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Vaccine Profile
Abstract
Rabies poses a threat to more than 3.3 billion people worldwide and is estimated to cause
about 60,000 deaths a year. However, according to the WHO, it is still one of the most
neglected diseases in developing countries. Human rabies vaccinations are critical
components of pre-exposure and post-exposure prophylaxis. Rabipur®, the first purified
chick embryo cell-culture vaccine, was licensed in Germany in 1984, and later in more than
60 countries worldwide. The immunogenicity, efficacy and safety of Rabipur have been
assessed in numerous clinical trials in pre- and post-exposure regimens, using both
intramuscular and intradermal routes of administration. The trial populations have involved
adults and children, including healthy volunteers and individuals bitten by laboratory-proven
rabid animals, malnourished children and immunocompromised individuals. Extensive,
worldwide clinical experience with Rabipur over the past 30 years has shown the vaccine to
In this article
be immunogenic, effective and generally well tolerated.
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be u oge c, e ect e a d ge e a y e to e ated.
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Keywords: cell-culture vaccine, efficacy, exposure, immunogenicity, intradermal, intramuscular, post-
exposure prophylaxis, pre-exposure
Reprints & Permissions prophylaxis, purified chick embryo cell
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vaccine, rabies, Rabipur®, safety, vaccine
Rabies is a zoonotic viral disease of mammals that is transmitted from animals to humans,
although there have been exceptional reported cases of direct human-to-human
transmission and indirect transmission via infected transplants [1–3]. The rabies virus is a
member of the genus Lyssavirus, which belongs to the family of Rhabdoviridae. The
incubation period is typically 1–3 months, but can vary from a few days to more than 1 year
[1,4]. Cases of up to 6 years incubation period have been discussed [5]. Initial
symptoms are usually nonspecific, including fever and headache. Unfortunately, as the virus
enters into the CNS an acute encephalitis or meningoencephalitis develops. This can result in
various forms of neurological and psychological manifestations, usually followed by paralysis
and coma, and finally death [1]. Once clinical symptoms of the disease develop, rabies is
nearly always fatal [6].
Rabies is known to be present on all continents (except Antarctica) and infects both wild and
domestic animals [7]. This disease poses a potential threat to more than 3.3 billion people
and is estimated to cause about 60,000 deaths each year [7,8]. Given that reliable data are
unavailable in many regions due to under or no reporting and inadequate surveillance, it is
estimated that in some countries the incidence of rabies could be as much as 15-times
higher than that of official reports [1,9]. According to the WHO, rabies is still one of the
most neglected diseases in developing countries [10]. The majority of human fatalities
occur in Asia and Africa where rabies is mainly transmitted by dog bites. In contrast, human
rabies in Europe and North America is rare; countries in these regions are either free of
terrestrial or canine rabies, but the virus circulates in other mammalian animal reservoirs,
including bats. In Latin America and the Caribbean, cases of human rabies transmitted by
dogs have been significantly reduced in the past 20 years [1,8].
While in countries where rabies is endemic, all people are at risk of being exposed. Children
in these countries have the highest risk due to several behavioral factors. Examples include
children’s attraction toward animals, lack of awareness of potential dangers and reluctance
to report bites or scratches. Moreover, their small stature makes them more susceptible to
be bitten in the face, head and hand, which decreases the incubation period of the rabies
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be b tte t e ace, ead a d a d, c dec eases t e cubat o pe od o t e ab es
virusupon infection.
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Rabies prevention and control consists of different methods including wild and domestic
animal vaccination programs, animal birth control, responsible pet ownership, and rabies
education and awareness. Human rabies vaccination is one of the most important elements
of preventing rabies in humans. Officially recommended pre-exposure prophylaxis (PrEP)
and PEP regimens should be followed before potential or after actual exposure, respectively
[1,8].
Originally, rabies vaccines were derived from animal nerve or brain tissue, so-called nerve
tissue vaccines (NTVs). Nowadays, rabies vaccines are mostly cell-culture and embryonated
egg-based vaccines (jointly referred to as CCEEVs) and only a few countries still use NTVs
[8]. The first reported rabies vaccination with an NTV was in 1885 when Louis Pasteur
successfully treated a young boy who had been severely bitten by a rabid dog with a series
of vaccinations consisting of a spinal cord suspension of increasing virulence derived from
rabid rabbits [12]. Improvements were later made to the vaccine’s safety by inactivating
the virus with phenol. However, there were still severe side effects following administration
of NTVs, including some cases of paralysis and even death. A major factor is due to patient
hypersensitivity to myelin [12,13]. Nerve tissue-derived vaccines produced from brains of
suckling animals were later used as these contain smaller amounts of myelin [14]. A
modified preparation produced with suckling mouse brain tissue is still used in a small
number of Latin American countries, and NTVs from virus-infected goat or sheep brain
tissue are still utilized in a few countries in Asia and Africa [15]. However, as NTVs can
induce severe adverse reactions and are less immunogenic than CCEEVs, the WHO does not
recommend the production and use of rabies NTVs [8,16].
Rabies vaccine production later focused on finding sources of virus propagation in materials
free of neural tissue [17]. This led to the development of embryonated egg-based and cell-
culture-based vaccines. For embryonated duck egg-based rabies vaccine, the complete
embryo is utilized for virus propagation. In contrast, cell-culture-based vaccines contain the
rabies virus that has been propagated in cell substrates (e.g., primary hamster kidney cells,
human diploid cells, chick embryo cells or Vero cells) [8,18–21]. Research also addressed
which viral strains should be used. Investigations in humans using low-egg-passage (LEP)
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which viral strains should be used. Investigations in humans using low egg passage (LEP)
Fluryvirus showedthat
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the immunization of humans against rabies – although at that time (the early 1950s) the
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vaccine was not highly immunogenic [22]. Experiments with a high-egg-passage Flury
vaccine resulted in better immunogenicity, but were still inferior to NTVs [23]. An
inactivated duck embryo virus vaccine appeared to be more promising, but its immunizing
potency was again not as high as that of NTVs [17].
In the late 1950s, work began on cultures of human fetal fibroblasts, which were diploid cells
that had a finite lifetime. Fetal fibroblasts were soon shown to be susceptible to human
viruses and free of latent viruses [24]. By the early 1960s, the highly immunogenic human
diploid cell line WI-38 was being used for rabies virus propagation [24,25]. With some
modifications (including a switch to the MRC-5 cell line), the resulting rabies vaccine
produced using human diploid cells vaccine (HDCV) had a better tolerability profile and
induced a far greater immune response in animals and humans than any other vaccine of
that time [25–27]. Indeed, Garner and colleagues reported that in their clinical experience,
HDCV was associated with less severe and persistent local inflammation, lymphadenopathy,
headaches and fever than the duck embryo virus vaccine [28]. Human diploid cells vaccine
was first licensed for pre- and post-exposure immunization in Europe in 1976 and in the USA
in 1980 and is still available now [27].
Large-scale production of rabies virus in human diploid cell strains is a complex process with
a low virus yield in comparison to other cell systems. It results in high production costs and a
limited output of vaccine for HDCV [29]. Over subsequent years, a series of different
vaccines have been developed with similar immunogenicity to HDCV [12]. Licensed in
1985, a purified Vero cell rabies vaccine (PVRV) has comparable immunogenicity to HDCV
with the advantages of a better safety profile [30].
Investigations into a purified chick embryo cell-culture vaccine (PCECV) for rabies started in
the late 1970s in Marburg, Germany [28]. In the 1980s, an immunogenic PCECV containing
inactivated rabies virus (LEP Flury strain) was developed. In a series of animal laboratory
tests, PCECV showed comparable immunogenicity and tolerability to that of HDCV [29]. In
human studies, PCECV induced similar immunogenicity to HDCV [31–34]. The purified
chick embryo cell-culture vaccine was subsequently licensed in Germany in 1984 as Rabipur®
(Novartis Vaccines). The availability of HDCV, PVRV and PCECV (Rabipur) has enabled dosing
schedules to be vastly reduced and side effects minimized compared with NTVs [35].
Based on these cell culture production platforms, recently other rabies vaccines have been
developed. Some of them are using different virus strains [36–38].
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de e oped. So e o t e a e us g d e e t us st a s [36 38].
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Rabipur is produced using Flury LEP rabies virus strain grown in a culture of primary chick
embryo fibroblast cells using specific pathogen-free eggs in compliance with current
applicable pharmacopeia and with WHO requirements. The Flury LEP rabies virus is
inactivated with β-propiolactone, purified via continuous density-gradient centrifugation,
resulting in a highly concentrated formulation stabilized with polygeline (a processed gelatin
product), and then lyophilized [39]. Rabipur is produced in two WHO pre-qualified
manufacturing facilities: Marburg, Germany and Ankleshwar, India [40]. In Marburg,
Germany, a new state-of-the-art manufacturing facility for Rabipur has been approved as of
2014. Batches of Rabipur from the two sites have been shown to be clinically comparable:
noninferiority in immunogenicity and tolerability of the vaccine produced in India to the
vaccine produced in Germany has been demonstrated [41,42]. Additionally, all batches
compared reach or exceed the minimum potency of ≥2.5 international units per single
intramuscular (IM) dose, as specified by the WHO and approved by regulatory authorities
[8]. PCECV has been found to have 1000-fold lower concentration (0.024 mg/dose) of
human serum albumin, which is a stabilizer and a considerable component in most vaccines,
compared to PVRV, HDVC and primary hamster kidney vaccines [43]. Moreover, tested
batches of PCECV were shown to contain Flury LEP rabies virus strain with no deviations
from published genetic sequences [43]. PCECV is marketed globally as Rabipur, with a few
exceptions: in South Africa and Namibia it is marketed as Rabipor (licensed in 2000) and in
the USA and Canada as RabAvert® (licensed in 1997 and 2003, respectively). Throughout this
manuscript, PCECV will be referred to as Rabipur.
Vaccination regimens
Rabies differs from many other infectious diseases in that, despite following exposure to the
infectious agent, clinical manifestation of the disease may be prevented through timely
immunization (in adherence with WHO protocols) as long as clinical symptoms have not
developed [8,44]. Thus, both PEP and PrEP regimens are effective in immunizing against
rabies [45].
Post-exposure prophylaxis
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The key immunological objective of PEP is to neutralize and destroy the rabies virus
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inoculated in the victim’s body immediately following exposure so that clinical manifestation
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of rabies does not develop. PEP has three main components: wound treatment, vaccine
administration and rabies immunoglobulin (RIG) administration, if indicated [8,44]. The
WHO recommendations for PEP depend on the type of contact with the suspected rabid
animal and the vaccination status of the individual based on three categories of risk and
exposure (I-III). Definition of categories of exposure and the use of rabies biologicals are as
follows:
Category II is minor scratches or abrasions without bleeding and requires vaccine; and
In deploying PEP, the immunization schedule should begin as soon as possible following
exposure and must be followed exactly as recommended, regardless of when the patient
comes in for treatment after the initial contact. In individuals who have not been vaccinated
with the rabies vaccine or individuals with uncertain immune status, Rabipur is administered
via IM injection using the Essen five-dose regimen (one dose on Days 0, 3, 7, 14 and 28) or
the Zagreb four-dose regimen (two doses on Day 0, followed by one dose on Days 7 and 21).
Recently, Advisory Committee on Immunization Practices and WHO have amended their PEP
recommendations to reduce the Essen five-dose regimen to four doses (one dose on Days 0,
3, 7 and 14). This shortened regimen may be used as an alternative for healthy, fully immune
competent, exposed people provided they receive wound care plus RIG in category III as well
as in category II exposures and a WHO-prequalified rabies vaccine [8,46]. This, however,
until today has not been reflected in the labels of any rabies vaccine. In countries where the
intradermal (ID) route of administration has been endorsed by national regulatory
authorities, the WHO recommends the ID 2-site regimen (updated Thai Red Cross; two doses
of 0.1 ml ID at two different lymphatic drainage sites on Days 0, 3, 7 and 28) [8,16].
Pre-exposure prophylaxis
PrEP simplifies post-exposure care by eliminating the need for RIG and reducing the number
of doses of vaccine needed for immediate post-exposure immunization. Individuals who
have previously been vaccinated with a rabies vaccine will only need two doses of Rabipur
for PEP (given on Days 0 and 3) as soon as possible after exposure. For PrEP, immunization
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o (g e o ays 0 a d 3) as soo as poss b e a te e posu e. o , u at o
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deltoid muscle (anterolateral region of the thigh in small children). The three-dose regimen
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can also be administered ID, in countries where ID route of administration is endorsed by
national regulatory authorities [8,45].
The immunogenicity, efficacy and safety of Rabipur have been assessed in more than 50
clinical trials since 1983 in both PEP and PrEP regimens, using IM as well as ID
administration. The trial populations have comprised of adults and children aged 12 months
and older. Subjects included healthy individuals, individuals bitten by suspect or laboratory-
proven rabid animals, malnourished children and immunocompromised persons.
Summaries and overviews of relevant clinical trial results are provided in Tables 1–6, and
individual trials and published case studies are provided exemplarily in detail in the review
text.
At the time of the vaccine development, a PEP six-dose Essen regimen was officially
recommended by the WHO for all cell-culture rabies vaccines. Consequently, Rabipur was
initially assessed in clinical trials with a six 1.0 ml/dose IM Essen regimen for PEP and was
licensed as such. According to WHO guidelines, the PEP six-dose Essen regimen produced an
adequate antibody response (specific antibody level of ≥0.5 IU/ml) [8,44,45]. Alternatively,
the Zagreb regimen was developed with an abbreviated schedule (2-1-1) of two doses on Day
0 and one dose on Days 7 and 21. Over time, the sixth dose of the Essen regimen on Day 90
became optional and, in 1992, the WHO published new guidelines that recommended a five-
dose Essen regimen (without the dose on Day 90) for which Rabipur was later indicated
[47].
Rabipur has been investigated extensively in PEP and simulated PEP regimens in humans
and has a well-established immunogenicity and tolerability profile for both the Essen and
Zagreb regimens. An overview and summary of the relevant clinical trials investigating the
immunogenicity of Rabipur in PEP and PrEP IM regimens is provided in Table 1.
single 1.0 ml IM dose on Days 0, 3, 7, 14, 30 and 90); another 14 volunteers received Rabipur
in the PEP five-dose Essen regimen (a single 1.0 ml IM dose on Days 0, 3, 7, 14 and 30).
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t e e dose sse eg e (a s g e .0 dose o ays 0, 3, , a d 30).
Rabies virus
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subjects by Day 14, which has been well established as an adequate antibody response after
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vaccination [48]. Volunteers noted the following reactions to the vaccine: general systemic
reactions (31.2%); local adverse reactions – mostly mild (56.5%); moderate or severe general
reactions, including fatigue, headache and dizziness (15.1%); and moderate or severe local
reactions including pain, induration or redness (16.4%).
Historically, the simultaneous administration of RIG together with rabies vaccines for PEP
raised discussion on possible interference of RIG on the patient’s own active immune
response to the vaccine. A study using human rabies immunoglobulin at the recommended
concentration of 20 IU/kg observed partial interference with the initial active development of
RVNA when administered concomitantly with different types of rabies vaccines applied by
the Zagreb regimen [50]. When Rabipur was administered in different IM and ID regimens
for PEP simultaneously with either equine rabies immunoglobulin or human rabies
immunoglobulin, initial effects on antibody concentrations were observed in some instances.
However, none of this interference was clinically relevant as RVNA concentrations were
always above the adequate level of 0.5 IU/ml [51–55].
Rabipur PrEP regimens have been shown to be immunogenic and well tolerated when
administered in humans (Table 1). In a pivotal PrEP study in healthy adults, Rabipur was
given in a three-dose series and followed by a 2-year booster. Vaccination with Rabipur via
an IM or ID regimen resulted in adequate immune response by Day 28, which was sustained
at Day 365 [33]. Comparable results were found in a similar study comparing Rabipur with
HDCV [34].
The standard route of administration of Rabipur is IM injection into the deltoid muscle of
adults or the anterolateral region of the thigh in small children [56]. However, Rabipur
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adu ts o t e a te o ate a eg o o t e t g s a c d e [56]. o e e , ab pu
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The immunogenicity of 0.1 ml Rabipur for ID administration has been well established in
clinical trials (Table 2). A study of 211 patients with WHO category II or III rabies exposure in
Thailand was designed to assess whether Rabipur for ID PEP treatment could effectively be
reduced to 0.1 ml per site. Geometric mean RVNA concentrations on Day 14 after Rabipur ID
(0.1 ml at two sites on Days 0, 3 and 7; one site on Days 30 and 90) were noninferior to
patients who received IM Rabipur (1.0 ml on Days 0, 3, 7, 14, 30 and 90) and were ≥0.5 IU/ml
[52]. This study employed the Thai Red Cross regimen, which was the former official WHO-
endorsed ID regimen. However, over the years, the dosing schedule for ID administration
has evolved as evidence from clinical trials has become available. The WHO now
recommends the updated Thai Red Cross 2-site regimen as the most cost–effective and
widely used ID regimen: 0.1 ml at two different ID sites on Days 0, 3, 7 and 28 [8].
The WHO-defined minimum vaccine potency of 2.5 IU per IM dose has been established as
effective for use in ID administration as well [51]. A study by Beran and colleagues
investigated whether the 1.0-ml dose of Rabipur for IM administration was still sufficient to
induce an adequate antibody response after a several-fold dilution and following 0.1 ml ID
administration. The study showed that an adequate RVNA response (≥0.5 IU/ml) was elicited
and maintained when Rabipur was administered via the ID route of administration in the
Thai Red Cross 2-site regimen. These data confirm that the WHO-recommended minimum
potency of 2.5 IU for IM administration is adequate also for the 0.1 ml ID dosing regimen
[51].
Immunogenicity in children
Children in rabies endemic countries are at particular high risk due to their attraction toward
animals, lack of awareness of potential dangers, potential reluctance to report bites or
scratches and their small stature (making them more susceptible to face, head and hand
bites from animals, which decreases the incubation period). Exposure to the rabies virus
occurs disproportionately in children: on average, 40% of PEP is administered to children
aged 5–14 years [1]. A number of clinical trials have demonstrated Rabipur to be
immunogenic with an acceptable safety profile in children for both PEP and PrEP (Table 3).
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immunogenic with an acceptable safety profile in children for both PEP and PrEP (Table 3).
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A study in children (n = 11) aged 2–15 years who had single IM doses of Rabipur (1.0 ml) on
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for PrEP showed RVNA concentrations ≥0.5 IU/ml by Day 14. No serious
adverse events (SAEs) were reported after vaccination [57]. Another study (n = 175)
comparing three IM doses of Rabipur (reconstituted in 1.0 ml or 0.5 ml diluent) or PVRV with
single doses on Days 0, 7 and 28 for PrEP in children aged 6–13 years demonstrated that
RVNA concentrations were ≥0.5 IU/ml by Day 49 [58]. Similar findings have been observed
in children aged 12–18 months receiving IM or ID Rabipur (1.0 or 0.1 ml, respectively) on
Days 0,7 and 28 for PrEP, with concomitant administration of Japanese encephalitis vaccine
[59]. Rabipur has also demonstrated immunogenicity in older children when administered
by ID injection for PrEP [56,60]. Rabipur is generally well tolerated in children; reported
typical adverse reactions in clinical trials included fever, tenderness, and pain and redness at
the injection site. No serious adverse reaction related to the vaccine occurred [57,61–64].
A PEP study assessing Rabipur immunogenicity was carried out in children bitten by either
confirmed or suspected rabid animals (mainly dogs, followed by monkeys, cats and
mongoose). Two hundred and seventy one children aged 1–13 years received PEP on Days 0,
3, 7, 14, 30 and 90. The serological response was adequate, with all children demonstrating
RVNA concentration of ≥0.5 IU/ml with a maximum immune response measured 10–15 days
after the last vaccination. The vaccine was well tolerated and no failures were observed
[65].
The anamnestic response to simulated post-exposure booster doses of Rabipur has also
been demonstrated in children aged 5–8 years at the time of primary vaccination. Two
booster doses (Days 0 and 3) of Rabipur were administered ID 1, 3 or 5 years after three
primary vaccination doses and resulted in adequate RVNA concentrations (≥0.5 IU/ml) in all
children (n = 312) by Day 14 after booster [61].
A clinical case study reported on the vaccination of a newborn baby with Rabipur after her
mother developed clinical rabies during pregnancy following a dog bite 3 months prior to
giving birth. A healthy female baby was delivered (gestational age 40 weeks), following which
the baby received a total of five doses of Rabipur: 1.0 ml IM at birth and a four-dose series
(Days 3, 7, 14 and 30). Seven days after the final dose of Rabipur, the baby’s RVNA level was
2.34 IU/ml and, at the age of 2 years, the child was healthy and developing normally [66].
Asia is home to over half of the world’s malnourished children. Approximately 50% of pre-
school age children suffer mild-to-moderate malnutrition, and over 90% of reported human
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sc oo age c d e su e d to ode ate a ut t o , a d o e 90% o epo ted u a
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examining the immune response to vaccination in children suffering from malnutrition have
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reported varying results. Antibody responses to BCG for tuberculosis, and in some cases
polio vaccines, have been reported to be depressed in children with severe malnutrition,
whereas measles vaccine appears to be efficacious even in malnourished children [67]. In
a study by Sampath and colleagues, 45 malnourished children aged 8 months to 16 years
who presented to the anti-rabies clinic in Hyderabad, India, for PEP were enrolled to be
investigated for their response to Rabipur. Thirty six children received five doses, three
received four doses and six received less than four doses of the vaccine. The 39 who
received four or more doses made it through to the per-protocol set [63]. All bites were
evaluated as category II or III, in accordance with the WHO criteria [8]. All children had
developed RVNA levels ≥0.5 IU/ml by Day 14. There was no significant difference in RVNA
concentrations between the malnutrition categories – immune response to Rabipur was
independent of the extent of malnutrition. In addition, there were no SAEs reported,
indicating that Rabipur is well tolerated in malnourished children (Table 3) [63].
Immunogenicity in pregnancy
Rabies presents an intermediate risk to the unborn fetus of pregnant women [68,69].
Whether the rabies virus can cross the placenta remains uncertain due to confounding
reports. A report from 1977 describes a pregnant woman infected with rabies who delivered
a premature baby before dying. Although the baby was not vaccinated, it did not develop
rabies. Other publications have also suggested that placental transmission of rabies virus in
humans is highly improbable [68]. In 1981, however, a woman who was 9 months
pregnant presented to a hospital 34 days after being bitten by a rabid dog. Two days after
the mother was admitted to the hospital, the baby was born following induction of labor and
died suddenly 40.5 h later. The autopsy confirmed that both mother and baby had rabies.
This was the first reported case of human rabies acquired by placental transmission [69].
The administration of Rabipur in pregnant women for PEP has been documented in a
retrospective case series on two pregnant women who had WHO category III exposure to a
suspected rabid animal at gestational Week 12. Each of the pregnant women got a total of
five doses of Rabipur: 1.0 ml IM on Days 0, 3, 7, 14 and 28 (Essen regimen) and equine rabies
immunoglobulin. Both vaccine and equine rabies immunoglobulin were well tolerated with
no reports of systemic or local AEs. The women had normal deliveries of healthy babies with
The immunogenicity of Rabipur following a booster dose has been proven in PrEP in healthy
volunteers who have previously received Rabipur or HDCV (Table 5) [34]. In addition, the
anamnestic response to booster doses of Rabipur has been demonstrated 14 years after the
last vaccination [81]. Individuals were vaccinated with either IM or ID Rabipur according to
a three-dose PrEP schedule, followed by a 1.0 ml IM booster dose 2 years later. Subjects did
not receive any further booster doses. Fourteen years later, 10 individuals who provided
serum samples for analysis had adequate RVNA titers of >1:5, as defined by the Advisory
Committee on Immunization Practices, and received one 1.0 ml IM booster dose [71].
Blood samples taken 24–45 days following the second booster demonstrated a high
anamnestic response of an approximate 10-fold increase in RVNA titers [81]. Another
study demonstrated RVNA levels ≥0.5 IU/ml in individuals at least up to 6 years following
PrEP or PEP Rabipur regimens [82].
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Although the majority of human cases of rabies occur after exposure to classical rabies virus
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transmitted by dog bite, bat-transmitted nonclassical rabies strains, such as European bat
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lyssavirus type I (EBLV-I) and II and Australian bat lyssavirus, represent a source of human
rabies. The immunogenicity (cross-neutralizing activity) of Rabipur to these related lyssavirus
species was assessed in a laboratory study in which samples from healthy volunteers who
had received Rabipur in a simulated ID PEP regimen as part of a separate clinical trial were
analyzed. Rabipur induced adequate neutralizing antibodies to EBLV-1, EBLV-II and
Australian bat lyssavirus in 97, 100 and 100% of samples, respectively [83].
Efficacy
Although there is no specific level of RVNA that is recognized as being ‘protective’ against
rabies in humans, the WHO recommends an RVNA concentration of ≥0.5 IU/ml as being
proof of an adequate immune response to vaccination [8,44,45]. However, while
immunogenicity of a vaccine is a surrogate parameter, and no correlate of protection can be
established in humans for obvious ethical reasons, vaccine efficacy can be assessed by
investigating whether survival after an exposure has occurred. This is ideally done by looking
at survival after initiation of proper PEP following category II or III exposure to a laboratory-
confirmed rabid animal [45]. Real survival data are available following administration of
Rabipur to rabies-exposed patients (Table 6). A prospective clinical trial assessing the efficacy
of a 0.1-ml dose of Rabipur administered ID was conducted in 113 patients presenting with
category III exposure from laboratory-confirmed rabid animals. Patients in the study were
vaccinated with 0.1 ml Rabipur via the Thai Red Cross regimen and monitored monthly for 1
year post exposure. The vaccine was well tolerated and no SAEs were reported. All patients
survived 1 year post exposure, confirming the efficacy of Rabipur [53].
The safety of PEP and PrEP with Rabipur has been assessed in a 10-year post-marketing
surveillance study in India in 1289 individuals including children from 1 year of age.
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su e a ce study da 89 d dua s c ud g c de o yea o age.
Vaccination with Rabipur
Full Article Figureswas well tolerated,
& data Referenceswith only 4% ofsubjects
Citations Metrics reporting AEs, all of
which were mild to moderate. The most commonly reported local adverse reactions in
Reprints & Permissions PDF
subjects were injection-site pain (n = 26, 2.1%) and injection-site induration (n = 14, 1.1%).
Mild fever (37.2–37.8°C) occurred in six subjects (0.5%), which lasted 12–24 h following the
third or fourth vaccination [64].
Nearly 30 years of global usage of Rabipur confirms the well-balanced safety and tolerability
profile seen in clinical trials. The overall adverse drug reaction reporting rate for Rabipur in
the past 28.5 years is approximately 12.3 events per 100,000 doses sold. The vast majority
(nearly 80%) of reported events from Asia, Europe and the USA were nonserious reactions
known from clinical trials. The Medical Dictionary for Regulatory Activities, a clinically
validated international terminology dictionary, is organized by System Organ Class (SOC)
under which most of the reported Rabipur adverse drug reactions are classified.
Characteristics of SOC include general disorders and administration site conditions (24%),
nervous system disorders (18%) or musculoskeletal and connective tissue disorders (10%).
Within these SOCs, the most often reported symptoms were systemic reactions, such as
headache, dizziness, influenza-like illness and associated symptoms (e.g., fever, asthenia and
myalgia), and local injection-site-related reactions (e.g., redness, swelling and pain). Reports
on serious adverse drug reactions were in line with what is described in the current Rabipur
Core Safety Information or were reactions for which a causal relationship to Rabipur has not
been established. The general safety profile of Rabipur is as expected for an inactivated
vaccine and remains consistent with that shown in clinical trials.
There are reported incidences of people exposed to rabies virus developing clinical rabies
despite the administration of PEP. However, investigation into these cases shows that for the
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desp te t e ad st at o o . o e e , est gat o to t ese cases s o s t at o t e
majority
Fullof patients
Article there was
Figures an omission
& data of atleast
References one ofthe
Citations essential steps of PEP
Metrics
However, there are very rare reported cases in which clinical rabies has developed in
immunologically healthy people despite apparently correct PEP regimen, including wound
treatment and timely administration of RIG and vaccine. A systematic review reported a total
of eight probable true vaccine failure cases in which Rabipur was administered in one case,
Rabipur and PVRV were given in a second case and an unknown vaccine in a third case
[89]. More recently, a case of atypical initial clinical rabies symptoms that led to delayed
diagnosis was reported. The patient died despite appropriate PEP and administration of
Rabipur [90].
Expert commentary
This review covers clinical trials that have contributed in a relevant and significant way to the
clinical development of Rabipur and to the definition of appropriate rabies vaccination
regimens. The development of rabies vaccines has come a long way, and cell-culture rabies
vaccines, such as Rabipur, have the benefit of inducing less severe adverse reactions
compared to formerly used NTVs. Not only does Rabipur induce an immune response after
IM administration, but it is also capable of stimulating a comparable immune response via
an ID route. Moreover, ID administration has significantly contributed to the affordability of
rabies vaccines in endemic, developing countries where it is endorsed by national health
authorities. Due to replacement of NTVs with cell-culture vaccines such as Rabipur, several
countries in Asia have come up with novel ID administration techniques to compensate for
logistical and economic challenges. With this shift to cell-culture vaccines, the management
of rabies represents a significant unmet global need, particularly in endemic, developing
countries. Despite the availability of effective vaccines, the number of human deaths from
rabies is unacceptably high [91]. Human rabies vaccination is a critical component of the
PrEP and PEP regimens that should be followed before potential or after actual exposure to
the rabies virus. Three decades of widespread clinical use of Rabipur confirms its
immunogenicity and tolerability for both pre- and post-exposure vaccination regimens
among diverse populations. Wider use of human rabies vaccination for PrEP and PEP in
conjunction with programs to eradicate rabies from animal populations would be the right
direction in reducing the burden of disease. The most vulnerable populations to benefit from
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d ect o educ g t e bu de o d sease. e ost u e ab e popu at o s to be e t o
such collaborated efforts
Full Article Figuresare children,
& data particularly
References in developing
Citations countries. Technology exists
Metrics
Five-year view
For over three decades, global and local health organizations and institutions have engaged
in the prevention and control of rabies, particularly in low- and middle-income countries. The
value of rabies vaccination remains unchanged, especially considering that several countries
aim to become rabies-free from 2020 to 2025. Widespread use of ID administration and
shorter ID PEP regimens could become a more common practice in other countries in Asia
and elsewhere. To support countries in their efforts to eliminate rabies, there is a need to
continue with and strengthen measurements such as enhancing awareness, rabies
education, teaching general prevention measures and providing appropriate rabies
immunization based on recommended vaccination regimens. The pathways to rabies
vaccine development have produced successful prophylaxis prevention and treatment used
to save individuals exposed to rabies. Furthermore, NTVs may be phased out in the next 5
years in the remaining few countries that still use this vaccine. PrEP and PEP regimens will be
further improved to maximize uptake and reduce clinical symptoms, for example, reduced
number of doses for IM PEP and condensed PEP ID regimens to 1 week. An abbreviated PrEP
regimen schedule for Rabipur may become officially available.
Acknowledgements
The authors wish to thank all of the many individuals who have participated in the clinical
development of Rabipur over the past 30 years.
The authors are employees of Novartis Vaccines. The authors have no other relevant
affiliations or financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the manuscript. P
Cates, of Apothecom, provided writing assistance that was paid for by Novartis Vaccines. K
Jenks, N Tong, of Novartis Vaccines, provided editorial support. D Gniel was an employee of
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10/15/2018 30 years of rabies vaccination with Rabipur: a summary of clinical data and global experience: Expert Review of Vaccines: Vol 14, …
Je s, o g, o o a t s acc es, p o ded ed to a suppo t. G e as a e p oyee o
Novartis
FullVaccines and
Article Diagnostics
Figures atReferences
& data the time ofparticipation
Citations and writing of this manuscript.
Metrics
Key issues
Rabipur efficacy in preventing rabies after exposure to the virus has been
demonstrated in several clinical trials, and the vaccine showed a favorable
tolerability and safety profile.
30 years of clinical experience with Rabipur confirms the value of the vaccine in
human rabies prophylaxis.
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