Rabies

recommendations and administration

immunoglobulin (if indicated).

Diagnosis

Prompt local treatment of all potentially contaminated

bite wounds and scratches with immediate, thorough
flushing and washing of the wound for a minumum of 15
minutes with soap and water, detergent, povidone iodine
or other substances with virucidal activity is an effective
means of protection.

To date, there are no tests available to diagnose human

rabies infection ante-mortem, or before the onset of
clinical disease. However, rabies should be included in
the differential diagnosis of all patients who present with
unexplained, acute, progressive viral encephalitis, even in
areas where the disease is not endemic.
WHO defines a clinical case of rabies as a subject
presenting with an acute neurological syndrome (i.e.
encephalitis) dominated by forms of hyperactivity (i.e.
furious rabies) or paralytic syndromes (i.e. dumb rabies),
progressing towards coma and death, usually by cardiac
or respiratory failure, typically within 7-10 days after the
first sign, if no intensive care is instituted.
As diagnosis based on clinical ground alone is difficult
and often unreliable; it is recommended to confirm a
clinical case of rabies through the use of laboratorybased techniques. For post mortem diagnosis, the goldstandard diagnostic technique is to detect rabies virus
antigen in infected tissues, preferably brain smears or
touch impressions collected from a biopsy, by
fluorescent antibody test (FAT). FAT is recommended by
WHO and in 95-99% of cases, gives reliable results on
fresh specimens within a few hours. Other methods for
detection of lyssavirus antigens such as direct rapid
immunohistochemistry tests are proven to have
sensitivity and specificity comparable to the FAT. WHO
recommends further development of direct rapid
immunohistochemistry tests as an alternative to the FAT
for improved decentralized laboratory-based surveillance
in endemic areas.
Ante-mortem diagnosis, or diagnosis of rabies during life
(by intra-vitam techniques) is difficult and dependent on
widespread dissemination of virus through the nervous
system. It is strongly discouraged for rabies diagnosis in
animals as sensitivity varies widely according to the stage
of the disease, immunological status, intermittent viral
excretion and training of the technical staff.

Treatment
All cases of suspected exposure to rabies should be
treated immediately in order to prevent the onset of
symptoms and death. Post-exposure prophylaxis (PEP)
consists of local treatment of the wound, a course of
potent, effective rabies vaccine that meets WHO

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of

rabies

The recommended post-exposure prophylaxis depends

on the category of exposure to suspected or confirmed
rabid animals (see table).
Recommended post-exposure prophylaxis for rabies
infection
Category of exposure to
suspect rabid animal

Post-exposure measures

Category I
touching or feeding
animals, licks on intact
skin (i.e. no exposure)

None

Category II
nibbling of uncovered
skin, minor scratches or
abrasions without
bleeding

Immediate vaccination and

local treatment of the wound

Category III
single or multiple
transdermal bites or
scratches, licks on
broken skin;
contamination of
mucous membrane with
saliva from licks,
exposures to bats.

Immediate vaccination and

administration of rabies
immunoglobulin; local
treatment of the wound

WHO recommends replacement of the nerve tissue

vaccine with modern concentrated and purified cell
culture derived and embryonated egg-based rabies
vaccines. Intradermal vaccination has been shown to
be as safe and immunogenic as intramuscular
vaccination and requires a lower volume for both
pre- and post-exposure prophylaxis, leading to lower
direct costs. This alternative should thus be
considered in settings constrained by cost and/or
supply issues.
Other factors that should be taken into consideration
when deciding whether to initiate post-exposure
prevention include:

The likelihood of the implicated animal being

rabid
The clinical features of the animal and its
availability for observation and laboratory
testing
In developing countries, the vaccination status of the
suspected animal alone should not be considered when
deciding whether to initiate prophylaxis or not.

Prevention
The prevention of human rabies is dependent upon the
effective and verifiable control of the disease within the
domestic dog population, being the most common
reservoir of the virus and cause of more than 95% of
human cases. Dog-mediated human rabies is completely
preventable using biologicals and tools that could be
accessible even in low-resource settings. Public
awareness, health education, dog vaccination and the
availability and accessibility of PEP are key for rabies
prevention and control.
Rabies vaccine banks have begun to support countries in
their control efforts, providing incentive for them to
engage in and leverage investments. A vaccine bank for
dog vaccination in Asia has been set up by OIE, and by
WHO in South Africa. National mass dog vaccination
campaigns are the most cost-effective strategy for
preventing rabies. At least 70% of the dog population
must be vaccinated in order to break the cycle of
transmission in dogs and to humans. Preventing human
rabies through control of domestic dog rabies is a
realistic goal for large parts of Africa and Asia where
rabies is a significant public health issue, and is justified
financially by the future savings of discontinuing postexposure prophylaxis for people.
The elimination of rabies however, requires several
components in addition to mass vaccination, including
the effective engagement of communities and
policymakers, dog population assessment and
management, and surveillance capacity and legislation.
WHO strategies for dog rabies control and eventual
elimination:
WHO promotes organization of sustainable
mass dog vaccination campaigns and dog
population management through reduction of
stray populations (by implementing animalbirth-control programs); control of trade and
movement of dogs
Oral vaccination of domestic carnivores as dog
accessibility to vaccination by the parenteral
route is one of the major obstacles for dog
rabies control in many different parts of the
world. WHO has stimulated studies on oral
vaccination of dogs (OVD) and the development

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of safer and effective vaccines and baits for

OVD.
WHO strategies for human rabies prevention:
WHO promotes wider access to appropriate
post-exposure treatment using the costeffective multi-site intradermal regimen with
modern tissue culture or avian embryo-derived
rabies vaccines
Possible domestic production of rabies
biologicals, particularly rabies immunoglobulin,
which are in critical short supply globally
Continual education of health and veterinary
professionals in rabies prevention and control
Public health educational strategies at the
community level within endemic regions
WHO's strategy for pre and post exposure
vaccination

Top 10 General Considerations in

Rabies PEP
1.
2.

3.

4.

5.

6.

7.

8.

9.

Wounds must be immediately washed/flushed

for 15 minutes and disinfected
Rabies PEP should be instituted immediately.
PEP consists of a course of potent, effective
rabies
vaccine
that
meets
WHO
recommendations and administration of rabies
immunoglobulin
PEP must be applied using vaccine regimens and
administration routes that have been proven to
be safe and effective
PEP does not have contraindications if purified
rabies immunoglobulin and vaccine are used.
Pregnancy and infancy are not contraindications
to PEP
If rabies immunoglobulin is not available on first
visit, use can be delayed by up to 7 days from
the date of the first vaccine dose
Initiation of PEP should not await the results of
laboratory diagnosis or be delayed by dog
observation when rabies is suspected
When suspect rabid animal contacts (excluding
bats) occur in areas free of carnivore-mediated
rabies and where there is adequate surveillance
in place, PEP may not be required.
Patients presenting for rabies PEP even months
after having been bitten should be treated as if
the contact had recently occurred
PEP should be administered even if the suspect
animal is not available for testing or
observation. However, vaccine and
immunoglobulin administration may be
discontinued if the animal involved: is a

vaccinated dog (cat or ferret) that following

observation for 10 days, remains healthy or is
humanely killed and declared negative for rabies
by a WHO prescribed laboratory test
10. In areas enzootic for (canine and wildlife) rabies,
PEP should be instituted immediately unless
adequate laboratory surveillance and data
indicates that the species involved is not a
vector of rabies

Rabies Post-Exposure
Prophylaxis Modalities
Wound treatment:

Should be immediate
Is essential even if the person presents long
after exposure
Consists of:
Immediate washing and flushing wound for
15 minutes with soap and water, or water
alone
Disinfection with detergent, ethanol
(700ml/l), iodine (tincture or aqueous
solution), or other substances with virucidal
activity
Bleeding at any wound site indicates potentially
severe exposure and must be infiltrated with
either human or equine rabies immunoglobulin
Other treatments include
Administration of antibiotics and tetanus
prophylaxis

Administration of
Rabies Immunoglobulin (RIG)

Administration of rabies immunoglobulin (RIG)

to wounds classified as category III exposure, is
of upmost importance in wound management.
Bites to the head, neck, face hand and
genitals are category III exposures
Infiltrate RIG into the depth of the wound and
around the wound
RIG should be infiltrated around the
wound as much as anatomically
feasible
Remaining RIG should be injected at an
intramuscular site distant from that of
vaccine inoculation (e.g. into the
anterior thigh)

Quantities/volume of RIG:
20 IU/ kg for Human RIG (HRIG) or 40 IU/ kg of
Equine RIG (ERIG)

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Total recommended dose should not be

exceeded
If RIG is unavailable on first visit, its
administration can be delayed by a maximum of
7 days from the date of first vaccine dose
If the calculated dose of RIG is insufficient to
infiltrate all wounds, sterile saline may be used
to dilute it 2 to 3 fold to permit thorough
infiltration

There are no scientific grounds for performing a skin

sensitivity Immunoglobulin (ERIG).
The treating physician should be prepared to
manage anaphylaxis which, however rare, could
occur at any stage of the ERIG administration

Rabies Post-Exposure Prophylaxis Modalities

Non-specific care
Postpone suturing if possible; if suturing is
necessary ensure that RIG has been applied
locally
Apply antimicrobials and tetanus toxoid if
necessary

Intramuscular regimens for rabies

Post-Exposure Prophylaxis
There are 3 intramuscular schedules for category II and III
exposures:
The 5 dose regimen
The 2-1-1 regimen
The 4 dose regimen with RIG in both categories
II and III
Vaccines should be injected into the deltoid muscle for
adults and children aged 2 years and more. The
anterolateral thigh is recommended for younger
children.
Vaccines should not be injected into the gluteal
region
The 5 dose intramuscular regime: (1-1-1-1-1)
One dose of the vaccine should be administered
on days 0, 3, 7, 14 and 28
Given in the deltoid region or, for young
children, into the antero-lateral area of the
thigh muscle
The 2-1-1 regimen:
(2-0-1-0-1)
Two doses are given on day 0 in the deltoid
muscle, right and left arm
An additional one dose is administered in the
deltoid muscle on day 7 and day 21

Intradermal regimen for rabies

Post-Exposure-Prophylaxis
The intradermal (ID) regimen requires a reduced
volume of vaccine to be utilised than any of the
intramuscular regimens therefore, reducing
vaccine cost by 60-80%
This method is appropriate where vaccine
or/and money are in short supply, particularly in
rural areas with high-flow clinics
The volume per intradermal (ID) site is 0.1 mL
Using the ID route of administration, PVRV
(Verorab) and PCECV (Rabipur) have been
proven to be safe and efficacious
0.1mL per ID site is used, according to WHO
recommended ID regimen
Vaccine administered ID must raise a visible and
palpable bleb in the skin. In the event that a
dose of vaccine is inadvertently given
subcutaneously or intramuscularly, a new dose
should administered intradermally

PEP for immunosuppressed individuals

Intradermal PEP regimen for Category II and III

Exposures
The 2-site intradermal method: (2-2-2-0-2)
One dose of vaccine, of 0.1 ml is given
intradermally at two different lymphatic
drainage sites
Usually administered in the deltoid muscle on
the left and right upper arm and suprascapular
area
Given on days 0, 3, 7 and 28.
Adopting the ID route for PEP
Any country willing to adopt the WHO
recommended ID regimen need not repeat
immunogenicity studies in their own Population
WHO recommends use of the WHO prequalified
rabies vaccines that can be used by the ID route.
Intradermal route:
Requirements for new rabies vaccines
To be approved for intradermal use:
Manufacturers should provide clinical evidence
that new products are immunogenic, effective
and safe when given intradermally
Administration should adhere to WHO guidance
for that route and prior approval by relevant
national authorities
In particular:
Any new candidate vaccine should be proven
potent by the mouse protection potency test

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(NIH test) and have at least 2.5 IU per single

immunizing (intramuscular) dose
The efficacy and/or immunogenicity and safety
should be demonstrated with the volume of 0.1
ml per intradermal site using the WHO
recommended PEP regimen

Thorough wound treatment should be further

stressed for immunosuppressed individuals
RIG should be administered deeply into the
wound for both category II and III exposures
Vaccine should always be administered and no
modification of the recommended number of
doses is advisable
An infectious disease specialist with expert
knowledge of rabies prevention should be
consulted
When possible, the rabies virus neutralizing
antibody response should be determined 2-4
weeks after vaccination to assess whether an
additional dose of vaccine is required

Interchangeability of modern rabies vaccine

types and routes for PEP

When completion of PEP with the same modern

rabies vaccine is not possible, the switch can be
done provided vaccines being used are one of
the WHO recommended cell culture or
embryonated egg vaccine
No extensive study has been done yet on
change of the route of vaccine administration
and vaccine immunogenicity (from intradermal
to intramuscular and vice versa) during PEP.
Preliminary results indicate that this practice
should remain the exception

Short rabies PEP of previously vaccinated

persons

Local treatment of wound(s) should be ensured

Two active immunization schedules are available
No RIG should be applied
However full PEP should be given to persons:
Who have received pre-or post-exposure
prophylaxis with vaccines of unproven
potency
Where immunological memory is no longer
assured as a result of HIV/AIDS or other
immunosuppressive causes

Schedule 1:
One dose to be injected intramuscularly of
intradermally on days 0 and 3

The dose is either 1 single immunizing intra

muscular (IM) dose (1 ml or 0.5 ml, depending
on vaccine type) or one intradermal (ID) dose of
0.1 ml per site

Schedule 2:
A 4-site intradermal (ID) PEP can be used
Consists of 4 injections of 0.1 mL equally
distributed over left and right deltoids, thigh or
suprascapular areas during a single visit

The vaccination series listed above must be completed at

the stipulated times. However, there is no need to
restart the series if the doses are not given on the exact
schedule

Booster vaccination and monitoring of

previously immunized persons

(Decision to use schedule 1 or 2 is left with the

health care provider in consultation with the patient)

Pre-exposure rabies prophylaxis (PrEP)

PrEP is recommended for anyone who is at continual,
frequent or increased risk for exposure to the rabies
virus, as a result of their occupation or residence such as:
Groups of persons at high risk of exposure to
live rabies virus (laboratory staff, veterinarians,
animal handlers and wildlife officers)
Children living in or visiting rabiesaffected areas
may be immunized preventively on a voluntary
individual basis or in mass campaigns when
there are no economic, programmatic or
logistical obstacles
Travellers to rabies-affected areas according to
the level of risk in that area.

Pre-exposure rabies prophylaxis regimens

(PrEP) with vaccines fulfilling WHO
requirements
Intramuscular:
One intramuscular dose is given on each of days
0, 7 and 21 or 28
Site of injection: deltoid area of the arm for
adults; anterolateral area of the thigh is
recommended for children aged less than 2
years
Intradermal:
One intradermal injection of 0.1 ml is given on
each of days 0, 7, and 21 or 28
If antimalarial chemoprophylaxis is applied
concurrently, intramuscular injections must be
used

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Persons working with live rabies virus in

diagnostic laboratories, research laboratories,
vaccine production laboratories at permanent
risk of exposure to rabies should have:
One serum sample taken every six months
A booster dose when the titre falls below
0.5 IU/ml
Others professions (veterinarians, animal
handlers, wildlife officers etc) working in rabies
endemic areas should have:
One serum sample taken every two years
A booster dose when the titre falls below
0.5 IU/ml
Routine booster vaccine doses after primary
rabies vaccination are not required for the
general public living in areas of risk.