Download - Rabies prevention

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Dr (Lt Col) Ashutosh Ojha

151 Army Base Hospital,India

[email protected]

Understanding Rabies Disease and Prevention

Rabies disease background

Section 1

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Rabies is virtually 100% fatal

Benenson 1995

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Pneum

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Cholera

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Dengue

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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.

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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

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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

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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

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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

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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

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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)

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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

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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

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

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)


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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

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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

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†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)

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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

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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)

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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

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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

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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

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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

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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