Rabies prevention
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Transcript of Rabies prevention
1
Dr (Lt Col) Ashutosh Ojha
151 Army Base Hospital,India
Understanding Rabies Disease and Prevention
Rabies disease background
Section 1
3
Rabies is virtually 100% fatal
Benenson 1995
0102030405060708090
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Rabie
s
Inha
latio
n ant
hrax
Pneum
onic P
lague
M. m
enin
gitis
Cholera
Yello
w feve
r
Dengue
Hanta
viru
s
Smal
lpox
Mal
aria
Cas
e fa
tali
ty r
ate
No treatment Treatment
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Rabies
Rabies is an ancient disease
Painting of a rabid dog biting a manArabicA.D. 1224Baghdad school, by Abdallah ibn al-Fadl
Picture courtesy of Smithonian Institution, Washington D.C.
5
The rabies virus
Taxonomy:
Family: Rhabdoviridae Genus: LyssavirusSpecies: Rabies virus
bullet-shaped, ~180 nm long and ~75 nm wide single-strand,
negative senseRNA
CDC 2007; Bleck 2005
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Pathogenesis: Exposure
Bite transmissionHuman infection by rabies virus usually occurs as a result of a transdermal bite from an infected wild or domestic animal
Non-bite transmissionScratches from a rabid animalSaliva from a rabid animal comes into contact with a victim’s mucous membranes or fresh skin lesions
Rare cases have been reported via:Inhalation of virus-containing aerosolsHuman-to-human transmission through transplantation
1. Bleck 2005; 2. WHO 2004
How does the Rabies virus travel from wound to brain
8
Human rabies: Clinical stages
Death usually occurs within a few days after theappearance of clinical symptoms
First neurologic
signs
Clinicalstage
Incubationperiod
Prodrome phase
Acuteneurologic
phaseComa
Usual duration
First clinical
signs
Exposure Onset of
comaDeath
2-10 days
2-7 days 0-14 days
Onset of rabies symptoms may start rather late, ie, onset of symptoms documented months, even years, after exposure
20-90 days
1. Jackson 2007; 2. Hemachudha 2002
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Clinical rabies in humans
Two forms of rabies are distinguished:
Furious (75-80%) (encephalitic; three-forth of all cases):
– Rabies transmitted from dogs is usually furious
Paralytic (20-25%) (dumb; one-fourth of all cases)
Clinical Presentation:First clinical symptoms: non-specific, i.e., malaise, fever, and headacheParesthesia: pain and abnormal feelings at the wound site are commonAcute neurologic phase: including throat spasms with an inability to swallow, and anxiety, confusion, and hallucinations: – Hydrophobia (only documented in humans),
respiratory spasms with aerophobia, hyperactivity only exhibited with furious rabies
– Ascending paralysis or a symmetric quadriparesis only exhibited with paralytic rabies
Coma and death
Jackson 2002
10
Rabies in children
Due to their short stature, children are susceptible
to bites on face, scalp, and upper part of the body
Children are more susceptible to animal bites
by playing in open grounds or in streets
Children cannot ward off animals easily
Children are more likely to provoke animals
Children might not report a bite or scratch
40-60% of all animal bite cases are reported tooccur in children <15 years of age
WHO 2008
Epidemiology of rabies
Section 2
12
Worldwide risk of rabies (2008)
WHO 2009
No risk Low risk Medium risk High risk
India carries highest Rabies disease burden
Estimated 20,000 human rabies deaths per year
Principal reservoir of the disease is dogs
No surveillance system of rabies cases – lack of reliable data
Estimated 27 million dogs – although the number of stray dogs is unknown
17.4 million dog bites annually
131. Cliquet 2007; 2. Sudarshan 2007
Rabies vaccines
15
Historical development of rabies vaccines
1885: Louis Pasteur developed the first rabies vaccineInfected rabbit spinal cord partially inactivated by desiccation
1911: Semple vaccine; Sir David Semple improved Pasteur treatmentInactivated virus using formalin and phenol Infected adult rabbit, sheep, or goat brain tissueReactogenic, poorly immunogenic, up to 23 daily injections
1955: Fuenzalida vaccine; Drs Fuenzalida and PalaciosSuckling mouse brain (SMB) vaccineDecreased reactogenicity with improved immunogenicity; 10-15 doses required
1956: Duck embryo vaccine; first effective cell-culture vaccineDuck embryo vaccine (DEV)Poorly immunogenic, high rate of allergic reactions. STOPPED 1980s
1970s: Modern cell-culture vaccinesHighly immunogenic with good safety profile
Plotkin 2008
16
Currently produced rabies vaccines IHuman diploid cell vaccines (HDCV):
First-generation cell-culture rabies vaccine
Virus grown on human diploid cells, Pitman-Moore strain
Good immunogenicity and tolerability (hypersensitivity reactions are however reported with the unpurified HDCV)2
Suitable for pre-exposure vaccination and post-exposure prophylaxis
Purified Vero cell rabies vaccines (PVRV):
Second-generation cell-culture rabies vaccine
Continuous cell line produced on Vero cells (vervet monkey origin), virus grown in microcarrier system
Good immunogenicity and tolerability
Clinical trials not permitted in the US; no FDA approval due to risk of residual DNA associated with continuous cell line
1. Plotkin 2008; 2. CDC 1988
†Intradermal administration is currently licensed in India, the Philippines, Sri Lanka, Thailand, and Vietnam;
regulatory approval will continue to be adapted for other countries
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Purified chick embryo cell-culture vaccine (PCECV):Second-generation cell-culture rabies vaccine
Prepared in primary chick embryo cells using Flury LEP strain of fixed rabies virus
Good immunogenicity and tolerability
High purity and potency
Approved by the US FDA (intramuscular regimen only)
Recommended for each and every established WHO vaccination schedule where intradermal administration is licensed†
Currently produced rabies vaccines II
Plotkin 2008
†Intradermal administration is currently licensed in India, Myanmar the Philippines, Sri Lanka, Thailand, and Vietnam; regulatory approval will continue to be adapted for other countries
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CategoryType of contact with a suspect or confirmed
rabid domestic or wilda animal, or animal unavailable for testing
Type of exposure
Recommended post-exposure prophylaxis
ITouching or feeding animals, licks on
intact skin (ie, no exposure)None No prophylaxis is required
IINibbling of uncovered skin, minor
scratches or abrasions without bleedingMinor Administer vaccine immediately
III
Single or multiple transdermal bites or scratches, licks on broken skin,
contamination of mucous membrane with saliva from licks, exposures to bats
SevereAdminister rabies immunoglobulin and vaccine
immediately.
WHO categories (I-III): Schedules forpost-exposure prophylaxis
1. WHO 2004; 2. CDC/ACIP 2008
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Post-exposure prophylaxis
Wound treatment (all WHO categories)
Vaccine administration (WHO category II and III)
– Active immunization with highly immunogenic
rabies vaccine
RIG administration, if appropriate (WHO category III)
– Passive immunization followed by administration of
specific antibodies
Prevention of human rabies The 5 Important Things
Magico-Religious Practices(e.g. witchcraft, turmericpowder etc.) DO NOTHELP
Wash the woundthoroughly with plenty ofwater and soap
Apply an antiseptic(povidone iodine) or evenalcohol
Do not cover or Suturethe wound
Vaccinate Immediatelye.g. Raibipur 1 mL IM
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Rabies immunoglobulin (RIG)
Courtesy Medi-Vision and B. Quiambao, RITM, Manila
RIG needs to be administered to all Category III wounds along with complete course of ARV, 5 doses (0,3,7,14,&,28 days) for 1st exposure
Subsequent exposure will require only 2 doses of ARV (0 & 3 days) and no RIG’s
RIG infiltrated in and around wounds
Two types of RIG
– Human RIG, dose 20 IU/kg of body weight
– Equine RIG, dose 40 IU/kg of body weight
RIG provides passive immunity
– Immediate access to rabies virus-neutralizing antibodies (RVNA)
– Provides protection until active immunity begins (7-10 days post-vaccination)
22
Prevention of human rabies Vaccine administration
Post-exposure prophylaxis IM regimens:
– Essen regimen: 5 doses, 5 patient visits (DCGI
approved regimen)
– Zagreb regimen: 4 doses, 3 patient visits
Post-exposure prophylaxis ID regimens:
– Updated Thai Red Cross: 8 doses, 4 patient visits
(DCGI approved regimen)
– Thai Red Cross: 8 doses, 5 patient visits
– Oxford 8-site: 14 doses, 4 patient visits
1. WHO 2004; 2. WHO 2007 National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
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Post-exposure prophylaxis IM administration:Essen regimen
One IM dose of vaccine on Days 0, 3, 7, 14, and 28
RIG is always recommended for transdermal wounds
5 doses – 5 visits
1. WHO 2004; 2. WHO 2007
1 mL (IM) into deltoid (adults)
or into anterolateral area of thigh
(children)
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Post-exposure prophylaxis IM administration: Updated Thai Red Cross (2-2-2-0-2)
8 doses – 4 visits
RIG is always recommended for transdermal wounds
Days 0, 3, 7, and 28 – two 0.1 mL doses
0.1 mL per site
Administered in right and left deltoid
1. WHO 2004; 2. WHO 2007
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DCGI recommended post-exposure IM and ID regimens: Summary
Regimen Day 0 Day 3 Day 7 Day 14 Day 21 Day 28 Day 90 mL Visits
Thai Red Cross
(updated)
2 x 0.1 mL
2 x 0.1 mL
2 x 0.1 mL
– –2 x
0.1 mL– <1 4
Regimen Day 0 Day 3 Day 7 Day 14 Day 21 Day 28 Day 90 Vials Visits
Essen 1.0 mL 1.0 mL 1.0 mL 1.0 mL – 1.0 mL – 5 5
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
26
Post-exposure prophylaxis in patients previously vaccinated with a cell-culture rabies vaccine
x1 x1
Day 0 3
Two doses administered IM or ID Administered into (IM) or
above (ID) deltoid
No RIG is required
1. WHO 2004; 2. WHO 2007
National Guidelines for Rabies Prophylaxis andIntra-dermal Administration of Cell Culture Rabies Vaccines
Intra-muscular (IM) Regimen
The currently available vaccines and regimen in India for post exposure IM administration are described below.
Vaccines
1. Cell Culture Vaccines
Human Diploid Cell Vaccine (HDCV)
Purified Chick Embryo Cell Vaccine (PCEC)
Purified Vero Cell Rabies Vaccine (PVRV)
2. Purified Duck Embryo Vaccine
Regimen
Essen Schedule: Five dose intramuscular regimen on days 0, 3, 7, 14 and 28.
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines
Intra-dermal (ID) RegimensGeneral guidelines for use of IDRV
Vaccines to be applied by intra-dermal route of administration should be approved by DCGI.
The vaccine package leaflet should include a statement indicating that the potency as well as immunogenicity and safety allow safe use of vaccine by ID pre- and post-exposure.
Post Marketing Surveillance (PMS) data should be maintained for minimum of two years by vaccine manufacturers on a pre-designed and approved protocol.
Intra-dermal injections must be administered by staff trained in this technique.
Vaccine vials must be stored at 2º to 8ºC after reconstitution.
The total content of reconstitute vial should be used as soon as possible, within 8 hours.
Rabies vaccines formulated with an adjuvant should not be administered intra-dermally.
Vaccine when given intra-dermally should raise a visible and palpable bleb in the skin.
In the event that the dose is inadvertently given subcutaneously or intra-muscularly or in the event of spillage, a new dose should be given intradermally in near by site.
Animal bite victims on chloroquine therapy (anti-malarial therapy) should be given ARV by intramuscular route.
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines
DCGI approved ARV for use by intra-dermal route.• PVRV – Verorab, Aventis Pasteur (Sanofi Pasteur) India Pvt. Ltd.• PCECV – Rabipur, Chiron Behring Vaccines Pvt. Ltd.• PVRV – Pasteur Institute of India, Coonoor• PVRV – Abhayrab, Human Biologicals Institute.
Regimen
Updated Thai Red Cross Schedule (2-2-2-0-2).
This involves injection of 0.1ml of reconstituted vaccine per ID site and on two
such ID sites per visit (one on each deltoid area, an inch above the insertion
of deltoid muscle) on days 0, 3, 7 and 28
(Note: A DCGI order dated 9th August 2006, has revised the eligibility criteria for intradermal administration of tissue culture rabies vaccines at anti- rabies clinics (ARC) in India from those with a minimum attendance of 50 patients per day to those with a minimum of 10 patients per day)
National Guidelines for Rabies Prophylaxis and Intra-dermal Administration of Cell Culture Rabies Vaccines, 2007
30
Composition
Active ingredient:– Rabies virus† (inactivated, Flury LEP strain ) potency 2.5 IU
Other ingredients‡
– Powder:◦ TRIS-(hydroxymethyl)-aminomethane ◦ Sodium chloride◦ Disodium edetate (Titriplex III)◦ Potassium-L-glutamate◦ Polygeline◦ Sucrose
– Diluent:◦ Water for injection
Rabipur SmPC 2007
Composition: one vial of powder and diluent for solution,for one immunization dose (1 mL) contains:
†Produced on purified chick embryo cells; ‡May contain traces of neomycin, chlortetracycline, amphotericin B, and chicken proteins
LEP: Low egg passage
31
Clinical database since 1981
More than 90 completed clinical trials
– More than 30 pre-exposure trials
– More than 50 post-exposure trials
– 7 booster trials
– 8 efficacy trials
Total: ~6000 subjects vaccinated
Rabipur Product Monograph 2008
33
†Current Essen regimen administration is Days 0, 3, 7, 14, and 28‡ 0.5 IU/mL
PCECV Immunogenicity (Essen regimen)
Adults administered IM rabies vaccine on Days 0, 3, 7, 14, 30, and 90†
– Rabipur 1.0 mL (n=15)
PCECV demonstrated consistent and high antibody concentrations using the standard WHO IM regimenAdverse reactions were mainly mild (31.2% systemic reactions, 56.5% local reactions)
Scheiermann 1987
0.1
1
10
100
0 7 14 30 90
‡
GM
C (
IU/m
L)
Time following immunization (days)
34
Efficacy studies (IM)
100% survival rate of subjects after exposure to laboratory-confirmed rabid animals
StudyNo. of
subjects
(total)
No. of subjects bitten by
proven rabid animals
Schedule/vaccination
day
No. of subjects
who received RIG
Follow-up period
(months)
Survivalrate after bite
by proven rabid animal
(%)
1 45 45IM (Essen)†
6 dose45 (HRIG) >12 100
2 28 28IM (Essen)†
6 dose28 (HRIG) >6 100
3 21 21IM (Essen)†
6 dose4 (HRIG)
15 100
4 56 56IM (Essen)†
6 dose41 (ERIG) 19-34 100
5 1252 145IM
2-6 doseno RIG >12 100
References on note page†Current Essen regimen administration is Days 0, 3, 7, 14, and 28
PVRV
36
0.1
1
10
100
0 7 14 30 90
PCECV
Immunogenicity following the Thai Red Cross ID regimen
Adults who had received WHO Category II and III wounds administered ID rabies vaccine on Days 0, 3, and 7 (two sites) and Days 30 and 90 (one site) – PCECV 0.1 mL – PVRV 0.1 mL
Rabipur is well-tolerated and immunogenic when following the Thai Red Cross ID regimen
Briggs 2000
†
†0.5 IU/mL
GM
C (
IU/m
L)
Time following immunization (days)
37
Efficacy studies (ID)
†All subjects received PCECV
100% survival rate of subjects after exposure to laboratory-confirmed rabid animals
StudyNo. of
subjects (total)
No. of subjects
exposed to proven rabid
animals
Category of
contact
Vaccination schedule
No. of subjects who received RIG
Follow-up period (months)
Survivalrate (%)
1 148 148 I, II, or IIIID 2-site
(TRC)<3% (ERIG) ≥12 100
2 113 113 IIIID 2-site
(TRC)113
(HRIG/ERIG)≥12 100
3 32 32 III ID 8-site12 (HRIG)10 (ERIG)
36100
References on note page
38
Post-marketing Surveillance Study
In a post-marketing surveillance study (n=1252) with PCECV– 4.0% reported
adverse events, all were mild-to-moderate
Occurred mainly after Dose 1 or 2 but resolved spontaneously within 48 hoursMild fever was the most common systemic adverse event, reported by 0.5% of individuals
Sehgal 1995
Su
bje
cts
rep
ort
ing
ad
ver
se e
ven
ts (
%)
1.1%
2.1%
0
2
4
6
8
10
Injection-site pain Injection-site induration
Summary
Section 6
40
Summary - I
Rabies is a viral zoonosis that is transmitted from animals to humans – Human infection usually occurs as a result of a transdermal bite
or scratch from an infected animalDogs are the principal vector causing transmission of rabies to humans in Africa, Asia, and parts of Latin AmericaThere are no immediate clinical symptoms following exposure to rabies virusRabies is almost invariably fatal following the onset of clinical symptoms Rabies is present throughout the world and >3 billion people are at risk of infection in >100 countries – The WHO estimates that the annual number of human rabies
deaths worldwide is ~55,000, and most occur in Asia and Africa
41
Summary - II
There are two active immunization strategies available to prevent rabies in humans: – Pre-exposure vaccination protects against potential exposure
to rabies particularly vulnerable children, individuals who live in or travel to high-risk areas or work in high-risk occupations
– Post-exposure prophylaxis (PEP) is administered following contact with a suspected or confirmed rabid animal. The WHO and CDC provide guidelines for both strategies
PCECV is a purified chick embryo cell-culture rabies vaccine which provides active immunization and protection Approved by the US FDA (intramuscular regimen only)Recommended for each and every established WHO vaccination schedule where intradermal vaccination licensed†
†Intradermal administration is currently licensed in India, Myanmar, the Philippines, Sri Lanka, Thailand, and Vietnam; regulatory approval will continue to be adapted for other countries
42
Summary - III
PCECV has been available for post-exposure and pre-exposure prophylaxis since 1984
The immunogenicity, efficacy, and safety profiles of PCECV are well established and have been evaluated in >90 clinical trials worldwide