4
STATE-OF-THE-ART CLINICAL ARTICLE
Rabies
Stanley A. Plotkin
Even in these days of modern plagues such as AIDS and
Ebola virus disease, rabies is regarded with terror. Undoubtedly
much of the terror derives from the inexorable death that fol-
lows after the development of symptoms and the long incu-
bation period that leaves dangling the risk of rabies for months
and even years. Although we are now very successful at pre-
venting rabies after known exposure, neither the pathogenesis
of disease nor the mechanism of protection is completely un-
derstood, which adds interest for the scientist. Moreover, for
the public health professional, rabies is a headache both in
developed countries where the occasional case causes panic and
in developing countries where control of the disease in dogs is
elusive. Rabies is an ancient disease that remains a modern
problem in much of the developing world and in the United
States, where the disease is enzootic in bats and wild terrestrial
mammals.
Clinical Description
The incubation period of rabies in humans is generally 20–60
days. However, fulminant disease can become symptomatic
within 5–6 days; more worrisome, in 1%–3% of cases the in-
cubation period is 16 months. Confirmed rabies has occurred
as long as 7 years after exposure, but the reasons for this long
latency are unknown.
The first signs of illness are nonspecific: fever, anxiety, and
malaise. Often there is tingling and severe pruritus at the site
Received 22 July 1999; electronically published 6 January 2000.
Publication of this State-of-the-Art Clinical Article has been made possible
by an educational grant from Roche Laboratories.
The “Conflict-of-Interest Policy” of the Office of Continuing Medical
Education, UCLA School of Medicine, requires that faculty participating
in a CME activity disclose to the audience any relationship with a phar-
maceutical or equipment company which might pose a potential, apparent,
or real conflict of interest with regard to their contribution to the program.
Dr. David A. Relman serves as a consultant for the Applied Biosystems
Division of the Perkin-Elmer Corporation and receives research reagents
from PE-ABD. In addition, he serves on the Scientific Advisory Board of
Cepheid.
Reprints or correspondence: Dr. Stanley A. Plotkin, Pasteur Mérieux
Connaught, 4650 Wismer Road, Doylestown, PA 18901 (splotkin@us.pmc-
vacc.com).
Clinical Infectious Diseases 2000; 30:4–12
q 2000 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2000/3001-0003$03.00
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From Pasteur Mérieux Connaught, Swiftwater; Department of
Pediatrics, University of Pennsylvania; and Wistar Institute,
Philadelphia, Pennsylvania
of the animal bite. After 2–10 days, frank neurological signs
become manifest, ranging from hyperactivity to paralysis. In-
deed, the disease is usually divided into encephalitic and par-
alytic forms. In the former form, signs of irritation of the CNS
predominate, including agitation, confusion, hydrophobia, aer-
ophobia, hyperventilation, hypersalivation, priapism, and con-
vulsions. These symptoms reflect both cerebral dysfunction and
autonomic dysfunction. The unnerving aspect of this hyper-
activity, both to the patient and to the physician, is its episodic
nature, between which the patient is cooperative and oriented.
In some cases, paralysis involving the peripheral nerves is
the presenting sign, which is usually accompanied by fever but
in the absence of sensory involvement. Eventually, however,
patients who present with signs of encephalitis also become
paralyzed. The principal differential diagnosis in paralytic cases
includes rabies and Guillain-Barré Syndrome. In the latter
form, there is sensory involvement, absence of fever, and ab-
sence of encephalitic signs in oxygenated patients. Specific di-
agnostic tests for rabies, which are discussed below, are valuable
in making the distinction between rabies and Guillain-Barré
syndrome.
Within 2–12 days, coma begins, and cardiorespiratory failure
is only a matter of time. A handful of recoveries from rabies
have been claimed, although these recoveries are associated
with severe neurological disabilities (and almost always occur
in patients who have been partly vaccinated). No known treat-
ment is of avail.
Virology
Rabies virus is serotype 1 of 7 serotypes of the genus Lys-
savirus, which belongs to the larger classification of rhabdo-
viruses. At least 6 of these viruses have been found in bats,
and it is possible that rabies virus itself is really a bat virus that
has crossed species. The lyssaviruses are bullet-shaped, with the
core containing the viral RNA, a nucleocapsid protein, a phos-
phoprotein, and a viral transcriptase. The outer part of the
cartridge contains the matrix protein and a glycoprotein on
which are located the epitopes that induce neutralizing anti-
bodies.
Both the glycoprotein and the nucleocapsid protein induce
protection against rabies in experimental animals, the former
through the induction of neutralizing antibodies and the latter
 CID 2000;30 (January) Rabies 5

Table 1. Antemortem diagnostic test results for 20 human patients with rabies in the
United States, 1980–1996.
No. of patients Earliest
positive for rabies virus/ positive result,
Test total no. tested (%) day of illness
RT-PCR analysis of saliva for rabies virus RNA 10/10 (100) 5
Brain biopsy for rabies virus antigen 3/3 (100) 8
a
Nuchal skin biopsy for rabies virus antigen 10/15 (67) 5
b
Virus isolation from saliva 9/15 (60) 5
c
Antibody to rabies virus in serum 10/18 (56) 5
Rabies virus antigen in touch impression from cornea 2/8 (25) 14
d
Antibody to rabies virus in CSF 2/13 (15) 15
NOTE. Data are from [1]. RT, reverse transcriptase.
a
Two patients had earlier skin biopsies that were negative, but a subsequent biopsy was positive.
b
One patient had an earlier test that was negative.
c
Latest negative result was on day 24; median time to positive result was 10 days.
d
Latest negative result was on day 24.

through the induction of cytotoxic T cells. The glycoprotein
contains 524 amino acids, and changes in the sequence have a
strong influence on viral virulence. The glycoprotein alone has
been used successfully to protect animals against rabies.
Cases of rabies caused by Lyssavirus serotypes 2–7 are rare,
and protection by standard rabies vaccine has thus far been
uniform in humans; however, because animal experiments
sometimes reveal vaccine failures, there is still speculation as
to whether antigens from additional viruses need to be added
to the vaccine.
Pathogenesis
Although much is known about the pathogenesis of rabies,
some essential points yet remain mysterious. Clearly, early after
implantation the virus is cell-free, since both washing of the
wound and injection of antiserum reduce infection. However,
in the absence of specific prophylaxis, the virus becomes hidden,
only to invade the CNS weeks, months, or years later. Where
is the virus during this period? There is some evidence for slow
replication in muscle cells and for latency in macrophages, but
there is no certainty that these account for the long incubation
periods.
The next clear point is that the rabies virus glycoprotein has
homologies to neurotoxins and that the virus attaches to neural
axons through lipoprotein receptors, including that for acetyl-
choline. Other receptors, such as the neutral cell adhesion mol-
ecule (NCAM), may also be involved. The virus then enters
the axon and travels passively to the nucleus of the neuron at
rates variously estimated as 1–40 cm/d. The virus replicates in
neurons and passes to other neurons through the fiber con-
nections. Virus also passes down axons to the skin and to the
salivary glands, where it is released into the saliva.
Damage in the brain is curiously limited. Neuronal death is
not pronounced, but neuronal dysfunction is considerable, per-
haps mediated through inhibition of the synthesis of neural
transmitters. The Negri body is in fact a virus-induced cyto-
plasmic inclusion, which contains considerable amounts of
viral antigen. Anatomically, most of the damage is in the hy-
pothalamus, but it is interference with cardiorespiratory control
that results in death.
Immune Responses
During the incubation period, rabies virus is evidently seg-
regated from the immune system, since no antibody responses
are seen. Only after neurological symptoms develop do anti-
bodies appear in the serum and later in the CSF. Antibodies
in the CSF reflect active local production in the CNS, as well
as passive transfer, and are absent after vaccination. Demon-
stration of antibodies is thus useful diagnostically only in late
phases of the disease. Prior vaccination of a patient with rabies
may confuse the issue, but in disease, titers increase to levels
not seen in vaccinees.
Immunopathologic studies in mice show that neutralizing
antibodies are an essential component of the protective re-
sponse. However, “knockout” mice who are unable to mount
a T cell–mediated IFN response do less well than control mice,
despite the presence of antibodies, and it is evident that cellular
immunity plays at least a minor role in protection.
Diagnosis
As in many diseases, clinical suspicion is critical to a timely
diagnosis of rabies. Rabies should be included in the differential
diagnosis of any case of encephalitis of unknown origin, par-
ticularly when the patient has a history of an animal bite and
signs of autonomic disturbance in the absence of coma. Thus,
hyperventilation, hypersalivation, aerophobia, and hydropho-
bia are all part of the clinical picture. Flaccid paralysis and
localized paresthesias may also be signs of rabies. Clinically,
rabies may be confused with Guillain-Barré syndrome, polio-
myelitis, and other viral encephalitides.
Postmortem diagnosis is relatively easy and is based on dem-

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 6 Plotkin CID 2000;30 (January)

onstration of rabies virus antigens in brain tissue specimens by Table 2. Principal animal vectors of rabies.
fluorescent antibody techniques or ELISA and, more recently, Location Vectors
by demonstration of rabies virus nucleic acid by reverse tran- North America Skunks, raccoons, foxes, bats
scriptase (RT)–PCR analysis. Eosinophilic intracytoplasmic in- Western Europe Foxes, bats
Eastern Europe Foxes, dogs
clusions, called Negri bodies, may also be seen during routine
Latin America Dogs, bats
histological examination, but this technique may have false- Caribbean Mongooses
positive and false-negative results. Virus isolation in cell culture Africa Dogs, jackals, mongooses, foxes
Asia Dogs, cats, monkeys, mongooses, arctic foxes
or from animals can be used as a confirmatory technique, but
it takes time.
Intravitam diagnosis depends on the demonstration of an-
Epidemiology
tibodies to rabies virus in serum or CSF specimens from pa-
tients with a prolonged clinical course, viral antigen in touch The epidemiology of human rabies is an exact reflection of
impressions from the cornea, viral antigen in highly innervated the epizootiology of the disease in animals. From the viewpoint
hair follicles obtained by biopsies along the hairline of the neck, of public health, the dog or other canid species are the only
and virus isolation from or nucleic acid detection in saliva. important vector for humans, being responsible for most in-
However, negative results early in the disease do not rule out fections in Asia, Africa, and Latin America. However, with the
the diagnosis of rabies, and in most cases rabies is diagnosed retreat of canine rabies from most of the developed world,
clinically at autopsy. rabies transmitted by wild mammals, including bats, has be-
Noah et al. [1] summarized the diagnostic and epidemiolog- come more prominent.
ical findings of 32 United States cases of human rabies that Thus, in the United States at this point, raccoons and skunks
occurred during 1980–1996. The median incubation period account for most rabies virus–infected animals. However, in
from bite to symptoms was 85 days, with hospitalization fol- terms of risk to humans, bats, dogs, and cats are the most likely
lowing usually 1–10 days later. As shown in table 1, the test threats to transmit rabies to Americans. The distribution of
that gave the best results (positive in 100% of cases) was RT- major terrestrial reservoirs of rabies in the United States is
PCR analysis, which revealed viral RNA in saliva. The next shown in figure 1 [2]. The major change in recent years has
best test for antemortem diagnosis was nuchal skin biopsy (pos- been the extension of raccoon rabies into the northeast.
itive in 67% of cases). Rabid bats have become the predominant rabies risk to hu-

Figure 1. Distribution of major terrestrial reservoirs of rabies in the United States. Reprinted with permission from W. B. Saunders [2]. The
skunk and the fox are infected with several geographic variants.

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 CID 2000;30 (January) Rabies 7

Table 3. Important past and present rabies vaccines for humans.

a
Type of vaccine, name Manufacturer(s) Type Substrate Remark(s)
Nerve tissue vaccine
Pasteur None Inactivated by drying Rabbit spinal cord Residual live virus
Fermi Few Phenolated live virus Sheep, goat, or rabbit brain Contained nerve tissue and
perhaps residual live virus
Semple Many Phenol-inactivated Sheep, goat, or rabbit brain Contains nerve tissue
Fuenzalida Many Inactivated Suckling mouse brain Decreased myelin content
Avian embryo vaccine
PDEV Berna b-propiolactone–inactivated Duck embryo Purified by ultracentrifugation
DEV None Inactivated Duck embryo Allergy to avian antigens
Cell culture vaccine
HDCV Chiron Behring, b-propiolactone–inactivated Human cultured fibroblasts Expensive world standard
PMC, Berna
RVA Bioport b-propiolactone–inactivated Fetal rhesus lung cell culture Fewer allergic reactions
PHK Local Formalin-inactivated Primary Syrian hamster kidney cell culture Used in PRC and former USSR
PCECV Chiron Behring b-propiolactone–inactivated Chick embryo cell culture Purified by ultracentifugation
PVRV PMC b-propiolactone–inactivated Vero cell line Purified by ultracentrifugation
NOTE. DEV, duck embryo vaccine; HDCV, human diploid cell culture vaccine; PCECV, purified chick embryo cell culture vaccine; PDEV, purified duck embryo
vaccine; PHK, primary hamster kidney; PMC, Pasteur Mérieux Connaught; PRC, People’s Republic of China; PVRV, purified vero rabies vaccine; RVA, rabies vaccine
adsorbed.
a
Locations of manufacturers: Berna, Bern, Switzerland; Bioport, Lansing, Michigan; Chiron Behring, Marburg, Germany; PMC, Lyons, France.

mans in the United States because of a combination of viro-
logical, biological, and ecological factors. In particular, the sil-
ver-haired and eastern pipistrelle bats have been prominent
recently because the virus recovered from them may infect hu-
man skin more easily than other rabies virus strains and because
the small teeth of the bat may leave little evidence of a bite.
Moreover, human exposures appear to be more frequent, per-
haps because of increasing encroachment of human habitation
in formerly rural areas. From 1980 to 1996, 21 of 36 cases of
domestic human rabies could be attributed to bats by nucleic
acid analysis; of these 21 patients, only 1 had a firm history of
a bite [4]. These facts have led to new recommendations relative
to prophylaxis for rabies, which are given below.
Bats are the source of another type of human rabies, aerosol
infection, that is fortunately rare; aerosol infection may occur
in caves inhabited by millions of bats. Rabies in research lab-
oratory workers who are accidentally exposed to aerosols of
the virus is also rare but well documented.
Although dogs and cats are uncommonly rabid in the United
States owing to the widespread use of prophylactic vaccines
and other public health measures, these pet animals may fre-
quently expose humans to rabies, particularly along the border
with Mexico.
Corneal transplants from donors who died of unspecified
encephalitis have transmitted rabies in the past, but transplan-
tation practice now forbids the use of tissues from such donors.
The major foci of rabies in the world today are the Indian
subcontinent, Southeast Asia, and most of Africa. Data from
India suggest that there are 30,000 cases each year in that coun-
try, and one estimate of the death rate associated with rabies
is 35.5 deaths per 1 million people. Although rabies vaccination
services in Thailand are well organized, ∼75 Thai people still
die of rabies each year. The World Health Organization esti-
mates that there are 50,000 cases of fatal rabies in the world
each year. On a list of worldwide causes of mortality, rabies
ranks ahead of yellow fever, polio, and meningococcal men-
ingitis. However, some countries, particularly islands, are free
of rabies. The prominent vectors for rabies in various regions
of the world are listed in table 2; this list may be useful in
assessing the risk for travelers.
Vaccination
The principles of prophylaxis for rabies have not changed
for many years, but there have been important recent modifi-
cations that deserve emphasis. The basic principles are to re-
move free virus from tissues by both washing and neutralization
and to induce a rabies virus–specific immune response in the
exposed individual before rabies virus can replicate in the CNS.
The history of vaccine development for rabies is a colorful
one. It starts with the well-known and dramatic story of Louis
Pasteur and his rabbit spinal cord vaccine and continues to this
day with the demonstration of protection in animals by rabies
virus reverse transcriptase DNA plasmid vaccination or by
feeding them plants that contain chimeric plant viruses that
code for rabies virus glycoprotein. However, in terms of use in
humans, vaccines may be divided into nerve tissue vaccines,
avian embryo vaccines, and cell culture vaccines.
Regrettably, nerve tissue vaccines are still the most widely
used type for prophylaxis for rabies. They are dangerous in
terms of induction of autoimmune CNS disease, require mul-
tiple injections, and are not always efficacious. The Fuenzalida
vaccine, which is produced from rabies virus grown in suckling
mouse brain, is an improvement over prior vaccines with regard

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 8 Plotkin CID 2000;30 (January)

Table 4. Regimens for preexposure and postexposure vaccination with rabies vaccines.
Vaccination, route Days doses are given Remark(s)
Preexposure
a
im 0, 7, and 21 or 28 Standard regimen
b
id 0, 7, and 21 or 28 Economical, but not to be used in those people taking antimalarial medications
c
Postexposure
a
im 0, 3, 7, 14, and 28 US and WHO recommendations
a
im 0 (2 doses), 7, and 21 Used in some countries when RIG is not indicated
b
id 0, 3, 7 (2 doses each), 28, and 90 Used in Thailand with PVRV, PCECV, or PDEV
b
id 0 (8 doses), 7 (4 doses), 28, and 90 Used in developing countries with cell culture vaccine
Booster dose (for reexposure)
a d
im 0 and 3 Only after documented vaccination with cell culture vaccine
b,d d
id 0 and 3 Only after documented vaccination with cell culture vaccine; not recommended in the US
NOTE. Id, intradermally; PCECV, purified chick embryo cell culture vaccine; PDEV, purified duck embryo vaccine; PVRV, purified vero rabies
vaccine; RIG, rabies immune globulin; WHO, World Health Organization.
a
Dose of 0.5 or 1 mL, depending on the vaccine given into the deltoid.
b
Dose of 0.1 or 0.2 mL, depending on the vaccine given over the deltoid.
c
Together with RIG.
d
Or demonstrated presence of virus-neutralizing antibodies after immunization with other vaccines.

to reduced myelin content, but it still provokes neurological Preexposure Vaccination

problems. The vaccines originally produced from rabies virus
grown in duck embryo contained no myelin, but the potency
The advent of cell culture rabies vaccines has allowed safe
of the unconcentrated vaccine was low.
immunization of people likely to be exposed to rabies, accord-
Today the optimal rabies vaccine is one produced by the
ing to the same principles that govern the use of other vaccines.
growth of virus in cell culture or culture of avian embryos,
As summarized in table 4, 2 doses of a cell culture vaccine are
followed by inactivation, purification, and concentration. The
given 1 week apart, and a third booster dose is given 2–3 weeks
first one commercially developed, which is still the standard,
later. Antibody response is virtually 100%, and the individual
was human diploid cell culture vaccine (HDCV). The advan-
remains sensitized indefinitely.
tages of HDCV and the cell culture vaccines that followed are
If a person who has been vaccinated previously is exposed
freedom from heterologous protein, a high level of immuno-
to rabies, 2 doses of vaccine are administered 3 days apart. An
genicity that permits a rational dosing schedule, and efficacy
anamnestic response is seen within 1 week. A vaccinated person
demonstrated in trials that were not placebo-controlled but
at continuous risk should receive a single booster dose 1 year
were at least done with careful observation. The disadvantage
after primary immunization. We have observed that a titer of
of these vaccines is cost of production, particularly for the
antibody to rabies virus that is measured 14 days after this
original HDCV. Subsequently developed vaccines have used less
fourth dose is useful in predicting the need for further booster
expensive cellular substrates to reduce their price.
doses: titers 130 IU indicate prolonged seropositivity, whereas
The cell culture vaccines are considered equivalent in terms
of efficacy and freedom from serious allergic reactions (table subjects with lower titers should undergo more frequent re-
3). If necessary (although it is not recommended), these vaccines testing to be certain that their titers remain 10.5 IU, which is
may be used interchangeably in the same patient, at least for generally considered to be an acceptable level [3].
the intramuscular regimens. Preexposure vaccination is recommended for people who will
be exposed to rabies virus in the laboratory or who will have
contact with mammals, including bats. Included on this list are
Table 5. Human rabies vaccines—United States, 1999.
b
veterinarians, trappers, dog catchers, speleologists, biologists
Vaccine, route Product name Manufacturer(s), phone no.
who work with mammals, and laboratory workers likely to
HDCV, im, id Imovax Rabies, PMC, (800) 822-2463 come in contact with rabies virus–infected specimens. Individ-
Imovax Rabies I.D.
a
RVA, im RVA BioPort, (517) 327-1500 uals with less certain indications for preexposure vaccination,
PCECV, im RabAvert Chiron Behring, (800) 244-7668 which should be influenced by geography and by information
RIG Imogam Rabies H-T, PMC, (800) 822-2463;
from veterinary authorities, include hunters, mail carriers, and
BayRab Bayer, (800) 288-8370
travelers to countries where rabies is enzootic. Travelers who
NOTE. HDCV, human diploid cell culture vaccine; id, intradermal; im, in-
tramuscular; PCECV, purified chick embryo cell culture vaccine; PMC, Pasteur
keep to the usual tourist routes are probably not in much dan-
Mérieux Connaught; RIG, rabies immune globulin; RVA, rabies vaccine ger. However, those travelers who remain in remote areas, par-
adsorbed. ticularly children, are at risk; vaccination is recommended for
a
Temporarily unavailable.
b
Locations of manufacturers: Bayer, Wset Haven, Connecticut; Bioport, Lan- peace corps workers. One survey conducted in Thailand showed
sing, Michigan; Chiron Behring, Marburg, Germany; PMC, Lyons, France. that 0.5% of travelers needed rabies vaccination because of

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 CID 2000;30 (January) Rabies
Table 6. Guide for postexposure prophylaxis for rabies in the United States, 1999.
Animal vectors Evaluation and disposition of animal
Dogs, cats, and ferrets Healthy and available for 10-d observation
Rabid or suspected rabid
Unknown (escaped)
b
Skunks, raccoons, foxes, and most other Regarded as rabid unless animal is from
carnivores; bats digeographic area where rabies is not
enzootic and laboratory tests prove that
the animal is negative for rabies
Livestock, small rodents, ferrets, and Consider individually
lagomorphs (rabbits and hares); large
rodents (woodchucks and ferrets);
and other mammals
NOTE. Data are from [4].
a
During the 10-day holding period, begin prophylaxis at the first sign of rabies in a dog, cat, or ferret who has bitten someone. If the animal exhibits clinical
signs of rabies, it should be killed immediately and tested.
b
The animal should be killed and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if results of immunofluorescence
for the animal are negative.
exposures to potentially or proven rabid animals; therefore,
there is ample justification for preexposure immunization.
Children living in areas where rabies is enzootic can be easily
immunized against rabies (even as part of routine infant vac-
cination), although such practice is not yet recommended, in
part for financial and logistic reasons.
Postexposure Prophylaxis
Optimal postexposure treatment consists of local cleansing,
administration of passive antibody, and active immunization.
All 3 elements are essential, since rabies has occurred when 1
of the elements was omitted.
The choice of cleaning solution is probably less important
than the copiousness of the fluid administered. Soap and water
are fine, although 0.1% benzalkonium chloride, 70% alcohol,
or 1% povidone-iodine may be usefully applied to the wound
after washing. Tetanus vaccine, tetanus antiserum, and anti-
biotic treatment should be provided as indicated.
After a wound has been cleansed, the physician can decide
whether the threat of rabies justifies vaccination. The factors
influencing that decision include the following:
1. If there is high suspicion that the biting animal has rabies
on the basis of compatible clinical signs, prophylaxis should be
started immediately.
2. If the biting animal has always been a domestic pet, such
as a dog, cat, or ferret, it can be quarantined and observed for
rabies for 10 days. Dogs and cats are still potential vectors in
a few areas of the United States, particularly along the southern
border. If the animal remains healthy, no vaccination is needed.
In countries where dog rabies is enzootic, prophylaxis should
be started immediately and should be discontinued if the animal
remains healthy.
3. If the biting animal is wild and has been killed, the brain
can be examined for signs of rabies. This step is particularly
important for raccoons, skunks, foxes, bats, and woodchucks
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9
Postexposure prophylaxis recommendation(s)
a
Should not begin prophylaxis unless animal develops signs of rabies
Immediate vaccination
Consult public health officials
Consider immediate vaccination
Consult public health officials. Bites of squirrels, hamsters, guinea
pigs, gerbils, chipmunks, rats, mice, other small rodents, rabbits,
and hares almost never require postexposure prophylaxis for
rabies
(groundhogs). The fluorescent antibody test for rabies virus
antigen in the brain is highly sensitive and specific.
4. If the biting animal has escaped, reference to veterinary
authorities should be made to determine whether the species
involved may possibly be infected with rabies in that particular
geographic area.
5. If the biting animal was a bat, prophylaxis for rabies
should always be given (see the section on bats below).
6. Provocation of the bite or lack of it is not a good criterion
for decision.
7. Exposure of mucous membranes to secretions of a rabid
animal is not as dangerous as a bite but is associated with the
risk of rabies. Exposure of intact skin is not a risk (see the
section on bats below).
If a decision is made to proceed with prophylaxis for rabies,
rabies immune globulin (RIG) should be administered. Two
forms of RIG exist: human RIG and equine RIG. However,
only human RIG is available in the United States. The currently
used equine RIGs are purified products and are associated with
relatively few allergic reactions and only rarely with anaphy-
laxis. Unfortunately, because strict regulation to eliminate ex-
traneous viral contamination, human RIG is in short supply.
The dose of human RIG is 20 IU/kg, whereas that for equine
RIG is 40 IU/kg. United States and WHO recommendations
call for local infiltration of the total dose at the site of the bite
to the extent that is anatomically feasible, rather than 50% of
the dose formerly recommended. The change in recommen-
dation was made because blood levels of antibodies to rabies
virus are not high after parenteral administration of RIG, and
local neutralization of the virus is key.
Active immunization against rabies should be started si-
multaneously with administration of antiserum. Although no
effort should be made to induce active immunization and pas-
sive immunization at different times, if one product is available
before the other, it should be administered promptly, and the
second product should be given when it becomes available.
 10 Plotkin CID 2000;30 (January)

Table 7. Schedule of postexposure prophylaxis for rabies in the United States, 1999.
a
Vaccination status, treatment Regimen
Not previously vaccinated
Wound cleansing All postexposure treatment should begin with immediate thorough cleansing of all wounds with soap and water.
If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds.
Human RIG Administer at a dose of 20 IU/kg of body weight. If anatomically feasible, full dose should be infiltrated around
the wound(s), and any remaining volume should be administered im at an anatomic site distant from vaccine
administration. In addition, RIG should not be administered in the same syringe as the vaccine. Because
human RIG may partially suppress the active production of antibody, no more than the recommended dose
should be given
b c
Vaccine (HDCV, RVA, or PCECV) One 1-mL dose im (deltoid area ) on days 0, 3, 7, 14, and 28.
d
Previously vaccinated
Wound cleansing All postexposure treatment should begin with immediate thorough cleansing of all wounds with soap and water.
If available, a virucidal agent such as a povidone-iodine solution should be used to irrigate the wounds.
RIG RIG should not be administered.
b c
Vaccine (HDCV, RVA, or PCECV) One 1-mL dose im (deltoid area ) on days 0 and 3.
NOTE. HDCV, human diploid cell culture vaccine; PCECV, purified chick embryo cell culture vaccine; RIG, rabies immune globulin; RVA, rabies
vaccine adsorbed. Data are from [4].
a
These regimens are applicable for all age groups, including children.
b
Deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, outer aspect of the thigh may be used. Vaccine
should never be administered in gluteal area.
c
Day 0 is day on which the first dose of vaccine is administered.
d
Any person with a history of preexposure vaccination with HDCV, RVA, or PCVEC; prior postexposure prophylaxis with HDCV, RVA, or PCECV;
or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination.

However, if RIG is available 11 week after vaccination has
been started, it is probably unnecessary as an active antibody
response will have begun.
A 5-dose schedule for postexposure vaccination against ra-
bies is internationally accepted, and im injection is the only
route acceptable in the United States. (However, see the section
on intradermal vaccination below.) Doses are given at 0, 3, 7,
14, and 28 days (table 4). After the fifth dose, antibodies are
always present, usually at a titer of 110 IU. Another vaccination
schedule, called 2-1-1, is used in some countries, but this sched-
ule is not as immunogenic if used together with human RIG.
Vaccine and antiserum should never be mixed or injected in
the same limb.
In the United States, there is a choice of 3 vaccines (table
5): HDCV, purified chick embryo cell culture vaccine, and fetal
rhesus lung cell culture vaccine (or rabies vaccine adsorbed,
which is temporarily unavailable). They are interchangeable,
but it is normal practice to use 1 for the complete vaccination
series. Outside of the United States, there are other choices,
including primary hamster kidney cell culture vaccine, monkey
vero cell vaccine, purified duck embryo vaccine, and numerous
nerve tissue vaccines. If a traveler returns to the United States
after having received 1 of the cell culture vaccines, the vacci-
nation schedule may be completed with 1 of the 3 licensed
vaccines, but if the patient has received a nerve tissue vaccine,
rabies vaccination should be started without reference to the
prior doses.
Titers should be measured in immunosuppressed persons,
including those with HIV infection, after vaccination, to ensure
that seroconversion has occurred.
There has been concern that vaccination might not protect
against Lyssavirus serotypes 2–7, but fortunately, experimental
studies suggest that there should be sufficient cross-neutrali-
zation with most strains to give protection.
The 1999 recommendations concerning postexposure pro-
phylaxis for rabies by the Advisory Committee on Immuni-
zation Practices [4] are summarized in tables 6 and 7.
Intradermal Vaccination
The higher cost of cell culture vaccines has induced physi-
cians to look for ways of reducing doses. Accordingly, Warrell
et al. [5] and Wilde and et al. [6] have developed vaccination
schedules by using the intradermal route. In the United States,
the intradermal route is approved only for preexposure vac-
cination. Details of the intradermal immunization schedules are
provided in table 4. The principles that allow intradermal vac-
cination are the better response to an equal volume of antigen
when placed in contact with the Langerhans’ cells of the epi-
dermis and the use of multiple sites of vaccination to obtain
maximum drainage of antigen-presenting cells to the lymph
nodes. The intradermal regimens have had remarkable success,
particularly in Thailand. However, some expertise is necessary
for correct intradermal injection, and the choice of vaccine is
important. The intrasdermal dose is one-fifth of a vial for int-
eded intramuscular injection, which may be 0.1 mL or 0.2 mL,
depending on the brand of vaccine.
Individuals receiving antimalarial prophylaxis with chloro-
quine or related compounds should be vaccinated by the im
route, since their antibody responses to intradermal vaccination
may be lower than normal.

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 CID 2000;30 (January) Rabies 11

Bats or the Return of Dracula Reactions and Contraindications to Vaccination

Rabies virus is only one of a number of lyssaviruses enzootic

Reactions to human RIG are uncommon. Currently, man-
in bats and indeed may have been the original source of the
ufactured equine RIGs are associated with relatively few allergic
virus for other species. Bat rabies is an important problem for
reactions: serum sickness in only 1% of cases and very rare
the Americas, including the United States, where it occurs in
cases of anaphylaxis. Nerve tissue vaccines may induce local,
all 49 continental states. Although !1% of bats screened for
systemic, or neuroparalytic reactions. The latter reactions are
rabies are positive, in Colorado, 30% of bats who bit people
based on the induction of antibodies to myelin proteins or
and 50% of bats found in houses by wakening individuals were
gangliosides. Reactions to cell culture vaccines are relatively
rabid [7].
mild, although local pain, erythema, and swelling at the injec-
In recent years, insectivorous bats have been the predominant
tion site are commonly seen. Systemic reactions with headache
source of human infections in the United States, in particular
and malaise occur less frequently. Guillain-Barré syndrome has
the silver-haired bat, Lasionycteris noctivagans, and the eastern
been rarely reported after receipt of modern rabies vaccine, but
pipistrelle bat, Pipistrellus subflavus. The virus indigenous to
its association with the vaccine is uncertain.
these bats is a genetic variant of Lyssavirus serotype 1 that
The most significant problem is type I or III allergic reactions
adapts to epithelial and fibroblast cells in culture and may be
consisting of urticaria, arthritis, and angioedema, which are
more infectious than other strains. Disturbingly, most human
seen in about 6% of patients who receive a booster dose of
patients with rabies caused by the virus variant from these bats
HDCV. These reactions have been attributed to the formation
give no history of contact with bats or only a history of contact
of antibodies to the human albumin stabilizer chemically al-
without a bite. However, bat bites may be small or may be
tered by b-propiolactone. These reactions can be treated with
inflicted on a sleeping person who does not awaken. Therefore,
the usual drugs employed for allergic reactions, and another
a new recommendation by the Advisory Committee on Im-
rabies vaccine can be substituted for HDCV. The use of steroids
munization Practices [4] states the following: “Consequently,
should be avoided, but if these agents are administered, titers
postexposure prophylaxis should be considered when direct
of antibody should be measured after completion of the vaccine
contact between a human and a bat has occurred, unless the
series.
exposed person can be certain a bite, scratch, or mucous
There are no true contraindications, and vaccination is safe
membrane exposure did not occur. In instances in which a bat
in pregnancy. HIV-infected patients with CD41 cell counts be-
is found indoors and there is no history of bat-human contact,
low 300/mL respond poorly, and may need additional doses of
the likely effectiveness of postexposure prophylaxis must be
vaccine. Antibody titers can be monitored to verify responses.
balanced against the low risk such exposures appear to present.
In this setting, postexposure prophylaxis can be considered for
persons who were in the same room as the bat and who might
be unaware that a bite or direct contact had occurred (e.g., a
sleeping person awakens to find a bat in the room or an adult Treatment Failures
witnesses a bat in the room with a previously unattended child,
mentally disabled person, or intoxicated person) and rabies
In nearly all cases of rabies occurring despite vaccination,
cannot be ruled out by testing the bat. Postexposure prophy-
some aspect of the treatment did not follow the guidelines. The
laxis would not be warranted for other household members.”
common faults are late start of prophylaxis, insufficient cleans-
Vampire bats in Latin America also may transmit rabies. For-
ing of the wound, total omission of antiserum administration,
tunately, standard rabies vaccination elicits good neutralizing
or failure to inject antiserum into all wound sites. One treatment
antibody to viruses from bats.
failure did occur in a person prevaccinated by the intradermal
route; in that case, concomitant chloroquine medication may
have suppressed the patient’s response. However, it should be
Human-to-Human Transmission recognized that the size and placement of the challenge dose
of rabies virus are influential on the outcome. A highly con-
Aside from transmission through transplanted tissues, hu- taminated bite on the face, for example, may allow for rapid
man-to-human transmission lies largely in the realm of folklore. CNS invasion, and failures of protection have been reported
However, rabies virus may be present in the saliva of humans in that situation despite standard treatment.
with rabies, and possible contact transmission has been re- The best solution to human rabies still lies in the suppression
ported recently and in the past. Thus, bites, scratches, and or vaccination of animal reservoirs where feasible, particularly
mucous membrane exposures to a rabid patient are considered among domestic animals. More than 2000 years after the de-
indications for vaccination. The latter indication includes sexual scription of hydrophobia by Celsus, human rabies is far from
exposure shortly before the onset of symptoms. extinct.

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 12 Plotkin CID 2000;30 (January)

Acknowledgments
I thank Dr. Charles Rupprecht and Dr. Henry Wilde for critical
reading of the manuscript.
A supplemental reading list reading appears in the online edition of
CID (http://journals.uchicago.edu.CID/journal/).
References
1. Noah DL, Drenzek CL, Smith JS, et al. Epidemiology of human rabies in
the United States, 1980 to 1996. Ann Intern Med 1998; 128:922–30.
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persistence following preexposure regimens of cell-culture rabies vaccines:
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4. Advisory Committee for Immunization Practices. Human rabies preven-
tion—United States, 1999. MMWR Morb Mortal Wkly Rep 1999; 48(Suppl
RR-1):1–21.
5. Warrell MJ, Nicholson KG, Warrell DA, et al. Economical multiple-site in-
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