International Journal of Animal and Veterinary Advances 2(4): 104-129, 2010

International Journal of Animal and Veterinary Advances 2(4): 104-129, 2010
ISSN: 2041-2908
© M axwell Scientific Organization, 2010
Submitted Date: February 07, 2010
Accepted Date: February 24, 2010
Published Date: October 15, 2010
Rabies Vaccines: Its Role, Challenges, Considerations and Implications for the
Global Control and Possible Eradication of Rabies
I.O. O kon ko, 2 O.D . Eyarefe, 3 A.O . Adedeji, 4 M.O. O jezele, 5 E. Donbraye,
I. Shittu, 7 J.A. Alli and 8 O.G . Adewale
Department of Virology, Faculty of Basic Medical Sciences, College of Medicine, University of
Ibadan, U niversity C ollege Hospital (UCH ) Ibadan, N igeria. World Health O rganization Polio
Regional Reference Laboratory, World Health Organization Collaborative Centre for Arbovirus
Reference and Research, Wo rld Health Organization National Reference Centre for Influenza,
National Reference Laboratory for HIV and AIDS R esearch
Department of Veterinary Surgery and Reproduction, Faculty of Veterinary Medicine,
University of Ibadan, Ibadan, Nigeria
Department of Veterinary Microbiology and Parasitology, Faculty of Veterinary Medicine,
University of Ibadan, Ibadan, Nigeria
Departm ent of Nursing Science/Public H ealth, L ead City University , Ibadan, O yo State, Nigeria
Departm ent of Medical M icrobiolog y and Parasitolo gy, College o f Health Sciences,
Obafem i Aw olow o University, Ile-Ife, Osun State, Nigeria
Departm ent of Viral Research , National Veterinary Research Institute
P.M .B. 01, Vom, Plateau State, Nig eria
Departm ent of Medical M icrobiolog y and Parasitolo gy,
University College Hospital, Ibadan, Nigeria
Department of Biochemistry, Faculty of Basic Medical Science, Olabisi Onabanjo University,
Ikene, Ogun State, Nigeria
Abstract: This review reports on the rabies vaccines: Its role, considerations and implications for the global
control and possible eradication of rabies. Attempts to control human rabies have a long history; animal and
human vaccines provide efficient weapons for prevention. Vaccines are one of the m ost effective public health
interventions. Vaccines are the basis of the medical and veterinary medical future. Rabies vaccine is made from
killed rabies virus. Rabies vaccine can prevent rabies. It is offered to people at high risk of exposure. The
primary intention of vaccine is to produce stimulation to the cellular immune system, via the production of
antibodies. Methods for Rabies Virus (RAB V) manipulation have changed fundamentally from random
attenuation to defined m odifications. In 2001, WHO issued a resolution for the complete replacement of nerve
tissue vaccines by 2006 w ith cell-culture rabies vaccines? In recent years, purified and concentrated Vero cell
rabies vaccines using the 3aG and CTN -1 strains have been developed. The Purified Vero Rabies Vaccines
(PVRV), is also being developed to meet the increasing demand for human rabies vaccine. However, for
animals, all fixed RA BV strains recomm ended by W HO , such as PV RV , Challenge Virus Standard (C VS),
Flury-Low Egg Passage (LEP), High Egg Passage (HEP), Evelyn-Rokitnicki-Abelseth (ERA), and SAD
varian ts, have been successfu lly used in industrialized countries, where rabies is well controlled. Any potent
rabies vaccine will protect against rabies. A vaccine, like any medicine, is capable of causing serious problems,
such as severe allergic reactions, though the risk of causing serious harm, or death, is extremely small and very
rare. As international concerns increased, several corrective actions have been implemented in many countries
since 2005, which aimed at improving vaccination protoc ols and a consisten t vaccination strategy aiming to
eliminate the residual focus. However, we should bear in mind that vaccination is still the key to prevent rabies
in small anima ls and transmission to human beings. It is hoped that the various strategies, well coordinated and
corrective actions and initiatives for global control of rabies, to make important contributions in stemming the
magnitudes, roles and implications of vaccines for global control and possible eradication of rabies and other
rabies-related viruses which poses threat to global public health.
Key w ords: Elimination, global control, possible eradication, rabies vaccines, vaccination
Corresponding Author: I.O. Okonko, Department of Virology, Faculty of Basic Medical Sciences, College of Medicine,
University of Ibadan, University College Hospital (UCH) Ibadan, Nigeria
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
itself. Imm une responses to internal antigens play little
role in immunity (H unt, 2000). Often it is the glycop rotein
to which the population has not been exposed and thus,
against which the population has no immunity. Surface
glycoproteins are often referred to as protective antigens
(Hunt, 2000). To mak e a successful vaccine, it is likely
that the identity of these antigens will have to be known
unless the empirical approach of yesteryear is to be
followed. There may be more than one surface
glyco protein on a virus and one may be more important in
the immune response than the other (Hun t, 2000).
Neutralizing antibody that blocks infectivity is required of
a successful vaccine. This usually results from antibody
combining with surface protein that would otherwise bind
to 2 surface receptor of cell. Complement can also lyse
enveloped virions.
The two form s of vaccines available are the
Modified-Live Vaccines (MLV) and the killed vaccines.
How ever, for obvious reasons, the rabies vaccine is a
killed product. It cannot cause rabies. MLVs are the
viruses that were once alive and now have been
chem ically attenuated (altered) so that they are still
recognized by the body but are, theoretically, not able to
cause the full blown clinical disease (O'Driscoll, 2008).
Some of the new est types of vaccines are ca lled sub unit
and naked DNA vaccines. DNA vaccination is a novel
immunization strategy that has great potential for the
development of vaccin es and imm une therapeutics. T his
strategy has been highly effective in mice, while less
immunogenic in nonhuman primates and humans
(Muthumani et al., 2009). Without going into the
intricacies of their production, the y invo lve techniques
used in genetic engineering. Subunit vaccines generally
will insert a viral or bacterial DNA section into the DNA
from yeast, which is allow ed to reproduce in large
quantities. The protein intended for inclusion in the
vaccine is then separated from the ye ast cells. In the case
of naked DNA vaccines, the viral or DNA gene is first
reproduced, then spliced into a plasmid (which is
essentially free DNA, widely used in recombinant
technolog y), reproduced in bacteria or cells, and then
separated from them for inclusion in the vaccine
(McRearden, 2008). Recombinant gene vaccines can also
be produce d via these m ethods for instance; vaccinia virus
(VV)-rabies is now an exclusively recombinant vaccine.
One of the major concerns with these methods is the
unpredictability and interaction of the final vaccine
product with the proteins or DNA of the host
(McRearde n, 200 8).
In the past several years, millions of rabies-virus,
vaccine-laden baits has been distributed over rural and
urban areas in W estern Europe, Eastern Canada, and the
U.S. for wildlife rabies control and a number of attenuated
and recombinant rabies vaccines have been developed.
Oral Rabies Vaccines (ORV) have been successfu lly
Rabies, being a major zoon otic disease, significantly
impacts globa l public health. It is invariably fatal once
clinical signs are apparent. The majority of human
deaths occur in developing countries
(Nagarajan et al., 2008). Rabies is one of the oldest
known diseases of mankind. Despite these continuing
problems, there has been tremendous progress in the
control of rabies. Cheap and safe vaccines for animals as
well as humans have been developed over the years. The
development of the first rabies vaccine by Pasteur was
surely hoped to eliminate or at least drastically reduce the
incidence of rabies. It has been more than 100 years since
this first vaccine was developed for pre-exposu re
vaccination and post-exposure treatment, yet new patterns
and trends of rabies infection present a major challenge
and concern for animal scientists, veterinarians,
epidemiologists and virologists alike. Although a vaccinepreventable disease, effective rabies prevention in humans
with category III bites requires the combined
administration of Rabies Immunoglobulin (RIG) and
vaccine (Nagarajan et al., 2008). Rabies vaccine can
prevent rabies. It is usually given to people at high risk of
rabies to protect them if they are exposed. It can also
prevent the disease if it is given to a person after they
have been exposed. Since the first crude nerve tissue
vaccine, numerous other rabies vaccines for human use
have been developed and used with varying degrees of
effectiveness and safety. When used appropriately, new
cell culture vaccines provide nearly 100% protection with
a high degree of safety.
Furthermore, vaccines are one of the most effective
public health interventions (B lack, 2009 ). Vaccines are
the basis of the medical and veterinary medical future.
The remarkable growth of vaccine biotechnology
continues apace in basic science discovery, product
developm ent, mark et introduction, and ad option into
immunization programs (NFID, 2009). Typically, the
vaccines are injected into the body; subcutaneously (under
the skin) or intramuscu larly (in the muscle). Vaccination
makes use of the immune system to combat virus
infections. The primary intention of vaccine is to produce
stimulation to the cellular immune system, via the
production of antibodies. Antibodies attach onto the virus
and render it inactive and h armless. It is throug h this
stimulation and resultant production of antibodies that the
body is now prepared for a possible 'attack' by 'foreign
invaders' later down the line. These inva dersare are
typically known as ba cteria or viruses. This immunity w ill
later provide protection without having to go through the
disease itself. It is a bit like the vigilante minutemen
always on guard for a possible attack (Blanco , 2008 ).
Imm unity to a viral infection depends on the
development of an immune response to antigens present
on a virally infected cell or on the surface of the virion
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
developed for red, Arctic, and gray foxes; coyotes,
raccoon dogs, raccoons, skunks, and domestic dogs.
Today, the combination of serum and vaccine is the
recommended standard for prophylaxis in human rabies
exposure (Lyles and Rupprecht, 2007). In recent time,
new cytokines are identified, innate and induced immune
regulatory pathways unraveled, novel adjuvants and
antigen constructs prove effective, and recently-licensed
products achieve high coverage, already yielding
noticeable decreases in disease incidence (Morrow and
W einer, 2008; NFID, 2009). New strategies like
adjuvantation are explored in the development of new,
prophylac tic vaccines ag ainst challenging diseases and/ or
to target sp ecific populations. A djuva nt Systems (ASs)
are tailor-made combination s of conventional adjuvants
with immunomodulators designed to enhance protective
responses to specific vaccine antigens
(Garçon et al., 2006 ; Garç on, 20 09). O ne can env ision a
grow ing number of challenging maladies - including
chronic, non-infectious, and neoplastic - that may become
vaccine-p reven table or vaccine-treatable in the years
ahea d (NFID , 2009 ).
Given the progress in biotechnology, mode rn
generations of rabies vaccines will have both maximal
efficacy and safety while still being affordable in regions
with enzootic dog rabies (L yles and R upprech t, 2007).
Attem pts to control human rabies have a long history;
animal and human vaccines provide efficient weapons for
prevention. Oral vaccination of wildlife with recombinant
rabies virus vaccines began to reduce the incidence of
rabies among foxes and raccoons. Vaccination of stray
dogs also led to the eradication of rabies in countries
whe re dog rabies is the sole source of human exposure.
How ever, concerns about vaccine safety, both real and
imagined, can and have u ndermine d what w ould
otherwise be effective public health interventions
(Black, 2009). Th is review therefo re reports on the rabies
vaccines: its role, considerations and implications for the
global control and possible eradication of rabies.
with virulent smallpox and found these peo ple to also be
less susceptible to smallpox. For instance, he inoculated
8-year-old James Phipps with purulent material taken
from a cow pox pustule on the hand of milkmaid Sarah
Nelmes and in troduced it into an incision on the boy's
arm. Jenner subsequently proved that the boy became
immune to smallpox. He published the work in 1798,
coined the word vaccine from the Latin vacca for cow,
and designated the process as vaccination (Graham and
Crow e, 2007).
Although Jenner is commonly given the credit for
vaccination, variolation, the p ractice o f deliberately
infecting people with smallpox to protect them from the
worst type of the disease, had been practiced in China at
least 2000 years previously (Alan, 2005). In 177 4, a
farmer named Benjamin Jesty had vaccinated his wife and
two sons with cowpox taken from the udder of an infected
cow and had written about his experience. Jenner was the
first person to deliberately vaccinate against any
infectious disease (i.e., to use a preparation containing an
antigenic molecule or mixture of such molecules designed
to elicit an immune response) (Alan, 2005). Then, during
the Am erican Civil W ar, Louis Pasteur, an accomplished
microbiolo gist, was able to change the vaccines he was
using enough that some of the harmful effects were
diminished. He was famous fo r his work in cattle where
he was able to prove that vaccines could protect against
the deadly d isease, anthrax (O'Drisco ll, 2008).
In 1885, Pasteur experimented with rabies
vaccination, using the term virus (Latin for ‘poison’) to
describe the agent. Although Pasteur did no t discriminate
between viruses and other infectious agents, he originated
the terms virus and vaccination (in honour of Jenner) and
developed the scientific basis for Jenner’s experimental
approach to vaccination (Alan, 2005). Pasteur's research
on rabies is perhaps the most well known historical
achievement in the field (Lyles and Rupprecht, 2007).
First, through ad aptation of street (wild-type) v irus to
laboratory animals, he was able to change its properties.
Today, one could a pply th e term attenuated to his fixed
virus strains. Second, Pasteur and his team developed
concepts and experimental approaches to the first
protective vaccination against rabies (Koprowski, 1985
cited in Lyles and Rupprecht, 2007). Desiccated spinal
cords from rabies virus-infected rabbits became the first
rabies vaccine, and they were supposedly safe, although
now it is know n that the fixed viruses from w hich these
vaccines were derived were no t apathogenic bu t could
actually cause the disease. July 6, 1885, is a milestone in
the history of rabies. On that day, 9-year-old Joseph
Meister was bitten at multiple sites by a rabid dog and
received the first postexposure prophylax is w ith Pasteur's
vaccine. Rem arkab ly, Joseph su rvived (Koprow ski, 1985
cited in Lyles and Rupprecht, 2007 ). Each of the other
curren tly licensed live vaccine viruses has a relatively
clear lineage (G raham a nd Crowe, 20 07).
Historical backg round of vaccines and vaccinations:
The first unive rsally ap plied vaccine, vaccinia virus, is of
obscure origin. T he birth of vaccinations came when the
E nglish d oc to r E d w ard Jenner in Berkeley,
Gloucestershire, discovered that the people who worked
closely with cows seem ed to be less su sceptible to
smallpox (Alan , 2005 ). In 179 6, Jenner discovered
vaccination using vaccinia virus, the agent of cowpox,
since people who got cowpox were known to have
protec tive immunity against the much more virulent
smallpox (Hunt, 2000). He injected small amounts of the
cowpox crusts from Blossom into healthy ind ividuals
(Vaccinated including his own son) and then challenged
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
Pasteur's vaccine, with all its modifications, became
the accepted rabies prophylactic throughout the w orld in
the early 20th century. Thus, he started the new field of
medicine called im mun ology . Pasteur also became
famous for his co ncep t of the 'germ theory '. This is still
the theory modern medicine uses to explain all illness.
Thus we have created a 'war on bugs' that we seem to be
losing (O'Driscoll, 2008). It is interesting to note that on
his deathbed Pasteur recanted his prior work of blaming
the microorganism. His last words were "seed is nothing,
soil is everythin g". In C hinese medicine it is said that "it
is not the agent, but the terrain". Both are saying the same
thing - the germ is nothin g, but the host's resistance is
everything. These concepts lay the foundation for all
forms of holistic medicine (O'Driscoll, 20 08).
Postexposure prophylaxis against rabies through
simultaneous administration of antirabies serum and
vaccine was introduced in 1889 by B abes (1912 cited in
Lyles and Rupprecht, 2007). This approach found few
adherents and languished until about 1940, when interest
in the use of serum containing rabies virus antibodies in
India (Rao et al., 2004), was revived. In a trial organized
by the World Health Organization (WHO ) in 1954, the
combined use of serum and vaccine was found to be more
protective than vaccine alone, an observation later
corroborated by Chinese findings. Each of the other
curren tly licensed live vaccine viruses has a relatively
clear lineage (Graham and C rowe, 200 7). In the 1960s, a
rabies virus grown in hum an dip loid cells was used to
produce a safe and efficacious vaccine, eliminating many
of the problems connected with vaccines produced in
brain tissue (L yles an d Rupprecht, 2007). In 1961,
recommendations were made that a serum analysis of the
blood was the best way to determine the immunological
protection of vaccines. H istorically (1957-198 0s), several
major modern human rabies vaccines include Duck
Embryo Vaccine (DEV), which was com merc ialized in
1957; Human Diploid Cell Vaccine (HDCV ) was
introduced in 197 8; Purified Chicke n Em bryo Cell
Vaccine (PCECV) w as developed in 1984; and a Purified
Vero Cell Rabies Vaccine (PVRV) was developed in the
late 1980s (Wu et al., 2009 ).
Before the 1980s, nerve tissue-derived Sem ple
vaccine (NTV) was manufactured using the fixed RABV
Beijing strain 3aG, which was isolated in 1931
(W u et al., 2009). The development of safe and effective
rabies virus vaccines ap plied in attractive baits resulted in
the first field trials in Switzerland in 1978. Thereafter,
technical improvements occurred in vaccine quality and
production, including the design of recombinant viruses,
as well as in the ease of mass distribution of millions of
edible baits ov er large geog raphical area s (Ru pprecht et
al., 2004). Also, acc ording to W u et al. (2009), after the
1980s, Primary Hamster Kidney Cells (PHKC) rabies
vaccine using the same 3aG strain was investigated as a
for NTVs. The heteroploid VERO cell line was
introduced in 1982 to the production of inactivated rabies
vaccine; it retained all the advantages of the human
diploid cell system, while offering the possibility of the
large-scale industrial production of PV RV . In 198 8, cell
culture rabies vacc ines for hum an use, highly
immunogenic and well tolerated, were now used for preexposure immunization as w ell as for post-exposure
treatment. In 1992, W HO recommend s a new inactivated
rabies vaccine grown on Vero cells, (PVRV) with the
vaccine cultivated on Human Diploid Cells Vaccine
(HDCV), for both pre and post-exposure prophylax is
(Nagarajan et al., 2008). Following the widespread use of
HDCV and PVRV , many comparative clinical trials have
been conducted, studying the safety and predictive values
of these two vaccines. In 2001, WHO issued a resolution
for the complete replacement of NTVs by 2006 with cellculture rabies vaccines (Wu et al., 2009 ).
The viral vaccines used in the past have included live
attenuated vaccines, killed virus vaccines, and sub unit
vaccines. Both the killed virus vaccine and the
recombinant subunit vac cine we re new to the mode rn era
of virology (Levine and Enquist, 2007). New vaccine
technologies now include the use alone or in combination
of attenuated viral vectors such as vaccinia virus or
adenovirus and DNA plasmids that express viral proteins
from strong promoters. So-called therapeutic vaccines
will boost the immune systems of individuals using
specific cytokines or hormones in combination with new
adjuv ants to stimulate imm unity at specific locations in
the host or to tailor the production of immune effector
cells and antibodies (Levine and Enquist, 2007; Morrow
and Weiner, 2008). Considering that the first vaccines (for
smallpox) were reported in the Chinese literature of the
10th century (Fenner and Nakano, 1988), these ideas can
be traced back in time to the origins of virology (Levine
and Enquist, 2007). In recent years, the combination of
serum and vac cine is the recom mend ed standard for
prophylaxis in human rabies exposure. This vaccine and
others are used widely throughout the world, although for
econ omic reasons, several developing countries still use
nervous tissue vaccines (Lyles and Rupprecht, 2007).
Today purified and concentrated Vero cell rabies vaccines
using the 3aG and CTN-1 strains have been developed.
The PVRV, using a RA BV purified Vero (PV ) strain
imported from the US Centers for Disease Control and
Prevention (CDC), is also being developed to meet the
increasing demand for human rabies vaccine (W u et al.,
2009). According to Wu et al. (2009), from 1885, when
the first hum an rab ies vac cination occ urred, to 1994,
when the rabies v accine, Street-Alab ama -Dufferin (SAD)
B19 strain was engineered with reverse genetics, methods
for RAB V manipulation have ch anged fun dam entally
from random attenuation to defined modifications.
How ever, the basic concept for rabies vaccine
development has not changed for more than a century.
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
here is to utilize the genome of a well-understood,
attenuated virus to express and present antigens to the
immune system (Alan , 2005 ). Man y different viruses
offer possibilities for this type of approach, but the most
highly developed system so far is based on the vaccinia
virus (VV) genome. VV-rabies recombinants have been
used to eradicate rabies in European fox populations
(Alan, 2005). DNA vaccines and RNA interference
(RN Ai) are the newest type of vaccine and consist of only
a DNA molecule encoding the antigen(s) of interest and,
possibly, costimulatory molecules such as cytokines. The
deliberate introduction of a DNA plasmid carrying a
protein-coding gene that transfects ce lls in vivo at very
low efficiency and expresses an antigen that causes an
immune response. These are often called DNA vaccines
but would better be called DNA-mediated or DNA -based
immunization since it is not the purpose to raise
antibodies against the DNA molecules themselves. All of
the above means that DNA vaccines are cheap and
therefore likely to be developed against pathogens of
lesser economic importance (at least to drug companies)
(Hunt, 200 0; Kutzler and W einer, 2004).
The concept behind these vaccines is that the DNA
component will be expressed in vivo, creating small
amo unts of antigenic protein that serves to prime the
immune response so that a protective response can be
rapidly generated when the real antigen is enco untered. In
theory, these vaccines co uld be manufactured quickly and
shou ld efficiently induce bo th hum oral and cell mediated
immunity. Initial clinical studies have indicated that there
is still some way to go until this experimental technology
becomes a practical proposition (Kutzler and
W einer, 2004; A lan, 2005). It has been discovered that a
relatively newly discovered phenomenon known as RNAi
can be used to inhibit virus replication of a w ide variety
of viruses in vitro. Reminiscent of the triggering of
interferons, dsRNA serves as a trigger for RNAi. An
enzyme highly conserved in eukaryotic evolution, called
Dicer, cleaves dsRNA into 21- to 23-nt-long fragments
known as small inhibitory RNAs (siRNAs), which
ultimately result in destruction of the homologous target
RNA. In some species, but apparently not in humans,
siRNA can also direct the synthesis of more dsRNA,
leading to amplification of the effect and allowing the
effect of RN Ai to spread from cell to cell (Alan, 20 05).
Generations of vaccines production and the present
status of rab ies vaccine develop ment:
First vaccine revolution: Pasteur developed rabies
vaccine. It was the first attenuated viral vaccine that
passed throug h nerv e cord s of rabbits. Althoug h relative ly
effective, ‘killed’ vaccines are sometimes not as effective
at preve nting infection as ‘live’ virus vaccines, often
because they fail to stimulate protective mucosal and cellmediated immunity to the sam e extent. A more recent
concern is that these vaccines contain virus nucleic acids,
which may themselves be a source of infection, either of
their own accord (e.g., (+) sense RNA virus genomes) or
after recombination with othe r viruses (Alan, 2005).
Second vaccine revolution: There are three basic types
of vaccines under this category: subunit vaccines,
inactivated vacc ines, an d live-virus vaccines. Sub unit
vaccines consist of only some components of the virus,
sufficient to induce a protective immune response but not
enough to allow any danger of infection. In general terms,
they are com pletely safe, ex cept for very rare cases in
which adve rse imm une reactio ns may occur.
Unfortunately, at present, they are also the least effective
and most expensive type of vaccines. There are several
categories of such vaccines: synthetic, recombinant, and
virus vectors. Synthetic vaccines are short, chemically
synthesized peptides. None is currently in use
(Alan, 2005). M ost vacc ines in ccurrent use are
inactivated (Hunt, 200 0). Inactivated vaccines are
produced by exposing the virus to a denaturing agent
under precisely controlled conditions. The objective is to
cause loss of virus infectivity without loss of antigenicity.
Obviously, this involves a delicate balance; however,
inactivated vaccines have certain advantages, such as
generally being effective imm unogens (if properly
inactivated), being relatively stable, and ca rrying little or
no risk of vaccine-associated virus infection (if properly
inactivated, but accidents can and do occur) (Alan, 2005).
Live (attenuated) virus vaccines strategy relies on the use
of viruses with reduced pathogenicity to stimulate an
immune response without causing disease. The vaccine
strain may be a naturally occu rring viru s (e.g., the use of
cowpox virus by Jenner) or artificially attenuated in vitro
(e.g., the oral poliomyelitis vaccines p roduced by Albert
Sabin). The adva ntage of attenuated vaccines is that they
are good imm unogens and induc e long -lived, appropriate
immunity (Hunt, 2000; Alan , 2005).
New generations of rabies vaccines: Rab ies virus is
considered as a unique virus, 5 groups of rabies fixed
strains are used throughout the world to produce human
rabies vaccines: Pasteur, Beijing, Flury, Fuenzalida and
SAD strains. The different rabies vaccines should be
classified according to the cell system used to cultivate
the virus: Animal systems are still employed to produce
the old traditional vaccines-Semple and SMB-which
continue to be produced in several countries; Primary cell
Third vaccine revolution: Reco mbinan t vaccines are
produced by genetic engineering. Such vaccines have
been already produced and are better than synthe tic
vaccines because they tend to give rise to a more effective
immune response. Virus vectors are recombinant virus
genomes genetically manipulated to express protective
antigens from (u nrelated) path ogenic viruses. The idea
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
systems, particularly Hamster Kidney and Chick embryo
cells, are used (Nagarajan et al., 2008). The P asteurderived stra in s, d esig nated P V o r P M , are the most wide ly
used for the production of traditional vaccines of the
Sem ple or Suckling M ouse Brain (SM B) types, but also
for the production of modern cell culture vaccines:
Human Diploid an d Purified V ero Cell Vaccines (HDCV
and PVR V) (Nagarajan et al., 2008). However, new
generation of low-cost, purified rabies vaccines released
in the last 2 years promises a revolution in rabies
immunization in less-developed, rabies endemic
countries, providing protection comparable to that of
human diploid cell vaccine at the cost of Semple -type
vaccine. The principal human rabies vaccines produced
worldwide at prese nt using cell cu lture are com pared , in
terms of their technical characteristics and the ir capacity
econom ically to face worldwide vaccine need s. Cell
culture rabies vaccines have become widely available in
developing countries, virtually replacing the inferior and
unsafe nerve tissue vaccines (Nagarajan et al., 2008).
Today, the greatest needs are in tropical countries, wh ere
only a limited amount of modern cell culture vac cines are
administration. The use of the hum an dip loid cell system
permitted the development of the HD CV , the most
widely distributed cell culture rabies vaccine, and
reference vaccine
(Nagarajan et al., 2008 ).
Purified Vero cell rabies vac cine (PV RV ): Also, no
serious side-effects had occurred with PVRV. Some
vaccinees complaining of red ness, induration or local pain
and exceptionally of fever and lymphadenopathy have
also been reported (Nagarajan et al., 2008).
Purified chick embryo cell (PCEC) vaccine (Rabipur):
Several pre- and post-exposure contro lled vaccine trials
and clinical studies have shown that the PCEC vaccine,
Rabipur, is as safe and effective as the HDCV, which is
curren tly considered the gold standard. Additionally,
PCEC vaccine do es not result in immune-mediated
hypersensitivity reactions following booster doses seen in
about 6% of those receiving HD CV boosters following an
initial series of HDCV.
Purified rabies vaccine cultured on V ero cells
(Verorab, sanofi pasteur): Verorab, sanofi pasteur is
W HO-approved for pre- and post-exposu re prop hylax is
by intradermal and intramuscular routes as an effective
and inexpensive option for developing countries. During
20 years of use, over 40 million doses of Verorab have
been adm inistered in more than 100 countries. No serious
adverse even t due to Verorab has been reported in clinical
trials. Verorab is not associated with post-boosting serum
sickness. Extensive clinical experience supports the use of
Verorab for intramuscular and intradermal pre- and p ostexposu re prophylax is, including in special situations
(Too vey, 2007 ).
Hum an rabies vaccines: Ma jor human rabies vaccines
include NT V, PHKCV , DEV, HDC V, PCECV , and
PVRV (Wu et al., 2009). Since W HO had already
strong ly recomm ends the rep lacemen t of NTV s with
mode rn vaccines, ex tensive clinica l experience supp orts
the use of these vaccines for intramuscular and
intradermal pre- and post-exposure prophylaxis, including
in special situation s (Toovey, 2007). Cell culture rabies
vaccines have become widely available in developing
countries, virtually replacing the inferior and unsafe nerve
tissue vaccines (Nagarajan et al., 2008). For both HDCV
and PVRV , production security is guaranteed by the
existence of a master ce ll seed and w orking cell bank,
with a com plete history of the cell, a limited number of
passages and p erma nent and total quality control of the
cell substrate (Nagarajan et al., 2008). A year long
protection could easily b e prov ided w ith the bo th
vaccines, till to the 1st booster dose administration. For
both HDC V and PVR V, production security is guaranteed
by the existence of a master ce ll seed and w orking cell
bank, with a complete history of the cell, a limited
number of passages and perm anen t and total quality
control of the cell substrate (Nagarajan et al., 2008).
Animal rabies vaccines: In contrast to human rabies
vaccine development, animal rabies vaccine development
in most countries has not progressed. In the United States
alone, 11 different rabies vaccines are licensed for dogs,
12 for cats, 1 for ferrets, 3 for horses, 4 for cattle, and 5
for sheep (Briggs et al., 2007). However, in places like
China, only 1 pentavalent vaccine is licensed, and 1
Flury-Low Egg Passage (LEP) vaccine for dogs has been
tentative ly approved and no regional RA BV isolates were
characterized for animal vaccine development
(W u et al., 2009). Currently, High E gg Passage (H EP),
LEP, Evelyn–Rokitnicki-Abelseth (ERA), PV, and
Challenge Virus Standard (CVS) strains being developed
as vaccine candidates originate from other countries and
have an unclear biological background. Consequently,
development of animal rabies v accines using carefully
characterized RAB V strains should be prioritized as a
fundamental task (W u et al., 2009).
Hum an diploid cell vaccine (H DC V): HD CV is
curren tly considered the gold stand ard. N o serious sideeffects had occurred with HDCV, although some
vaccinees com plaining of red ness, induration or local pain
and exceptionally of fever and lymphadenopathy have
been reported. A year-long protection could easily be
provided with the vaccine, till to the 1st booster dose
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
Vaccinia rabies glyc oprotein (V-R G): V-RG vaccine
was the first recombinant rabies vaccine to be constructed,
field tested, and co nsidered for regulation in Europe and
North Am erica for wildlife rabies c ontrol. This vaccine
has been extensively review ed to ensure safety (tested in
>40 species of mammals and birds) and efficacy (proved
against severe rabies challeng e in target species).
Following the success of the V-RG vaccine against fox
rabies in Belgium and France, preliminary field trials
suggest its potential utility for rabies con trol in
raccoons, foxes, and coyotes in the U.S. (Lyles and
Rupprecht, 2007 ).
Ge netica lly modified, revers e-en ginee red live
vaccines: In
report by
Morimo to et al. (2001), a novel approach to the
development of rabies vaccines usin g gen etically
modified, reverse-eng ineered live attenuated rabies
viruses was described. This approach entails the
engineering of vaccine rabies virus containing G proteins
from virulent strains and modification of the G protein to
further reduce pathogenicity. Strategies employed
included exchange of the arginine at position 333 for
glutamine and modification of the cytoplasmic domain.
According to M orimo to et al. (2001 ), the ability to confer
protective immunity depended largely upon conservation
of the G protein antigenic structure between the vaccine
and challenge virus, as well as on the route of
Street-Alabama -Du fferin (SAD) B19: SAD B 19 is an
attenuated vaccine virus for oral vaccination of carnivores
against rabies. The safety of SAD B19 has been
investigated by Vos et al. (1999 ) who con clude d that it is
suitable for oral vaccination camp aigns for carnivores
against rabies. The use of the techniques and strategies of
oral immunization of foxes against rabies using SAD B19
can eliminate wildlife rabies among foxes and raccoon
dogs, as European experience has show n. The disease
then also disappears com pletely in dom estic animals and
Reverse genetics approach: Based on previous
observations indicating that the potency of a vaccine is
significa ntly increased if the G protein of the vaccine
strain is identical to that of the target virus, Dietzschold
and Schnell (2002) have used a reverse genetics approach
to engin eer viruses that contain G proteins from virus
strains associated with relevant wildlife species.
Furthermore, because recent data also indicate that the
patho genicity of a particular rabies virus strain is
inversely proportiona l to its ability to induce apo ptosis
and that low-level apoptosis-inducing ability is associated
with low anti-viral immune responses, Dietzschold and
Schnell (2002) inserted genes encoding pro-apoptotic
proteins to stimulate immunity or otherwise interfere with
viral patho genesis into these re com binan t viruses to
enhance their efficacy and safety. The application of
Reverse genetics technology in has also been applied in
the study of Rabies Virus (RV) pathogenesis and for the
development of novel RV vaccines (Schnell et al., 2005).
Vectored vaccine: An oral baculovirus-vectored vaccine
induces protective immunity in raccoons. Other
orthopoxviruses have been considered as vectors of
lyssavirus antigens, but these h ave n ot yet been fieldtested (L yles an d Rupprecht, 2007).
Novel appro aches a nd future trend in vaccine
production: Some believe that vaccine production should
reflect the design of matched field isolates for regional
control (Wu et al., 2009 ). However, vaccine-matching
investigations to address concerns about mismatch
between vaccine strains and epidemic RA BV isolates are
redundant (Dong et al., 2007). All fixed RAB V strains
recommended by W HO , such as PV , CV S, LEP, H EP,
ERA, and SAD variants, h ave b een succe ssfully u sed in
industrialized countries, where rabies is well controlled.
Any potent rabies vaccine will protect against rabies
(W u et al., 2009 ). The curren tly available m odified-live
rabies virus vaccines have either safety problems or do
not induce sufficient protective immunity in particular
wildlife species. Therefore, there is a need for the
development of new live rabies virus vaccines that are
very safe an d high ly effective in pa rticular w ildlife
species. Meanw hile, new types of vaccines are being
developed by applying g ene m anipu lation techniqu es to
rabies virus in order to overcome the disadvantages of
current vaccines (Sugiyama and Ito, 2007). The progress
made in the development of new-generation rabies
vaccines with the goal of elimination or control of rabies
in world include:
The RABV G protein gene: The RABV G protein gene
also has been inserted into the human adenovirus genome.
Preliminary expe rimen ts have shown adeq uate G protein
expression in cell culture and efficacy in several
immunization trials in captive animals. Newer constructs
(e.g., RABV glycoprotein inserts uing the adenovirus E1
region, incapable of replication in host tissue) are also
under consideration in a variety of species. A recombinant
plasm id pTargeT.rabgp containing the glycoprotein (G)
gene of Rabies Virus (RV) was constructed and produced
for immunogenicity studies on mice and dogs by
Rai et al. (2005). Their results indicated that the
pTargeT.rabgp plasmid co uld be used as a rabies DNA
vacc ine.
M o n o c l o n a l a n t ib o d y -bas e d hu ma n ra bi e s
immunoglob ulin (RIG ): Limitations inherent to the
conventional RIG of either equine or human origin have
prompted scientists to look for monoclonal antibody-
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
based human RIG as an alternative. Fully human
monoclonal antibodies have been found to be safer and
equally efficacious than conv ention al RIG when tested in
mice and hamsters (Nagarajan et al., 2008). These novel
human mon oclon al antibodies, their production, and the
significance of plants as exp ression platforms were
rabies vaccine. Fo r instanc e, pre-exposure prophylaxis
using Verorab is confirmed immunogenic in 1437
subjects by all routes, with prompt responses following
boosting; Verorab boosts effectively in subjects
pre-immunized w ith HD CV (Toove y, 2007).
Safety and efficacy of rabies vaccines: Vaccine safety is
a major conc ern for p atients, parents, healthcare
providers, public health officials an d vac cine
manu facturers (Loughlin et al., 2009 ). Doubt has
sometimes been cast upon the protective effect of rabies
antibodies in serum. Several studies of the safety of rabies
PEP for preg nant patients demonstrated no association
between treatment and adverse outcomes (Abazeed and
Cinti, 2007). Figueroa et al. (1994) reported 2 patients
with rabies exposure during the second and third trimester
of pregnancy that rece ived im mun ization respectively
with Vero cell vaccine and Fuenzalida vaccine. A study
by Sudarshan et al. (2007) on 14 pregnant women who
received rabies PEP showed that none had any adverse
even ts to either vaccine or equine RIG. In one study by
Abazeed and Cinti (2007), tissue culture-derived vaccines
and HIG did not lead to an increased risk for congenital
anomalies. Although these studies are not comprehensive
in their assessment of all reproductive outcomes,
they do suggest that PEP is generally safe.
M anickama et al. (2008) study on the efficacy of two
com merc ially available rabies vaccines and a 5- or 3-dose
vaccination regime indicated that none of the vaccinated
dogs showed any clinical signs of rabies at any stage. All
of their brain tissue samples taken at the end of the study
were found negative for rabies viral antigen. Both
vaccines were found to be safe and effective in preventing
rabies when inoculated intramuscularly applying the 5dose regime (0, 3, 7, 14 and 28 days). W HO
recommended PEP for rabies using PCEC -K is also
considered effective and safe (Yanagisawa et al., 2008).
Mode rn PEP is a com bination of active and passive
immunization, with 1 00% efficacy in rabies prevention if
the process strictly adheres to WH O recommended
guidelines (Rupprecht et al., 2006; Manning et al., 2008).
After rabies exposure in humans, PEP is initiated or
withh eld based on the postmortem diagn osis of a nimals
that were the source of exposu re. Because human rabies
vaccines are produced in cell culture using modern
technology, the vaccine quality should follow the standard
recommended by WH O (W u et al., 2009).
Considerations for rabies vaccines an d vaccina tions in
global rabies control and possible eradication: In
keeping pace with various vaccination recommendations
and considerations, people at high risk of expo sure to
rabies, such as veterinarians, animal handlers, rabies
laboratory workers, spelunkers, and rabies biologics
production workers should be offered rabies vaccine. The
vaccine should also be considered for: (1) people whose
activities bring them into frequent contact with rabies
virus or with possibly rabid animals, and (2) international
travelers who are likely to come in contact with anim als
in parts of the world where rabies is common
(CDC, 2006). How ever, this is a risky business; if
protection of the population falls below a critical lev el,
epide mics can easily oc cur.
Designing effective vaccines: According to Alan (20 05),
to design effective vaccines, it is important to understand
both the immune response to virus infection and the
stages of virus replication that are appropriate targets for
immune intervention. T o be effective, vaccines must
stimulate as many of the body’s defence m echa nisms as
possible. In practice, this usually m eans trying to mimic
the disease without, of course, causing pathogenesis-for
example, the use of nasally administered influenza
vaccines and orally administered poliovirus vaccines. To
be effective, it is not necessary to get 100% uptake of
vaccine. ‘Herd immunity’ results from the break in
transmission of a virus that occurs when a sufficiently
high proportion of a population has been vaccinated
(Alan, 200 5).
Types and sorts of rabies vaccines: Cell or tissue culture
vaccines e.g., Nobivac Rabies (Intervet), Rabisin (M erial),
Verorab (Sanofi pasteur) have been used extensively.
Purified rabies vaccine cultured on Vero cells (Verorab,
sanofi pasteu r) is W HO -approved for pre - and p ostexposu re prophylaxis by intradermal and intramuscular
routes. Nerve tissue origin vaccines, although used
exten sively in some parts of the world, are not
recommended if cell or tissue culture vaccines are
available (Toovey, 20 07).
Potency of rabies vaccines: A key factor for the success
of the dog rabies control program in Mexico was the
supp ly of potent canine rabies vaccines (Lucas et al.,
2008). The minimum potency for all cell-culture and
purified embryonated egg rabies vaccines is 2.5 IU per
intramuscular dose using the National Institutes of Health
test (W HO, 2005). Potency and efficacy of rabies
vaccines determined by Minke et al. (2009) by comparing
Doses and route of vaccination: The number of doses
and route of vaccination with a tissue culture or cell
culture origin vaccine differ in various regions of the
world. The administration of a RIG is generally
recommended in conjunction with the first dose of the
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
practicability of such systems (Servat et al., 2006). The
next way is to believe the biologics companies. This may
not be an ideal choice since most animal researchers and
clinicians would vaccinate animals and they would break
out with the disease many years ago. There have also been
cases were perfectly healthy animals com ing do wn with
the diseases they were being vaccinated against
(O'Driscoll, 2008).
antibody responses after vaccination of 30 laboratory dogs
with two inactivated rabies vaccines (RABISIN, Merial
France) and NOB IVAC, Intervet International) performed
differen tly in terms of magnitude and persistence of rabies
antibodies titers. RAB ISIN induces higher and sustained
antibody titres against rabies, increasing the flexibility for
the time of blood sampling after primo-vaccination.
Testing for potency, safety, effectiveness and efficacy
of rabies vaccines: The need to verify the effectiveness
of rabies vaccination has become widespread, particularly
in the context of international trad ing of d ome stic
carnivores from infected to rabies-free territories. In
compliance with regulato ry guidelines, imm unogenicity
as well as safety of adjuvanted candidate vaccines
shou ld be evaluated preclinica lly and clinically
(Garçon et al., 2006; Garçon, 2009). Preclinical safety
a n al y se s o f th e can d id ate v accin e ( p r o d u ct
characterization, lot-release testing, elucidation of the
mode of action and toxicology) are part of preclinical
safety packages on which clinical development plans and
safety evaluations are based (Verstraeten et al., 2008;
Garçon, 2009). Safety monitoring following introduction
of new vaccines includes assessmen t of potential new
onset Autoimmune Diseases (AID). Interpreting the
significance of these cases is difficult because knowledge
about AID background incidence rates is limited (Klein et
al., 2009). Causality assessment can be based on modified
WHO criteria that classify the causal relationship between
the vaccine and the adverse event (W HO, 2001;
Lou ghlin et al., 2009). In term of vaccine efficacy,
serological tests for rabies are also often used by
laboratories in infected territories to assess the efficacy of
campaigns aimed at the eradication of the disease via oral
vaccination of wildlife. The adaptation of these methods
shou ld provide the means to titrate specific antibodies in
dogs during mass parenteral vaccination in countries
infected by canine rabies (Serv at et al., 2006 ).
In term of effectiveness of vaccines, serology remains
the only way to monitor the effectiveness and
immunological protection of vaccination of humans and
animals against rabies (Servat et al., 2006). Though a
simple test, but there has been some controversy as to
what titer level w ill provide protection from the clinical
disease, and what level tells if there has been exposure to
the disease (O'Driscoll, 2008). Many techniques for
determining the level of rabies antibodies have been
described and this include seroneutralisation techniques
(such as tests for Fluorescent Antibody Virus
Neutralization, FAV N and Rap id Fluorescent Focus
Inhibition, RFFIT), Enzyme-Linked Immunosorbent
Assay (ELISA), and in-vivo tests (the mouse
neutralisation test, MNT). The standardization of
serological techniques, approval of laboratories and
proficiency tests are key concepts to ensure the
Challenges and Concerns Facing Current Rabies
Vaccines Appro aches: The reemergence of rabies in
China raises concerns. The high incidence of rabies
reported in this reemergence leads to numerous concerns
which include; a potential carrier-dog phenomenon,
undocumented transmission of rabies virus from wildlife
to dogs, counterfeit vaccines, vaccine mismatching, and
seroconversion testing in patients after their completion of
postexposure prophylaxis (PEP). These concerns are all
scientifically arguable given a modern understanding of
rabies (Wu et al., 2009 ). Rab ies virus is not a sin gle entity
but consists of a wide array of variants that are each
associated with d ifferent host species. These viruses differ
greatly in the an tigenic mak eup of their G proteins, the
primary determ inant of patho genicity and major inducer
of protective imm unity. Due to this diversity, existing
rabies vaccines have largely been targeted to individual
animal species (Morimoto et al., 2001). The prevalent
vaccine used in most developing countries is still the
NTV, which, altho ugh impro ved, necessitates the use of
long and p ainful application schedules and fails to provide
safe and reaction-free protection. Ho wev er, cell lines are
presently the most interesting approach for vaccine
production. Today , major technical problems w ere
associated with subunit vaccines, this include their
relatively poor antigen icity and the need for new delivery
systems, such as imp roved carriers and adjuv ants. Their
disadvantages is that they are not usually very effective
immunogens and very costly to produce; howev er,
because they can be made to order for any desired
sequence, they have great potential for the future
(Hunt, 200 0; Alan, 2005).
Inactivation: Problems remained with Pasteur vaccine,
how ever, because improperly inactivated virus caused
rabies, and animal brain tissue induced allergic reactions
leading to ne uropa ra lytic ac cidents. M oreover, perhaps
most importantly, the vaccine was not very effective in
cases of severe bites, such as those inflicted on the face
and neck by rabid wolves and dogs (Lyles and
Rupprecht, 2007). The challenges and concerns associated
with inactivated vaccines is their disadvantage. It is not
possible to produced inactivated vaccines for all viruses,
as denaturation of virus proteins may lead to loss of
antigenicity (Alan, 2005). Despite these difficulties,
vaccination against virus infection has been one of the
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
great triumphs of med icine during the twentieth century.
Although preve ntion of infection by pro phylactic
vaccination is much the preferred option, postexposure
therape utic vaccines ca n be o f great value in mod ifying
the course of some virus infections. This include rabies
virus, where the course of infection may be very long and
there is time for postexpo sure vaccination to generate an
effective immune response and prevent the virus from
carrying out the secondary replication in the CN S that is
respo nsible for the pathog enesis of rabies (Alan, 2005).
effects, including cancers”. Also, the technical problems
curren tly associated w ith RN Ai vaccines are in their
delivery into cells in the body. If this can be overcome,
RNAi could become an important new tool in treatment
and preve ntion o f virus diseases (Alan, 200 5). And to
reiterate the danger of tumorigenic cell lines, some
researchers said more recently, recombinant DNA
technology has expanded bey ond bacterial cells to
mammalian cells, some of which may also be tumorigen ic
(M cRearden, 2008; Blanco, 2008). Other major
challenges and concerns facing current approaches of
rabies vaccines include: misconceptions about vaccines,
annual pet vaccination, and lack of standard procedures
for assessing vaccine safety and efficacy and adverse
effects after vaccination.
Attenuation: Set against the advantages of live
(attenuated) virus vaccines are their many disadvantages.
They are often biochemically and genetically unstable and
may either lose infectivity (becoming worthless) or revert
to virulence unexpectedly. Another major challenge
facing attenuated vaccines is that despite intensive study,
it is not po ssible to produce an attenuated vaccine to
order, and there appears to be no general mechanism by
which different viruses can be reliably and safely
attenuated. Contamination of the vaccine stock with other,
possibly pathogenic viruses is also possible-this was the
way in which SV40 was first discovered in oral poliovirus
vaccine in 1960. Inapp ropriate use of live virus vaccines,
for example, in immunocompromised hosts or during
pregnancy may lead to vaccine-associated disease,
whereas the sam e vaccine given to a healthy individual
may b e perfectly safe (H unt, 2000; A lan, 2005).
M isconceptions about vaccines: Vaccines are the basis
of the medical and veterinary medical future, the belief
being that, if a vaccine can be made to every disease, then
all disease can be prevented. This presupposes that 1)
disease attacks from outside and has nothing whatsoever
to do with the person or animal themselves; 2) that
vaccines actually always protect 100% ; and 3) that
vaccines themselves are only beneficial and cannot cause
harm. None of these are true (O 'Drisco ll, 2008). There is
a growing list of research into and information on
the problems that can be caused by vaccines
(O'D riscoll, 2008; M cRearde n, 200 8; Blanco, 2008 ).
Recombinant DNA technology: Third generation of
vaccines also faces similar challenges, for instance,
recombinant vaccines are difficult to produce and no
human exam ple is clearly successful yet, although many
different trials are currently underw ay (Alan , 2005).
Enhancing DNA vaccine potency remains also a
challenge (Hung et al., 2006 ; Muthum ani et al., 2009).
According to McRearden (2008) and Blanco (2008), “One
of the major concerns with these methods is the
unpredictability and interaction of the final vaccine
product with the proteins or DNA of the host. A document
from the FDA states: Genetic toxicity: Integration of the
plasm id DNA vaccine into the genome of the vaccinated
subjects is an important theoretical risk to consider in
preclinical studies. The conc ern is that an integrated
vaccine may result in insertional mutagenesis through the
activation of oncogenes or inactivation of tumor
suppressor genes. In addition, an integrated plasmid DNA
vaccine may result in chromosomal instability through the
induction of chromosomal breaks or rearrangements?
Another group advises that research findings in gene
therapy and vaccine development show that naked/free
nucleic acids constructs are readily taken up by the cells
of all species including human beings. These nucleic acid
constructs can become integrated into the cell's genome
and such integration may result in harmful biological
Annual pet vaccination against rabies: There are lacks
of scientific evidence to support our current practices of
vaccination in animals. According to Schultz and Philips
(1992 cited in O'Driscoll, 2008), “A practice that was
started many years ago, that lacks scientific validity or
verification is annual vaccinations. Almost without
exception there is no immunologic requirement for annual
revaccination. Immunity to viruses persists for years or
for the life of the animal. Furthermore, revaccination with
most viral vaccines fails to stimulate an a nam nestic
response as a result of interference by existing antibodies
(similar to maternal antibody interference). The practice
of annual vaccination in our opinion should be considered
of questionable efficacy unless it is used as a mechanism
to provide an annual physical exam or is required by law
(i.e., certain states require annual revaccination for
rabies)."According to O'Driscoll (2008), there has been
much deba te on the subject of an nual pet vaccination,
chiefly in response to concerns voiced by pet owners. The
veterinary profession is largely unaware of the range of
side-effects vaccines can stimulate, and consequently they
go unrep orted. It is acknowledged that certain individuals
are genetically predisposed to suffer adve rse reactions to
vaccines. On the whole, the veterinary profession in the
UK has defended annual vaccination, on the basis of
inform ation largely supplied by the pharmaceutical
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
industry. Yet there are wider issues to consider. A radical
rethink of the vaccination programme is necessary immunisation programmes need not be abandoned, but
reassessed. The first subject for assessment is whether all
animals should be vaccinated, irrespective of their
genetic status (O'Driscoll, 2008; McRearden, 2008;
Blan co, 20 08).
understood as the disturbance of the vital force by
vaccination that results in mental, emotional and physical
changes that can , in some cases be a permanent condition
(Mc Rearden, 2008 , Blanco, 20 08).
Ch ronic symptoms after vaccination: Chronic
symptoms look very much like the acute illnesses but they
are often not life-threatening unless allowed to continue
for years and years. According to O'Driscoll (2008),
McR earden (2008) and Blanco (2008), for rabies we often
see: restless nature (suspicion of o thers, ag gression to
animals and people); changes in behavior (aloofness,
unaffectionate, desire to roam, OR clingy, separation
anxiety, 'velcro dog', voice changes e.g., hoarseness and
excessive barking, chronic poor appetite, very finicky,
eating wood, stones, earth and stool); paralysis of throat
or tongue, sloppy eaters and drooling; dry eye (loss of
sight and cataract); destructive behavior (shredding
bedding, seizures, epilepsy, twitching, increased sexual
desire, sexual aggression, irregular pulse, heart failure and
reverse sneezing) and restraining can lead to violent
behavior and self-injury self-mutilation (tail chew ing).
Lack of standardized procedure: In most cases of
vaccine efficacy assessment, recommended serological
tests are carried w ithout any standardized procedure.
According to Serv at et al. (2006), on the basis of past
experiences reported in rabies serology and its
harmonization throughout laboratories worldwide, most
researchers propose an adapted standard technique for the
serological monitoring for rabies in wildlife at the
European level. Such harmonization would allow the
monitoring of vaccination campaigns to be enhanced by
increasing the exchange of epidemiological data, with the
ultimate goal being the eradication of rabies in Europe
and in the world.
Adverse effects following vaccination: In the past, some
researchers faced with proven risks of rabies infection
have vaccinated free-ranging wild dogs. However, the
death from rabies of some of the vaccinated animals has
led several authors to question the value of rabies
vaccination as a too l in wild dog management (Ginsberg
and Woodroffe, 1997). There are clinical manifestations
and harmful effects of the use and abuse of vaccinations.
Unfortunately, adverse reactions to vaccines have been
considered to be the imm ediate hypersensitivity reactions
of anaphylaxis. This severely limits the types of reactions
that are ever even considered to be related to vaccines
(O'D riscoll, 2008; M cRearde n, 200 8; Blanco, 200 8).
Other problems surface which make accurate tallying of
adverse reactions difficult. Some authors hav e therefore
claimed that the vaccines provide protection by keeping
the body in a disea sed state of health. W hen a perfectly
healthy individual is given viruses that cause illness, the
animal is going to manifest illness-related symptom s. This
healthy individual is asked to maintain a low-level
stimulation state of rabies. According to these authors
(O'Driscoll, 2008; McR earden, 2008; Blanco, 200 8), often
the animal w ill not manifest the illness it is vaccinated for,
at least not in its ac ute form, but it will manifest in other
conditions. Usually these conditions are inherited
weaknesses. However, the adverse effects associated to
vaccinations include:
Familiar illness following vaccination: Some of the
familiar illnesses include any auto-immune disease (such
as lupus, red cell aplasia, auto-immune hemolytic anemia,
cardiomyopathies); neoplasias (such as fibrosarcomas,
mast cell tumors, thyroid tum ors, etc.,); inflamma tory
bowel disease, eczematous ears, any dermatological
condition, warts, lipomas, poor hair coats, stomatitis,
periodontal disease, thyroid disease, and the list goes
on and on (O'Driscoll, 2008; McRearden, 2008;
Blan co, 20 08).
An aph ylactic shock: Anaphy lactic shock is the most
well-known consequence, bu t other consequences are
possible, namely types I, II, III and IV hypersensitivity
reactions, which include tissue injury, arthritis, lupus, and
kidney and liver dam age. V accines sen sitize genetically
susceptible organism s. Animals from families that are
known to suffer allergic/inflammatory conditions are at
most risk from live vaccines. Frick and Brooks, in 1983,
demonstrated that dogs predisposed to deve lop atopic
derm atitis did not do so if vaccinated after being exposed
to an allerg en, but did develop the condition when they
were vaccinated first and then exposed to an allergen
(Mc Rearden, 2008 ; Blanco, 20 08).
Tc ell immunod eficiencies: Vaccines are als o
acknowledged to cause T cell immunodeficiencies
(Blanco, 2008). However, it should be borne in mind that
serum reactions are known to develop sometime after
vacc ine administration, an d that so me v accin e
com ponents are not easily metabolized, remaining in the
system for some considerable time.
Vaccino sis: Vaccinosis is the reaction from common
inoculations (vaccines) against the body's immune system
and general well being. These reactions might take
months or years to sho w up and will cause undue ha rm to
future generations. Vaccinosis, which is used to describe
the chronic illness that results from vaccination, should be
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
Generically stimulations of the body: As it has been
demonstrated that a wide range of human vaccines can
stimulate arthritis, it makes sense to consider, also, that
animal vaccines might also stimulate this condition
(O'D riscoll, 2008). Glickman and GogenEsch (1997)
showed that vaccinated group develo ped significant levels
of autoantibod ies aga inst fibron ectin, lam inin, DNA,
albumin, Cytoch rome C , transferring, cardiolipin and
collagen in a study on the effects of routinely used
vaccination protoc ol of comm ercial m ultivalent vaccine
and rabies vaccine on the immune and endocrine system
of Bea gles. According to O'Driscoll (2008), this is the
fundamental problem with vaccines: they are generically
stimulating to the body , usually creating illness w here
there once was none. Some researchers have suggested
that something in the vaccine could be one of the
etiologies (in the genetically susceptible dog) of such
diseases as cardiomyopathy, lupus, erythematosus,
glomerulonephritis, etc. How ever, other factors other than
generic reaction are also responsible for adverse reaction
after vaccination.
Adjuvants and Preserva tives: One other reason has been
traced to the other substances that are in the vaccine vials
that are poten tially prob lematic. Additional components
of the vaccines are the preservatives that do what
preservatives do. These ingredien ts are also known in
current medicine to be carcinogenic agents, including a
compound called thymersol, a mercury derivative and
aluminum, used to attenu ate the v iruses. T he po ssible
effects of aluminum are widely know n. Even the cells
these viruses are grown on can produce allergic reactions
in the body. Some of the tissue lines u sed is from ducks,
monkeys, pigs, and the like. These could be creating
much of the constant itching, inflamed bowel, and
eczematous ears tha t are so p revalent (O'Driscoll, 2008;
McR earden, 2008; Blanco, 2008). There are additional
ingred ients called a djuva nts. These are foreign proteins
that are added to give a generic, non-specific immune
response. These preservatives and adjuvants are what are
believed to be the major cause of the surging incidence of
fibrosarcomas in cats. Studies at Colorado State
University by Professor Dr. Den nis M acy show ed this
strong correlation. It is felt by the biologics companies
that if the body does not respond to the numerous viruses
that are in each vial of vaccine, than surely the body w ill
respond to other foreign proteins (O'Driscoll, 2008;
McRearde n, 200 8; Blanco, 2008 ).
Causes of vaccine associated problems: A vaccine, like
any medicine, is capable of causing serious problems,
such as sev ere allergic reactions. The risk of a vaccine
causing serious harm, or death, is extrem ely sm all.
Serious problems from rabies vaccine are very rare (CDC,
2006). The causes of vaccine-associated problems include
factors that are linked to vaccine, vaccinations, nutrition
and enviro nme nt.
Introduction of modified live virus (MLV) vaccines
and comb ination ML V vaccines: According to Dodds
(1993), "Many veterinarians trace the present problems
with allergic and immunologic diseases to the
introdu ction of MLV vaccines some twenty years ago”.
Dodds (1993) believed that MLV vaccines and
combination MLV vaccines are the causes of the
significant increase in autoimm une and allergic disorders
in companion animals over the past 20 years or so. Also,
according to Dodds (1993), "Combining viral antigens,
especially those of M LV type w hich m ultiply in the host,
provides a stronger antigenic challenge for the animal.
This is often viewed as desirable because a more potent
immunogen presumab ly mounts a more effective immune
response. However, it can also overwhelm the immunocompromised or even a healthy host that is con tinually
bombarded with o ther environmen tal stimuli. This
scenario may have a significant effect on the recently
weaned young puppy or kitten that is placed in a new
environm ent”.
Vaccine factors:
Type of vaccines: Vaccines usually have numerous
viruses as well as other ingredients in them . Exceptions to
this include the rabies, co rona, and bordatella vaccines.
Herein lays the first and secon d problem with the
vaccination process. The process of injecting numerous
viruses at one time into the body does not mimic in any
way what we would see in the natural world. There w ould
never be such an enormous exposure to that many
microorganisms at one time. These diseases ha ve neve r,
in the real world, occurred at one time, never
(Glick man , 2000 ).
Chemical agent used: Typically, the chemical agent used
to alter the virus is formalin or formaldehyde, a known
carcinogen. Attenuating the virus so that it cannot attach
to a cell wall and infect that cell is a goo d idea, but not all
the virus particles may be altered. Some may escape
attenuation and are free to cause disease. This may be part
of the reason that w hy 'breaks' are seen in vaccinated
animals. There has also been much speculation that these
MLVs have shed into the environment, exposing other
animals, including wild animals, to these diseases
(O'D riscoll, 20 08).
Vaccination factors:
Process of injecting viruses (route of vaccination) and
frequency of vaccinations: The process of injecting
viruses into the body is a very unnatural method of
introducing viruses, with the exception of Rabies virus.
Mo st other forms of exposure are through the mucous
mem branes - the n ose, throat/mouth, even the eyes. Th is
creates another huge insult to the immune system. First
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
we gather a whole bunch of viruses and other 'stuff', and
then we inject them into the body at one time
(Glickman, 2000). A ccording to Dodds (1993 ),
"furthermore, while the freq uency of v accinations is
usua lly spaced two to three weeks apart, some
veterinarians have advocated vaccination once a week in
stressful situations. This practice makes no sense from a
scientific or medical perspective. While puppies exposed
this frequently to vaccine antigens may not demon strate
overt adverse effects, it is clear that their immune systems
may still be immature. Conseq uences later in life may be
an increased frequency of chronic debilitating diseases”.
How ever, further research is indicated, but these findings
should have raised concern.
biologics com pany, at a m eeting on va ccines in 1997 said
quite emb arrasse d, “w e kno w how to turn the immune
system on, but we d o not know how to turn it off".
Nutritional factors: For ex amp le, pantothenic acid
(vitamin B5) is vital for the production of anti-stress
hormones. According to O'Driscoll (2008), in a study
conducted on puppies starved of vitamin B5, and then
vaccinated, all died. B5 is a highly unstable vitam in,
easily destroyed by he ating and freezing. W ithout B 5 in
the diet, which is vital for the production of anti-stress
hormones, an organism is less able to survive the vaccine
challenge. Similarly, insufficient vitamin C and zinc in a
diet can render an organism unable to deal with stress.
Vaccines, of course, are designed to stress the body so
that it mounts an immune response and develops
antibodies ag ainst a pathogen (O'D riscoll, 2008).
Horm onal status of the patient: Acc ording to
Dodds (1993), “veterinarians and vaccine ma nufacturers
have paid relatively little attention to the hormonal status
of the patient at the time of vaccination. Because of the
known role of hormonal change along with infectious
agen ts in triggering autoimmune disease, vaccinating
animals at the beginning, during, or immediately after an
estrus cycle is unwise. Similarly, vaccinating an animal
during pregnancy or lactation can be fraug ht with
problems, not only for the dam but also because a
newborn litter is exposed to shed vaccine virus. One can
even question using MLV vaccines on adult animals in
the same household because of exposure of the mother
and her litter to sh ed viru s."
Environmental factors: Last, but certainly not the least,
is the environmental factor. According to D odds (19 93),
"Some veterinarians trace environmental factors may have
a contributing role, the introduction of these vaccine
antigens and their environmental shedding may provide
the final insult that exceeds the immunological tolerance
threshold of the pet population”. A nimals can re act to
vaccines at any age. They might be vaccinated for many
years, without ill-effect, and then suffer an adverse
reaction. This has less to do with the animal's genes
(although it is well established that T cells can be
disrupted by vaccines), but to do with environmental
Immune system overload: W hen these viruses are
injected into the body, they find their way into the small
capillaries, then into the larger vessels and are filtered by
the lymp h nodes. T his sou nds fine except that usually
these viruses are first intro duced into the mouth and nose,
where the humoral imm une system is stimulated. It
produces the pow erful immunoglobulins (IgA , IgG, IgM ),
which provide the first line of defense. W hen this primary
defense mechanism of the humoral immune system is
bypassed, the body becomes dependent on the cellular
immune system only; this is the branch that produces
antibodies. Producing antibodies is a fine thing, but when
the natural pathways are bypassed it creates an extra load
on the system. H aving the natural stimulation of both
wings of the immune system is a more balanced approach
and is not what happens with injected vaccines
(O'D riscoll, 20 08; M cRearde n, 200 8; Blanco, 2008 ).
Implications of these vaccine associated problems:
According to O'Driscoll (2008), McR earden (2008) and
Blanco (2008), “Many veterinarians however, does not
see the need to report a suspected adverse reaction of
vaccines if an animal develops pancreatitis, arthritis,
ataxia, skin disease, epilepsy, behavioural problems,
allergies, colitis, etc., post-vaccination. At present time
there are no easy or effective reporting systems; many
vets are reluctant to report even those where an animal
dies, and the cause-effect relationship is not always clear.
Even to those who believe that many of the illnesses we
see, both acute and chronic, are directly related to overvaccination, it is still at times difficult to show how this
Financial implication of this vaccine associated
problem s: The financial implication of this vaccine
associated problems could be alarming for the veterinary
profession, and even more alarming for the vaccine
industry. However, there are many options available for
the veterinary profession to consider. Th e first option is to
conduct blood tests to assess the presence of circulating
antibodies. According to O'Driscoll (2008), vaccine
Production of autoantibodies: If autoantibodies are
being produced against laminin (co ats kidney cells), then
one would not be surprised if kidney damage followed a
vaccine event. Similarly, if vaccines stimulate the
production of autoantibodies to DNA, then the vaccine
may well be introd ucing gene tic defects. Accord ing to
O'D riscoll (2008), one representative from a major
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
companies have been using this measure as a marketing
tool for decades. Now that they run the risk of losing
booster income, however, they claimed that circulating
antibodies are no measure of immunity. T his is true, of
course, but titre testing does show that the organism has
been expo sed to the virus without succum bing to it, and
represents a safer alternative to over-vaccination. And so
it seems that the best option would be for the profession
to examine the frequency at which v accines are
administered, and become more aware of contraindications. From an income perspective, this would
represent the best option for vets.
biotechnology products use millions of litres of complex
med ia and gases as well as huge quantities of organic and
inorganic raw materials. These raw materials must always
be assum ed to contain contamination by adventitious
agents. And bec ause there are a potentially large number
of animal and human viruses (or viral segments) that
could be entering into the final vaccine products, it would
take an equally large bank of molecular probes, as well as
frequent, wide-spread testing, to screen for presence of
these contaminating agents. This would obviously add
time and expense for the m anufacturers (O'D riscoll, 2008;
McR earden, 2008; Blanco, 2008). What needs to be
decided is this, is the effort and cost involved in cleaning
up these admittedly filthy medical products, worth the
resultant bene fit to the pu blic health? And since certain
animal products are necessary for the production of
vaccines, it may also be necessary to clean house at
several levels, including the agricultural sector. It is no
secret for instance, that commercial chicken flocks raised
for meat and eggs are often carrying infectious avian
leucosis virus, mentioned earlier (O'Driscoll, 2008;
McRearde n, 200 8; Blanco, 2008 ).
Vaccination boyco tt: In recent time, pet ow ners are
becoming more informed about the vaccine issue, and
many are choosing not to vaccinate at all. The other
question concerns the vaccination of diseases that are not
seen at all in a particular region, or that vaccines are not
effective against because the viruses have many different
serovariants. Ma ny have been ridiculed for refusing
vaccination for themselves or their children, but
considering the occurrences of short-term adve rse events
and questionab le efficac y, possible lon g-term health
damage, and n ow also fac ing the poten tial of wideranging loss of civil liberties, is it so surprising that many
are questioning what the actual benefits are surrounding
most vaccination protocols? Are the cases of damaged
children, non-functional adults, and the huge increases in
cancer rates, immun e and chron ic diseases to b e simp ly
and blindly accepted by the public as tolerable losses?
(O'Driscoll, 2008; McRea rden, 2008; Blanco , 2008).
Current initiatives and recomm endations for control
of vaccine-associated problems the Vaccine A dverse
Event Reporting System (VA ER S): VAER S is the
principal passive surveillance system for vaccine adverse
even ts in the United States. Vaccination may be
coincidentally, not causally, related to the adverse event
reported to VAERS. Accurate reporting to VAERS
including review of medical records, and the use standard
for adverse events would improve
causality assessments (Varricchio et al., 2004;
Loughlin et al., 2009).
Wh ere do we go from here? It seems obvious that there
needs to be a new and open dialog regarding vaccines
among the regulatory ag encies, manufacturers, research
and medical community, and the public. As a citizen with
a right to good health, please be advised of the following
issues. Vaccine quality in the U.S. (therefore in the world)
relies for the most part, on manufacturers reporting to the
FDA. Here is a relevant statement from the CDC:
Manufacturers are required to submit the results of their
own tests for potency, safety, and purity for each vaccine
lot to the FDA. They are also required to submit samples
of each vaccine lot to FDA for testing. However, if the
sponsor describes an alternative procedure which provides
continued assurance of safety, purity and potency, CBER
may determine that routine submission of lot release
protocols (show ing results of ap plicable tests) and
samples is not necessary (O'Driscoll, 2008; McRearden,
2008; Blan co, 20 08). Y es, this is the scope of the qualitycontrol protocol that oversees a market worth billions of
dollars, yet allowing all these contaminants into the
vaccines. It may be helpful to have an idea of the scope of
the operation to understand what to deal w ith. We are
advised that large-scale cell culture operations for
The Vaccine Safety Datalink: The Vaccine Safety
Datalink is a collaborative effort of eight M edical Care
Organizations (MCO s) and the Centers for Disease
Control, which conducts post-licensure vaccine safety
monitoring. Data from nearly nine million M CO mem bers
are evaluated weekly, com paring adv erse events (AEs),
which occu r after vaccination to identical medical
outcomes, which occur among appropriate controls
(Lew is et al., 2009). Sequential (repeated) data analyses
require a balance between the need for timely detection of
real vaccine safety risks and the need to minimize false
alarms (Lieu et al., 2007). Lewis et al. (2009) presen ted
a new approach to sequential analysis, which uses exact
statistics, which are especially helpful when there are
small numbers of AEs, and/or variation over time in the
ratio of exposed (vaccinated people) to unexposed
(controls). This new method is simple, flexible, consistent
with well-established statistical theory an d suitab le to
population-based surveillance where, unlike in clinical
trials, vaccine coverage varies in unpredictable ways
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
across subgroups and ov er time (L ieu et al., 2007;
Lewis et al., 2009).
previously not available to the poorest countries of the
world. According to S alisbury (2009), unlike previous
immunization initiatives of WHO , GIVS includes
vaccines for individuals of all ages, thereby breaking out
of the previous constraints on vaccines for young
children. GIVS has four main aims: immunize more
people against more diseases, introduce a range of new ly
available vaccines and technologies, integrate other
critical health interventions with immunization, and
manage vaccination programs within the context of global
interdependence (Salisbury, 20 09). The period over which
GIVS will operate spans 2006 to 2015.
CD C’s Immu nization Safety Office (ISO ) Scien tific
Agenda/ National Vaccine Advisory Comm ittee
(NVAC) : In response to an Institute o f M edicine
recommendation (2005), CDC ’s Imm uniza tion Sa fety
Office (ISO) developed a draft 5-year Scientific Agenda
(Agenda) and asked the N ational Vac cine Ad visory
Committee (NV AC ) to review it (CDC, 2006). The goal
of the A genda is to identify and prioritize future ISO
vaccine safety studies (Broder et al., 2009). During 20072008, ISO reached out to 45 scientists in academia,
governm ent, and industry at three meetings and conducted
a selected literature review to identify vaccine sa fety
science gaps that ISO could address. Criteria for including
topics in an initial list were an ability to frame a vaccine
safety hypothesis that was consistent with ISO’s mission,
whe re a study could be initiated within five years. ISO
grouped topics into specific questions or thematic areas
and reviewed this second list with ISO-sponsored
researchers and CDC scientists to define possible research
needs (CD C, 2004; Brode r et al., 2009). The initial list
included 351 topics; 129 m et inclusion criteria. The
second list identified 18 specific questions and 42
thematic areas. Reviews yielded 30 possible research
needs for the draft Agenda. Seven were specific vaccine
safety questions (e.g., risk for neurological deterioration
after vaccination in children with mitochondrial
dysfunction and wheezing after live attenuated influenza
vaccine). Twenty-three were thematic areas around
vaccines/vaccination practices (e.g., simultaneous
vaccination, nonantigen vaccine components), special
populations (e.g., pregnant w omen, premature infants,
immunodeficient persons), and clinica l outcomes (e.g.,
encephalitis/ ence pha lopath y, neu rode velop men tal
disorders, postimmunization fever). Though a deliberative
process, ISO defined 30 possible vaccine safety research
needs. Further work will focus on de fining specific
questions in the thematic areas and prioritizing research
topics. CDC will finalize this first comprehensive vaccine
safety Agenda after receiving input from NVAC,
stakeholde rs, and the pub lic (Broder et al., 2009).
Emergency prevention-system for transboundary
animal and plant pests a nd disea ses (EM PR ES): W elte
and Vargas-Terán (2004) briefly described Food and
Agriculture Organization (FAO) EMPRES Livestock, its
vision, its mission, and its activities to assist FAO
developing member countries and regions in improving
the ability of veterinary services to reduce the risks of
introduction and/or dissem ination of transbou ndary
animal disease, by preventing, controlling, and eradicating
those diseases, assisting countries in building their own
surveillance/early warning systems, establish ing
contingency plans, and establishing a global information
system for disease monitoring.
Pan-african program me for the con trol of epizootics
(PACE): The potential partnership between the normative
function of the Food and Agriculture Organization (FAO)
in deve loping and promoting emergency preparedness and
the implementation of improved national and regional
disease surveillance by PAC E and o ther partners could
witness the commencement of more progressive control
of epidemic diseases in Africa and greater self-reliance by
African countries in coping with transboundary animal
disease em ergencies (R oeder et al., 1999 ).
American Animal Hospital Association (AAHA)
recomm endations: Vaccines are intended to be
administered to healthy dogs - it is an advisory issued on
vaccine labels, in veterinary literature and guidelines, as
a dog's health status can have an im pact o n a vaccine 's
effectiveness and fail to elicit an immune response.
Startlingly, the AAHA task force indicates that
vaccination in a "severely immunosuppressed" dog can
result in the dog acquiring the disease it is being
vaccinated to prevent (O'Driscoll, 2008; McR earden,
2008; Blan co, 20 08). A ccord ing to AAHA's (2006) "As
with pregnant dogs, veterinary medicine has advised
against vaccination during illness, due to concerns about
suboptimal sero-conversion, or wo rse, conversion of
vaccine to disease." In other words, if you vaccinate a
pregnant or sick dog, no t only do yo u run the risk of a
less-than-desirable immunological response, but you run
the risk of your dog contracting the disease it is being
The Allian ce for rabies con trol: The Alliance for Rabies
Control strongly favors post-exposure immunization, as
well as prophylactic vaccination, but points out that postexposure immuniza tion is no t a rabies supp ression
strategy, because it does not neutralize the host reservoir
(Clifton, 2007 ).
The World Health Organization (W HO ) Global
Imm unization Vision and Stra tegy (G IVS): WHOGIV S is a joint initiative with UN ICE F. Its purpose is to
identify opportunities that can be created to improve
immunization service delivery and accelerate the
availability of new v accines or vaccines that w ere
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
vaccinated against (O'Driscoll, 2008; McRearden, 2008;
Blanco, 2008). Also, acc ording to A AH A (2003a), " …an
attenuated patho gen in a host wh ich is severely
immunosuppressed, or genetically more susceptible, may
result in the vaccine causing the disease for which it was
designed to prevent." A AH A (2003b) cau tioned that:
"When vaccinating an animal, the age of the animal, the
animal's immune status, and interference by maternal
antibodies in the develo pme nt of immun ity must be
considered. Research has demonstrated that the presence
of passively acquired maternal antibodies significantly
interferes with the immuneresponse to many canine
vaccines, including CPV [parvo], CD V [distem per],
CA V-2 [hepatitis] and rabies vaccines."
recommendations and better specify the situations in
which rabies post- and pre-ex posu re prop hylax is shou ld
be administered. No new rabies biologics were presented,
and no changes were made to the vaccination schedules
(Manning et al., 2008). H owe ver, rabies vaccine adsorbed
(RVA, Bioport Corporation) is no longer available for
rabies postexposure or pre-exposure prophylaxis, and
intradermal pre-exposure prophylaxis is no longer
recommended because it is not available in the U nited
States (Manning et al., 2008).
alternatives: According to
Blanco (2008), “The body has incredible cap acity to
provide protection against all sorts of invaders. So, if our
approach to protection is from the standpoint of
supporting the body in doing its job, w hich it already
knows how to do, we are working at a more fundamental
level. If we support the energy and physical systems of
the body we will support the immune system, not
overload it. Clean hygiene, good nutrition, clean wa ter,
plenty of exercise, constitutional treatments (prefera bly
home opathic), good bree ding p ractices, and home opathic
nosodes, where needed (Blanco, 2008)”. Also, DNA
vaccination remains a promising means to develop
effective vaccines against infectious diseases and can cer.
How ever, their poor performance in primates has
demanded the use of genetic adjuvants or improved
delivery techniques. One of our approaches to improving
vaccine poten cy is to explo it genetic adjuvants. Although
cytokine, chemokine and growth factor adjuvants have
shown promise, it is believed that the most potent gene tic
adjuv ants will be those that mimic the inflammation and
Dendritic Cell (DC) maturation caused by natural
infections (Bag ley, 2009). D evising an appropriate
technology for human rabies immunization includes new
regimens of administration, one of which, a revised
intramuscular regimen requiring only four doses and three
clinic visits, proved highly e fficient for postexposu re
Advisory Comm ittee on Imm unization Practices
(ACIP) recomm endations: ACIP recommends that
prophylax is for the prevention of rabies in humans
exposed to rabies virus should include prompt and
thorough wound cleansing followed by passive rabies
immunization with Human Rabies Imm une Globulin
(HRIG) and vaccination with a cell culture rabies vaccine
(Manning et al., 2008). For persons who have never been
vaccinated against rabies, postexposure antirabies
vaccination should always include adm inistration of both
passive antibody (H RIG ) and v accine (Huma n Diploid
Cell Vaccine (HD CV ) or Purified Chick E mbryo C ell
Vaccine (PCECV)). Persons who have ever previo usly
received com plete vaccination reg imens (pre-ex posure or
postexposure) with a cell culture vaccine or persons who
have been vaccinated with other types of vaccines and
have previously had a documented rabies virus
neutralizing antibody titer should receive only 2 doses of
vaccine: one on day 0 (as soo n as the exp osure is
recognized and administration of vaccine can be arranged)
and the second on day 3 (Manning et al., 2008 ). HR IG is
administered only once (i.e., at the beginning of antirabies
prophylaxis) to previously unvaccinated pe rsons to
provide immediate, passive, rabies virus neutralizing
antibody cove rage u ntil the pa tient responds to HDCV or
PCECV by actively producing antibodies (Manning et al.,
2008). A regimen of 5 1-mL doses of HDCV or PCECV
shou ld be administered intram uscu larly to previou sly
unvaccinated persons. The first dose of the 5-dose course
shou ld be administered as soon as possible after exposure
(day 0). Additional doses should then be administered on
days 3, 7, 14, and 28 after the first vaccination (Manning
et al., 2008). Rabies pre-exposure vaccination shou ld
include three 1.0-mL injections of HDCV or P CECV
administered intramuscularly (one injection per day on
days 0, 7, and 21 or 28). These recommendations involve
no substantial changes to the recommended approach for
rabies postexposure or pre-exposure prophylaxis.
According to Manning et al. (2008), mo difications were
made to the lan guage of the guid elines to clarify the
Current trend s in rabies vaccin es for global rab ies
control and possible eradication: In the 1920s, long
before the recognition of bat and other wildlife rabies and
the availab ility of mo dern vaccines, rabies in Japan was
successfully controlled through mass vaccination of dogs
(W u et al., 2009). In the 1980s, large-scale oral
vaccination campaigns were first used to fight the
rabies epidemic successfully in foxes (Eisinger and
Thulke, 2008). N owa days, fixed-w ing aircraft deliver
vaccine-filled bait pieces, recording every drop with GPS
precision (Eisinger and Thulke, 2008). Howe ver, there is
still a debate on how m any baits per unit area should be
administered (WHO, 2005), what percentage of the fox
population need s to be immunized to ensure control
success and whether there is a thresho ld involved (Lloyd119
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
Smith et al. 2005). In 1981, a population model predicted
the threshold level to be about 70% for central European
densities of about 3 foxes per km2 (Eisinger and
Thulke, 2008). Su bseque ntly, large-scale and lon g-term
oral vaccination programm es in Europe were prepared to
implement this target level following W HO /OIE
guide lines.
Morbidity and M ortality W eekly Recommendations
and Reports (MM W R) in 1993 consolidates the
deliberations of the International Task Force for Disease
Eradication (ITFD E), w hich w as convened six times from
1989 through 1992 to evaluate diseases as potential
candidates for global eradication (CDC, 1992a, b;
WHO, 1993). CDC supports the findings, which indicated
a need for greater recognition of the potential to eradicate
targeted diseases. Three reports, covering results of the
first five meetings of ITF DE , were published previo usly
in the MMW R (CDC , 1992a, b), and reprinted in WHO's
W eekly Epidemiological Record (WHO , 1993). Largescale eradication of rabies using recombinant vacciniarabies vaccine was reported (W u et al., 2009). An
immunized dog population can be a solid ba rrier to
to humans
(Cleaveland et al., 2006; Zinsstag et al., 2007;
W u et al., 2009 ). Rab ies pre-exposure vaccination and
post-expo sure t re a tm e n t i s r ec o m mended for
occu pationally exposed persons. Some European
countries have already adopted recommendations through
specific protocols. Treatment of international travellers
after bat bites is also recommended. The promoting of
research programmes on bat rabies in Europe is underway
(Stantic-Pav linic, 200 5).
According to Clifton (2007), Dr Oscar Pedro Larghi
(Argentinian Medical Director) reported to the mem bers
of the International Society for Infectious D iseases in
May 1998, that “control of rabies in developing countries
can be very successful if based on appropriate planning,
health education of human populations, 70% vaccine
coverage of dog populations, and epidemiological
surveillance (Clifton, 2007 ). However, recent outbreaks
of rabies highlight the fact that rabies is a transboundary
disease and can reemerge in areas where successful
control programs have been active for many years
(Cohen et al., 2007). Summarily, ORV has evolved as a
significant adjun ct to conventional rabies prevention and
control efforts and has resulted in the successful
elimination of canine rabies from coyo tes in the U.S.A
review of the progress in domestic animal control in the
U.S. over the past 50 years was made by Ben Sun of the
California Department of Health. Building upon such
achievements, efforts are underway to repeat this success
in developing countries throug hout the world
(Rupp recht and Tumpe y, 2007).
the One Health Challenge in support of World Rabies Day
reflects the new generation of health professionals’ desire
to act at the local level in order to affect our global health.
The One Health definition, established by the
paraprofessional One Health task force, recognizes the
confluence of env ironm ental, animal, and human
interactions. The monumental amount of energy amon gst
the paraprofessional health team recognizes that there is
no more important disease to begin educating and
developing our efforts tha n rabies. W orld R abies Day is
a testimonial to the One Health concept. Our cooperative
efforts are infiltrating the larger communities throughout
the world and continuing to reduce cases of p reven table
rabies. World Rabies Day provides an opportunity for the
human spirit to sign ificantly im pact the lives o f others in
a positive way”.
America: Progressive elimination of rabies in wildlife has
been a general strategy in Canada and the United States;
according to Sterner et al. (2009) common campaign
tactics are Trap-Vaccinate-Release (TVR ), Point Infection
Control (PIC), and ORV . These tactics have proven
crucial to elimination of raccoon rab ies in Can ada and to
maintenance of ORV zones for preventing the spread of
raccoon rabies in the U.S. (Sterner et al., 2009). In recent
years, cases of rabies among humans in urban areas
(transmitted by domestic animals) have declined
(SalmónMulanovich et al., 2009 ). This is likely the result of an
aggressive initiative by the member states of the Pan
American Health O rganization (PAHO ) to eliminate
urban rabies in the Americas (Navarro et al., 2007;
(Salmón-Mulanovich et al., 2009). According to Miguel
Escob ar, M.D., associate director of Merial Inc., (which
is the world's largest manufacturer of anti-rabies
vaccines), "In 1990 there were 16,464 reported cases of
canine rabies in Latin America. In 1998 that was reduced
to 2,608. Human rabies cases were reduced from 252 to
74." Most of the rabies case reduction was in Buenos
Aires, Lima, and Sao Pa olo, all of which com pletely
eliminated rabies by vaccinating from 6 0 to 80 % o f their
estimated dog populations during a series of three-m onth
campaigns directed by Larghi in Argentina (Clifton,
In Canada, before rabies control programs were
implemented, red foxes accounted for .45% of all rabies
cases in Ontario (Rosatte et al., 2007a). During 19891995, ORV was used in On tario to progressively
eliminate arctic fox -varian t rabies that had spilled into
(i.e., had been transmitted to another species) red foxes
and spread sou thward (S terner et al., 2009). The last
report of a rabid fox in metropolitan Toronto was in 1996
(reporting period through September 2006), which
confirms that distributing ORV bait is a fea sible tactic for
the control of rabies in foxes in urban environme nts
(Rosatte et al., 2007a). The ground and aerial distribution
Trends and efforts in control of rabies across the
continents: According to Sobota (2008), "The creation of
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
of rabies vaccine bait in metropolitan an d greater
metropolitan Toronto, which resulted in immunization of
a substantial portion of the fox population against
rabies, eliminated rabies from that urban complex
(Rosatte et al., 2007a). Greater metropolitan Toronto has
been free of reported cases of rabies in red foxe s for a
decade (1997-2006) and is a notable success for the
Ontario M inistry of Natural Resources rabies control
programs (Rosatte et al., 2007a). To eliminate raccoonvariant rabies fro m the Ontario, a Point Infection Control
(PIC) tactic, which integrated population reduction (PR;
sometimes referred to as culling or depopulation), TVR,
and ORV , was implemented (and eliminated the variant
from Ontario (Sterne r et al., 2009). Elimination of
raccoon rabies from W olfe Island at the m outh o f the St.
Lawrence Rive r using similar tac tics was recently
reported (Rosatte et al., 2007b). A dditionally, to prevent
raccoon rabies from reemerging in southern Ontario, ORV
baiting for raccoon-varian t rabies continues in northern
New York (S terner et al., 2009 ).
Several brands of rabies vaccine are availab le in the
United States (CDC, 2006). Oral rabies vaccination
programs have been implemen ted to control the spread of
wildlife rabies in the U nited S tates. H owever, current
surveillance systems are inadequ ate for the efficient
management and evaluation of these large scale vaccine
baiting programs (Blanton et al., 2006). U.S. CDC rabies
program Chief Ch arles R upprecht on W orld Rabies Day
formally pronounced the U.S. free of canine rabies, but
similar informal proclamations have be en issued for years
(Clifton, 2007). Rabies in small animals has been
dram atically reduced in the U.S. since the introduction of
rabies vaccination of domestic animals in the 1940s. As
a consequence, the n umbe r of human rabies cases has
declined to only a couple per year. During the past several
years, the dog rabies variant has almost disappeared
com pletely (Lackay et al., 2008). Progress has also been
made in containing gray fox rabies in Texas (Rupprecht
and Tump ey, 20 07). A n attem pt beg un a y ear earlier to
eradicate coyote rabies in Texas, by airdropping vaccine
bait pellets, achieved a 98% reduc tion of canine rabies in
all species by 1998 (Clifton, 2007). Also, in Texas, the
use of ORV stopped the northward spread and led to the
progressive elimination of the DDC variant of rabies in
coyotes (Canis latrans). Progress ha s also b een m ade in
preventing the spread of raccoon rabies from the eastern
U.S. Neverthe less, the most profound challenge facing the
program is the need for baits an d oral vaccines w ith
improved effectiveness in other m esocarnivo re reservoir
species, such as skunks and mongoose (Rupprecht and
Tumpey, 2007). The preventive vaccination approach also
works in wildlife. Anne A rundel Co unty, M arylan d, for
example, had 97 cases of animal rabies in 1997, when
county officials began experimentally distributing oral
rabies vaccine pellets to immunize raccoons. Grad ually
expanding the program, the county had just 10 animal
rabies cases in 2006 (C lifton, 2007).
In Mexico, the national rabies control programme
using mass parenteral vaccination of dogs started in 1990.
As a result of the mass dog vaccination campaigns in
Mexico, human rabies cases due to dog-mediated rabies
decreased from 60 in 1990 to 0 in 2000. The number of
rabies cases in dogs decreased from 3,049 in 1990 to 70
cases in 2007 (Lucas et al., 2008). On the basis of rates of
spread of 30-60 km/year in the M id-Atlantic states before
1997 (Slate et al., 2005; Krebs et al., 2005 ), OR V is
viewed as having slowed m ovemen t of the virus and, with
contingency actions to eliminate some dispersed cases,
prevented westward spread of rabies among raccoons
(Sterner et al., 2009 ). Still, enhanced an d public health
surveillance indicate that areas in the North Am erica west
of the Appalachian Ridge remain free of raccoon-variant
rabies (Slate et al., 2005; Krebs et al., 2005;
Blanton et al., 2008; Sterner et al., 2009). Canada,
Mexico, and the United States continue to work toward a
North Am erican R abies Manag eme nt Plan that will
enhance rabies surveillance and control on a continental
framew ork (Rupprecht an d Tum pey, 200 7).
Europe: There have been many changes and
acco mplishme nts in rabies control and prevention since
the first International conference "Rabies in Europe" was
held in Kiev on June 15-18, 2005 (Briggs, 2008). The
elimination of rabies was demonstrated following oral
vaccination of foxe s in W estern Europe, where red foxes
are the reservoir host (Clifton, 2007). However, empirical
evidence indicates that, in regions with less then 70%
immunization coverage, rabies has still been eliminated
(Bugnon et al. 2004). The immediate challenge for rabies
control is to stockpile enough vacc ines for mass dog
vaccination campaigns (W u et al., 2009). Acc ording to
Harris et al. (2006), in a study on passive surveillance for
EBLVs in the U K and no active infection with EBLV
type 1 was record ed in their (Ha rris et al., 2006) study. In
Europe, primary efforts should be focussed on the
implemen tation of effective passive and active
surveillance systems for EBLVs in bats (van der
Poel et al., 2006). Two countries in the Central and
Eastern Europe are currently rabies free, and several
others are close to being rabies-free (Matouch, 2008). Due
to improvement and adaptation of vaccination strategies
that took into consideration the peculiar topographical
features of a fragmented landscape and the high fox
densities, the number of rabies cases in North Rhine
W estphalia, German y dec reased in 2001 (M üller et al.,
2005). The breakthrough in rabies control in the Saxony
region of the Czech Republic came when continuous
annual trilateral me etings with the countries involved
were initiated which led to a considerable improvement of
the vaccination strategies in the adjacent areas to Saxony.
According to Mü ller et al. (2005), for more than three and
a half years no rabies case has been reported from this
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
In 1993, the decisio n was made to apply ORV of the
red fox as a method of rabies control in Poland. ORV was
undertaken twice per year (spring and autum n). In 2002,
the vaccine campa ign co vered the w hole territory of
Poland. According to Smreczak et al. (2008 ), after 13
years of ORV , rabies incidence decreased sharply, from
3,084 cases in 1992 to 8 2 in 20 06 (a 9 7% decrease in the
number of rabies cases). The epidemiological situation in
2006 points to the constant decrease of rabies cases as a
result of OR V. The progress made over the past
decade demonstrates that Poland is meeting the
requirements to eliminate rabies in terrestrial animals
(Smreczak et al., 2008). The last endemic case of rabies
in Switzerland was diagnosed in 1996 after an adaptation
of the vaccination strategy (Zanoni et al., 2000). The last
instance of rabies in a native French animal was reported
in 1998 (Peigue-Lafeuille et al., 2004). According to
Peigu e-Lafeuille et al. (2004), vaccination is performed in
official rabies centers in France. In German y, ORV of
foxes using MLV vaccines offered a new method of
rabies control in wildlife (M üller et al., 2005). With the
enlargement of vaccination areas in West Germany
reaching a maximum size of about 215 000 km2 in 1995,
the policy of using ORV became increasingly successful
and rabies incidence decrease d drastically in subsequent
years (Mü ller et al., 2005). As a consequence, in the
eastern parts of Germany, a rapid decrease in the number
of rabies cases was observed in the early 1990s after the
implementation of ORV. These eastern regions have been
free of rabies for more tha n 10 years (Mü ller et al., 2005).
As a result of OR V, the rabies in cidence drastically
decreased during the past 20 years from 10 484 rabies
cases in 1983 to 56 in 1999; the lowest number of rabies
cases ever reported in G erma ny.
Summarily, once large-scale vaccination was applied
in the western regions, rabies was quickly eliminated.
During the past 10 years, as in other European countries,
the efficacy of oral fox vaccination campaigns has been
increased by a permanent adaptation and optimization of
the vaccination strategy based on analysis of the
prevailing cond itions an d recent scientific perceptions.
These measures have included (i) den baiting, (ii) double
baiting (repeated aerial distribution of baits 14 days after
the first vaccination campaign in the same area using
perpendicular flight lines with a distance of 1000 m etres),
(iii) summer vaccination, (iv) an increase of bait density
and (v) a redu ction of flight lines (Mü ller et al., 2005 ).
rabies postexposure prophylaxis after dog bites, but no
rabies occurred. According to Zhenyu et al. (2007), no
human rabies cases followed exposure to dogs that were
within 50 km during 2002-2004. However, these trends
have since been reversed. A steady increase has been
reported over the past 10 years with more than 3,200
cases reported in 2006. Although there are many factors
that contribute to the epidemic or ende mic nature of rabies
in these countries, the single most important factor is the
failure to imm unize dom estic dogs, which transmit rabies
to huma ns (Fu, 200 8). These reemerging rabies in China
has led to a carrier-dog myth and strict pet population
control policies (W u et al., 2009 ).
Recently, according to Nadin-Davis et al. (2007 ), a
national rabies survey in India, based on clinical diagno sis
and sponsored by the WH O, found that 20,000 persons
died of rabies each year (Sudarshan et al., 2006). These
observations indicate a great nee d to strengthen laboratory
diagn ostic capabilities for rabies in India and to use
genetic typing to improve knowledge of the nature of
the viruses that circulate in India. Using several
positive samples ide ntified by this m ethod , NadinDavis et al. (2007) studied the epidemiologic origins of
rabies from mu ltiple areas of the country. The resulting
increase in disease surve illance wou ld help justify
subsequent control measures. Accordingly, molecular
methods for rabies virus detection have been
introduced to the National Institute for M ental H ealth
and Neurosciences in Bangalore, India (NadinDavis et al., 2007). In Japan, no rabies case has been
reported for about 50 years. Since 1957 Japan has
successfully eradicated human and animal rabies through
registration, confinement and compulsory vaccination of
family dogs, and elimination of stray dogs. This was
successful since the government started the pre-exposure
vaccination (Tamashiro et al., 2007). Pre-exp osure
prophylax is recommended by WH O consists of 3 doses
given intramuscularly on days 0, 7, and 28, making it
possible to complete pre-exposure prophylaxis in one
mon th (Yanagisawa et al., 2008). Summarily, most
countries in Asia like China is planning increased
investment in rabies surveillance and preve ntion that will
include recom men ded laboratory support and should help
alleviate this situation in the future (Childs et al., 2007;
Zhenyu et al., 2007).
Africa: Altho ugh industrialized countries hav e been able
to contain recent outbreaks of zoonotic diseases through
enhanced mass vaccination initiatives, many resourcelimited and transitioning coun tries hav e not been able to
react adequately (Zinsstag et al., 2007). Cross-sectoral
assessments of interventions such as mass vaccination of
dogs for rabies in Chad consider human and animal health
so cietal economic perspective
(Zinsstag et al., 2007). Unfortunately, dog vaccination is
difficult in many developing countries like Mongolia and
Asia: Rabies control has not be effective in Central A sia
(Gruzdev, 2008). The only country with a steady decline
in Asian cou ntries is Thailand, w here the number of cases
has decreased from around 200 to about 20 cases per year.
The most dramatic changes were observed in China.
Human rabies cases declined from around 5,000 cases per
year in the 1980s to about 160 in the mid-1990s. During
the past 20 years in this county, .15,000 persons received
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
Chad because of high dog turnover rates, shortages of
funding and personnel, and competing priorities
(Cohen et al., 2007). Also, results from research projects
in eastern Africa show that mass vaccination of do mestic
dogs has the same result, even in areas such as the
Serengeti ecosystem, which comprise a wide diversity of
wildlife species. W hen sufficient domestic dog s are
vaccinated, rabies also declines in wildlife, and human
exposures to the rabies virus are significantly reduced
(Clifton, 2007 ).
In South Africa w here rabies had be en w ell
controlled for >10 years, Cohen et al. (2007) described an
outbreak of hum an rab ies in a province of South Africa.
According to Cohen et al. (2007), in South Africa,
central-point dog vaccination campaign s in villages in the
affected area were intensified after identification of the
increased numbers of rabies cases in dome stic dog s. A
com mun ity awareness program related to the hazards of
dog bites an d the im portan ce of tim ely visits to the clinic
for rabies p ostexposu re prop hylax is was established in
February 2006. Fu rthermore, hea lthcare wo rkers were
educated regarding appro priate managem ent of dog bites.
Vaccine and im mun oglob ulin availability was improved
by increasing the number of facilities providing the
vaccine and b y ensuring that patients did not have to pay
for treatment (Cohen et al., 2007). The combined number
of doses of hu man rabies vaccine used in Limpopo
Province, South Africa in the public sector increased from
3,000 in 2004 to 6,000 in 2005 and 56,000 in 2006. Also,
use of anti-RIG also increased over the same period with
.100 doses given in 20 04, increasing to 500 in 2005 and
2,500 in 2006 (Cohen et al., 2007 ). As a result, the
number of human rabies cases in Limpopo Province,
South Africa decreased after May 2006; no further human
cases had occurred as of June 30, 2007. This d ecrease is
likely due to the introduction of coordinated control
measures (including ag gressive PE P). An increased
awareness of rabies after interventions for control may
have contributed to increased case reporting after
February 2006; this situation may have affected apparent
trends in hum an case numbe rs and contributed to
the delay in observed decline in dog cases
(Cohen et al., 2007 ).
Seghaier et al. (1999) reported that puppies in Tunisia
responded to vaccination with no significant interference
by passive maternal immunity. Based on these
percentages, a 93% rate of protection may be expected for
vaccinated dogs. Their study confirms that all dogs (even
those less than 3 months of age) must be vaccinated
during mass cam paign s. The expe cted protection
conferred by locally produced po tent vaccines reaches 7999% based on the age of the dogs. In Nigeria where dog
bites continue to be the m ain mode of transmission of the
disease to man and remains a serious public health hazard,
the most logical and cost-effective approach to rabies
control is elimination of stray and owner less dogs
combined with a programme of single mass immunization
in the shortest possible time, at least 80% of the entire dog
population (Aw oyomi et al., 2007). Summarily, the key
for controlling zoonoses such as rabies, echinococcosis,
and bruce llosis is to focu s on the anim al reserv oir. In this
respect, ministries of health question whether the public
health sector really benefits from interventions for
livestock (Zinsstag et al., 2007). Dog rabies control relies
princip ally on the mass imm uniza tion of dogs in order to
achieve population immunity levels su fficient to inhibit
rabies transmission. In Africa, such high levels of
population immunity are rarely achieved due to a number
of reasons. Oral immunization has been shown to be an
effective means of inducing high levels of imm unity in
fox populations in several European countries, and this
technique has been mooted as a means of overcoming the
logistical problems of delivering injectable rabies
vaccines to dogs (Cohen et al., 2007 ). Altho ugh highly
effective if administered correctly, PEP is much more
costly than vaccination of domestic dogs (Rupprecht and
Gibbons, 2004; Cohen et al., 2007 ).
Future trends in rabies vaccines and its roles and
implication for global ra bies control an d possible
eradication: Experts have recognized for decades that
rabies is wholly eradicab le from all species exc ept bats
through targeted mass immunization - and the chief
obstacle to eradicating bat rabies is that no one has
developed an aerosolized vaccine that could be sprayed
into otherwise inaccessible caves and tree trunks.
Inventing such a vaccine is considered difficult but
possible (Clifton, 2007 ). Recently, the heroic recovery of
an unvaccinated teenager from clinical rabies offers hope
of future specific therapy (Rupprecht et al., 2006). W hile
post-expo sure vaccination is essential, an d sho uld
continue, with improvement to achieve consistently
positive results, progress toward eliminating rabies has
been markedly faster in nations that have emphasized
preventively vaccinating dogs (Clifton, 2007). In most
countries, canine rabies was already close to elimination,
but not because there were fewer dogs. Rather, canine
rabies had nearly disappeared because unvaccinated street
dogs had b een replaced by an almost equal number of
vaccinated pets (Clifton, 2007). As international concerns
increased, several corrective actions have been
implemented in many countries since 2005, which aimed
at improving vaccination protocols and a consistent
vaccination strategy in the respective federal states aiming
to eliminate the residual focus (Mü ller et al., 2005). Many
disease agents like rabies have developed strategies to
overcome extremes of reservoir qualities like population
size and density. Every infectious agent spreads easier
when its hosts are closer together (Murphy, 2008). Recent
epidemics of these rabies diseases have served as a
reminder of the existence of infectious diseases and of the
capa city of these diseases to occur unexpectedly in new
locations and anim al spec ies.
Int. J. Anim. Veter. Adv., 2(4): 104-129, 2010
In terms of the control of rabies, advances will come
from the enhanced ability to control the spread of RABV
among wild animal populations as well as the
development of newer, more effective vaccine strategies
(Rupprecht et al., 2004). Several new recombinant RABV
vaccines are under developme nt for po tential use in
animal populations. In addition, advances in the reverse
genetics of these viruses should see the application of
genetically engineered versions for a variety of
therapeutic purposes. The recent report of a rabies
survivor after drug-induced coma and antiviral treatment
demonstrates the type of future milestones in need of
basic and applied re-evaluation (W illoughby, 2005). As a
result of the efforts in developing recombinant RABV as
vaccine vectors and as cytolytic agents, it is likely that
clinical trials of genetically engineered RAB V in humans
will take place in the near future. A number of issues need
to be considered in the use of such agen ts, such as their
safety for use in humans, as well as the protection of
animal populations that may be exposed to such viruses.
Nonetheless, the advances in understanding virus
replication and pathogenesis should make it feasible to
address these issues, so that these viruses that have long
been a burden to humanity can instead be a benefit (Lyles
and R upprech t, 2007).
The potential for manipulation of the RABV genome
has been simplified by the generation of infectious virus
entirely from cloned cDNA . If future recom binan t,
replication-incomp etent, inactivated, or DNA -based
vaccines prove both efficacious and economical, they may
render most previous biosafety concerns obsolete, paving
the way for m ore w idespread, free-ranging wildlife and
dog rabies control, particularly in developing countries
(Lyles and R upprecht, 2007). At present, no evidence
suggests that prophylaxis failure is cau sed by antigenic
variation of RABV (WH O, 1992). Rather, vaccine
failures are usually associated with inadequate wound
care, omission o f potent serum, failure to infiltrate the
wound with immune globulin, delay, or failure to follow
recommended procedures (Lyles and Rupprecht, 2007).
Future tactics for globa l hum an rab ies prev ention will
continue to focus on the need for enh ance d public health
commu nications, continuing professional education;
poten t, inexpensive pre- and post-exposure vaccines and
new schedules; and viable alternatives to rabies
monoclonal antibodies
(Marissen et al., 2005)). Based on the recognition that
rabies at its source can be effectively controlled and
sometimes eliminated, safer, more effective, and
inexpensive medical and veterinary vaccines are a
nece ssity for animal reservoirs, vectors, or victims of the
disease (Ly les and R upprech t, 2007).
According to BB C N ews headlined worldwide on
September 8, 2007, “Rabies could be gone in a decade”.
“Rabies could be w iped o ut across the w orld,” “if
sufficient vaccinations are carried out on domestic dogs,
according to experts (BBC News, 2007; Clifton, 2007).”
Though, rabies is indeed a typical zoonotic disease which
has been known since ancient times; more than 4300
years (Takayama, 2008) and effective methods to treat
rabies patients have not yet been available, the only
means to esca pe rab ies dea th is to receive the postexposu re prophylax is of rabies with rabies vaccine as
soon after animal bite as possible (T akay ama , 2005 ). W e
shou ld keep in mind that rabies is preventable but
incura ble and that vaccination is still the key to prevent
rabies in sma ll anima ls and rabies transmission to human
beings (Lackay et al., 2008 ). Appropriate use of a highly
effective vaccine can help eradicate a major disease when
humans are the only natural host for the virus, and there
is no natural reservoir or intermediate host. Live virus
vaccines have played and continue to play a central
role in these current eradication efforts (Graham and
Crowe, 2007). Surveillance strategies for rabies viruses
and other rabies-related viruses in Africa must be
improved to better understand the epidem iology of this
virus, roles of vaccines and its implication for global
public health, and to make informed decisions on future
vaccine strategies because current evide nces are
insufficient that current rabies vaccines provide protection
again st these other rabies-related viruses.
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