RABIES IS FATAL,

RABIES IS PREVENTABLE

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RABIES

EPIDEMIOLOGY AND MEDICAL PERSPECTIVES

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 A killer disease of antiquity

Rabies came from sanskrit word

rabbahs which means to do violence

3000 B.C. in India: God of death was

depicted being attended by a dog

The first description dates from 2300 B.C.

in the pre-Mosaic Eshnunna Code of
Babylon

Ancient Egypt: The god Sirius was

imagined as a form of a furious dog

1st Century A.C. Celsus invented term

hydrophobia , which refers to the fear of
water and is one of the main symptoms of
rabies
Fang ZF. Rabies and rabies research : Past, Present and Future. Vaccine. 1997;15:S20-S24.
Plotkin SA, Rupprecht CE, Koprowski H. Chapter 37 Rabies vaccine. In : Plotkin SA, Orenstein WA. Vaccines 5th Ed. Philadelphia : Saunders, 2008.

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Louis Pasteur: the first vaccination of history

Joseph Meister was the first vaccinee of

History (1885).

Bitten by a rabid dog at 9 years old,

Louis Pasteur took the risk on using an
untested vaccine.

He received 13 doses in 10 days (dried

spinal cord of rabbit).

He survived. Following this success,

Pasteur Institute was founded.

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Rabies remains highly enzootic in Asia and Africa where it
represents a risk
Rabies: an ancient for local
disease populations
but modern problem and travelers

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Highest incidence in Asia: 31,000 deaths
( 20,000 in India)

Mongolia

Japan
S.Korea
China
Iran

Nepal
Pakistan Bhutan

India Bangladesh Taiwan

Myanmar
Laos

Thailand

Cambodia Philippines
Vietnam

Human rabies deaths

0 Malaysia

1-100
101-1,000 Indonesia
1,001-10,000
>10,000

WHO. Maps. Online

Menezes. CMAJ, 2008;178(5)

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Rabies burden in Indonesia

Endemic in 24 provinces, only 10 provinces declared as rabies-

free

Rabies outbreak in Bali from 2009-2012

Number of rabid animal bites (GHPR) is 69,136 in 2013

Infodatin 2014

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Epidemiology: important facts

Rabies Virus from the Rhabdoviridae family, Lyssavirus genus

All mammals can be infected, but the main origin of exposure is dog

On average 30-60% of rabies cases in human occur in children under

15 years of age

(1) International Committee on Taxonomy of Viruses

WHO Expert Consultation on Rabies second report, 18-20 September 2012. TRS 982 WHO Geneva 2013.
Gibbons RV. Rabies and related diseases. Encyclopedia of life sciences. Chichester: John Wiley & Sons, Ltd.; 2001.
*Sanofi Pasteur internal data

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Rabies Clinical Symptoms

Prodromal Phase (2-12 days)

Non-specific (flu-like symptoms)
Malaise, Fatigue, Headache, Fever
Pain or paresthesia (close to the site of exposure)

Clinical Symptoms (2-10 days)

Encephalitic
Encephalitic (furious) rabies (70%
(Furious) rabies,
Paralytic
of cases):
(Dumb) rabies,
80% of cases Fluctuating consciousness (agitation,
20% of cases depression, aggressiveness)
Phobic spasms (hydrophobia)
Autonomic dysfunction (fixed dilated pupils and hypersalivation)
Paralysis
Paralytic rabies (30% of cases):
Guillain-Barr-like syndrome
Complete paralysis

Coma and death (5-13 days)

Jackson A. Rabies. Handbook of clinical virology.2014;123:601-618

Rupprecht C. Plotkin S. Rabies vaccines. Vaccine 6th edition. 2014 | 9
 100% fatal disease BUT
RABIES Prevention 100% preventable

2013.
WHO Expert Consultation on Rabies second report, 18-20 September 2012. TRS 982 WHO Geneva
eds. Adv Pediatr Infect Dis. Lyon. 1998;13:219-55.
Lang J, Plotkin SA. Rabies risk and immunoprophylaxis in children. In: Mosby-Year Book, Inc.
According to WHO, Pre-Exposure prophylaxis
(PrEP) is recommended for anyone at
increased risk of exposure to rabies virus

To protect
Persons with unrecognized exposure or
those for whom PEP might be delayed

To simplify
Eventual PEP by decreasing the number
of doses of vaccine required

To eliminate
The need for RIG

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Rabies PrEP: Target populations (1/2)

SUBJECTS AT PERMANENT RISK MUST BE VACCINATED

(Diagnostic, research and production, laboratory staff)

SUBJECTS AT FREQUENT RISK SHOULD BE VACCINATED

(Nurses, medical staff, animal handlers and veterinarians)

IN PARTICULAR CHILDREN SHOULD BE VACCINATED

Children are at higher risk of animal bites

Their small size makes them less intimidating to animals
They fail to recognize and avoid threatening behavior
They are less able to shelter themselves or escape when attacked
Their stature make them especially vulnerable to severe facial and head bites,
which carry the highest risk of disease

WHO position paper. Rabies vaccines. WER No. 32, 2010, 85, 309320
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 Rabies PrEP: Target populations (2/2)

TRAVELERS ARE PARTICULARLY LIKELY TO BE EXPOSED

Travelers are at higher risk of rabies exposure

Outdoor activities such as camping, bicycling, hiking etc. increase the risk for travelers to be exposed to
rabies, even if the trip is brief

Travelers have an increase risk of

developing rabies
Risk of delay in rabies PEP
Risk of no access to medical services and PEP
abroad
Risk of unapparent or unrecognized exposure
to rabies virus

WHO recommends PrEP:

LOW risk areas: For people likely to get in contact with bats
MEDIUM risk areas: Travelers/people likely to get in contact with bats and other wildlife
HIGH risk areas: Travelers/people likely to get in contact with domestic animals and other rabies vectors

WHO Expert Consultation on Rabies second report, 18-20 September

2012. TRS 982 WHO Geneva 2013.
WHO. International travel and health. Geneva, 2014 | 12
 Rabies PrEP: vaccination schedule

Primary course:

Days

IM route (0,5 mL)

In the deltoid muscle in adults and children
In anterolateral part of the thigh in infants and toddlers

Alternatively ID route (0.1 mL)

In countries where ID route for vaccine administration is approved by Health Authorities
For vaccines that are recommended by WHO for intradermal use
0,1 mL injection at D0, D7, D21*

* D21 injection may also be given at D28

WHO Expert Consultation on Rabies second report, 18-20 September 2012. TRS 982 WHO Geneva 2013.

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Principle for post-Exposure Prophylaxis

Inoculation

Early intervention
before symptoms
begin may
prevent the To remove free virus from tissues
disease by both washing and neutralizing
Incubation
and to induce a rabies virus-specific
immune response in the exposed
Nothing can be individual before rabies virus can
done, after
Prodromal
phase replicate in the central nervous system[9]
symptoms begin, to
stop progression of
disease
Acute phase

Coma and DEATH

9. Plotkin SA. Rabies. Clin Infect Dis. 2000;30(1):4-12.

Rabies Post-Exposure Prophylaxis (PEP)
WHO categorization of contacts

Category Type of contact Recommended immunization

I Touching or feeding of animals, licks on intact None, if reliable case history is

skin, contact of intact skin with secretions or available
excretions of a rabid animal or human
II Nibbling of uncovered skin, minor scratches or Administer vaccine as soon as
abrasions without bleeding possible *
III Single or multiple transdermal bites or Administer rabies
scratches, licks on broken skin, contamination immunoglobulin and vaccine at
of mucous membrane with saliva from licks, distant sites as soon as possible.
exposure to bats ** Immunoglobulin
can be administered up to day 7
after injection of the first
dose of vaccine. *

* Stop treatment if dogs or cats remain healthy throughout an observation period of 10 days or if animal is euthanized and
found to be negative for rabies by appropriate laboratory techniques
** PEP should be considered when contact between a human and a bat occurred unless the exposed person can rule out a
bite or scratch, or exposure to mucous membrane

WHO Expert Consultation on Rabies second report, 18-20 September 2012. TRS 982 WHO Geneva 2013.

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 Rabies Post-Exposure Prophylaxis

Aims to remove as much of the virus as possible from the site of inoculation by :
- Physically removing virus particles
- Further inactivation of the remaining virions by chemical disruption
- Delaying as much as possible the suturing of the wound
WHO Expert Consultation on Rabies. Second report. Geneva, World Health Organization, 2013. WHO Technical Report Series, No. 982.
http://apps.who.int/iris/bitstream/10665/85346/1/9789240690943_eng.pdf?ua=1 (accessed April 2014)
Dutta AK, Kanwal SK. Rabies and its preventions. Pediatrics today. 1998;1(2):183-8.
Bompart F, Dutta AK, Wood SC. Rabies immunoglobulins in WHO category III Exposure. Journal of APCRI. 2000:1(2):7-11.

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 Rabies Post-Exposure Prophylaxis

Step 2: Rabies Vaccine

injection

Intramuscular
D0 D3 D7 D14 D28
ESSEN
RIG (category III exposure)

DOG BITE
POST-EXPOSURE
PROPHYLAXIS
Intramuscular
D0 D7 D21
Not previously ZAGREB
immunized subject
RIG (category III exposure)

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 Rabies Post-Exposure Prophylaxis
WHO-recommended schedule for non-immunized subjects (1/2)

Intramuscular (IM) schedules:

Essen regimen * Zagreb regimen

(Standard 5-dose IM schedule) (4-dose 2-1-1 IM schedule)

* An alternative for healthy, fully immunocompetent, exposed people who receive wound care plus high quality
rabies immunoglobulin plus WHO-prequalified rabies vaccines, is a post-exposure regimen consisting of 4 doses
administered intramuscularly on days 0, 3, 7 and 14

WHO Expert Consultation on Rabies second report, 18-20 September 2012. TRS 982 WHO Geneva 2013.
WHO. Rabies vaccines. WHO position paper. Wkly Epidemiol Rec 2010;85:309-320.

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Rabies Post-Exposure Prophylaxis

Step 3: RIGs injection*

*RIGs administration 20 IU/Kg (HRIG) and 40 IU/Kg (ERIG) body weight; If feasible, full dose should be
administered in the wound and remaining volume should be administered IM at distance from vaccine site
injection

CDC, MMWR. ACIP recommendations. Human rabies prevention. 2008

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 Sanofi Pasteur ERIG portfolio:
Evolution from PARS to Favirab
1972 : Exportation license of Pasteur EQUINE PLASMA
Hyper-immunized with an absorbed
and inactive rabies vaccine (PM strain)
Antirabies Serum (PARS) ERIG

1977 : French license for SAR Pasteur

EUGLOBULIN
PRECIPITATION
Protein discard (albumin)
Virus elimination
(800 IU / 5 mL)

1996 : Modification of French license CHROMATOGRAPHY

Elimination of albumin, a-, b-
globulins, non-specific IG
(1000 IU / 5 mL)
IgG/ IgGT Extration

2000 : French license for FAVIRAB, PEPTIC

HYRDOLYSIS
Cleavage Fc / F(ab)2
Virus inactivation
highly purified, heat-treated ERIG
F(ab)2

Elimination of aggregates, pepsin,

CHROMATOGRAPHY
Fc fragments
Double chromatographic purification: Purified F(ab)2
Patient safety
HEAT TREATMENT
Risk of hypersensitivity reactions >60C 10h
59-61C
Virus inactivation

Purified, Heat treated F(ab)2

Pasteurization (heat treatment)
Viral safety

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Favirab : a purified Equine Rabies Immunoglobulin

Pepsin
Treatment

Fc, if of heterologous origin is responsible for hypersensitivity reactions, such as

anaphylaxis by activating the complement cascade

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Favirab : a purified Equine Rabies Immunoglobulin

Purification

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Favirab : Clinical database

Completion Number of
Clinical trial Country Trial description
year Subjects

SRC01194 1995 Thailand Phase III clinical trial prospective randomized controlled trial in healthy volunteers 15

Phase III clinical trial prospective randomized controlled trial, comparison of

SRC02295 1995 Philippines 35
immunogenicity of Favirab or PARS associated with PVRV in healthy volunteers

Phase III efficacy clinical trial. Assessment of PEP with different route of vaccine
RAB27 2008 Philippines 102
administration in association with Favirab

Phase III randomized multi center controlled clinical trial. Assessment of PEP with different
RAB28 2006 India 405
route of vaccine administration in association with Favirab, WHO category III only

PMCS 2004 Philippines Phase IV Case series study in patients with category III exposure 7660

Phase IV Prospective study in patients with category III exposures to a proven rabid animal
FAV04 2006 Philippines 193

Phase IV Prospective prescription monitoring study 1-year follow up when used in rabies
post exposure treatment among patients with category III exposures to a proven rabid
FAV03 2008 Thailand 178
animal

Phase III open-label, randomized, controlled multi-center, clinical trial Verorab

RAB40 On going Philippines immunogenicity and safety after a one week, 4-site, intradermal (ID) post-exposure 400
prophylaxis regimen followed by a one visit, 4-site, ID booster at five years
TOTAL 8988

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Favirab : Clinical database

Cumulative Subject Exposure To Favirab from Completed*

Clinical Trials by Age

Age Range (Years Old) Number of Subjects

04 1828
59 1707
10 19 1312
20 + 3338
Total** 8185

*Ongoing and completed clinical trials as of 21 May 2014 ** 803 subjects where not classified by age range

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Favirab in practice

Person bitten by a dog with a category III of severity of exposure

50 Kg of body weight

Posology: 40 IU/Kg

How many Favirab vials should I inject (with rabies vaccine)?

One vial = 5 mL X 200 IU/mL = 1,000 IU (at least)

50 Kg X 40 IU/ Kg = 2,000 IU should be administered

50 Kg of Body Weight

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Favirab Post-Marketing Experience
Around 2 million* Favirab vials have been distributed worldwide since its launch in
May 2000

Middle East
7%

Europe
6%

Latin America
3%

Asia Pacific Africa

82% 2%

Worldwide distribution of Favirab

An estimated 650,000 to 1 million patients* have been treated

*Includes cumulative data obtained from 22 May 2000 through 31 May 2014

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Thank you

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