Name :- Ronak b.

lashkari
Iar no- 12694
Subject:- vaccinology assignment
Paper code:- bt-616
m.sc biotechnology sem 2

Historical Prospective And Development Of Rabies

Vaccine

Abstract:-
Rabies vaccines have a long and esteemed history, dating back to the
earliest stages of modern understanding of viruses and how
immunity protects against disease. To prevent the disease, it is
essential to receive prompt treatment including vaccination and
administration of anti rabies immunoglobulin. Rabies vaccines have
been developed over the years in response to changing needs. The
first anti rabies vaccine was performed in the 19th century, and since
then a variety of different types have been created. Advances in
molecular biology and biotechnology have allowed for the
development of effective and safe technologies for vaccine
production. This has made it possible to create vaccines against
many different diseases, some of which were previously very difficult
or impossible to develop. Inactivated tissue culture-derived vaccines
are very effective at preventing rabies, with few failures reported.
Vaccination is possible for a variety of animals, including wildlife,
companion pets and livestock. This can be done through the use of
inactivated tissue culture-derived viruses Additionally, there are
currently no means to prevent exposure to rabies once it enters the
central nervous system (CNS). Rabies vaccines are currently being
developed using recombinant rabies virus strains or individual rabies
G protein antigen-molecules. These new products can be Produced
from viruses that are not pathogenic, from plants, or as DNA
vaccines.

Introduction:-
Rabies is a zoonotic viral disease caused by a negative-sense single-
stranded RNA virus of the genus Lyssavirus . A wide range of animals
can become infected and transmit disease, but only carnivores and
mammals act as reservoirs of disease . It affects all warm-blooded
mammals, and the viral tint in the saliva of clinically ill animals that
is transmitted through bites. Once clinical symptoms appear, the
mortality rate is almost 100%. It can be prevented by vaccination
and controlled by vaccination of exposed people and source animals,
mainly dogs . Domesticated dogs are important vectors of human
rabies and account for approximately 97% of all human rabies-
related deaths worldwide . The rabies vaccine is tool for rabies
prevention. It can be used to prevent rabies before exposure to the
virus and for some time after exposure. The immunity that develops
persists long after administration of the full dose, usually given by
injection into the skin or muscle. Post-exposure vaccination is usually
used in combination with rabies immune globulin, and in most cases
it is recommended and prudent to receive high-risk vaccination prior
to potential exposure. Vaccines work on both human and animal.
The first vaccine for pre-exposure vaccination and post-exposure
prophylaxis was developed by Louis Pasteur in 1885. Modern rabies
vaccines produced in cell culture or embryonated eggs are safe and
effective. Due to the high cost of modern cell culture-based rabies
vaccines, outdated nerve-derived rabies vaccines are still
administered to the majority of socially and economically
disadvantaged people at high risk of infection.

(a) WHAT IS RABIES ?

Rabies is a viral disease that causes acute encephalitis
( inflammation of brain ) in warm blooded animals and a zonotic
disease which most often transmit through the bite of rabid
animal.
 The Rabies virus infect the central nervous system of mammals,
ultimately causing disease in the brain and death .

SYMPTOMS OF RABIES:-

After rabies exposure, the rabies virus has to travel to the brain
before it can cause symptoms. This time between exposure and
appearance of symptom is the incubation period.
The first symptom of rabies maybe similar to the flu including this
comfort or weakness fever and headache. There may be itching
sensation at the sites of bite. This symptoms last for days. Symptoms
than progress to cerebral dysfunction, anxiety, confusion, agitation.
As the disease progress the person may experience abnormal
behaviour, insomnia, hallucination, hydrophobia and delirium.

RABIES VIRUS:-
Rabies virus is a neurotrophic virus that causes rabies in human and
animal. Rabies Lyssavirus has a cylindrical morphology and is a
member of the Lyssavirus genus of the Rhabdoviridae family. This
virus is are enveloped and have a single standard RNA genome. This
virus has a bullet like shape with length of about 180 nm and 75 nm
diameter.
The RNA genome encodes five proteins.
N- Nucleoprotein
P - phosphoprotein
M- Matrix protein
G - glycoprotein
L- viral RNA polymerase
All viruses have two major structural components:-
A helical Ribonucleoprotein
And a surrounding envelope.
Nucleoprotein, phosphoprotein associated with Ribonucleoprotein.
Matrix protein associated with both the envelope and
Ribonucleoprotein. Glycoprotein form knob like spikes around the
lipoprotein envelope.
The arrangement of this protein and the RNA genome determine
the structure of the rabies virus.

(b)Pathogenesis :-
1.Transmission of rabies is most likely to occur following a bite from
a rabid animal.
2. After inoculation of infectious saliva by bite virus may persist and
replicate in muscle tissue.
3. Virus bind to nicotinic acetylcholine receptor at neuromuscular
Junction.
4. Virus travel with in axon in peripheral nerves via retrograded fast
axonal transport.

5.Virus replication take place in the spinal cord and local dorsal root
ganglia and rapid ascent to brain.
6. Virus infect brain neurons with neuronal destruction.
7. Centrifugal spread along nerves to salivary gland, skin, cornea
and other organs.
In rabid person virus is present in saliva, tears, cerebrospinal fluid
and neurological tissue

( C )history:-

In 18th century rabies begin to be classified among

other human infectious disease. In 1880, Louis
Pasteur applied his experimental method to the study
of human disease. Because rabies is a disease of the
 nervous system together with Emil Roux, he decided
to Conduct experiment on rabbit. He then attempt to
develop a vaccine with attenuated virulence. He
suspend sections of spinal cord from rabid rabbits
inside flask to dry in a moisture free atmosphere. He
injected this final for sections into a rabid dog
followed by preparation of increasing virulence. In
1885, Louis Pasteur vaccinated Joseph Meister, a 9
year old boy who had been bitten by a rabid dog.
Joseph Meister received a total of 13 injection of
rabid spinal cord that were progressively more
virulent. The first vaccination was success and Joseph
Meister never developed rabies and became the first
human to be vaccinated.

(D) Development in rabies vaccine

 Unfortunately, both Pasteur's vaccine and the Semple
rabies vaccine are created from nerve tissue and the
concentration of myelin as well as other potential
allergens in infected brains limited the use of these
vaccines, leading to grave unwanted effects.
 Later, it was noticed that these problems could be
evaded by generating vaccines from the brain tissue of
new born suckling mice, since the substances causing
 these adverse effects were mostly missing from
embryonic and new born animal nerve tissues.
 Hence, the rabies vaccine was spawned using this
technique .
 However, the vaccine was still not fully liberated from
brain tissue elements such as myelin, and severe
adverse reactions were still reported .
 A different method to address these difficulties utilized
embryonated eggs, such as chick or duck embryos, to
generate rabies vaccines.
 Despite these tactics slightly enhancing the quality of
vaccines, they were not able to completely resolve the
security matters and were not as effective with poor
immunogenicity, thus significantly inhibiting the
widespread implementation of these vaccines, and thus
resulting in their discontinuation in many parts of the
world .
 The recent progression of current cell culture methods
has enabled the production of top-notch rabies
vaccines from cell culture.
 A noteworthy advancement was that, in spite of the fact
that RABV is strongly neurotropic, it can lose its tissue
tropism and adjust to in vitro cultured cells, a trait that
can be utilized to propagate RABV in numerous distinct
cell types, so as to attain high virus yields.
 The primary licensed human rabies vaccine developed
from cell culture was the primary hamster kidney cell
vaccine, which was produced by cultivating viruses in
primary hamster kidney cells .
 Subsequently, modified RABV was adapted to the
human diploid cell type, first with the lung-derived cell
line WI-38, but subsequently changed to the fetal lung
cell variety MRC-5, to yield the human diploid cell
immunization .
 As the first purified, concentrated, and lyophilized
rabies vaccine, the human diploid cell vaccine
demonstrated notably superior immunogenicity and
 resulted in much fewer adverse effects than other
rabies vaccines, making it the recommended gold
standard reference vaccine by the WHO.
 Unfortunately, the lower virus yields and higher
manufacturing costs make the human diploid cell
vaccine difficult to mass-produce and often
unaffordable for many developing nations, where the
majority of human fatalities from rabies are recorded.
 Consequently, other cell culture vaccines, like the
purified duck/chick embryo cell vaccine, have been
developed and proven to be as effective as the human
diploid cell vaccine, and are now generally used for
human rabies prevention globally.
 Nevertheless, as the main culture cells possess a
limited capability to split, they are technically complex to
adjust to large-scale industrial cultivation for vaccine
manufacturing.
 For this purpose, the Vero cell line was utilized to
generate purified Vero cell rabies vaccine .

 Vero cell cultivation can be conveniently increased and

the virus titers produced in Vero cells are usually
superior to those in primary culture cells.
 Notably, the Vero cell line has a prolonged record of
being employed in vaccines with no safety worries .
 The multiple benefits of Vero cells have drastically
decreased the price of rabies vaccines, making them
accessible to many underdeveloped nations.
 It is likely that Vero cells will remain a commonly used
platform for the manufacturing of human rabies
immunizations in the years to come.
 Throughout history, several varieties of rabies
inoculations have been formulated, manufactured, and
used to protect both humans and animals from the
virus.
  Louis Pasteur's original methods of vaccine production,
including attenuation and inactivation, are still
fundamental components of vaccinology In recent
times, however, the refinement of specific microbial
substances, genetic alteration and a deeper
understanding of immune responses have enabled the
manufacture of weakened mutants, the expression of
vaccine proteins and polysaccharides .

DISCUSSION:-
Because rabies is widespread and life-threatening, affecting all
warm-blooded mammal species and occurring worldwide. The rabies
disease is endemic and poses a threat to both urban and rural
communities due to large numbers of stray dogs and types of wild
predators. Rabies is a major public health problem in most parts of
the country, where dogs play a major role as reservoirs and
transmitters of the disease to humans. Rabies has a vaccine but no
cure, so pre-exposure vaccination is best for source animals and
high-risk populations. Mass vaccination of dogs is more important
and should therefore be done as much as possible around the
world, mainly in developed countries. However, rabies remains
endemic in many parts of the developing world where appropriate
PEP resources are limited, infrastructure and facilities are
inadequate and, most importantly, awareness of rabies is missing. In
these cases, an inexpensive, safe, and effective vaccine is needed.
This situation is even clearer considering the fact that the most
important and perhaps the only practical way to control rabies on a
global scale is by mass vaccination of dogs as well as reservoirs.
rabies. The vaccine is given as pre exposure and post exposure with
or without rabies immunoglobulin and it have no mass vaccination of
dogs, proper post exposure management, appropriate surveillance
system, and increasing the awareness of the community about the
disease needs special attention for prevention and control of the
disease, vaccination as prevention is better than curing especially for
rabies due to its fatality.

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