Africa and Asia. An estimated 31 000 people die
from dog rabies in Asia each year. In Africa the annual death toll is 24 000. Dog rabies is responsible
for more than 14 million courses of post-exposure treatment to prevent the onset of disease. The
economic burden of rabies in the developing world also takes a large toll. The average cost of rabies
immunizations after a suspicious animal bite is US$ 40 in Africa, and US$ 49 in Asia. This post-
exposure treatment is a major financial burden for most households in these countries, where the
average wage is about US$ 1 to US$ 2 per day, per person.

Poor people, especially children, are at highest risk of dog rabies. About 30% to 60% of the victims of
dog bites (the primary mode of virus transmission) are children less than 15 years of age. Children
often play with animals and are less likely to report bites or scratches.

In areas known for rabies, professionals with frequent exposure to animals (e.g. veterinarians), or
who spend a lot of time outdoors (e.g. wildlife specialists or researchers), particularly in rural areas,
should be vaccinated preventively. This also applies to travelers and hikers who visit areas where
bats are commonly found.

Treatment after exposure

Wound cleansing and immunizations, done as soon as possible after suspect contact with an animal
and following WHO recommendations, can prevent the onset of rabies in virtually 100% of
exposures. Recommended treatment to prevent rabies depends on the category of the contact:

Category I: touching or feeding suspect animals, but skin is intact

Category II: minor scratches without bleeding from contact, or licks on broken skin

Category III: one or more bites, scratches, licks on broken skin, or other contact that breaks the skin;
or exposure to bats

Post-exposure care to prevent rabies includes cleaning and disinfecting a wound, or point of contact,
and then administering anti-rabies immunizations as soon as possible. Anti-rabies vaccine is given for
Category II and III exposures. Anti-rabies immunoglobin, or antibody, should be given for Category III
contact, or to people with weaker immune systems.

When humans are exposed to suspect animals, attempts to identify, capture or humanely sacrifice
the animal involved should be undertaken immediately. Post-exposure treatment should start right
away and only be stopped if the animal is a dog or cat and remains healthy after 10 days. Animals
that are sacrificed or have died should be tested for the virus, with results sent to responsible
veterinary services and public health officials so that the situation in the area is well documented.
More about immunizations

The WHO guide on preventive immunizations against rabies is aimed to ensure that effective and
potent treatment is provided, even where vaccines are in very short supply - as is the case in many
developing countries. Alternative, more economical vaccination approaches have been successful in
developing countries where funding for vaccines and vaccine supplies are limited. Health staff must
be well trained in techniques and vaccines must be stored appropriately for effectiveness.

Rabies immunoglobulin (antibody) vaccines - which are recommended for use in Category III cases
and for exposures in immunosuppressed people - are expensive and can be in short supply or non-
existent in most developing countries. Purified equine (horse) rabies immunoglobulin provide at
least a partial solution to current problems of insufficient quantities and the high cost of human
immunoglobulin in developing countries.

Prevention

Safe and effective vaccines are available to prevent rabies in animals, and in humans before and
after suspected exposures. Vaccination of domestic animals (mostly dogs) and wildlife (such as foxes
and raccoons) has led to reduced disease in several developed and developing countries. However,
recent increases in human rabies deaths in South America and parts of Africa and Asia evidence that
rabies is re-emerging as a serious public health issue.

The most cost-effective strategy for preventing rabies in people is by eliminating rabies in dogs
through animal vaccinations. A lack of awareness of the effectiveness and feasibility of this
prevention approach hinders elimination of human cases. As shown in several countries - such as
Japan and Malaysia - elimination of rabies in dogs can result in elimination of transmissions to
people and other animals. Preventing human rabies through control of domestic dog rabies is a
realistic goal for large parts of Africa and Asia.

Prevention of human rabies must be a community effort involving both veterinary and public health
services. Rabies elimination efforts that focus on mass vaccinations of dogs are financially justified
by the future savings of discontinuing post-exposure preventive treatment for people.

Guide for post-exposure prophylaxis

The recommendations given here are intended as a general guide. It is recognized that, in certain
situations, modifications of the procedures laid down may be warranted. Such situations include
exposure of infants or mentally disabled persons and other circumstances where a reliable history
cannot be obtained, particularly in areas where rabies is enzootic, even though the animal is
considered to be healthy at the time of exposure. Such cases may be treated as category II or III.

Post-exposure treatment, which consists of local treatment of the wound, followed by vaccine
therapy (with or without rabies immunoglobulin) should be initiated immediately with contacts of
categories II and III. Treatment may be discontinued if the animal involved (dog or cat) remains
healthy throughout an observation period of 10 days; or if the animal is killed humanely and found
to be negative for rabies by laboratory examination. Any biting animal suspected of being rabid
should be immediately killed humanely and tissues examined using appropriate laboratory
technique(s). Modification of the recommended procedures would be indicated in a rabies-free area
where animal bites are encountered. In areas where canine or wildlife rabies is epizootic, adequate
laboratory and field experience, indicating that there is no infection in the species involved, may
justify local health authorities in not recommending specific anti-rabies treatment.

The indication for post-exposure vaccination with or without rabies immune globulin depends on the
type of contact with the rabid animal.

Types of contact are:

category I – touching or feeding animals, licks on the skin

category II - nibbling of uncovered skin, minor scratches or abrasions without bleeding, licks on
broken skin

category III – single or multiple transdermal bites or scratches, contamination of mucous membrane
with saliva from licks; exposure to bat bites or scratches

For category I no treatment is required, whereas for category II immediate vaccination and for
category III immediate vaccination and administration of rabies immune globulin are recommended
in addition to immediate washing and flushing of all bite wounds and scratches. Depending on
vaccine type, the post-exposure schedule prescribes intramuscular doses of 1 ml or 0.5 ml given as
four to five doses over four weeks. For rabies-exposed patients who have previously undergone
complete pre-exposure vaccination or post-exposure treatment with cell-derived rabies vaccines,
two intramuscular doses of a cell-derived vaccine separated by three days are sufficient. Rabies
immune globulin treatment is not necessary in such cases. The same rules apply to persons
vaccinated against rabies who have demonstrated neutralizing antibody titres of at least 0.5 IU/ml.

In order to reduce the cost of post-exposure treatment, intradermal multi-site regimens using a
fraction of the intramuscular volume per intradermal inoculation site have been developed. Purified
Vero cell vaccine has been given intradermally to more than 70 000 recipients in Thailand, where it
has been in routine use for several years. Intradermal rabies vaccination is also recommended by the
ministries of health of Sri Lanka (since 1995) and the Philippines (since 1997). In each of these
countries the introduction of this route for post-exposure treatment has permitted the
discontinuation of the local production of vaccines prepared on brain tissue. Only the cell-derived
vaccines that meet the WHO requirements regarding safety, potency and efficacy for this application
may be considered for intradermal use. Although rabies vaccines are usually administered under
qualified medical supervision, field experience from routine infant immunization programmes with
other intradermally injected vaccines highlights the potential difficulties in assuring proper delivery.
This emphasizes the need for appropriate staff training to ensure correct storage, reconstitution and
injection. Provided that a correct sterile technique is used, the remaining doses may be kept in the
vial at 2–8°C and used for another patient within six hours after reconstitution.

Tissue-culture or purified duck-embryo vaccines of potency at least 2.5 IU per single intramuscular
immunizing dose should be applied according to the following schedules.
Intramuscular schedules

One dose of the vaccine should be administered on days 0, 3, 7, 14 and 30. All intramuscular
injections must be given into the deltoid region or, in small children, into the anterolateral area of
the thigh muscle. Vaccine should never be administered in the gluteal region.

Abbreviated multisite schedule

In the abbreviated multisite schedule, the 2-1-1 regimen, one dose is given in the right arm and one
dose in the left arm at day 0, and one dose applied in the deltoid muscle on days 7 and 21. The 2-1-1
schedule induces an early antibody response and may be particularly effective when post-exposure
treatment does not include administration of rabies immunoglobulin.

Intradermal schedule

WHO recommended the following intradermal regimens and vaccines for use by the intradermal
route:

8-site intradermal method (8-0-4-0-1-1) for use with HDC (Rabivac TM) and PCEVC (Rabipur TM)

The 8 sites regimen should be particularly considered in emergency situations when no RIG is
available

2-site intradermal method (2-2-2-0-1-1) for use with PVRV (Verorab TM, Imovax TM, Rabies vero TM,
TRC Verorab TM) and PCECV (Rabipur TM)

For 8-site intradermal method (8-0-4-0-1-1)

For use with:

Human diploid cell vaccine (HDCV) (Rabivac TM) and

Purified chick embryo cell vaccine (PCECV) (Rabipur TM) both vaccines at 0.1 ml per intradermal site

For 2-site intradermal method (2-2-2-0-1-1)

The volume per intradermal site is:

0.1 ml for PVRV (Verorab TM, Imovax TM, Rabies vero TM, TRC Verorab TM)

0.1 ml for PCECV (Rabipur TM)

Brain-tissue vaccines

The use of brain-tissue vaccines should be discontinued. WHO does not recommend any schedule
using brain-tissue vaccine. National authorities should recommend a schedule of immunization that
has been shown to induce an adequate level of protection when brain tissue vaccines are available
in that country.
Combined immunoglobulin-vaccine

Combined immunoglobulin-vaccine treatment was considered in the eighth report of the WHO
Expert Committee as the best specific systemic treatment available at that time for the post-
exposure prophylaxis of rabies in humans, although experience indicated that vaccine alone was
sufficient for minor exposures (category II). Immunoglobulin should be given in a single dose of 20 IU
per kg of body weight for human anti-rabies immunoglobulin, and 40 IU per kg of body weight for
heterologous (equine) immunoglobulin; the first dose of vaccine should be inoculated at the same
time as the immunoglobulin, but in a different part of the body. Sensitivity to heterologous
immunoglobulin must be determined before it is administered. The physician should be prepared to
deal with anaphylactic shock reactions. Administration of rabies immunoglobulin (RIG) should be
infiltrated into the depth of the wound and around the wound as much as anatomically feasible. Any
remainder should be injected at an intramuscular site distant from that of vaccine inoculation e.g.
into the anterior thigh.

Treatment should be started as early as possible after exposure, but in no case should it be denied to
exposed persons whatever time interval has elapsed.

Local treatment of wounds

Local treatment of wounds involving possible exposure to rabies – recommended in all exposures.

Criteria for application withholding of post-exposure treatment

The combination of local treatment of the wound, passive immunization with rabies
immunoglobulins (RIG) and vaccination is recommended for all severe exposures (category III) to
rabies. Prompt and thorough cleansing of the wound, and administration of purified equine or
human rabies immunoglobulins (ERIG or HRIG) and cell-culture rabies vaccine immediately after
exposure virtually guarantee complete protection, and the risk of post-exposure treatment
complications is much lower than with brain-tissue vaccines. Pregnancy and infancy are never
contraindications to post-exposure rabies vaccination. Since prolonged incubation periods have
been noted, persons who present for evaluation and treatment even months after having been
bitten should be dealt with in the same manner as if the contact occurred recently.

Factors that should be considered in deciding whether or not to initiate post-exposure treatment
are:

the nature of the contact

the presence of rabies in the area where the contact occurred or from which the animal involved
came

the species of the animal involved

the vaccination and clinical status of the animal involved, the type of vaccine used and the
availability of the animal for observation

the results of laboratory testing of the animal for rabies, if available

An apparently healthy dog or cat that bites a person may or may not justify the initiation of
treatment, depending on the perceived risk. If the animal involved is a recognized rabies vector in
the area where the contact occurred, initiation of treatment should never await the results of
laboratory diagnosis. If the animal is suspected of being rabid, immediate euthanasia and laboratory
examination of the brain should be performed. Wound treatment must be completed and serum
and vaccine therapy instituted as soon as possible after any exposure. If the species involved is
unlikely to be infected with rabies, treatment may be deferred pending the outcome of laboratory
testing provided that diagnosis can be made within 48 hours. A report from a reliable laboratory
indicating a negative result usually justifies cessation of treatment.

If the animal involved is a dog or cat, it should be kept under observation, preferably under
veterinary supervision, for 10 days. Treatment may be discontinued if the dog or cat remains healthy
during this period. The eighth report of the WHO Expert Committee suggested, however, that
people in contact with animals other than cats and dogs that are suspected of being rabid should
receive full post-exposure treatment unless the animal is available and can be killed humanely and
examined for rabies in a reliable laboratory immediately.

First aid treatment

Since elimination of rabies virus at the site of infection by chemical or physical means is the most
effective mechanism of protection, immediate washing and flushing with soap and water, detergent
or water alone are imperative (this procedure is recommended for all bite wounds, including those
unrelated to possible exposure to rabies). Then apply either ethanol (700 ml/l) or tincture or
aqueous solution of iodine.

Treatment by, or under direction of a physician

Treat as described above and then:

apply anti-rabies immunoglobulin by careful instillation in the depth of the wound and by infiltration
around the wound

postpone suturing of the wound

if suturing is necessary, ensure that immunoglobulin has been applied locally as described above

where indicated, begin anti-tetanus treatment and administer antimicrobials and drugs to control
infections other than rabies.

Local treatment of wounds

The eighth report of the WHO Expert Committee emphasized the importance of prompt local
treatment of all bite wounds and scratches that may be contamined with rabies virus, even if the
person presents after a prolonged period.

Photo by David Warrell

Recommended first-aid procedures are immediate thorough flushing and washing of the wound with
soap and water, detergent or other substances of proven lethal effect on rabies virus. People who
live in rabies infected areas should be educated in simple local wound treatment and warned not to
use procedures that may further contaminate the wounds. If possible, suturing of wounds should be
avoided; however, if suturing is necessary, anti-rabies immunoglobulin should be infiltrated around
the wound. Other treatments, such as administration of antibiotics or anti-tetanus procedures, when
indicated, should follow the local treatment.

Administration of rabies immunoglobulin

Rabies immunoglobulin (RIG) should be given for all category III exposures, irrespective of the
interval between exposure and beginning of treatment. Two kinds of rabies antibody preparations
may be used: human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). A skin
test must be performed prior to the administration of ERIG. As much as possible of the
recommended dose (20 IU/kg of body weight of HRIG or 40 IU/kg of body weight of ERIG) should be
infiltrated around the wounds if anatomically feasible. The remainder should be administered
intramuscularly (into gluteal region) in a single dose and followed by a complete course of vaccine.

Rabies immunoglobulin of human origin (HRIG) is available in some countries; however, it is

expensive and only limited amounts are available.

Rabies immunoglobulin of equine origin (ERIG) is available in many countries and is considerably
cheaper than HRIG. Most of the currently available preparations of ERIG are highly purified and quite
safe; however, a skin test should always be carried out prior to its use.

Certificate of post-exposure treatment

A certificate of post-exposure rabies treatment should be filled in and given to each vaccinee.

Post-exposure treatment of previously vaccinated persons

Local treatment of wounds should always be carried out. On the basis of the information available at
the time, the eighth report of the WHO Expert Committee recommended that persons who had
previously received full pre- or post-exposure treatment with a potent cell-culture vaccine should be
given only two booster doses, either intramuscularly or intradermally, on days 0 and 3, but no rabies
immunoglobulin. Persons who have previously received pre- or post-exposure treatment with
vaccines of unproven potency, and those who have not demonstrated an acceptable rabies
neutralizing antibody titre, should receive a complete post-exposure course, including rabies
immunoglobulin if indicated.

Complications of anti-rabies treatment

Anti-rabies immunoglobulin

It has been shown that purified equine rabies immunoglobulin products cause adverse reactions in
1-6% of vaccinees, even when sensitivity tests are performed prior to their administration.
Unpurified anti-rabies sera should be avoided whenever possible.
Nerve-tissue vaccine

Repeated inoculations of homogenates of brain tissue may induce immune responses to some
neural antigens. In the case of Semple-type vaccine, these neurological complications are attributed
to myelin basic protein and some of the ganglioside and phospholipid constituents. Though properly
prepared suckling-mouse brain vaccines contain virtually no myelin, neurological complications still
occur, but at a much lower rate than with adult nerve-tissue vaccines.

Patients who develop neurological complications from Semple-type vaccines have higher levels of
rabies virus-neutralizing antibodies than vaccinees without complications. Dexamethasone is
beneficial in managing such reactions, but significantly depresses the virus-neutralizing antibody
level, even when a full vaccination schedule is repeated, using a cell-culture vaccine. The eighth
report of the WHO Expert Committee therefore suggested that such patients should receive twice
the normal amount of cell-culture vaccine when dexamethasone is given.

Cell-culture vaccines and purified duck-embryo vaccine

These vaccines have not been casually associated with serious adverse effects. Mild serum sickness-
like and urticarial reactions have occasionally been observed following booster doses of some of
these vaccines.