RABIES
ZEYNEP AKKUTAY-YOLDAR,
ASSOCIATE PROFESSOR
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Rabies
• Rabies is a zoonotic
disease associated with
carnivores, such as dogs.
• The disease is
characterized by loss of
consciousness,
hydrophobia and
paralysis.
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Notifiable
• The virus is excreted in the saliva of
infected animals and following
infection it moves through the
nervous system to attack the brain,
causing aggressive behavior which
results in the animal biting humans
and animals with which it comes
into contact and thereby spreading
the virus infection.
Etiology
• Rhabdoviridae, Lyssavirus
• Bullet-shaped, with short glycoprotein spikes.
• ANTIGENICITY: There is one type
serologically. Only one type required in
vaccine
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Etiology Rabies lyssavirus is an enveloped, negative
stranded non segmented RNA virus
Family Rhabdoviridae
Genus Lyssavirus
Species Rabies lyssavirus
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Biotypes
• The pathogenic rabies virus is
STREET VIRUS
• FIX VIRUS is obtained by
passaging the STREET VIRUS in
rabbit brain.
• FLURY strain is obtained by ECE
passage of pathogenic virus.
Biotypes
Street Virus Fix Virus
• Found in saliva • Does not found in saliva
• Causes Negri Bodies • Does not cause Negri Bodies
• Pathogen for all mammals • Only pathogen for rabbits
• Incubation period is longer (60-80 days) • Incubation period is shorter (4-6 days)
Transmission
Transmitted by bites
through infected saliva and
by aerosols where high
concentrations of virus
found. (eg: in caves where
there are high
concentrations of bats).
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• In dogs, virus exists in the saliva and sheds
the virus 5 days before the first clinical
signs.
Transmission • Virus also exists in urine, milk, gaita and
blood.
Epidemiology
Found throughout
All mammals are
the world but
susceptible
some countries
including bats
are free.
Epidemiology
• Europe - Fox, badger,
weasel, stoat.
• Russia and the Middle East
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– Wolf, dog.
• U.S.A. - Fox, skunk, wildcat]
• Africa, India - Dog
• S. America - Bat - vampire.
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Bats are reservoir of
different viruses
including RABIES
• Bats may be persistently
viremic and shed virus in
saliva.
• They are the only
species where rabies is
always avirulent.
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Epidemiology in Turkey
• Cat, Dog,
• Cattle, Sheep, Goat
• Donkey,Horse,
• Fox, Wolve, Weasel
This
Photo
by
Unkno
wn
Autho
r is
licens
ed
Majority of the animal cases seen in Eastern
and Southestern Anatolia Region.
Animals Zoonotic
• Foxes and wolves transmits the virus to • Human rabies infections mostly caused
shepherd dogs, cattles, sheeps and by rabid dogs (≈%90), cats (≈%6), and
goats. wild animals (≈%4).
Buzgan, T., Irmak, H., YILMAZ, G. R., Torunoğlu, M. A., & Safran, A. (2009). Epidemiology of human rabies in Turkey: 1992-2007. Turkish Journal of Medical
Sciences, 39(4), 591-597. Gürçay, M., Turan, T., Özkaraca, M., & İrehan, B. (2010). Türkiye’nin Doğu ve Güneydoğu Anadolu Bölgelerinde hayvan kuduzunun
epidemiyolojisi. FÜ Sağ. Bil. Vet. Derg, 25(2), 61-66.
Pathogenesis
• After inoculation in muscle fibers,
virus replicates there and
migrates towards brain
(centripetal migration).
• It continues to replicate in brain
then travels through cranial
nerves to reach salivary gland
and cornea (centrifugal
migration).
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BY-NC-ND
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Pathogenesis
Incubation period is variable and can be long:
10 days to 12 months (even 7 years) but usually less than 3
months;
Distance of the bite is important.
Primary replication occurs in the muscle fibres then gains
access to the nerve fibres where the virus travels towards the
brain (centripetal migration)
Where it replicates followed by "centrifugal" migration down
the cranial nerves replicating in the salivary gland and cornea.
Pathogenesis
• Virus excretion in saliva
and tears.
• Virus may be shed before
classical symptoms.
• Obvious clinical signs
develop after salivary
excretion of virus.
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Pathogenesis in the brain
• No gross signs
• Negri bodies
• Neuronal degeneration (apoptosis)
• Infiltration by mononuclear cells
Clinical
Signs
Clinical Signs
• Nonspecific prodromal
signs may be seen during
the early stage of rabies.
• They can include malaise,
fever or headache, as well
as discomfort, pain,
pruritus or other sensory
alterations at the site of
virus entry.
• After several days,
§ anxiety,
§ confusion and
§ agitation may appear,
§ and progress to insomnia,
§ abnormal behavior,
§ hypersensitivity to light and sound,
§ delirium,
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§ hallucinations,
§ slight or partial paralysis,
§ hypersalivation,
§ difficulty swallowing,
§ pharyngeal spasms upon exposure to liquids,
§ convulsions and
§ other neurological signs.
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There are two forms of the disease
1-Furious (fatal) rabies
• Animals may be anxious, highly excitable and/or
aggressive.
• Animals with this form of rabies may demonstrate sudden
behavior changes, and attack without provocation.
• As the disease progresses, muscular weakness,
incoordination and seizures are common. Death results
from progressive paralysis.
2-Dumb Rabies (Paralytic)
• Animals with this form of rabies may be depressed or unusually This Photo by Unknown Author is licensed under CC BY-SA
docile. The animal will often have paralysis, generally of the face,
throat and neck, causing abnormal facial expressions, salivate
and inability to swallow. Paralysis first affects the hind legs. The
paralysis progresses rapidly to the whole body with subsequent
coma and death.
• In humans, early signs can include fever or headache. As the
disease progresses, symptoms may include confusion,
depression, sleepiness, agitation or paralysis of the face, throat
and neck. Death generally results from progressive paralysis.
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Diagnosis
1-Seller's staining Method:
Rabies suspects specimens are stained
Searching negri body.
2-Fluorescent Antibody Method; (GOLD STANDARD)
Direct antigen detection. Used routinely.
3-Histopathological method:
Searching for Negri bodies.
4-Experimental Animals
Inoculation to mice, IF and search for Negri
bodies.
Currently, Cell culture are using.
5-Electron microscopy
Diagnosis
• Molecular methods,
• RT-PCR and other amplification
techniques, are playing an important role
but are not recommended currently for
routine post-mortem diagnosis of rabies if
brain tissue is available, when the FAT
should be used.
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Prevention
and Control
Unfortunately, there is no
treatment of rabies.
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Prevention and Control
• The animals with suspected rabies held in
quarantine for 10 days.
• Animals with rabies die within a maximum of 10
days from the first appearance of rabies
symptoms.
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Vaccination is most efficient way for
prevention.
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Oral vaccination programs are most
suitable way to prevent wildlife animals.
In pet animals: Apply first Rabies
vaccine at 3 months old, then
repeat annually.
For humans: 4 dose Rabies
vaccination after bitten; 0th, 3rd
and 7th day and then 1 other
dose between 14th and 28th day.
Vaccination
• [Link]
While some rabies
vaccinations are
licensed for one
year, others are
labeled for three
years.
Two approaches in Europe
1. Vaccination of domestic animals with inactivated or live
attenuated vaccines
2a. Control of the wildlife reservoir: population density of
reservoir species reduced by gassing & shooting
2b. Vaccination of wildlife. Has been effective in reducing the
prevalence of rabies but as a consequence the fox
population is increasing! Vaccines are either attenuated virus
or a recombinant vaccinia vaccine. Fed in bait. A successful
strategy in Europe.
Nervous Tissue Vaccines
Fermi & Semple vaccines replaced by modern
rabies vaccines • Inactivated Virus:
• Live Virus:
• Hoegyes’s Dilution Method: • Semple’s Phenol Method:
Diluted Fix Biotype Virus. Very similar to Fermi’s method,
phenolized virus suspension (%1),
incubation at 37˚C for 24 hrs then
• Fermi’s Phenol Method: minimum 30 days at room
temperature.
Inactivation of virus-infected brain
tissue with phenol
• Neonatal Brain Tissue Vaccines
• Etherized Vaccines: Prepared from immature or
Suspension with infected brain and suckling rabbits.
ether, then emulsify with ether.
The Flury Vaccine
The rabies virus Flury strain (isolated from a
girl who died of rabies in Macon, GA, USA)
was adapted to 1-day-old chicks in 1940. This Photo by Unknown Author is licensed under CC BY-
SA
Kelev Vaccine
It is obtained by CAM inoculation of Kelev Strain to the ECE.
Primary Hamster Kidney Tissue:Propagated in
hamster kidney cells and inactivated by
formaldehyde.
Human Diploid Cell Tissue Vaccine:Human
fibroblast cells are concentrated with by
ultrainfiltration or with centifuge and inactivated
by beta-propiolactone.
Tissue
Culture Vero cell rabies vaccine
Vaccines
Wu, Xianfu & Smith, Todd & Rupprecht, Charles. (2011).
From brain passage to cell adaptation: The road of human rabies
vaccine development. Expert review of vaccines. 10. 1597-608.
10.1586/erv.11.140.
• Breakthroughs in vaccine substrates and their influence
on rabies vaccine development. HDCV: Human diploid cell
vaccine; PCEC: Purified chicken embryo cell; PDEC:
Purified duck embryo cell; PHKC: Primary hamster kidney
cell; PVRV: Purified Vero cell rabies vaccine.
Rabies in Humans
• Incubation period lasts 30-90
days.
• The first symptoms are pruritus,
burning, and pain.
• Larynx and Pharynx spasm
results in Hydrophobia,
Aerophobia, Photophobia and
Strong Salivation
• Wound treatment is
applied to people bitten
by animals suspected of
rabies.
• The wound should be
washed with soapy warm
water and disinfected with
Alcohol and Iodine.
• NO Stitches.
A person who is exposed and
has never been vaccinated
against rabies
• Should get 4 doses of rabies vaccine. The
person should also get another shot called
rabies immune globulin (RIG).
• A person who has been previously vaccinated
should get 2 doses of rabies vaccine and does
not need Rabies Immune Globulin.
[Link]