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JIACM 2006; 7(1): 39-46

REVIEW ARTICLE

Post-exposure Prophylaxis for Rabies


C Shayam*, AK Duggal**, Ulka Kamble***, AK Agarwal****

Rabies (rage or madness in Latin) has been the subject 2. Solid organ transplant (liver, kidney) from an infected
of fear ever since the disease was recognised. person.
Worldwide the number of deaths annually, due to 3. Bite from a rabid human; theoretical risk but no
rabies, is estimated to be between 35,000 to 50,000 confirmed cases reported as yet.
approximately1. The highest incidence of rabies is in 4. Kissing an infected person; theoretical risk but no
India with approximately 30,000 cases of rabies confirmed case reported as yet.
reported annually2. The causative agent of rabies is a
* Contact with body fluids other than saliva and neural tissue (i.e.,
Lyssavirus type 1. It is a bullet shaped virus and is found blood, urine or faeces) is not considered an exposure.
in the wild as well as some domestic animals3. Rabies
** Rabies virus is inactivated by desiccation, UV radiation and
is essentially a zoonotic disease with man being the heating or cooking at > 60. Thus, dry material from a rabid animal
dead-end host. Rabies is transmitted to man most can be considered non-infectious.
commonly as a result of bites or scratches by a rabid
animal but there are some other uncommon modes Antirabies vaccines are of 2 types-Neural and Non-neural
of transmission of rabies as listed in Table I. Since rabies vaccines (Figure 1).
is 100% fatal (only six cases reported so far where
survival occurred after developing clinical rabies), Neural vaccines
prevention of rabies is the best and only option for Although WHO has directed its member nations not to use
cure4, 5. Post-exposure rabies vaccination forms the the neural tissue vaccines, still many developing nations
most integral part of prevention of rabies. This article use neural vaccines because of their low cost.
discusses the various available vaccines for rabies
prophylaxis and their schedules. 1. Semple Vaccine was developed by Semple at Central
Research Institute, Kasauli, and it has been the most
Table I: Modes of transmission of Rabies. widely used vaccine for over half-a-decade. It is a 5%
Animal to man suspension of sheep brain infected with fixed virus and
1. Bites of rabid animals. inactivated with phenol at 37C6.
2. Scratches by rabid animals.
2. Beta propionilactione vaccine (BPL) is a modification
3. Licks on abraded skin or mucous membranes.
of the Semple vaccine in which BPL is used as an
Aerosols inactivating agent instead of phenol. It is believed to
1. In caves harbouring rabies infested bats. be more antigenic, so a smaller dose is required7.
2. In laboratories handling rabies infected neural tissue*.
3. Suckling mouse brain vaccine was developed with the
Oral**
aim to reduce the encephelitogenic properties of the
1. Drinking unboiled raw milk of rabies infected cow or
rabies vaccine. The infant mice (< 9 days old) are used
goat.
for vaccine production. The amount of myelin in infant
2. Eating meat of rabid animal can theoretically lead to
brain is scanty and this results in a lower incidence of
rabies.
neuroparalytic side effects8.
Man to man
1. Corneal transplant from an infected person. Neural tissue vaccines (NTV) have many disadvantages:

* Chief Medical Officer, ** Medical Officer, *** Medical Specialist and Assistant Professor,
**** Consultant, Professor and Head, Department of Internal Medicine,
Dr. Ram Manohar Lohia Hospital, New Delhi - 110 001.
Fig. 1: Type of anti rabies vaccine

Antirabies vaccines

Neural (nerve tissue) vaccines Non-neural vaccines


Semple vaccine
BPL vaccine
Suckling mouse brain vaccine
Duck embryo vaccine Cell Culture vaccine
1st generation: HDCV
2nd generation: PCECV
PVRV
RVA
PHKV

1) poor immunogenecity as they contain mostly Non-neural vaccines


nucleocapsid antigen with only small quantities of
Non-neural vaccines were developed with the aim of
glycoprotien G which is the sole protective agent; 2) they
reducing the neuroparalytic complications associated with
may contain infectious agent which may not be
the nervous tissue vaccines. They are of 2 types: avian embryo
inactivated during vaccine production and storage; 3)
vaccines and primary cell culture vaccines.
the neuroparalytic adverse effects9. NTV contain myelin,
which is responsible for the neuroparalytic side effects Avian embryo vaccines: the prototype avian embryo
of these vaccines (Table II) 10. The incidence of neural vaccine is the duck embryo vaccine that was first made
complications with vaccines prepared from brains of available in 1957. It was widely used before the first
adult animals is between 1:200 and 1:2,000 and from that generation cell culture vaccines became available. This
of infant mice is 1:3,000 to 1:24,000 8,10. These vaccine contains no detectable myelin protein but contains
complications usually occur after the sixth or seventh traces of avian antigens. The chief disadvantages of use of
injection of the vaccine. The onset of symptoms is usually duck embryo vaccine are poor immunogenecity and
within 30 days (88% within 20 days). The condition may presence of avian antigens that could lead to anaphylactic
result in serious residual paralysis and even death8. There reaction12.
is no definite treatment of these neuroparalytic
Primary cell culture vaccines: modern cell culture
complications, but high dose corticosteroids, plasma
exchange and immunoglobulins have been used with vaccines were first developed in 1964 but were beset with
variable results8. tolerability problems9.
1. Human diploid cell vaccine (MIRV-HDC in India): the
Because of the above reasons, WHO has recommended
vaccine is prepared from Pitman Moore strain of
phasing out of NTVs by the year 200611. The Government
rabies virus grown on MRC-5 human diploid cell
of India has discontinued the use of NTV from December,
culture line, concentrated by ultrafiltration and
2004.
inactivated by BPL13. It is supplied in two forms:
Table II: Neuroparalytic complications of neural
a) Intramuscular administration: a single dose vial
vaccines.
containing lyophilised vaccine that is
1. Meningoencephalitis reconstituted in the vial with the accompanying
2. Meningoencephelomyelitis diluent to a volume of 1 ml.
3. Mononeuritis multiplex
b) Intradermal administration: a single dose syringe
4. Dorso-lumbar transverse myelitis
containing lyophilised vaccine that is
5. Ascending paralysis of Landrys type
reconstituted in the syringe to a final volume of

40 Journal, Indian Academy of Clinical Medicine  Vol. 7, No. 1  January-March, 2006


0.1 ml before administration14. Potency of anti rabies vaccines
The WHO regards the HDCV as the gold standard WHO recommends that the rabies vaccine for human use
among all rabies vaccines. In one of studies in Iran, none must have a potency of at least 2.5 IU/dose using the NIH
of the 45 persons who received HDCV developed rabies test21 for NTVs the minimum potency is 0.3 antigenic value.
following severe bites by rabid dogs or wolves15. All WHO recommended modern cell vaccines are safe and
effective. To be effective in preventing rabies, specimens
2. Purified chick embryo cell vaccine (PCECV- RabipurTm): collected 2 - 4 weeks after post-exposure prophylaxis
PCECV is prepared from fixed rabies virus strain FLURY should completely neutralise challenge virus at a 1:5
LEP grown in primary cultures of chicken fibroblasts9. serum dilution by the RFFIT4.
The vaccine was first marketed in 1984 and is now
available in more than 70 countries and more than Adverse effects of cell culture vaccines: the modern cell
30 million doses of PCECV have been administered culture vaccines are generally considered safe and have
worldwide. It is available as a single dose vial very few adverse effects. Table III enlists the common
containing lyophilised vaccine that is reconstituted adverse effects associated with modern cell culture
with diluent to a final volume of 1 ml. Various studies vaccines4.
have shown that PCECV is atleast as effective as the
Table III: Adverse effects of cell culture vaccines.
HDCV16-18. It is cheaper than HDCV.
1. Local: pain, erythema, swelling, or induration (in 15 to
3. Purified Vero Cell Rabies Vaccine (PVCV AbhayrabTm, 74 per cent of recipients)
VerorabTm): PVCV contains Wistar strain of virus, with 2. Itching
the vero cell line as the substrate, which is a continuous
3. Local lymphadenopathy
cell line9. The vaccine induces a good immune
response after primary as well as secondary 4. Headache, malaise, myalgia, or dizziness (10 to 25 per
immunisation, the results being comparable to those cent)
of HDCV19. But the continuous cell lines like vero cell 5. Gastrointestinal symptoms (in less than 10 percent);
line are abnormal, as their genetic make-up has been 6. Allergic reactions during primary vaccination (in 0.1
altered to allow continuous replication. Therefore they per cent [less than 10 per cent of whom have
may contain potentially oncogenic substances and anaphylactic reactions]).*
vaccines produced in such cell lines must be 7. Type III hypersensitivity reactions (in 6 to 10 per cent
monitored for residual DNA that is present in each after booster doses of human diploid cell vaccine and
dose. According to European Pharmacopoeia, the in fewer during primary vaccination).
content of residual DNA per human dose should be
*Allergic reactions are fewer with 2nd generation cell culture
less than 100 pg. The FDA, USA has not yet approved
vaccines.
the is vaccine for use in USA.

4. Rabies Vaccine Adsorbed (RVA): is prepared from Dosage and schedule of cell culture vaccines
Kissling strain of challenge virus standard (CVS) rabies
Rabies post-exposure prophylaxis (PEP) is an emergency and
virus adapted to foetal rhesus lung diploid cell culture20.
as a rule should not be delayed or deferred. There are no
The vaccine virus is inactivated by BPL and
contraindications if modern cell culture vaccines are used.
concentrated by adsorption to aluminum phosphate.
It is a liquid rather than lyophilised vaccine and is Indications for Antirabies vaccination: post-exposure
approved only for Intramuscular use as a 1 ml dose9. prophylaxis

5. Primary Hamster Kidney Cell Vaccine (PHKCV): this a. In endemic countries like India where terrestrial rabies
vaccine is used in China and Russia locally. The virus is is rampant, post-exposure prophylaxis should be given
propagated in primary kidney cells of Syrian hamsters6. to all patients with animal bites except if the dog at

Journal, Indian Academy of Clinical Medicine  Vol. 7, No. 1  January-March, 2006 41


the time of exposure is more than a year old and has a i. Bite by a wild animal
vaccination certificate indicating that it has received at ii. Unprovoked bites
least 2 doses of a potent vaccine, the first not earlier
iii. If the biting animal cannot be traced
than 3 months of age and another within 6 - 12
months later. In this case the dog may be observed iv. Laboratory tests of the brain of the animal are
for 10 days and if the dog shows any sign of illness positive for rabies
during the observation period, the patient should
PEP for rabies is not indicated if the biting animal is a small
receive full post exposure prophylaxis11.
rodent or rabbit22. Larger rodents like the woodchuck are
b. In other areas where rabies is not terrestrial, more frequently reported to be rabid4. Figure 2 shows a
indications for post-exposure prophylaxis are8: suggested algorithm for post-exposure prophylaxis of rabies4.

Did an exposure to rabies occur ?


Did an animal bite the patient, or did
a potentially unrecognised exposure
occur ?
Was there direct contact of the patients
open bleeding wound, broken skin,
or mucous membranes with potentially
infectious material such as animal saliva Yes Was the animal a mammal ?
No No Yes

No PEP Yes Was the animal a small rodent or rabbit ?


No

Observe the animal Yes Is the animal available Yes Was the animal a dog, cat, or ferret ?
for 10 days. Does it for observation ?
exhibit signs of rabies ? No
No

Consult public health Yes Was the animal domestic livestock ?


No Yes officials for local rabies
epidemiology. No
Was the animal a bat,
or is terrestrial rabies
present ? No Is the animal (brain) available for testing ?
No
No
Yes
Did the animal Negative for rabies Positive for rabies
exhibit any
signs of rabies ?

No
Yes
No PEP PEP No PEP PEP No PEP PEP

Fig. 2: Algrithm for post-exposure prophylaxis (PEP) of rabies.

42 Journal, Indian Academy of Clinical Medicine  Vol. 7, No. 1  January-March, 2006


Indications for Antirabies vaccination: pre-exposure a. Classic 5 dose intramuscular regimen (Essen regimen)
prophylaxis pre-exposure vaccination is recommended in which one dose of vaccine, i.e., 1 ml of HDCV, PCECV
for persons at risk: laboratory workers, diagnosticians, or 0.5 ml of PVEV is administered on day 0, 3, 7, 14,
veterinarians and their staff, animal control officers, rabies and 28.
researchers, and some travellers to endemic areas where
b. Alternate 2 - 1 - 1 regimen in which 2 doses of vaccine
rabies is prevalent23. WHO recommends that toddlers and
are given on both deltoids on day 0 and then one dose
children in highly endemic areas may also be considered
each on day 7 and 2111.
for rabies pre exposure vaccination.
Since the cell culture vaccines are very expensive,
Categorisation of bites (WHO)11 developing countries like India cannot afford the
universal use of cell culture vaccines as recommended
Category I: touching or feeding of animals or licks on
by the WHO11. In India alone, approximately 2.5 million
intact skin. In such a case if the history is reliable no
animal bites occur annually. If RabipurTm (PCECV) is used
treatment is required as there is no exposure to the
then the annual cost would be approximately Rs. 8.7
rabies virus.
billion. The WHO therefore recommends the use of cell
Category II: minor scratches or abrasions without bleeding, culture vaccines by intradermal route. Intradermal
or licks on broken skin and nibbling of skin. This requires a vaccination reduces the volume of vaccine required and
full course of antirabies vaccine. the cost of vaccination by 60 - 80%11. The efficacy and
immunogenecity of the intradermal regimen has been
Category III: single or multiple transdermal bites or established by various studies in Thailand, Sri Lanka and
contamination of mucous membrane with saliva. In this India27, 28. However, certain precautions are required that
case both immunoglobulin and vaccine should be used. include proper staff training, use of appropriate 1 ml
syringe and short hypodermic needles. Two regimens
Schedule for pre-exposure vaccination are used, the 8 site Oxford regimen and the 2 site Thai
Red Cross regimen8 (Table IV).
Pre-exposure vaccination simplifies the management
of subsequent exposure as fewer doses of vaccine are
required and rabies immunoglobulin is not required23.
Efficacy of post-exposure rabies prophylaxis
Three doses of vaccine are given on day 0, 7, and 28 The modern cell culture vaccines are highly effective.
by intramuscular route23. Alternatively, 0.1 ml of HDCV Various studies done with the cellular vaccines have
may be injected intradermally also24. Of note here is shown that the seroconversion rate (i.e., an antibody
the interference of chloroquine with the immune titre of > 0.5 IU/ml) after 14 days is 100%30-32. On the
response of anti-rabies vaccines. So HDCV should not other hand, the amount of glycoprotein antigen in NTVs
be given intradermally if the person is receiving is much less. So patients receiving NTVs may
chloroquine25. The need for booster vaccination may seroconvert late or may not seroconvert at all. In a study
be monitored by serologic testing performed every comparing NTV with PCECV, 14% of patients receiving
six months to 2 years and booster dose is given when NTV did not seroconvert, and the average antibody titres
titres fall below 0.5 IU/ml23. in NTV group (3.2 IU/ml) was much less than the PCECV
group (13.4 IU/ml)33.
Schedule for post-exposure vaccination
The cellular vaccines have been in use for over 40 years
Traditionally, modern cell culture vaccines are given now. In USA there have been no reported failures after
intramuscularly. The vaccines should not be administered post-exposure prophylaxis with the cellular vaccines. But in
in the gluteus muscle to avoid injury to the sciatic nerve South-east Asia and India there have been failures even
and to lessen the delivery of vaccine to the adipose tissue26. with the use of cellular vaccines34, 35. Most of these failures
Two regimens are used: have occurred when there have been deviations from the

Journal, Indian Academy of Clinical Medicine  Vol. 7, No. 1  January-March, 2006 43


recommended schedule and guidelines. Of importance to have occurred. Because RIG can partially suppress
here is the proper management of the wound and use of active production of antibody, no more than the
ARG especially in severe category III bites34. recommended dose should be administered34.

Table IV: Regimens for post-exposure vaccination for rabies.


Oxford regimen Thai Red Cross regimen
8 site intradermal regimen 2 site intradermal regimen
1. Vaccines used: HDCV, PCECV 1. PVRVORPCECV
2. Dose: 0.1 ml of HDCV OR PCECV 2. Dose: 0.1 ml of PVRV or 0.2 ml of PCECV
3. Schedule: (8 - 0 - 4 - 0 - 1 - 1) 3. Schedule: (2 - 2 - 2 - 0 - 1 - 1)
0.1 x 8 0.1 x 4 0.1 0.1 0.1 x 2 0.1 x 2 0.1 x 2 0.1 x 1 0.1 x 1


day 0 day 7 day 28 day 90 day 0 day 3 day 7 day 28 day 90
4. Particularly useful in emergency situations 4. To be avoided in emergency situation
where no RIG is available because antibody
response at 7 days is greater29.
5. Total of less than 2 vials used on 4 visits. 5. Total of less than 2 vials used on 5 visits.

Antirabies serum (ARS)/rabies Prior to administration, a skin test should be done. A


immunoglobulin (RIG) treatment test dose of 0.1 ml of 1 in 10 diluted ERIG is injected
intradermally into the left forearm. An equivalent
Even with the more potent cellular vaccines, the protective
intradermal injection of physiological saline is used as
antibody levels are achieved only after 10 - 14 days35. Thus
control. An induration of > 10 mm is taken as positive38.
ARS/RIG are needed to cover this vulnerable short
The problem however is that a positive skin sensitivity
incubation period in class III exposures or severe wounds
test does not accurately predict anaphylaxis or serum
from high-risk category of animals. It provides a short
sickness like reactions39. The immediate reactions that
immunity with half-life of 21 days36. The failure of modern
occur after use of heterologous sera are either IgE
cellular vaccines in most cases has been because ARS/RIG
mediated (anaphylactic) or complement mediated
was not used in high-risk category III cases34. RIG or ARS are
(anaphylactoid). The skin test detects the anaphylactic
made of readymade antirabies antibodies, which provide
reactions but not the anaphylactoid reactions40. WHO
passive immunity and immediate protection. Two types of
in 1995 had recommended that skin test may not be
ARS/RIG are available:-
done prior to ERIG administration39. In Brazil a study
1. ARS or Equine Rabies Immunoglobulin (ERIG): Potent was done in which none of the 1,054 patients who
antirabies serum has been prepared in horse and were given ERIG were subjected to skin sensitivity test.
other animals. ERIG is widely used in India. It should They were however given ERIG under the cover of
be given as early as possible, preferably on day 0. It antihistamines (anti H1+ anti H2 ) and corticosteroids.
can however be given irrespective of the interval All the patients were observed for 60 - 180 minutes.
between time of exposure and initiation of None of the patients showed any adverse effects41. In
treatment. It should never be given alone without 1997 WHO recommended that if the skin test is positive,
concomitant use of antirabies vaccine. It can be given preferably HRIG should be used. However, if HRIG is not
within 7days of starting antirabies vaccine37. Beyond available then desensitisation for horse serum may be
the seventh day, RIG is not indicated since an considered. Alternatively, ERIG may be given under
antibody response to cell culture vaccine is presumed cover of antihistamines and intramuscular adrenaline/

44 Journal, Indian Academy of Clinical Medicine  Vol. 7, No. 1  January-March, 2006


epinephrine42. If however, ERIG cannot be given, then in animals, their efficacy in phase I human trials has
after proper wound toilet the patient should preferably largely been disappointing46.
be given 2 doses of a cellular vaccine on day 0 in both
To conclude, although post-exposure vaccination forms
deltoids.
an integral part of rabies control, control of rabies can
Dose of ERIG is 40 IU/Kg of body weight. As much as only be achieved by health education and vaccination
possible ERIG should be infiltrated around and into the of dogs and cats. However availability of cheap and
wound(s), even if the lesion has begun to heal. If the effective human rabies vaccine is of prime importance
calculated dose of ERIG is insufficient, then sterile saline for preventing mortality from rabies in a country like
can be used to dilute it 2 - 3 times to permit thorough India.
infiltration. Any remaining ERIG is injected
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