Post-exposure Prophylaxis (PEP)

 Post-exposure prophylaxis is a medical urgency and is indicated following a significant contact

with any warm-blooded animal. These include dogs, cats, cows, buffaloes, sheep, goats, pigs,
donkeys, horses, camels, foxes, jackals, monkeys, mongoose, bears, and others.
 Rabies due to rodent bites has not been reported in India till date and PEP is not normally
recommended for these bites.
 PEP should be initiated as soon as possible and should not be delayed till results of lab tests or
animal observation is available.
 Because rabies is a lethal disease, there are no contraindications for PEP including infants, and
pregnant and lactating women.
 Persons presenting several days/months/years after the bite should be managed in a similar
manner as a person who has been bitten recently as rabies may have a long incubation period
and the window of opportunity for prevention remains.

Rabies exposure may be classified as per WHO into three categories

Category Type of contact Type of Recommended postexposure

exposure prophylaxis
I Touching or feeding of animals None None, if reliable case history is
Licks on intact ski available
II Nibbling of uncovered skin Minor Minor Wound management +
scratches or abrasions without Antirabies vaccine
bleeding
III Single or multiple transdermal bites Severe Wound management +
or scratches, licks on broken skin Rabies immunoglobulin
Contamination of mucous +
membrane with saliva (i.e. licks) Antirabies vaccin

 Bites from unidentified animal is classified as category III

 1. CARE OF ANIMAL-BITE WOUNDS

 The first step is thorough cleansing of the wound with soap and flushing under running
water for 10 minutes.
 This should be followed by irrigation with a virucidal agent such as 70% alcohol or povidone
iodine.
 Antimicrobials and tetanus toxoid should be given if indicated.
 Rabies immunoglobulin (RIg) should be infiltrated in and around the wound in category III
bites.
 Any suturing of wound should be avoided. When suturing is unavoidable for purpose of
hemostasis, it must be ensured that RIG has been infiltrated in the wound prior to suturing.

2. RABIES IMMUNOGLOBULIN

Dosage:

It contains specific antirabies antibodies that neutralize the RABV and provide passive protection till
active immunity is generated.

There are two types of RIg:

1. Human rabies immunoglobulin (HRIg—dose is 20 U/kg body weight, maximum dose 1,500 IU)
2. Equine rabies immunoglobulin (ERIg—dose is 40 U/kg, maximum dose 3,000 IU).

 Human rabies immunoglobulin is preferred, but if not available/ unaffordable ERIg may be used.
 Most of the new ERIg preparations are potent, safe, highly purified, and less expensive as
compared to HRIg, but do carry a small risk of anaphylaxis.
 As per latest recommendations from WHO, skin testing prior to ERIg administration is not
recommended as skin tests do not accurately predict anaphylaxis risk and ERIg should be given
whatever the result of the test.

Administration:

 RIg is indicated in all cases of category III wounds where it should be infiltrated thoroughly into
and around the wound.
 The remaining part if any is to be injected intramuscularly (IM) into the deltoid region or
anterolateral aspect of thigh away from the site of vaccine administration to avoid vaccine
neutralization.
  In case RIg dose (quantity) is insufficient for adequate infiltration of extensive or multiple
wound, it may be diluted with equal volume of normal saline so that all the wounds can be
thoroughly infiltrated.
 If RIg could not be given when antirabies vaccination was began, it should be administered as
early as possible but no later than the 7th day after the first dose of vaccine was given. From the
8th day onward, RIG is not indicated since an antibody response to the vaccine is presumed to
have occurred.
 RIg is also not indicated in individuals who have received pre-exposure prophylaxis/PEP in the
past.

Adverse reactions: Include tenderness/stiffness at the injection site, low-grade fever; sensitization may
occur after repeated injections.

3. RABIES VACCINES

The currently available vaccines are:

1. The cell culture vaccines (CCVs) and include purified chick embryo cell vaccine (PCECV), human
diploid cell vaccine (HDCV), purified Vero cell rabies vaccine (PVRV); and
2. Purified Duck Embryo vaccine (PDEV).

It is to be noted that all CCVs and PDEV should have potency (antigen content) greater than 2.5 IU
per intramuscular dose irrespective of whether it is 0.5 mL or 1.0 mL vaccine by volume.

Efficacy and effectiveness:

 The vaccines are available in lyophilized form with sterile water as diluent, are stable for 3 years
at 2–8°C and should be used within 6 hours of reconstitution.
 All CCVs have almost equal efficacy and any one of these can be used.
 These vaccines induce protective antibodies in more than 99% of vaccinees following
preexposure prophylaxis/PEP.
 In both pre-exposure and post-exposure use, these vaccines induce an adequate antibody
response in almost all individuals.
 Prompt post-exposure use of CCVs combined with proper wound management and
simultaneous administration of RIG is almost invariably effective in preventing rabies, even
following high-risk exposure.
Duration of immunity:

The current CCVs possess immunological memory after vaccination, and individuals who had
received their primary series 5–21 years previously showed good anamnestic responses after
booster vaccination even when antibodies are no longer detectable.

Adverse effects:

 The main adverse effects are local pain, swelling, and redness and less commonly fever,
headache, dizziness, and gastrointestinal side effects.
 Systemic hypersensitivity reactions in vaccines have been reported with HDCV particularly
following booster injections but not with PCEC/PVRV.
 Intradermal vaccination may cause more local irritation as compared to the intramuscular
route.

Schedule of Vaccination
1. Essen protocol

 The standard schedule (Essen protocol) is five doses on days 0, 3, 7, 14, and 30, with day “0”
being the day of commencement of vaccination.
 A regimen of five 1-mL doses of HDCV or PCECV should be administered IM to previously
unvaccinated persons.
 The first dose of the five-dose course should be administered as soon as possible after
exposure. This date is then considered day 0 of the PEP series.
 Additional doses should then be administered on days 3, 7, 14, and 28 after the first
vaccination.

2. Shortened Essen regimen

 A reduced, four-dose vaccine schedule (1-1-1-1-0) for healthy people is supported by the
peer-reviewed literature, unpublished data, epidemiological reviews, and expert opinion.
This shortened Essen regimen, consisting of one dose on each of days 0, 3, 7, and 14, may be
used as an alternative regimen.
 Most interruptions in the vaccine schedule do not require reinitiation of the entire series.
For most minor deviations from the schedule, vaccination can be resumed as though the
patient were on schedule.
 3. Zagreb schedule - Alternative 4-day Schedule, if an Accelerated Response is Considered
Necessary
 As an alternative, the 2-1-1 regimen (Zagreb schedule) may be used.
 Two doses are given on day 0 in the deltoid muscle, right and left arm.
 In addition, one dose in the deltoid muscle on day 7 and one on day 21 are
administered.
 This schedule is, however, not approved for use in India

 The dose is same at all ages and is 1 mL IM for HDCV, PCEV, PDEV, and 0.5 mL for PVRV.
 Any of the CCVs may be used intramuscularly in anterolateral thigh or the deltoid.
 Rabies vaccine should never be injected in the gluteal region.
 Interchange of vaccines is permitted only in special circumstances but should not be done
routinely.
 If RIg is not available, then two doses of the vaccine may be given on day 0 (this is, however,
not a substitute for RIg).
 If the animal remains healthy over a 10 days observation period, further vaccination may be
discontinued.
 It is, however, desirable to administer one more dose on day 28 in order to convert to the
pre-exposure prophylaxis schedule.

Intradermal Vaccination
 Intradermal vaccination is a cost-effective alternative to intramuscular vaccination as the dose
required is only 0.1 mL.
 Only two of the three WHO-prequalified vaccines—purified Vero cell rabies vaccine and purified
chick embryo cell vaccine—have been shown to be safe and effective when administered
intradermally at a dose of 0.1 mL in a WHO-recommended pre-exposure prophylaxis or PEP.
 The schedules permitted in the first phase include the Thai Red Cross Regimen (2-2-2-0-1-1, two
intradermal doses on the deltoid on days 0, 3, and 7, and one dose on day 30 and 90) and the
Updated Thai Red Cross Regimen (2-2-2-0-2-0 and two doses on days 0, 3, 7, and 30).
 Another schedule not currently approved by DCGI is the 8-site regimen (8-0-4-0-1-1; eight
intradermal doses on each upper arm, each lateral lower abdominal quadrant, each thigh, and
each suprascapular region on day 0; four doses on day 7 on each thigh and upper arm; and one
dose on days 30 and 90 on upper arm).
 The intradermal route should not be used for immunocompromised patients and those on
chloroquine therapy.
Post exposure Prophylaxis of Immunocompromised Patients

 Several studies of patients with human immunodeficiency virus/ acquired immunodeficiency

syndrome have reported that those with low CD4 (<200 counts) will mount a significantly lower
or no detectable neutralizing antibody response to rabies.
 In such patients and those in whom the presence of immunological memory is no longer assured
as a result of other causes, proper and thorough wound management and antisepsis
accompanied by local infiltration of RIG followed by antirabies vaccination are of utmost
importance.
 Even immune-compromised patients with category II exposures should receive RIG in addition
to a full post exposure vaccination.
 Preferably, if the facilities are available, antirabies antibody estimation should be done 10 days
after the completion of course of vaccination.

Postexposure prophylaxis in previously vaccinated children :

 Children who have received previously full rabies PEP or pre-exposure vaccination (either IM or
ID route) with CCV/PDEV should be given only two booster doses, either intramuscularly (0.5
mL/1 mL) or intradermally (0.1 mL at a single site only, using ID compliant vaccine) on days 0 and
3.
 This is given irrespective of the duration of previous vaccination.
 In these situations, treatment with RIg is not necessary.
 As always, proper wound toilet should be done.
 In case of travelers who cannot come for the second visit, a single-visit four-site (0.1 mL × 4 ID
sites, two deltoids and two suprascapular or thighs) ID booster may be given as per WHO
recommendation.
 Pre-exposure Prophylaxis
Pre-exposure prophylaxis is particularly important where the exposure may be unrecognized
(lab) or unreported (children).
Preexposure prophylaxis eliminates the need for RIG (awareness, cost, and availability of RIg is a
problem).
It also reduces PEP to two doses only.

Pre-exposure prophylaxis is recommended for certain high-risk groups enumerated as follows:

1. Continuous exposure: Lab personnel involved with rabies research and production of rabies
biologics. Source and exposure may be unrecognized.
2. Frequent exposure: Veterinarians, laboratory personnel involved with rabies diagnosis, medical,
and paramedical staff treating rabies patients, dog catchers, zoo keepers, and forest staff.
3. Infrequent exposure: – Postmen, policemen, and courier boys – Travelers to rabies endemic
countries particularly those who intend to backpack/trek.

 Most Indian children are at risk for rabies.

 Therefore, Advisory Committee on Vaccines and Immunization Practices (ACVIP) recommends
offering pre-exposure prophylaxis to children at high risk of rabies exposure after discussion
with parents.
 Any of the tissue culture vaccines can be given for this purpose.
 Three doses are given intramuscularly in deltoid/anterolateral thigh on days 0, 7, and 28 (day 21
may be used if time is limited but day 28 preferred).
 The intradermal schedule is 0.1 mL of any vaccine by the intradermal route on days 0, 7, and
21/28.
 Routine assessment of antirabies antibody titer after completion of vaccination is not
recommended unless the person is immunocompromised.
 It is desirable to monitor antibody titers every 6 months in those with continuous exposure and
every year in those with frequent exposure. A booster is recommended if antibody levels fall
below 0.5 IU/mL.
 When serologic testing is not available booster vaccination every 5 years is an acceptable
alternative.
 For re-exposure at any point of time after completed (and documented) pre-exposure
prophylaxis or PEP, two doses are given on days 0 and 3. RIg should not be used as it may
inhibit the relative strength or rapidity of an expected anamnestic response.