ABSTRACT

Rabies, a neglected tropical illness caused by lyssaviruses,

remains a major public health concern, leading to tens of
thousands of fatalities annually, primarily in underdeveloped
regions of Africa and Asia. This zoonotic conditions, which
results in nearly complete mortality once clinical signs appears,
is chiefly transmitted through bites from infected creatures,
with domestic dogs acting as the primary reservoir and vector.
Although preventable through immunization and post exposure
treatment (PEP), Rabies continues to inflict a significant
burden on both human and animal population, emphasizing the
critical need for effective control and eradication measures.

The global impact of rabies is frequently underestimated due to insufficient monitoring and reporting
mechanisms, especially in endemic areas. The estimated 60,000 deaths each year likely underrepresents the true
scope of the disease, as numerous cases remains unacknowledged. Rabies disproportionately impacts vulnerable
populations, such as children and people in rural locales with limited healthcare access, highlighting the socio-
economic inequalities associated with the disease.

A thorough approach to rabies control is crucial, with the "One Health" framework at its foundation,
acknowledging the interdependence of human, animal, and environmental well-being. Mass vaccination
initiatives aimed at domestic dogs, using safe and potent vaccines, are essential to reducing human exposure.
Moreover, oral rabies vaccines have proven effective in managing the disease in wildlife reservoirs, including
foxes, raccoons, and bats, thereby contributing to wider efforts to control the illness.

1. INTRODUCTION

The word Rabies is derived from the Latin word “rabere” which means “to be mad”. The disease is recognised
since the beginning of civilization. Rabies is an animal transmitted viral infectious disease which meant to be
spread by animals to human. In humans, affected or rabid animals are the source to transmit rabies virus hence
humans are affected by this infection. Rabies is a dangerous zoonotic disease and is spread generally by
carnivores to humans and cattle. We can call it as a neglect-able disease because the reason behind is, rabies
remains an ignored zoonotic disease in many developing countries including Asia and Africa is lack definite
diagnostic and investigation techniques. Rabies is one of the 17 chief discounted tropical diseases. Hence it is a
discounted animal transmitted sickness so its regulation is tougher and is widespread in most of the world. The
first rabies vaccine was found by Louis Pasteur and Émile Roux in 1885 (Baer). In 2000, it was also evaluated
rabies become the 11th reason for human death. It can be said as the ancient and lethal diseases to humans for
thousand years.[1]

In addition, individuals aged 0-14 years and 15-49 years were more expected to become victims of rabies.
Children aged 0-14 years may be prone to be bitten by dogs due to a lack of enough self-defence ability. From
1990 to 2019, the global incidence of rabies in children aged 0-14 years has decreased year by year, whereas the
number of middle-aged individuals aged 15-49 years has hardly declined in the past 30 years. As a result, the
gap between the incidence of rabies in the 0-14 years age group and the 15-49 years age group has gradually
restricted over the last 30 years. The possible reasons are as follows. At first, more attention was provided to
children, and currently, a higher ratio of children bitten by dogs had taken after exposure vaccinated against
rabies.[4]

1.1 THE WORLDWIDE RABIES BURDEN: DATA ANALYSIS

Worldwide, the number of patients with rabies decreased from 24,744.66 (95% UI: 9201.76-40,728.99) in 1990
to 14,075.51 (95% UI: 6124.33-21,618.11) in 2019, and the EAPC was -0.43% (95% UI: -0.64% to -0.2%). The
ASIR of rabies decreased from 45.99 (95% UI: 17.74-75.23)/10,000,000 in 1990 to 18.45 (95%UI: 7.89-
28.18)/10,000,000 in 2019. The higher the SDI level, the lower the rabies ASIR. In 2019, the low SDI region
had an ASIR of 48.70 (95% UI: 22.06-85.80)/10,000,000, whereas the high SDI region had only 0.14 (95% UI:
0.07-0.19)/10,000,000. It showed that SDI level was significantly negatively correlated with ASIR of rabies. In
terms of trend, in the past 30 years, the global rabies ASIR has shown a considerable downward trend, and it has
decreased in different levels of SDI regions. Between sexes, the incidence cases and ASIR of rabies in males
were higher than in females in both 1990 and 2019; however, in the past 30 years, the ASIR of rabies has shown
a downward trend for both men and women.[2]

Age-standardized rates per 100,000 people were extracted from the GBD database. The age-standardized rate
was calculated using the following formula:

where ai is the age-specific rate in the ith age group, and Wi represents the number of people (or the weight) in
the same age group among the GBD standard population. N is the number of age groups. The 95% Uls were
defined as the 25th and 975th values of the ordered 1000 draws. [5]

Year Number of patients

1990 24,744.66
2019 14,075.51

1.2HIGH GEOGRAPHIC DISTRIBUTION AND CASE FATILITY RATE

These countries may still report imported cases and incur costs for maintaining disease freedom or surveillance
of endemic transmission in wildlife.

Asia

Rabies is a major burden in Asia, with an estimated 35 172 human deaths per year. India accounts for 59.9% of
rabies deaths in Asia and 35% of deaths globally. The cost of Post Exposure Prophylaxis (PEP) is highest in
Asia, with estimates up to US$ 1.5 billion per year. The Association of Southeast Asian Nations (ASEAN) have
implemented a regional elimination strategy with an aim to eliminate human rabies in the Region by 2020.

Africa

An estimated 21 476 human deaths occur each year in Africa due to dog-mediated rabies. Africa is estimated to
spend the least on PEP and have the highest cost of human mortality. With improved access to PEP and reduced
prevalence of dog-mediated rabies, a significant number of lives could be saved.

Dog-mediated rabies has been eliminated from Western Europe, Canada, the United States, Japan and some
Latin American countries. Australia and many Pacific Island nations have always been free from dog-mediated
rabies. Nevertheless, these countries may still report imported cases and incur costs for maintaining disease
freedom or the surveillance of endemic transmission in wildlife. In South America, efforts to eliminate canine
rabies have been enormously successful. the occurrence wildlife-mediated rabies. Other animals, such as bat
species, are also reservoirs for the rabies virus. As can be seen, rabies virus vectors and reservoir species are
widespread.[3]

2. EPIDEMIOLOGY OF RABIES

Rabies is caused by neurotropic viruses of the genus Lyssavirus in the family Rhabdoviridae.[6] It is transmissible
to all mammals and it is almost uniformly fatal. Contact with infected saliva through a bite from a rabid animal
is the main route of rabies virus (RABV) infection in humans [7] ,although it can also occur through contact with
infected saliva in open wounds or mucous membranes.[8]

Transmission of rabies virus usually occurs when virus-containing infected saliva of a rabid host is passed to an
uninfected organism mostly through the bite as well as other rare Susceptibility to intra-cranial and peripheral
inoculation, pathogenesis and clinical presentations varies with lyssaviruses, depending on viral factors (viral
species and lineage, type/strain of virus (street/fixed), virulency and immunogenicity of virus, inoculation dose
and route) and host factors (species of host, histological and anatomical site of exposure to virus) . [9]

Rabies virus is a negative-strand RNA virus. Its RNA genome is condensed by the viral nucleoprotein (N), and it
is this N-RNA complex that is the template for transcription and replication by the viral RNA-dependent RNA
polymerase complex. Here we discuss structural and functional aspects of viral transcription and replication
based on the atomic structure of a recombinant rabies virus N-RNA complex. We situate available biochemical
data on N-RNA interactions with viral and cellular factors in the structural framework with regard to their
implications for transcription and replication. Finally, we compare the structure of the rabies virus nucleoprotein
with the structures of the nucleoproteins of vesicular stomatitis virus, Borna disease virus and influenza virus,
highlighting potential similarities between these virus families.[10]
2.1. RABIES PREVELENCE ACROSS CONTINENTS

Rabies encompasses multiple biomedical realities and defines the stuff of collective nightmares: an ancient relic
of past domestications and subsequent colonisations; a fundamental disease of nature that ensures perpetuation
by exploitation of basic mammalian behaviours. Currently, the greatest burden falls within lesser developed
countries of Africa and Asia, associated primarily with the bites of rabid dogs. [11]

The objective of this communication is to provide an update on rabies in the tropics (narrowly defined as those
geographic regions between the Tropic of Cancer and the Tropic of Capricorn) and progress in human and
animal case reduction towards the goal of “Zero by Thirty” (ZBT). [11]

South Africa

In South Africa, rabies cycles are maintained in both domestic and wildlife species. A total of 9580 specimens
were submitted for rabies diagnosis between 1998 and 2022. The highest positive case rates were from
companion animals (1733 cases, 59.71%), followed by livestock (635 cases, 21.88%) and wildlife (621 cases,
21.39%). Rabies cases were reported throughout the year, with the majority occurring in the mid-dry season. [12]

the epidemiology of rabies is confined to two cycles of transmission, namely sylvatic, which involves wildlife
host species, and domestic (urban rabies), which involves principally domestic dogs and spillover hosts. [13]

Asia

India bears the highest burden of global dog-mediated human rabies deaths across Asia. Despite this, rabies is
not notifiable in India and continues to be underprioritized in public health discussions. India has the dubious
distinction of bearing the largest burden of at least 11 of these neglected tropical diseases. [14]

Of the 59,000 annual human deaths estimated to occur globally due to dog-mediated rabies, about 35% occur in
India.[15] More than 95% of cases are caused by dog bites, largely because of the approximately 60 million
stray/free-ranging dogs in the country. [16]
Current estimates of the burden of rabies in India (over 20,000 human deaths annually) are based on an
epidemiological study conducted in 2003[17], and even this may be an underestimate of the true disease burden.
Another study estimated that 12,700 human deaths from symptomatically identifiable furious rabies occurred in
India in 2005 [18]. Most recently, a multicentric survey conducted in 2017 across seven Indian states estimated an
annual incidence of animal exposures (bite, scratch or lick) of 1.26%, which was reportedly lower than previous
estimates from India.[19]

2.2 UNDERESTIMATION OF GLOBAL RISK MORTALITY

The host immune status and the nature of the exposure (for example, dose, location, and depth of inoculation)
can influence whether an exposure results in a lethal or abortive infection. Strain-level differences among
RABVs that influence the outcome of exposures are increasingly evident, particularly in comparisons between
bat and terrestrial carnivore-associated variants [20]. For example, silver-haired bat rabies virus (SHBRV), but not
dog-derived RABV isolates, are capable of hematogenous spread in mice after intravenous inoculations, which
suggests that viremia could be an alternate route to the CNS in some strains [21].

The annual mortality of the disease in humans has been estimated at 59000 with the socially and economically
disadvantaged sectors of society being the most vulnerable (Barbosa Costa et al. 2018; Regea 2017; Tiwari et
al. 2019a). It is primarily maintained and transmitted through the bites of Free-Roaming Dogs (FRD) (Isloor et
al. 2020) and is widespread in countries that either do not have legislation regulating movement and ownership
of dogs or do not implement them strictly (Özen et al. 2016; Taylor et al. 2017). Although wild carnivores and
bats are the natural reservoirs of rabies virus, it is the domestic dog, Canis lupus familiaris, that usually acts as
the most common host and chief source of infection for humans (World Health Organization 2018).{25}

3. TRANSMISSION AND RISK FACTORS

Rabies virus (RABV) causes an acute, fatal neurological infection in humans and other mammals, transmitted
through the saliva of rabid animals via a bite or scratch. From the site of infection the virus travels along
neurons to the central nervous system (CNS), where viral replication leads to symptoms and systemic spread.
Once symptomatic, the disease is nearly 100% fatal. However, the disease is 100% vaccine-preventable through
the prompt administration of human postexposure prophylaxis (PEP) and vaccination of animal reservoirs.
While RABV has a broad host range, domestic dogs cause over 99% of all human cases, killing 59000 people
every year. Human PEP is costly (US$11–150 per dose) and often difficult to obtain. Dog vaccination is a
considerably more cost-effective and feasible method to reduce the incidence of human rabies. With this in
mind, the World Health Organisation (WHO) and partners have set a target for the global elimination of dog-
mediated human rabies, through control of the disease in dogs, by 2030.{22}

3.1. PRIMARY ROLE OF INFECTED DOGS

To investigate whether healthy animals are potential carriers of rabies virus in China, 153 domestic dogs were
collected from a rabies enzootic area, Anlong county in Guizhou Province, and monitored for 6 months.
Initially, findings of rabies virus antigen in the saliva of 15 dogs by an enzyme-linked immunosorbent assay
(ELISA) test suggested they might be carriers. These 15 dogs were kept under observation for 6 months. None
of the dogs showed any clinical signs of rabies during the observation period. Moreover, using the ELISA test
alone, detection of rabies virus antigen in saliva of some animals was not consistent during the observation
period. However, none of the saliva samples collected either at the time of acquisition or during the observation
period was found to be positive for rabies virus RNA by reverse transcriptase-polymerase chain reaction (RT-
PCR). Furthermore, neither viral antigen nor viral RNA was detected in the brain samples collected at the time
of euthanasia. These results do not provide support for the contention that healthy dogs act as carriers in rabies.
Caution is urged when preliminary and nondefinitive tests, such as ELISA, are used to infer clinical status
related to rabies.

3.2. HUMAN EXPOSURE AND RISK POPULATION

After a case of rabies, healthcare workers (HCWs) had fear of contagion from the infected patient. Although
transmission of rabies to HCWs has never been documented, high-risk exposures theoretically include direct
contact of broken skin and/or mucosa with saliva, tears, oropharyngeal secretions, cerebrospinal fluid, and
neural tissue. Urine/kidney exposure posed a concern, as our patient's renal transplant was identified as the
infection source.{24}

Our risk assessment included

(1) identification of exposed HCWs;

(2) notification of HCWs;

(3) risk assessment using a tool from the local health department;

(4) supplemental screening for urine/kidney exposure; and

(5) postexposure prophylaxis (PEP) when indicated.

A total of 222 HCWs including diverse hospital staff and medical trainees from university affiliates were
evaluated. Risk screening was initiated within 2 hours of rabies confirmation, and 95% of HCWs were assessed
within the first 8 days. There were 8 high-risk exposures related to broken skin contact or mucosal splash with
the patient's secretions, and 1 person without high-risk contact sought and received PEP outside our hospital.
Nine HCWs (4%) received PEP with good tolerance. Due to fear of rabies transmission, additional HCWs
without direct patient contact required counseling. There have been no secondary cases after our sentinel rabies
patient. Rabies exposure represents a major concern for HCWs and requires rapid, comprehensive risk screening
and counseling of staff and timely PEP. Given the lack of human-to-human rabies transmission from our own
experience and the literature, a conservative approach seems appropriate for providing PEP to HCW. {24}

4. STRATEGIES FOR RABIES ELIMINATION

(a) Educational outreach

The promotion of awareness about rabies is one of the foundational pillars of any strategy to eliminate rabies.
The importance of enhancing the understanding of it has been emphasised over the past few decades in
communities of countries where the disease is endemic. Although the general awareness of the disease has
increased, there remain gaps in the way the dog-bite wounds are managed, and early provision of PEP is sought.
The negative attitudes of communities towards FRD in these countries also needs to be altered. Educating
communities about the need for better welfare for FRD and promotion of responsible ownership of dogs should
form part of rabies awareness drives. There are vulnerable groups, such as children, who remain bereft of
essential information about the disease. The educational outreach drives should include such vulnerable groups
in their ambit. Further, the lack of application of preventive practices for bite wound management or PEP
compliance could be attributable to little refresher training of paramedical staff (Penjor et al. 2020). Hence,
educational outreach programs must be sustained and not one off-exercises. {25}

(b) Human, canine anti-rabies vaccination and dog population management

Rabies is preventable if a dog-bite victim is provided PEP within 48 h of the bite. The poor affordability of the
anti-rabies vaccines has been addressed in China and Kenya by including the cost of PEP in the insurance
scheme for medical claim settlement or by their free provision (Liu et al. 2017; Wambura et al. 2019). While
there could be an improvement in the delivery of anti-rabies vaccines in remote areas through efficient
forecasting, the challenge of cold chain maintenance at the stockists and local vaccines centres could be
mitigated by incentivising the local pharmacists with refrigeration facilities. Solar energy powered refrigeration
units could be adopted to maintain the cold chain in remote areas where other sources of energy are unavailable.
{25}

4.1. IMPORTANCE OF CANINE RABIES CONTROL

More than 50,000 people die of rabies each year; most are children in developing countries, and almost all have
been bitten by dogs. Eliminating canine rabies throughout the world would save thousands of lives and would
reduce the economic impact of the disease by dramatically reducing the requirement for postexposure
prophylaxis (PEP). Lengthy experience in the industrialized countries and ongoing programs in Latin America,
Africa, and Asia have shown that the elimination of rabies in dogs is an achievable goal. The presence
of canine rabies in developing countries is associated with poverty, and most deaths occur in the lowest
socioeconomic sectors. To be successful, national rabies control programs should share responsibility with local
communities for prevention and control activities and maintaining disease-free status. Legislation should be
adapted to local conditions and the realities of dog ownership. While the provision of PEP to all bite victims is
affordable in many countries, it is usually beyond the capacity of impoverished nations, which deal with many
other health priorities. Ministries of health should provide PEP, either free or with a charge preferably at a
subsidized price, replacing the current system in many countries, in which biologics are sold by government-
owned and private clinics at a cost beyond the means of bite victims. The public health sector should assume
responsibility when animal control strategies are not effectively implemented or when PEP is not administered
correctly or is not available. A global strategy is needed to identify gaps in surveillance and diagnosis, improve
access to PEP and enhance canine immunization and population management. Such approaches based on a “One
Health” model should be coordinated across regions, and should extend control efforts to other dog-related
zoonoses. This article introduces a symposium in Antiviral Research on the elimination of canine rabies.{32}
4.2. LIMITATIONS OF HUMAN PROPHYLAXIS EXPANSION

4.2.1.Reverse genetics system for generation of infectious c-DNA

In this method plasmid expressing full length anti-genomic RNA (genome plasmid) and three plasmids
expressing N, P and L protein of the virus (helper plasmids) are transfected into a cell. The anti-genomic RNA
and the proteins form an anti-genomic ribonucleoprotein (RNP) complex. The anti-genomic RNP complex has
the same biological activity as occurs in virus infected cells, genomic RNA is synthesized using this anti-
genomic RNP as a template, followed by synthesis of mRNA from genomic RNP and expression of viral
protein. The assembly of the genomic RNP and other viral proteins as M and G proteins results in generation of
an infectious recombinant rabies virus. Using this manipulation system of rabies virus, an attenuated live virus
vaccine can be established quickly than conventional cell culture vaccine with change in biological characters
such as improved safety and immunogenicity.{26}

4.2.2.Insertion of foreign gene into the viral genome

A recombinant rabies virus expressing a proapoptotic protein cytochrome c (SPBN-Cyto c(+) strain) strongly
induced apoptosis in infected cells, found to be more attenuated than negative control virus carrying inactivated
cytochrome c gene (SPBN-Cyto c(-) strain) and induced protective immune response in mice .{27}

4.2.3.Mutation of rabies virus at 333 position of G protein

In rabies virus, the presence of an arginine or lysine residue at position 333 in the G protein is well known for
pathogenicity . Many recombinant viruses harbouring the G gene from various rabies virus strains with amino
acid other than arginine or lysine have been found to be attenuated . The deletion of dynein light chain binding
site in P protein which is necessary for axonal transport of the virus reduces peripheral infectivity of the
recombinant virus in suckling mice. {28}

4.2.4.Insertion of additional G gene in the genome

To enhance the immunogenicity of the attenuated vaccine virus, the expression level of G protein in infected
cells has been increased by insertion of an additional G gene into the genome . Both the G genes contain
alteration of amino acid at position 333 position and recombinant rabies virus (SPBNGA-GA strain) produced
twice the quantity of G protein in cultured cell compared to virus carrying only a single G gene and that the
recombinant virus induced apoptosis more strongly and more efficient protective immunity compared to control
one. {29}

4.2.5.Recombinant rabies virus lacking the P gene

Recombinant virus lacking the P gene (def-P) has been recovered from the genome plasmid with
supplementation of the P protein from helper plasmid. The def-P virus can be produced in cell lines stably
expressing P protein. On the other hand, the def-P virus did not effectively grow in normal cells that did not
express the P protein.{30}

4.2.6. Recombinant rabies virus lacking the M gene

M gene deficient rabies virus (RCHLΔ M) has been developed using gene manipulation system of RC-HL strain
used in vaccine production in Japan . The M protein is essential for viral assembly and budding. {31}

5. RABIES VACCINATION PROGRAMS

Dog vaccination against rabies is considered one of the most effective strategies at preventing human deaths
from rabies and is a key strategy for eliminating dog-mediated human rabies deaths. Vaccination remains the
foundation for preventing the infection that causes this viral disease in exposed individual. Several types of
rabies vaccines are available and utilized today. The limitations of the live-attenuated vaccine include inducing
rabies in animals due to mutations in the host and resistant viral capabilities to cause infection [33].

5.1 HISTORY OF RABIES VACCINE

The first generation of vaccines began in 1885 with Louis Pasteur, who used an infected rabbit spinal cord that
was inactivated via sun drying to develop a vaccine. The consistency of inactivation of the virus in the vaccine
was questioned, given that post-vaccine rabies cases were being reported. Using Pasteur’s work, other
researchers added their advancements, including adding phenol to inactivate the virus, using baby animal brains
to create vaccines as they contained less myelin, using embryonated chicken and duck eggs to make a live
attenuated vaccine, and using the cell culture system to enhance the production of a vaccine [34,35].

Rabies has been known since around 2000 BC. [36] The first written record of rabies is in
the Mesopotamian Codex of Eshnunna (c. 1930 BC), which dictates that the owner of a dog showing symptoms
of rabies should take preventive measures against bites. If another person were bitten by a rabid dog and later
died, the owner was heavily fined.[37] Rabies was considered a scourge for its prevalence in the 19th century. In
France and Belgium, where Saint Hubert was venerated, the "St Hubert's Key" was heated and applied to
cauterize the wound. By an application of magical thinking, dogs were branded with the key in hopes of
protecting them from rabies.[38]

5.2 MASS PARENTRAL VACCINATION CAMPAIGNS

Cell culture-derived vaccines can be used for the parenteral vaccination of companion animals and livestock,
and have also been used to develop oral vaccines for wildlife immunization [39].

Parenteral vaccination with tissue culture-derived vaccines has been administered since the 1970s, and has been
used extensively in all continents of the world. They have low levels of side effects, can be produced at low cost
and have found application in both human and veterinary medicine [40].

The virus is harvested from infected human diploid cells, MRC-5 strain, concentrated by ultrafiltration and is
inactivated by beta-propiolactone. One dose of reconstituted vaccine contains less than 100 mg human albumin,
less than 150 mcg neomycin sulphate and 20 mcg of phenol red indicator. Beta-propiolactone, a residual
component of the manufacturing process, is present in less than 50 parts per million [41].

The finished, freeze-dried vaccine is provided for intramuscular administration in a single dose vial containing
no preservative. After reconstitution, immediately administer the full 1.0 mL amount of vaccine. If it cannot be
administered promptly, discard.The potency of one dose (1.0 mL) of Imovax Rabies vaccine is equal to or
greater than 2.5 international units of rabies antigen.

5.2.1PRE EXPOSURE IMMUNIZATION

High titer antibody responses to the Imovax Rabies vaccine made in human diploid cells have been
demonstrated in trials conducted in England , Germany, France and Belgium. Seroconversion was often
obtained with only one dose. With two doses one month apart, 100% of the recipients developed specific
antibody, and the geometric mean titer of the group was approximately 10 international units. In the US, Imovax
Rabies vaccine resulted in geometric mean titers (GMT) of 12.9 IU/mL at Day 49 and 5.1 IU/mL at Day 90
when three doses were given intramuscularly during the course of one month. The range of antibody responses
was 2.8 to 55.0 IU/mL at Day 49 and 1.8 to 12.4 IU at Day 90. The definition of a minimally accepted antibody
titer varies among laboratories and is influenced by the type of test conducted. CDC currently specifies a 1:5
titer (complete inhibition) by the rapid fluorescent focus inhibition test (RFFIT) as acceptable. The World Health
Organization (WHO) specifies a titer of 0.5 IU[41].

5.2.2 POST EXPOSURE EMMUNIZATION

Post-exposure efficacy of Imovax Rabies vaccine was successfully proven during clinical experience in Iran in
which six 1.0 mL doses were given on days 0, 3, 7, 14, 30, and 90, in conjunction with anti-rabies serum. Forty-
five persons severely bitten by rabid dogs and wolves received Imovax Rabies vaccine within hours of and up to
14 days after the bites. All individuals were fully protected against rabies. Studies conducted by the United
States centers for Disease Control and Prevention (CDC) have shown that a regimen of 1 dose of Rabies
Immune Globulin (RIG) and 5 doses of HDCV induced an excellent antibody response in all recipients. Of 511
persons bitten by proven rabid animals and so treated, none developed rabies. Do not inject Imovax Rabies
vaccine in the gluteal area as there have been reports of possible vaccine failure when the vaccine has been
administered in this area. Presumably, subcutaneous fat in the gluteal area may interfere with the immune
response to human diploid cell rabies vaccine (HDCV). [42] For adults and older children, Imovax Rabies vaccine
should be administered in the deltoid muscle. For infants and younger children, the anterolateral aspect of the
thigh is also acceptable, depending on age and body mass (see DOSAGE AND ADMINISTRATION).

5.3 ADVANCES IN ORAL VACCINES FOR WILDLIFE

Oral rabies vaccination (ORV) represents a socially acceptable methodology that may be applied on a broad
geographic scale to manage the disease in specific terrestrial wildlife reservoirs, as well as in free-ranging or
feral dog (Canis familiaris) populations, where parenteral vaccination is impractical. [43] Since the first proof of
principle experimental study in the 1970s, oral rabies vaccines have gained a great reputation in controlling and
eliminating rabies in wildlife. The major wildlife disease problems for which oral vaccination is currently under
consideration as a disease management tool, and also focuses on the technological challenges that face wildlife
vaccine development.

ORV requires substantially less labour and expertise. Recent studies conducted in Asia and the Americas have
shown that although capture–vaccinate–release (CVR) techniques applied to inaccessible dog populations are
inefficient (reaching only 10–20 dogs per vaccinator per day), vaccinators using ORV in these same dog
[44]
populations can far exceed 50 successful vaccinations each day. In settings where alternative vaccination
methods are necessary to reach adequate herd immunity, scalability will likely require inclusion of ORV to
effectively eliminate dog-mediated rabies. To better ensure strategic ORV planning that would lead to greater
program stability and effectiveness, WS formed a Rabies Management Team in 1997 composed of WS
operations and research personnel (National Wildlife Research Centre—NWRC), other APHIS expertise, and
external expertise from CDC, cooperating states, and universities.

5.3.1 TYPES OF ORAL RABIES VACCINE

There are two types of Oral Rabies Vaccine currently being used under commercial license for the vaccination
of various wildlife species; these are modified live vaccines (MLVs) and vector-based vaccines (VBVs). The
active component of MLVs is live, replication-competent rabies virus that has been modified so that it no longer
causes disease, but still induces the body’s natural immune response. [45] In contrast, VBVs are created by
inserting antigenic glycoprotein encoding genetic material from the rabies virus into other vector viruses, which
then express rabies virus glycoprotein within the vaccinated individual, inducing an immune response.

Modified Live Vaccines (MLVs)

Almost all modified live rabies virus vaccines in use today are derived from a single rabies virus strain, named
Street Alabama Dufferin (SAD), isolated by the CDC in the USA in 1935. This strain underwent extensive
passaging through non-neural cell lines (hamster kidney, pig kidney cells and embryonated chicken eggs) and
thermal stabilization to varying degrees to form a range of highly attenuated ORVs, including SAD-Bern, ERA
and SAD-B19. This first generation of ORVs were the foundation of rabies control in Europe and remain the
most widely used ORVs globally.[46]

The safety profile of first-generation ORVs was improved by inducing selection mutations using monoclonal
[47]
antibodies, resulting in the creation of the second generation ORVs, including SAG1 and SAG2 . The
development of 3rd generation MLVs has resulted from modern technologies of reverse genetics, which have
enabled site-directed mutagenesis, targeting specific changes at selected locations in the rabies virus genome.
Although originating from different parent vaccine virus strains, both vaccines have similar mutations at residue
333 of the G-protein.[46]

Vector-Based Vaccines (VBVs)

Vector-based ORVs were developed to avoid the theoretical risks associated with the use of live rabies virus
vaccines. VBVs are created through the insertion of a segment of cDNA encoding the rabies virus glycoprotein
[48]
into the genome of a vector virus, which is subsequently expressed within the vaccinated individual . Two
VBVs are currently commercially licensed for use in wildlife, both of which express the rabies virus
glycoprotein; RABORAL V-RG, which uses recombinant vaccinia virus (Orthopoxvirus genus) as the vector,
and ONRAB, which uses recombinant human adenovirus 5 as the vector.

One of the problems encountered with the use of VBVs is the potential for disease caused by the vector virus.
Human exposure to V-RG has been associated with severe skin inflammation. Another disadvantage of VBVs is
the potential interference by pre-existing immunity against the vector, which may inhibit uptake and generation
of sufficient immunity against rabies. [49] Therefore it is possible that the efficacy of campaigns using VBVs may
be hindered in settings where a large proportion of the animal population has immunity against the vector virus.

6 . IMPACT OF RABIES CONTROL MEASURES

The public health and economic burden of rabies has led to major intersectoral initiatives worldwide to reduce
its burden. Over the last decade, the impact of rabies prevention and control programmes in real-world settings
has become increasingly evident, especially in countries where most rabies exposures and deaths occur, but they
have yet to successfully eradicate rabies due to limited access to health care services. Dog vaccination was
found to be an effective method for the control of rabies and its transmission to humans in many locations, in
both rabies-epidemic and non-rabies-epidemic areas. All studies found that rabies control through
canine vaccination was likely to be effective in terms of reducing the incidence of rabies in dogs and/or humans,
with most studies suggesting 70% annual coverage was adequate.[50]

Completeness of vaccine coverage is an importance issue, and in some areas, such as India, coverage levels of
70% might be hard to achieve. The study in India, Tamil Nadu, suggested that annually vaccinating stray dog at
coverage levels of 7–55% (assuming base case PEP of 83% and an owned dog vaccination rate of 34%) would
reduce human deaths due to rabies by 70–94% within 5 years. Several studies concluded that global elimination
of canine rabies is achievable through sustained domestic dog vaccination if campaigns are appropriately
designed.[51]

6.1 TEERESTORIAL CARNIVORES SUCCESFUL ELIMINATION

Mass vaccination campaigns, particularly of dogs, and the use of oral vaccines for wildlife, have led to the
successful elimination of rabies in terrestrial carnivores in some countries, significantly reducing
human rabies cases. The disease is preventable through the application of post-exposure prophylaxis (PEP) and
its elimination has been demonstrated in many countries by applying multiple interventions simultaneously.
Nonetheless, rabies is still widespread in many developing countries, primarily due to the poor implementation
of intervention strategies that include inadequate dog-bite wound management practices,
unavailability/unaffordability of PEP by the communities, failure to control the disease in free-roaming dogs and
wildlife, improper dog population management, weak surveillance and diagnostic facilities and a lack of a One
Health approach to the disease. The realistic aim in the 21st century is to enhance efforts towards the elimination
of rabies in dogs with the resultant reduction of human mortality.[52]

Globally, an estimated 60,000 people die annually from rabies infection, with the highest fatality rates
attributable to the dog-mediated rabies virus variant (DMRVV) in African and Asian countries. However,
established dog population management and vaccination methods have successfully eliminated DMRVV in most
Western countries, Reported infections in domestic animals have decreased since the implementation of animal
control and vaccination programs.[53]

6.2 A DECREASE IN CASE OF HUMAN RABIES

Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated
global rabies burden. India is estimated to suffer the greatest rabies burden of any country, both in terms of
annual human deaths and disability-adjusted life years. Therefore, the World Health Organization (WHO),
World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations
(FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog
vaccination programs demonstrating elimination remain limited in Africa and Asia. The development of a data-
driven rabies elimination program from 2013 to 2019 in India, culminating in human rabies elimination and a
92% reduction in monthly canine rabies cases. vaccinate over 95,000 dogs at 70% vaccination coverage, and
rabies education teams to reach 150,000 children annually. This One Health program demonstrates that human
rabies elimination is achievable at the state level in India.[54]

7. ONE HEALTH APPROACH TO RABIES CONTROL

One Health is an integrated, unifying approach that aims to sustainably balance and optimize the health of
people, animals and ecosystems. It recognizes that the health of humans, domestic and wild animals, plants, and
the wider environment (including ecosystems) are closely linked and interdependent. More than 75%
of emerging infectious diseases and 60% of known human infectious diseases are transmitted from animals.
Among these zoonoses, rabies is of outmost public health significance due to its lethality.

Three of the region's biggest countries – India, Pakistan and Bangladesh – are among the world's top five rabies
endemic countries[55]. The OH approach has been found helpful in controlling zoonoses and has been practised
effectively in some countries over several years. Bhutan, Sri Lanka and Bangladesh have successfully reduced
deaths from rabies over time using the OH approach[56].

The aim of One Health Approach would be the most effective way to control rabies in low- and middle-income
countries (LMICs) like Nepal. Rabies is endemic to Nepal and it has been listed as one of the prioritized
zoonotic diseases. Approximately, 96% of reported Human Rabies cases in Nepal are due to dog bites and the
remaining 4% cases are due to interactions with other animals [57].

7.1 STRATEGY FOR RABIES ELIMINATION

The two major orientations of a rabies control programme, i.e., prevention of the disease in man by intensifying
and modernizing post-exposure treatment (strategy A) and canine rabies elimination by controlling the disease
in the animal reservoir (strategy B).

Developing a national policy framework and a dedicated national coordination body that emphasizes the
importance of Oral vaccination of dogs (OVD) strategy in rabies control to oversee the implementation and
monitoring of Oral vaccination of dog campaigns as well as ensuring the availability and safety of vaccine is the
first step. At the same time, determining the population size of street dogs is essential for planning and
evaluation of mass rabies vaccination. [58] To be cost-effective, Oral vaccination of dogs (OVD) should
complement the ongoing parenteral vaccination to reach free-roaming, inaccessible dog populations. Increasing
the number of dogs vaccinated per day has a huge impact on the success of the program. Therefore, training and
capacity building of veterinary personnel, field workers, and volunteers on the principles of OVD, including
vaccine handling, storage, and administration techniques, need to be focused.[59]

7.2 Role of Dog Vaccination And Population Control

The ancient disease of rabies continues to spread unchecked in the free-roaming dog populations across much of
the developing world. Whilst examples of elimination through mass dog vaccination stretch back a century,
these methods are yet to be implemented at the scale needed to control the rabies virus in much of Africa and
Asia. The use of oral rabies vaccination (ORV) in dogs has been proposed for the past 30 years, and has been the
foundational tool for the elimination of rabies virus from wildlife species across the world for over 50 years.
Today there is overwhelming support from global institutions, including WHO and OIE, for the operational
evaluation of ORV of dogs in rabies-endemic settings to complement parenteral approaches. [60]

Dog population management (DPM) is a major social and health challenge in many urban and rural areas of
developing countries. Free-Roaming Dogs populations are on the rise due to poor population management
schemes and a cultural barrier and perceptions towards the adoption of FRDs. Understanding dynamics of free-
roaming dog (FRD) population is critical for planning and implementation of dog population management
programs, many countries witness an increasing population of Dogs. FRDs are potentially capable of
transmitting several zoonotic infections to humans including Rabies. Using a population dynamics model, we
simulated five neutering coverages to explore the impact of female neutering on free-roaming dog population
size. The 5-year projections of the model have shown that 50% annual female dog sterilization significantly
reduced free-roaming dog population by 0.44 comparing to the baseline population. Controlling dog population
size is likely to result in reduced public health risks and improved animal welfare in developing countries [61].

Dogs vaccination and population control of free roaming dogs play an major role in preventing the disease in
Dogs and consequently, in Human.

CONCLUSION

Rabies remains a significant public health challenge, particularly in developing countries where access to
healthcare and vaccination programs is limited. Despite being 100% preventable through mass dog vaccination,
Post exposure prophylaxis (PEP), and awareness campaigns, the disease continues to cause tens of thousands of
deaths annually, disproportionately affecting children and rural populations. The economic burden of rabies is

also significant, costing billions of dollars globally each year due to treatment expenses, livestock losses in
reduced productivity. Global efforts, including “One Health” approach, emphasise the interdependence of
human, animal and environmental health, highlighting the need for sustained vaccination programs, improved

surveillance and better healthcare infrastructure. Successful rabies elimination in some western countries

demonstrates that with strong policies and coordinated efforts, rabies can be eradicated. Achieving the 2030 goal
of Zero human deaths from dog mediated rabies requires stronger government commitment, increased funding,
and community participation in rabies prevention and control measures. Research into novel treatments and
improved vaccine formulation and contribute to better rabies prevention and management strategies. Efforts
such as the “Zero by 30” initiative by WHO, OIE and FAO highlights the importance of eliminating human
deaths caused by dog mediated rabies by 2030. Moving forward, a multidisciplinary approach involving
veterinarians, health care professionals, policy makers, and communities is essential for rabies eradication.
Strengthening healthcare infrastructure, ensuring rapid access to life saving intervention, and promoting
responsible animal care are key to achieving this goal. With sustained commitment and coordinated global
efforts, rabies can be eliminated, preventing unnecessary deaths and improving public health worldwide.

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