Advances Volume 24 No.

6
in Therapy® November/December 2007

Rabies: Epidemiology,
Pathogenesis, and Prophylaxis
Alexander K. C. Leung, MBBS, FRCPC, FRCP (UK&Irel), FRCPCH
Department of Pediatrics
University of Calgary
Alberta Children’s Hospital
Calgary, Alberta, Canada
H. Dele Davies, MD, FRCPC
Department of Pediatrics and Human Development
Michigan State University
East Lansing, Michigan
Kam-Lun Ellis Hon, MD, FAAP
Department of Pediatrics
Chinese University of Hong Kong
Prince of Wales Hospital
Shatin, Hong Kong SAR, China

ABSTRACT
Rabies is a viral zoonosis that causes approximately 50,000 to 100,000
deaths per year worldwide. Most deaths occur in developing countries.
Dogs are the major vector, especially in developing countries. The virus is
usually transmitted to humans by infected saliva through the bite of
a rabid animal; the incubation period averages 30 to 90 d. Hyperexcitability,
autonomic dysfunction, hydrophobia, and aerophobia are characteristic
of encephalitic rabies, which accounts for 80% of cases. The paralytic form
is characterized by flaccid paralysis in the bitten limb, which ascends
symmetrically or asymmetrically. Once symptoms develop, the disease is
invariably fatal. Animal rabies can be controlled by proper induction of
herd immunity, humane removal of stray animals, promotion of respon-
sible pet ownership through education, and enactment of leash laws.
Preexposure vaccination with modern cell culture vaccine is recommend-
ed for people at high risk of exposure to rabies and for travelers who
spend longer than 1 mo in countries where rabies is a constant threat, or
who travel in a country where immediate access to appropriate care is lim-
ited. Postexposure prophylaxis consists of prompt and thorough wound
cleansing and immunization with modern cell culture vaccine, together
with administration of rabies immune globulin to those individuals who
have not previously received preexposure prophylaxis.

Keywords: rabies; fatal; dogs; vaccine; immune globulin

©
2007 Health Communications Inc Address correspondence to
Transmission and reproduction of this material in whole Dr. Alexander K.C. Leung
or part without prior written approval are prohibited. #200, 233-16th Avenue NW
Calgary, Alberta T2M 0H5
1335 Canada
Email: aleung@ucalgary.ca
1340
INTRODUCTION
The word rabies is derived from the Sanskrit word rabhas, which means “to rage,”
or from the Latin word rabere, which means “to rave.”1 Rabies is a viral zoonosis.
The rabies virus belongs to the genus Lyssavirus (Greek Lyssa, meaning “frenzy”)
within the family Rhabdoviridae. Rabies is an important public health problem
that ranks 11th among infectious diseases that cause the greatest number of human
deaths worldwide2 and rabies has the highest case fatality rate.2 Once rabies encepha-
litis develops, the disease is almost always fatal. Prevention is the primary approach
to this disease.

EPIDEMIOLOGY
Globally, it is estimated that approximately 50,000 to 100,000 people die from
rabies each year, although the actual number is probably much higher because of
underreporting.3,4 Most human deaths from rabies occur in developing countries.5
Dogs are the major vectors of rabies throughout the world, especially in developing
countries.4 Worldwide, transmission from dogs accounts for more than 90% of
human cases.6,7 In developed countries, bats, foxes, coyotes, raccoons, and skunks
are major reservoirs.4,8
A child is at least 4 times more likely to be bitten than an adult in developed and
developing countries.9 Boys are affected more often than girls,9 and younger chil-
dren are at increased risk for facial injury.10

VIROLOGY
The rabies virus, which is highly neurotropic, is bullet-shaped and measures
75 nm in diameter and 200 nm in length.11 The negative, single-stranded genome is non-
segmented RNA that is approximately 12,000 nucleotides long.12 The genome encodes
5 structural proteins: (1) a nucleoprotein (N), (2) a phosphoprotein (P), (3) a large,
RNA-dependent polymerase (L), (4) a matrix protein (M), and (5) a glycoprotein (G).13
The major component of the riboprotein core is the N protein.13 Approximately
1800 N molecules are noncovalently bound to the genomic virion RNA, forming the
helical RNP complex, which also contains the P and L proteins.13 The virus comprises
an envelope that consists of an outer surface membrane that is covered with peplom-
ers composed of trimers of the G protein.13 Spikes of the G protein project through
the envelope.4

PATHOGENESIS
The virus is usually transmitted to humans by infected saliva through the bite of
a rabid animal. Less commonly, the virus can be transmitted by contamination of an
open wound, scratch, abrasion, or mucous membrane with fresh saliva from a rabid
animal. Rarely, the virus can be transmitted through aerosol inhalation or by corneal
or organ transplants.1,3

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 After entry through a skin break, the virus may remain latent near the inoculation
site. Subsequently, the virus replicates slowly within muscle cells. The neuromuscu-
lar junction is the major site of entry into the neurons.14 G protein plays an impor-
tant role in viral entry and interaction with various cell receptors such as nicotinic
acetylcholine receptors at the neuromuscular junction, the neural cell adhesion mol-
ecule, and the p75 neurotropic receptors on neural cell membranes.14,15 The rabies
virus then migrates along peripheral nerves to the central nervous system via retro-
grade fast axonal transport at a rate of 12 to 100 mm/d.14,16 The P protein may be an
important determinant in the retrograde transport of the virus within the axons.13
When the central nervous system is reached, massive viral replication occurs with-
in neurons, causing widespread neuronal inflammation and necrosis.17 Microscopic
examination of rabies-infected neurons often shows eosinophilic intracytoplasmic
inclusions, known as Negri bodies, which contain masses of viral RNA, ribosomes,
and virions.18 From the central nervous system, the virus spreads centrifugally to the
rest of the body, especially the salivary glands, via the peripheral nerves.8 It is at this
stage that productive viral replication occurs with budding, particularly in the sali-
vary glands, resulting in high viral concentrations in the saliva.17

CLINICAL MANIFESTATIONS
The incubation period is, on average, 30 to 90 d long but may last from a few days
to several years.8 In general, multiple deep lacerations and bites on the head and
neck are associated with short incubation periods.12 Typically, a prodrome lasts 2 to
10 d, and this duration correlates with viral invasion of the central nervous system.8
Prodromal symptoms are nonspecific and include influenza-like symptoms and
paresthesia, hyperesthesia, anesthesia, pain, and pruritus at the site of viral entry.1,12
Progression of the disease occurs in 2 forms: the encephalitic (“furious”) form in
about 80% of patients and the paralytic (“dumb”) form in about 20% of patients.8
Patients with intact T-cell immunity to rabies and a high concentration of serum
interleukin-2 and interleukin-6 often present with the furious form, whereas those
who are lacking such responses often present with the paralytic form.15 Hyper-
excitability, autonomic dysfunction (hypersalivation, sweating, lacrimation, mydri-
asis, and hyperpyrexia), hydrophobia, and aerophobia are characteristic of
encephalitic rabies. Hydrophobia and aerophobia may be triggered by an attempt to
drink water or by air blowing on the face, both of which cause painful spasms of the
pharynx and larynx.8 The disease runs its entire course in no more than a few days
and ends fatally.12 The paralytic form is insidious. Flaccid paralysis develops, usual-
ly in the bitten limb, which ascends symmetrically or asymmetrically.17 The patient
ultimately develops paraplegia/triplegia/quadriplegia, urinary and fecal inconti-
nence, and respiratory and bulbar paralysis over a period of days to a few weeks.
With both forms, cardiac arrhythmia and coma ensue, and death is almost always
inevitable.

DIFFERENTIAL DIAGNOSIS
Rabies should be suspected in an acute, unexplained neurologic disease of sus-
pected viral origin, especially if the illness rapidly runs a downhill course.4 This is
especially so in an endemic area, regardless of whether a history of animal exposure

A. K. C. Leung, et al
Rabies: Epidemiology, Pathogenesis, and Prophylaxis
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has been documented. Tetanus may be confused with the encephalitic form. Both
can follow an animal bite. Tetanus can be distinguished from rabies by its shorter
incubation period, trismus and spasmodic contractions of the muscles of the body,
and absence of meningoencephalitis.12,17 In addition, hydrophobia and aerophobia
are uncommon in patients with tetanus. Other differential diagnoses include
diphtheria, botulism, delirium tremens, and drug intoxication (eg, phenothiazine,
amphetamine).17 The differential diagnosis of paralytic rabies includes Guillain-
Barré syndrome, Japanese encephalitis, cerebral malaria, and poliomyelitis.4

LABORATORY DIAGNOSIS
If possible, the animal that is suspected of having rabies should be captured.
If it is not overtly rabid, it can be quarantined for 10 days and observed for signs
of rabies. If the animal exhibits signs of rabies, it should be euthanized and its
brain tissue should be tested through immunofluorescence or polymerase chain
reaction (PCR).
In a living human, the diagnosis can be made by demonstration of rabies virus
RNA with reverse transcriptase–PCR in the saliva, or by full-thickness skin biopsies
of specimens taken from the nuchal region.4,17 Detection of rabies viral antibodies in
the serum can be diagnostic in unvaccinated individuals. On the other hand, rabies
antibodies in the cerebrospinal fluid are produced only in infected, not vaccinated,
individuals.4 Therefore, detection of rabies antibodies in the cerebrospinal fluid sup-
ports the diagnosis of rabies. Rabies virus can also be isolated for culture from sali-
va or from material obtained for brain biopsy.7

TREATMENT
Once rabies symptoms have developed, the disease is invariably fatal.18 Treatment
is mainly supportive and may include the use of supplemental oxygen with mechan-
ical ventilation, heavy sedation, analgesia, and anticonvulsants. Theoretically, combi-
nation therapy with rabies vaccine, rabies immune globulin, ribavirin, interferon-α,
and ketamine may be superior to therapy with a single agent.14 On the whole, such
treatment has not proved useful.16

PREVENTION
Because rabies is untreatable, prevention is of utmost importance. Death can be
minimized through timely and proper wound care, as well as with the use of mod-
ern cell culture rabies vaccine and by means of postexposure administration of
rabies immune globulin to those individuals who have not previously received pre-
exposure prophylaxis.

Control of Rabies
Animal rabies can be controlled by proper induction of herd immunity through
vaccination of domestic animals and wildlife vectors, routine veterinary care,
humane removal of stray animals, early spaying and neutering programs, promo-
tion of responsible pet ownership through education, and enactment of leash laws.19

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Unfortunately, no means of controlling rabies is available in some inaccessible vector
species. Contact with wildlife and unknown domestic animals should be avoided.
Children should be taught not to approach an unfamiliar dog or play with any dog
unless they are closely supervised.20 Children should also be taught not to disturb a
dog that is eating, sleeping, or caring for puppies, and they should be encouraged to
treat dogs with respect and not to chase or tease them.20

Preexposure Prophylaxis
Preexposure vaccination is recommended for people at high risk of exposure to
rabies, such as veterinarians, animal handlers, and rabies research personnel.1
Travelers who are at high risk for exposure during travel, who spend longer than
1 mo in countries where rabies is a constant threat, or who travel to or within a coun-
try where immediate access to appropriate medical care, including biologic agents,
is limited should be considered for preexposure vaccination.21,22
In developed countries, modern cell culture vaccines have replaced the original
nerve tissue vaccines pioneered by Pasteur in 1885. Unfortunately, nerve tissue vac-
cines are still widely used in many developing countries because of perceived
affordability. Such vaccines should be discontinued whenever feasible because of
low potency and a high incidence of serious neurologic complications such as
Guillain-Barré syndrome and encephalomyelitis.6,23 These neurologic complications
are attributed to myelin basic protein and to some of the ganglioside and phospho-
lipid constituents.6
Modern cell culture vaccines are more expensive but are safe and immunogenic.
Vaccine strains may be grown in cultured human diploid cell lines or in develop-
ing eggs. Currently, human diploid cell vaccine (HDCV; Imovax Rabies, Sanofi
Pasteur, Lyon, France) and purified chick embryo cell culture vaccine (PCECV;
RabAvert, Novartis Vaccines & Diagnostics, Inc., Emeryville, Calif) are licensed and
are used widely in North America and the United Kingdom.16,18,24 Rabies virus
strains are inactivated by β-propiolactone. Imovax Rabies and RabAvert are lyophi-
lized and contain at least 2.5 IU of rabies antigen per milliliter.4,24 Rabies vaccina-
tion induces long-term immunologic memory, as well as high titers of protective
rabies virus–neutralizing antibody.2 Preexposure vaccination simplifies postexpo-
sure prophylaxis because fewer doses of vaccine are needed and rabies immune
globulin is not required.4
The standard preexposure regimen consists of 3 doses of 1 mL modern cell cul-
ture vaccine on days 0, 7, and 21 or 28. The vaccine should be given intramuscular-
ly in the deltoid muscle of adults and in the anterolateral aspect of the thigh of
infants because administration in the adipose tissue might result in lower antibody
titers.24,25 The seroconversion rate is about 98% after primary vaccination.17 Booster
vaccinations are recommended for those at high risk of rabies exposure if antibody
titers are below acceptable levels.25 The World Health Organization (WHO) approves
the intradermal route of vaccination whereby 0.1 mL of vaccine is administered on
days 0, 7, and 21 or 28.26 This approach would help to lower the cost of vaccination
because the total volume of vaccine required is less than the amount required
for intramuscular administration; however, the intradermal route is technically
more difficult to use, and this approach might result in lower antibody levels.27,28

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The intradermal route should be avoided in immunocompromised individuals and
in those who are taking corticosteroids or chloroquine.24 The use of chloroquine has
to be delayed for at least 1 mo after vaccination if the intradermal route is used.
Cell culture vaccines are inactivated by β-propiolactone and can be safely admin-
istered during pregnancy.7,29 Local adverse effects, which are not uncommon,
include pain, tenderness, erythema, induration, and pruritus at the injection site.6
Systemic adverse effects occur in 1% to 10% of vaccine recipients and include
headache, nausea, dizziness, myalgia, arthralgia, fever, lymphadenopathy, and rash.24
Immune-mediated hypersensitivity reactions occur in 6% of patients given HDCV
boosters after an initial series of HDCV, although such reactions do not follow
PCECV boosters.18,30 If possible, the same product should be used for the entire vac-
cine series,19 but switching to another product is reasonable if the patient develops
hypersensitivity to the vaccine.19 In comparison with HDCV, PCECV is less expen-
sive.31,32 As of December 2005, 66.3 million doses of PCECV had been administered
globally.31 From October 1997 though December 2005, the Vaccine Adverse Event
Reporting System received 336 reports of adverse events that followed vaccination
with PCECV.31 Serious events, including 20 hospitalizations and 13 neurologic events,
were described in 24 reports (7%). There was no pattern among the 13 neurologic
adverse events suggesting a plausible relationship to vaccination.

Postexposure Prophylaxis
Approximately 30% to 50% of individuals who are bitten by a known rabid ani-
mal and who have not received postexposure prophylaxis contract rabies.7 Wound
care is essential to the prevention of rabies infection. The wound should be imme-
diately washed with copious amounts of water and cleansed with soap. Alcohol,
cetrimide, quaternary ammonium compounds, iodine, and povidone should be
used if available.5 Tetanus toxoid and antibiotics should be administered if indicat-
ed.20,21 Suturing of the wound should be avoided.21
For those individuals who have not previously received preexposure prophylax-
is within 2 y, human rabies immune globulin (HRIG) should be given as soon as pos-
sible and within 7 d of exposure.8,21 HRIG provides immediate rabies-neutralizing
antibodies for a short time before the person begins to make active antibodies to the
vaccine.1 HRIG is standardized at a concentration of 150 IU/mL, and the recom-
mended dose is 20 IU/kg of body weight.21 The full dose of HRIG should be infil-
trated around the wound if feasible.5,8 Any remaining HRIG should be administered
intramuscularly at a site distant from the site of vaccine administration because
rabies immune globulin may interfere with immune uptake of the vaccine.8,25 HRIG
should not be administered in the same syringe that is used for vaccine administra-
tion.12,25 The most common complications are pain and soreness at the injection site.1
If HRIG is not available, equine rabies immune globulin (ERIG) at a dose of 40 IU/kg
body weight may be used instead.17,21 The use of ERIG is associated with a higher
rate of hypersensitivity reactions, including anaphylaxis.17,21 Pregnancy is not a con-
traindication to the administration of HRIG or ERIG.1,6,29
Individuals who have not been vaccinated previously should receive 1 mL of mod-
ern cell vaccine given intramuscularly on days 0, 3, 7, 14, and 28.17 To reduce the high
cost of modern cell culture vaccine, 0.1 mL of the vaccine can be given intradermal-

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ly at 8 different sites on day 0, at 4 sites on day 7, and at 1 site on days 28 and 91.16,26
Those previously vaccinated require only 2 intramuscular doses of the vaccine on
days 0 and 3.5,17

CONCLUSION
Rabies is a highly fatal disease. Unfortunately, human exposure to this deadly dis-
ease cannot be eradicated, and no effective therapeutic agents are available. Elimina-
tion of stray animals, avoidance of exposure, immunization of those at risk, and prop-
er postexposure prophylaxis are the primary strategies used to control rabies.

ACKNOWLEDGMENT
Publication of this manuscript was made possible through an unrestricted educa-
tional grant provided by Merck Frosst Canada Ltd.

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