ARTICLE IN PRESS

Travel Medicine and Infectious Disease (2007) 5, 327–348

www.elsevierhealth.com/journals/tmid

REVIEW

Preventing rabies with the Verorabs vaccine:

1985–2005
Twenty years of clinical experience
Stephen Toovey

Burggartenstrasse 32, 4103 Bottmingen, Switzerland

Received 6 July 2007; accepted 12 July 2007

Available online 17 September 2007

KEYWORDS Summary Purified rabies vaccine cultured on Vero cells (Verorabs, sanofi pasteur)
Rabies; is WHO-approved for pre- and post-exposure prophylaxis by intradermal and
Verorabs; intramuscular routes. During 20 years of use, over 40 million doses of Verorabs
Pre-exposure; have been administered in more than 100 countries. No serious adverse event due to
Prophylaxis; Verorabs has been reported in clinical trials involving 3937 persons, and Verorabs is
Post-exposure better tolerated than human diploid cell vaccine (HDCV).
treatment; Pre-exposure prophylaxis is confirmed immunogenic in 1437 subjects by all
Rabies vaccine; routes, with prompt responses following boosting; Verorabs boosts effectively
Vero cell subjects pre-immunized with HDCV. Unlike HDCV, Verorabs is not associated with
post-boosting serum sickness. In the absence of data in immunodeficient/HIV-
positive individuals, pre-exposure immunization is urged as early as possible.
Essen, Zagreb, Thai Red Cross Intradermal (TRC-ID) and other post-exposure
intramuscular and intradermal regimens are documented. Two thousand one
hundred and eighty-three subjects received post-exposure prophylaxis, including
874 high risk, severe or confirmed rabid attacks. Co-administration of rabies immune
globulin (RIG) does not affect neutralizing antibody levels when Essen or TRC-ID
regimens are employed; levels are lower with the Zagreb regimen.
Verorabs has been administered safely and effectively post-exposure to 251
pregnant women, without any increase in congenital malformations or spontaneous
abortions. From a pediatric perspective, safety and efficacy have been demon-
strated in 759 children (0–15 years).
Intradermal post-exposure Verorabs is an effective and inexpensive option for
developing countries. Inadvertent subcutaneous administration does not reduce
immunogenicity. WHO already strongly recommends the replacement of nerve tissue

Tel.: +41 61 421 7872; fax: +41 61 421 7063.

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1477-8939/$ - see front matter & 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tmaid.2007.07.004
 ARTICLE IN PRESS
328
vaccines with modern vaccines. Extensive clinical experience supports the use of
Verorabs for intramuscular and intradermal pre- and post-exposure prophylaxis,
including in special situations.
& 2007 Elsevier Ltd. All rights reserved.
‘‘There are no contraindications for vaccinating
a rabies exposed person’’.
Chutivongse, Wilde, et al.1
1. Introduction
It is 120 years since Louis Pasteur administered the
first rabies vaccine to a human being,2 and 20 years
since the introduction into clinical practice of
purified rabies vaccine cultured in Vero cells (PVRV,
Verorabs, sanofipasteur, France).
The introduction of a Verorabs was an important
step forward in the fight against rabies, recognized
as such by Rupprecht et al.3 in their history of
rabies. Prior to Verorabs, the world depended
upon the human diploid cell culture vaccine
(HDCV), or vaccines produced in nerve tissue
(NTV). Very large-scale production of HDCV is not
practicable, while Verorabs is eminently suited to
production scale up.4–6 Verorabs is now licensed
for use in over 100 countries, and over 40 million
doses have been administered. One year after its
introduction, Suntharasamai et al.7 predicted that
Verorabs was ‘‘likely to replace human diploid cell
strain vaccine as the most widely used tissue
culture rabies vaccine’’. On its twentieth anniver-
sary, a review of the vaccine’s efficacy and safety,
and its place in the prevention of rabies, is timely.
2. Search strategy
The keywords Vero, rabies, and PVRV were used in
searches for publications conducted using PubMed,
ISIS Web of Knowledge, and Ovid, and links to
related articles were followed. Further information
was sought from the manufacturer. Thirty-five
publications specifically reporting Verorabs effi-
cacy, immunogenicity, or safety were identified.
The search was not language restricted.
3. Rationale of rabies vaccination
A brief review of the rationale underlying rabies
vaccination follows in order to contextualize the role
of Verorabs. Following inoculation of rabies virus
into a human subject by a rabid animal (or during a
laboratory accident), the virus replicates locally in
S. Toovey
non-nervous tissue before invading the nervous
system.8 This delay provides a window of opportunity
to neutralize the virus, as once the virus has gained
access to the nervous system, it is beyond immune
attack and agonizing death is virtually inevitable.
Only six survivors of documented human rabies are
known, and five of these had received at least some
vaccine before symptom development9–11; the sixth,
treated with experimental anti-excitotoxic coma,
survived with choreoathetotic sequelae.12
Although the most recently reported survivor had
antivirals included in her treatment cocktail,12 anti-
virals have never been shown effective in vivo against
rabies, and have never prevented clinical disease or
death.8 Forestalling clinical rabies relies upon immune
clearance of the virus before symptoms manifest, for
which the presence of neutralizing antibody is
required. The prevention of rabies, therefore, rests
upon a vaccine inducing neutralizing antibody.9,13
Rabies immunoglobulin (RIG) is added when post-
exposure prophylaxis is applied to previously unvacci-
nated individuals; this provides neutralizing antibody
cover in the first few days after immunization until
vaccinees produce their own antibodies.
In individuals with an immune system primed
against rabies by pre-exposure immunization with
adequately immunogenic vaccine, neutralizing anti-
body will be present upon challenge. Potential rabies
exposures in the pre-immunized may thus be effec-
tively treated with just 2 boosting doses of vaccine
compared to 5 in untreated individuals: immunologi-
cal memory ensures a rise in titer and obviates the
need for RIG. No case of clinical rabies has ever been
reported in any pre-immunized individual boosted
with an accepted post-exposure regimen and vaccine.
Although pre-exposure vaccination simplifies
post-exposure prophylaxis and avoids the need for
RIG, other benefits accrue from its use: it may
protect against unrecognized exposures, and it
‘buys time’ for exposed individuals lacking im-
mediate access to post-exposure prophylaxis.
4. Vaccines available prior to Verorabs
introduction
4.1. Nerve tissue-derived vaccines
Louis Pasteur’s first rabies vaccine was compounded
from the desiccated spinal cord of rabid animals.2,9
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005
Many countries, mostly in the developing world,
still use NTVs; harvesting rabies antigen from
deliberately infected animals.
In Chile, a head-to-head trial of Verorabs against
a suckling mouse brain NTV (Fuenzalida-Palacios,
CRL) was conducted in seronegative volunteers.14
Verorabs was administered intramuscularly using
the pre-exposure prophylaxis regimen on days 0, 7,
and 28 (N ¼ 30), NTV was administered subcuta-
neously on days 0, 3, 7, and 28 (N ¼ 23). Serum
antirabies titers were determined on days 7, 42,
and 365. Five of the 30 Verorabs vaccinees had
protective antibody levels by day 7, while no
subject in the NTV group achieved a protective
titer; by day 42 all subjects were protected. All of
the Verorabs group retained protective levels at
day 365 but only 10 of the NTV group still had
protective levels (p ¼ 0.05). The authors concluded
that Verorabs generated protective antibody levels
sooner than Chilean NTV, and that Verorabs was
superior with respect to duration of protection, an
important factor given the possibility of prolonged
incubation in rabies, and the rationale behind pre-
exposure immunization.8,9,15
As well as immunogenicity concerns,16–18 NTVs
have a poor safety record and may provoke
encephalitis in their own right. There are ample
reports of NTV-associated ‘neuroparalytic acci-
dents’, with encephalitis, myeloradiculopathy,
Guillain-Barré syndrome, peripheral neuropathy
and other neurological entities reported.9,19–26
Although the costs of NTV are commonly perceived
to be less than those of modern cell culture
vaccines, the WHO reminds us that the true costs
of NTV must include the neurological adverse
events associated with their use.27 Other autho-
rities echo this, emphasizing that the true cost of
post-exposure rabies vaccination must include all
costs to society and to the patient.28,29
In 1984 the WHO recommended the discontinua-
tion of NTV, stating ‘‘in view of the hazard of
encephalitogenic reactions, the discontinuation of
nerve-tissue vaccines should be considered’’.13,30
The latest WHO Expert Consultation on rabies is
unequivocal, ‘‘strongly recommend(ing) that
nerve-tissue vaccines should be discontinued’’.27
The fourth International Symposium on Control in
Asia called for cessation of NTV manufacture by
2006.31 WHO is very concerned with safety and
immunogenicity, and particularly about death
from ‘‘vaccination failure related to sub-potent
vaccines’’.13
An additional concern is that individuals adminis-
tered pre-exposure prophylaxis with these poorly
immunogenic NTVs may have no useful immune
memory against rabies, and be unable to mount an
329
anamnestic response when boosted after expo-
sure.17 Thongchareon et al. examined the sera of
10 paediatric rabies cases immunized post-ex-
psoure with NTV32: neutralizing antibody was
detected in only three, and at low titers. These
findings confirm the inability of NTV immunization
to protect against clinical rabies or to guarantee
seroprotection.17,32 In cases of potential exposure,
individuals previously immunized with NTV should
be treated as immunologically naı̈ve and receive
full post-exposure immunization with a tissue
culture derived vaccine.33 Immunogenicity and
safety concerns led the WHO to recommend that
only cell culture origin vaccines are used for pre-
exposure prophylaxis in 1992.13
4.2. Human diploid cell vaccine
HDCV was the first tissue culture vaccine to be
introduced (Imovaxs Rabies, sanofi pasteur,
France) and has acted as a reference vaccine.
HDCV is more difficult to produce than Verorabs,
which is accordingly cheaper to manufacture, an
important factor for developing countries.34,35
5. Verorabs immunogenicity and
efficacy
The WHO has declared a minimum protective
titer of 0.50 IU/mL, based on the correlation
between neutralizing antibody titers and protec-
tion against clinical rabies.27 Although other med-
iators of immunity, including interferon, T-helper
and T-cytotoxic cells are known to be important in
human defence against rabies,13 the WHO minimum
titer is the benchmark of rabies vaccine immuno-
genicity.27 Verorabs has been assessed by this
standard in a large number of clinical situations and
studies.
5.1. Immunogenicity in pre-exposure
prophylaxis
Table 1 summarizes studies that examined Veror-
abs in a pediatric pre-exposure setting; Table 2
summarizes the results from principally adult
studies.
Lang et al. examined the immunogenicity of
intramuscular Verorabs in 43 Vietnamese infants,
given simultaneously with diphtheria toxoid, teta-
nus and pertussis vaccines (DTP-IPV). Vaccine was
administered at 2 and 4 months of age during
expanded program on immunization (EPI) ses-
sions.36 A control group of 41 infants received
 ARTICLE IN PRESS
330
DTP-IPV alone. One month after the final immuni-
zation in the series, i.e. at 5 months of age, all
infants demonstrated seroprotective anti-rabies
titers; no interference with DTP-IPV immunogeni-
city was found.
A second study by Lang et al. examined the
immunogenicity of Verorabs by intramuscular and
intradermal routes when co-administered with
DTP-IV.37 Vietnamese infants (N ¼ 117) received
either 0.1 mL of intradermal Verorabs with DTP-
IPV at 2, 3, and 4 months of age, or 0.5 mL of
intramuscular Verorabs with DTP-IPV at 2 and 4
months of age (N ¼ 118). Antibody titers were
measured 1 month after the last dose of rabies
vaccine. Seroprotection against rabies was
achieved by both routes: GMT in the intradermal
group was 12.0, and 30.6 IU/mL in the intramus-
cular group. The authors concluded ‘‘There was no
evidence for any interference between DTP-IPV and
rabies vaccine.’’
Dureux et al. trialed Verorabs in 71 subjects
using the currently recommended 3 dose pre-
exposure regimen (days 0, 7, and 28).38 An
additional 52 subjects were immunized with the
now obsolete day 0, 28, and 365 pre-exposure
regimen. Administration was either subcutaneous
or intramuscular although the results were not
reported by route of administration. Neutralizing
antibody titers were measured pre-immunization
on days 28 and 42. All subjects were seronegative
on enrolment.
Seroprotective levels were present on days 28
and 42 in all subjects immunized with the days 0, 7,
and 28 regimen. Of subjects immunized accor-
ding to the now abandoned day 0, 28, and 365
regimen, 86% were seroprotected by day 28, i.e.
Table 1 Studies reporting exclusively pediatric pre-exposure prophylaxis experience.
Study Routea Regimenb
Lang et al., 1997 im 2, 4 mo age
Lang et al., 1999 id 2,3,4 mo age
Lang et al., 1999 im 2, 4 mo age
Sabchareon et al. id 0,7,28,365
Sabchareon et al. im 0,7,28,365
Total
a
im, intramuscular; id, intradermal.
b
Indicates either subjects age, or days in injection series.
c
DTP-IV: combined diphtheria, tetanus, and whole cell pertussis vaccine, with inactivated polio vaccine.
S. Toovey
after a single injection. All were seroprotected by
day 42.
A study by Aijan et al. compared neutralizing
antibody titers in subjects administered a primary
immunization course of either Verorabs (N ¼ 72) or
HDCV (N ¼ 73); no boosters were given.4 No subject
was seropositive on entry. Doses were administered
intramuscularly on days 0, 7, and 21; titers were
assayed on days 21, 28, 126, 420, and 588.
All Verorabs recipients demonstrated protective
levels of antibody at their first assay on day 21,
with levels remaining protective in all subjects up
to day 420. Seroprotection fell to 98% at day 588.
All HDCV recipients demonstrated protective anti-
body levels from day 21 to day 126, thereafter
falling to 87% on day 420, but rebounding to 94%
at day 588. The fact that titers in the Verorabs
group were significantly higher than those in the
HDCV group is unlikely to be of clinical significance,
as all protective titers greatly exceeded the WHO
minimum.
Another Verorabs versus HDCV study was re-
ported by Vodopija et al.39 Subjects were immu-
nized intramuscularly with Verorabs (N ¼ 21) or
HDCV (N ¼ 24) on days 0, 7, and 21. All subjects
were seronegative on study entry. Following im-
munization, neutralizing antibody titers were mea-
sured on days 7, 14, 21, 28, and 90. No statistically
significant inter-group differences were found
when comparing seroprotection or geometric mean
titer (GMT): 100% of Verorabs recipients had
protective antibody levels by day 14, and remained
seroprotected at all subsequent measurements;
97% of the HDCV recipients were seroprotected
by day 14, rising to 100% for all subsequent
measurements. In all cases, seroprotective titers
N Ages Results and conclusions
41 2, 4 mo 100% protection on day 28. No interference
with DTP-IVc
117 2,3,4 mo 100% protection on day 28. No interference
with DTP-IV
118 2, 4 mo 100% protection on day 28. No interference
with DTP-IV
95 5–12 yr 98.9% protection on day 56. Anamnestic
response to booster
95 5–12 yr 100% protection on day 56. Anamnestic
response to booster
466
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005 331

Table 2 Studies reporting principally adults pre-exposure prophylaxis experience.

Study Rationalea Routeb Regimenc N Results & Conclusions

Aijan et al. Pre im 0,7,21 72 100% protection to day 420; equivalent to HDCV
Dureux Pre sc/im 0,7,28 71 100% protection on day 28
Dureux Pre sc/im 0,28 52 100% protection on day 42
Favi et al. Pre sc 0,7,28 30 Superior to NTV
Fournier et al. Booster 1 yr 86 Anamnestic response; primary course was HDCV
Fournier et al. Pre sc 0,7,21 64 100% protection on day 14
Hacibektasoglu Pre im 0,7,21 30 100% protection on day 21; equivalent to HDCV
et al.
Jaiiroensup et al. Pre id 0,7,28 300 No serious adverse events
Jaiiroensup et al. Pre im 0,7,28 300 No serious adverse events
Kitala et al. Pre im 0,7,28 43 100% protection on day 28;equivalent to HDCV
Kositprapa et al. Booster im Booster 31 Good anamnestic response after primary im series
12–16 m
Kositprapa et al. Booster id Booster 35 Good anamnestic response after primary id series
12–16 m
Strady et al. Pre im Booster 49 96% protected 10 yr after 1 yr booster; equivalent
1 yr to HDCV
Suntharasamai Pre im 0,3,7 15 100% protection day on 14; equivalent to HDCV
et al., 1987
Suntharasamai Booster im 1 yr boost 14 Good anamnestic response
et al., 1988
Suntharasamai Booster im 1 yr boost 15 Good anamnestic response Human RIG given with
et al., 1988 primary course
Svetlicic et al. Pre im 0 30 100% protection on day 14
Svetlicic et al. Pre im 0,7,21 30 100% protection on day 35
Vodopija et al., Pre im 0,7,21 21 100% protection on day 14 Equivalent to HDCV
1986
a
pre, primary pre-exposure regimen; booster, boosting of a pre-exposure primary regimen.
b
im, intramuscular; id, intradermal; sc, subcutaneous.
c
indicates days in series when injections were administered, or interval to boosting.

were significantly higher than the WHO prescribed
minimum.
Svjetlicic examined the pre-exposure immuno-
genicity of intramuscular Verorabs in 2 separate
studies, each employing young adult male volun-
teers5; subjects were seronegative on entry. The
first group (N ¼ 30) received a single dose and had
serological assessments on days 14 and 30, when
GMTs were found to be 1.96 and 1.88 IU/mL,
respectively. A second group (N ¼ 30) was injected
on days 0, 7, and 21 and showed a GMT of 13.8 IU/mL
on day 35. Taken together, these studies demon-
strate potent and timely immunogenicity.
A Thai immunogenicity study conducted by
Sabcahreon et al. randomized children to receive
intradermal (N ¼ 95) or intramuscular (N ¼ 95)
Verorabs.40 Vaccine was administered on days 0,
7 and 28, and boosted by the original route on day
365. Serological assessment of neutralizing anti-
body titers was undertaken on days 0, 56, 180, and
before booster administration on day 365. Titers
were also measured 7, 180, 365, and 730 days
after the 1 year booster dose. All children were
seronegative on study entry.
At day 56, 1 month after completion of the
primary series, 98.9% of children in the intradermal
and 100% of children in the intramuscular group
demonstrated protective antibody levels above the
WHO minimum.
The percentage of children in the intradermal
group seroprotected according to the WHO criter-
ion fell to 80.6% at 180 days, and to 52.5% at 365
days. A booster dose at day 365 provoked a brisk
anamnestic response however, and 100% of children
were seroprotected by the WHO criterion 7 days
post-booster. The percentage seroprotected 180
days post-booster was 93.5%; at 365 days post-
booster 95.9% were seroprotected, and at 730 days
post-booster 88.3% were seroprotected.
In the group given intramuscular Verorabs, all
children were seroprotected at day 56; at day 180,
91% were seroprotected, and at day 365, 90.8%
 ARTICLE IN PRESS
332
were seroprotected. Boosting at day 365 elicited
a strong and rapid anamnestic response in this
group too, with all children seroprotected 7 days
later. At 180 days post-boosting the percentage
with seroprotective titers was 97.1%; at 365
days post-boosting the percentage protected was
100%, and at 730 days post-boosting 96.7%. The
seroprotection rate was significantly higher in
the intramuscular group on days 180 and 365
(w2, po0.001).
Kitala et al. compared neutralizing antibody
titers following intramuscular Verorabs and HDCV
administration.41 Forty-three subjects received
Verorabs and 37 HDCV on days 0, 7, and 28. All
subjects were seronegative on study entry. Titers
were measured on days 7, 28, and 49. No
statistically significant differences were found with
respect to antibody titers or the percentage of
subjects seroprotected, although a higher percen-
tage of Verorabs recipients than HDCV recipients
were seroprotected by day 7 (34% versus 17%). All
subjects were seroprotected at days 28 and 49,
with levels far in excess of the WHO minimum.
Adopting a classic double blind placebo con-
trolled randomized study design, Hacibektasoglu
et al. compared Verorabs against HDCV.42 Three
groups (n ¼ 30 each) were allocated to receive
Verorabs, HDCV, or placebo. Administration was
intramuscular on days 0, 7, and 21. Neutralizing
antibody titers were measured on days 7, 21, 28,
and 60. All subjects were seronegative on enroll-
ment. All subjects displayed protective anti-
body titers when assessed on day 21, with
protective levels persisting through to day 60. No
statistically significant differences in antibody
titers were found between the 2 groups. Unsurpris-
ingly, placebo recipients failed to develop protec-
tive antibodies.
Strady et al. measured protective antibody titers
every year for 10 years post-vaccination in subjects
immunized with a primary series of 3 intramuscular
Verorabs (N ¼ 49) or HDCV (N ¼ 17) doses; all
subjects were boosted at 1 year with the same
vaccine.43 No significant difference was found in
titers generated by Verorabs or HDCV, with all
subjects seroprotected on day 42. At least 96% of
subjects in both groups retained protective anti-
body levels for 10 years. Fournier et al. reported
the results of boosting by Verorabs in 86 subjects
previously given 3 doses of HDCV6; all subjects
mounted a good anamnestic response.
Verorabs whether administered intradermally or
intramuscularly for pre-exposure prophylaxis gives
adequate neutralizing antibody titers, although
levels tending to be lower following intradermal
administration. Following vaccination by either
S. Toovey
route, booster doses lead to a brisk and protective
immune response.40,43,44
5.2. Verorabs in post-exposure prophylaxis
settings
Studies reporting results post-exposure are sum-
marized in Table 3.
A 1987, a study by Suntharasamai et al. com-
pared the immunogenicity of intramuscular
Verorabs against a variety of intramuscular and
intradermal HDCV regimens, to establish which
vaccine and regimen gave the fastest neutralizing
antibody response. Verorabs was administered as
a single intramuscular dose on days 0, 3, and 7 in
one study arm (N ¼ 15), and as 2 single doses on
day 0, and 2 single doses on day 3 in a second arm
of the study.
Judged by day 7 titers, no single regimen or
vaccine gave a significantly faster response. By day
14 all subjects who had received intramuscular
Verorabs were seroprotected, while 2 subjects
who had received double doses of HDCV failed to
achieve seroprotection. Despite this observation,
no significant differences in terms of the speed and
titer of neutralizing antibody response were evi-
dent between vaccines or regimens.45 The authors
concluded that no vaccine or regimen was superior
to another.
5.2.1. Subcutaneous post-exposure prophylaxis
Thongcharoen et al. administered Verorabs sub-
cutaneously to 27 Thai children exposed to rabid
animals.32 Neutralizing antibody titers were deter-
mined at day 14 and were seroprotective in all
children tested. Importantly, no difference was
found in antibody levels between children adminis-
tered human RIG and children who received
Verorabs alone. Titers were found to be seropro-
tective in all children when re-examined 1 year
post-immunization. Treatment proved effective in
all cases, with all children alive and well 2 years
after exposure.
In Chadli et al.’s Tunisian study, 75 subjects are
reported following post-exposure prophylaxis with
a 6 dose subcutaneous regimen, with 0.5 mL/dose.
All subjects achieved neutralizing antibody levels
X0.5 IU/mL by day 14.46
5.2.2. Intramuscular
Verorabs meets WHO criteria for intramuscular
post-exposure prophylaxis by both the Essen and
Zagreb regimens.27
5.2.2.1. Essen (1-1-1-1-1) regimen. The Essen
regimen comprises post-exposure prophylaxis with
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005
0.5 mL of Verorabs into the deltoid or anterolat-
eral thigh on days 0, 3, 7, 14, and 28. The 6 dose
Essen regimen included an optional sixth dose on
day 90; this 6th dose has now been abandoned.
Dureux et al. studied post-exposure Verorabs in
90 French patients, 27 (30%) of whom had been
bitten by confirmed rabid animals.38 Immunization
followed the 6 dose Essen regimen, although a
number of patients received vaccine subcuta-
neously rather than intramuscularly; results were
reported without differentiation by route. Regard-
less of route, all subjects developed seroprotective
antibodies by day 30 (GMT 24 IU/mL); titers
remained protective at day 90 (GMT 8 IU/mL) and
day 120 (GMT 16.1 IU/mL). No case of clinical
rabies developed during 2 years of follow-up.
Jaiiaroensup et al. reported outcomes in 84
patients administered Verorabs and RIG for severe
bites from confirmed rabid animals47; 50% of bites
were to the hands or the head. Forty subjects were
administered intradermal Verorabs, and 44 re-
ceived Essen regimen Verorabs. Between 7 and 15
deaths would have been expected in these 84
subjects, but all subjects, whether immunized
intradermally or intramuscularly, were alive and
well 3 years post-immunization.
Wang et al. reported from China on Essen
regimen Verorabs efficacy in 163 patients, all
categorized as having severe exposures.48 Neutra-
lizing antibody tires were measured on days 0, 7,
14, 28, 90, and 180. All reported subjects were
seronegative on entry to the study, and all received
equine RIG. By day 7, seroprotective levels of
neutralizing antibody were noted in 27% of sub-
jects, rising to 100% by day 14, when the GMT was
50.3 IU/mL. All subjects displayed seroprotective
antibody levels up to and including day 90; 98.2% of
subjects showed seroprotection on day 180 and all
patients were alive 6 months post-treatment.
Neutralizing antibody titers in 71 volunteers
administered Essen regimen Verorabs were re-
ported by Lang et al.49 Subjects received Verorabs
in association with either commercially available
equine RIG, or a purified equine RIG fragment,
F(ab0 )2. Serological assessment of neutralizing anti-
bodies was performed on days 3, 7, 14, and 28. Co-
administration of RIG did not interfere significantly
with the development of seroprotection.
Suntharasamai et al. detailed Essen regimen
Verorabs experience with 106 Thai patients treated
for bites from confirmed rabid animals.7 Blood was
drawn for serology on days 14 and 365. No subjects
had previously received rabies vaccination.
All subjects responded with adequate neutraliz-
ing antibody titers, the minimum being 1.6 IU/mL
on day 14. All subjects were alive 1 year later, when
333
none had a neutralizing antibody level o1.6 IU/mL.
Human RIG was administered to 47 subjects and
found not to interfere with antibody development.
Seghal et al. reported their experience with 309
Indian patients given post-exposure prophylaxis
with Essen regimen Verorabs.50 Of the 309 initial
subjects, 206 completed a course of at least 5
immunizations. In 41 (26%) cases the offending
animal was kept under observation and determined
to be not rabid. Twenty-two subjects (7%) were
administered RIG. Of interest, 21 (6.8%) subjects
were immunized following contact with a rabid
human.
Serological assessment was conducted in all cases
10–15 days after the final dose of Verorabs. In all
cases, even in subjects who had received just 2
doses of vaccine, the minimum seroprotective level
was exceeded. No treatment failures occurred.
Svjetlicic examined the post-exposure immuno-
genicity of intramuscular Verorabs in young adult
male volunteers.5 All subjects were seronegative
on entry. Forty subjects were immunized with the 6
dose Essen regimen, GMTs were: day 7, 0 IU/mL;
day 14, 26.09 IU/mL; day 30, 17.44 IU/mL; day 90,
4.49 IU/mL; day 100, 9.40 IU/mL. Although the
study did not directly compare Verorabs with
HDCV, the authors believed that the day 14 serology
result was superior to that they could have
expected with HDCV.
Sudarshan et al. administered Verorabs to 29
pregnant subjects following potential exposures,
using the Essen regimen.51 No cases of clinical
rabies developed.
A study by Suntharasamai et al. compared
Verorabs with HDCV in a simulated post-exposure
setting.34 Thai veterinary students were immunized
with either Verorabs (N ¼ 30) or HDCV (N ¼ 30).
One half of the subjects in each group were
randomized to receive human RIG (20 IU/kg) on
day 0. Vaccine was administered intramuscularly in
a 6 dose Essen schedule; neutralizing antibody
titers were analyzed pre-vaccination on days 0, 7,
14, 28, and 91. Subjects previously immunized
were excluded from analysis.
From day 14 onwards all subjects displayed
seroprotective levels, with the minimum level
being 1.0 IU/mL. When comparing the titer differ-
ences between the Verorabs only group and the
HDCV only group, the HDCV group displayed higher
titers on days 14 and 91, but not on day 28. GMTs in
the Verorabs group were however sufficiently high
at all measurements to render differences clinically
irrelevant.
Another study led by Suntharasamai confirmed
Verorabs’s immunogenicity as a booster.44 Subjects
who had completed post-exposure prophylaxis with
 334

Table 3 Experience with post-exposure prophylaxis.

Studya Routeb Regimen N Children Ages Pregnant Severe Rabid RIGc Results & conclusions
years injury bites

Chanthanavich im Zagreb 29 29 7–13 yr 100% protection on day 14

Chanthanavich im Zagreb 26 26 7–13 yr 100% protection on day 14
1/2 dose
Chanthanavich im Zagreb 27 27 7–13 yr 100% protection on day 14, titers dose
1/3 dose dependent
Chutivongse im Zagreb 96 40e 0–15 yr 96 96 ERIG 100% protection on day 14; no human rabies.
1991 Essen titers4Zagreb
Chutivongse im Zagreb 4 4 4 HRIG 100% protection on day 14; no human rabies.
1991 Essen titers4Zagreb
Chutivongse id TRC-ID 96 19f 96 ERIG 100% protection on day 14; no human rabies
1990
Chutivongse id TRC-ID 4 4 HRIG 100% protection on day 14; no human rabies.
1990
Chutivongse id/im TRC-ID/ 65 65 65 ERIG No human rabies; no increase in pregnancy or
1995 Essen fetal abnormalities
Chutivongse id/im TRC-ID/ 3 3 3 HRIG No human rabies; no increase in pregnancy or
ARTICLE IN PRESS

1995 Essen fetal abnormalities

Chutivongse id/im TRC-ID/ 134 134 No human rabies; no increase in pregnancy or
1995 Essen fetal abnormalities
Colnot im Zagreb 50 96% protection on day 28
Dureux sc/im Essen 90 27 100% protection on day 30; no human rabies
Jaiiroensup id TRC-ID 40 40 E/HRIG No human rabies
Jaiiroensup im Essen 44 44 E/HRIG No human rabies
Jaiiroensup id TRC-ID 259 E/ No human rabies
HRIGd
Jaiiroensup im Essen 255 E/ No human rabies
HRIGd
Khawplod id 4 sites 42 Boosting possible with 4 id injections at 1 visit
Lang, Attanah im Essen 36 ERIG 100% protection on day 14
Lang, Attanah im Essen 35 PERIG 100% protection on day 14
Lang, im Zagreb 58 100% protection on day 28
Simanjuntak
S. Toovey
Lang, im Zagreb 33 ERIG 94.4% protection on day 28
Simanjuntak
Lang, im Zagreb 45 HRIG 90.7% protection on day 28
Simanjuntak
Phanupak sc 0,3,7 15 100% protection on day 14
Phanupak id 0,3,7 14 100% protection on day 14
Phanupak sc/id 0,3,7 15 100% protection on day 14
Seghal ? Essen 184 125e,f 0–15 yr 45 100% protection on day 10–15; no human rabies
Seghal ? Essen 22 22 RIGe 100% protection on days 10–15; no human rabies
Sudarshan im Essen 29 29 6 100% protection on days 14; no human rabies. No
increase in pregnancy or fetal abnormalities
Sudarshan, im Essen 17 17 100% protection on days 14 and 365; no
Gangaboriah immunosuppression by pregnancy
Sudarshan, im Essen 17 100% protection on day 14 and 365
Gangaboriah
Suntharasamai im Essen 59 2f 59 100% protection on day 14; no human rabies
1986
Suntharasamai im Essen 47 47 HRIG 100% protection on day 14; no human rabies
1986
Suntharasamai im Essen 15 HRIG 100% protection on day 14; equivalent to HDCV
1986
Suntharasamai im Essen 15 100% protection on day 14; equivalent to HDCV
1986
Preventing rabies with the Verorabs vaccine: 1985–2005

Svjetlicic im Essen 40 100% protection on day 14

Thangcharoen sc Essen 20 20 1–14 yr 20 100% protection on day 14; no human rabies
Thangcharoen sc Essen 7 7 1–14 yr 7 7 HRIG 100% protection on day 14; no human rabies
ARTICLE IN PRESS

Vodopija 1986 Zagreb 23 100% protection on day 14; equivalent to HDCV

Vodopija 1997 im Zagreb 9 100% protection on days 35, 1100;anamnestic
response
Wang im Essen 163 163 ERIG 100% protection on day 14; no human rabies
a
First author, with additional identifying author year where required for clarity.
b
im: intramuscular; id: intradermal; sc: subcutaneous.
c
Rabies immunoglobulin type: ERIG, equine RIG; HRIG, human RIG: PERIG, highly purified F(ab0 )2 equine RIG fragment.
d
Not all subjects received RIG.
e
RIG-type unspecified.
f
Proportion treated with RIG unstated.
335
 ARTICLE IN PRESS
336
HDCV (N ¼ 15), HDCV and human RIG (N ¼ 14),
Verorabs (N ¼ 14), or Verorabs and human RIG
(N ¼ 15) were administered an intramuscular dose
of Verorabs 1 year later. Neutralizing antibody
levels were assessed immediately pre-boosting and
14 days later. All subjects had titers X0.6 IU/mL
pre-boosting. A higher GMT post-boosting was seen
in subjects previously immunized with Verorabs
(p ¼ 0.001). Prior administration of RIG had no
effect on anamnestic response.
Kositprapa et al. studied the response to boosting
following intradermal (N ¼ 35) and intramuscular
post-exposure prophylaxis (N ¼ 31).52 Subjects
were boosted 12–16 months later by the same
route, when GMTs were 0.20 IU/mL for the intra-
dermal group, and 0.57 IU/mL for the intramuscular
group (p ¼ 0.32). A rise in titer followed boosting in
both groups, with protective levels in all subjects
by day 7, with the exception of 1 in the intradermal
group who showed a titer of 0.42 IU/mL; reassess-
ment on day 14 confirmed all subjects fully
protected. Although titers were generally higher
in the intramuscular group, the study demonstrated
intradermal efficacy.
Verorabs has demonstrated dependable efficacy
with the Essen regimen, which has become the de
facto standard intramuscular regimen for post-
exposure prophylaxis. All Essen regimen studies
have demonstrated solid immunogenicity and clin-
ical efficacy, with a number showing very rapid
development of neutralizing antibody.48,49 A pro-
longed duration of seroprotection has also been
demonstrated,5,7,38,48 a critical property given the
possibility of prolonged incubation with rabies.
5.2.2.2. Zagreb (2-1-1) regimen. The Zagreb re-
gimen consists of two doses on day 0, followed by
single doses on days 7 and 21; 0.5 mL of Verorabs is
administered intramuscularly into the deltoid or
the anterolateral thigh. It is also referred to as the
‘2-1-1’ regimen.
Vodopija et al. compared the efficacy of a
number of vaccines, including Verorabs, against
HDCV in a double blind study using the Zagreb
regimen.39 Twenty-six subjects received HDCV and
23 Verorabs; all subjects were seronegative on
study entry. No significant difference was seen in
the immunogenicity of HDCV and Verorabs: 18
(78%) of Verorabs recipients displayed seroprotec-
tive titers by day 7, as did 17 (65%) of HDCV
recipients. Subsequent titers on days 14, 21,
28, and 90 confirmed seroprotection in both
Verorabs and HDCV recipients, with little differ-
ence between groups.
A second Vodopija et al. study administered
Zagreb regimen Verorabs, with a single booster at
1100 days (N ¼ 9).53 Serological assessment at days
S. Toovey
35 and 1100 showed protection. A brisk anamnestic
response followed boosting.
A French study by Colnot et al. examined the
immunogenicity of the Zagreb regimen.54 No sub-
ject had a history of previous vaccination. Fifty
subjects were administered Verorabs according to
the standard Zagreb regimen. In this study, 34 (68%)
subjects had protective antibody levels by day 21,
rising to 96% by day 28.
Chutivongse et al. administered Verorabs, fol-
lowing the Zagreb regimen, along with equine or
human RIG to 100 Thai patients, all severely bitten
by animals proven rabid.55 All subjects in this study
were followed clinically for 1 year. Neutralizing
antibody GMTs were measured in 10 subjects, on
days 14, 90, and 365, and found to be 1.51, 1.15,
and 0.39 IU/mL respectively. All 10 subjects exam-
ined revealed protective antibody levels by day 14,
but seroprotection fell to 80% by 90 days, and 50%
by day 365. All of the 100 patients treated were
well when followed up 1 year later. Although the
treatment regimen proved clearly effective, as 13
rabies deaths could have been expected in this
group, the authors concluded that the 2-1-1 regi-
men is not suitable for co-administration with RIG,
as this appeared to interfere with the development
of WHO-defined seroprotection.
Lang et al. report the immunogenicity of Veror-
abs administered according to the Zagreb regimen,
looking principally at the effect of RIG on antibody
development.56 Subjects in the study arm that
received Verorabs alone displayed neutralizing
antibody titers above the WHO minimum when
tested on days 28 and 90. Seroprotective levels
were not reached by all subjects in the groups who
received RIG in addition to Verorabs.
No treatment failures are reported from use of
Verorabs and the Zagreb regimen, but the regimen
appears less immunogenic when co-administered
with RIG. Without RIG’s suppressive effect, a rapid
rise in antibody titer was observed.39 Despite the
Zagreb regimen retaining WHO approval,13 some
authors have called for restrictions on its use.57
5.2.3. Intradermal Verorabs for post-exposure
prophylaxis
Intradermal vaccine application uses lower total
doses than intramuscular regimens. Intradermal
administration is believed to derive its immuno-
genicity from exposure of antigen to densely
packed dendritic cells, and drainage from multiple
injection sites to different lymph node groups.15
The lower total dose of vaccine reduces cost,
facilitating replacement of NTV with modern cell
culture vaccines in developing countries.35 WHO
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005
approved Verorabs for use with the Thai Red Cross
intradermal (TRC-ID) regimen in 1992.13
The original TRC-ID regimen applied two 0.1 mL
doses of of Verorabs intradermally on days 0, 3,
and 7, with single doses administered on days 30
and 90. A total of 0.8 mL of vaccine was utilized, as
opposed to the 2.5 mL of the Essen intramuscular
regimen. The regimen has recently been updated
by WHO, with a double dose on days 0, 3, 7, and 28;
the day 90 dose is now omitted.27
Chutivongse-treated 100 Thai victims of bites
from rabid animals with the TRC-ID regimen.58 All
bites were severe and victims received RIG.
Seroprotection was assessed by measuring the
neutralizing antibody GMT of 10 subjects on days
14, 90, and 360, when it was found to be 3.47,
0.938, and 0.738 IU/mL, respectively. All subjects
tested were seroprotected, with titers above the
WHO minimum, and all subjects were alive and well
1 year after being bitten. Without intervention
between 9 and 18 deaths would have been
expected in the group.
The titers reported on days 14 and 360 in this
study are noticeably lower than Chutivongse et al.
reported in their study that combined RIG with
intramuscular Verorabs, even though studies
were conducted in parallel and used vaccines
from the same batch (lot A0254 with potency
3.17 IU/mL).55,58
The authors believe that the TRC-ID regimen
provokes a brisk immune response, as evidenced by
the high titer on day 14. They comment that this
includes a cell mediated response, which may be
important in the early containment of rabies.59
Over 70 000 TRC-ID Verorabs courses have been
administered in Thailand,31 with just a single death
reported, in an alcoholic subject with hepatic
cirrhosis who suffered severe bites to the hand,
and who delayed treatment initiation for 6 days.59
Jaiiaroensup et al.’s report of 40 subjects with
severe exposures from confirmed rabid animals also
confirmed efficacy, showing all 40 subjects alive 3
years after TRC-ID Verorabs co-administered with
equine or human RIG.47
A study by Khawplod et al. found that subjects
(N ¼ 42) who had been pre-immunized with Veror-
abs could be satisfactorily boosted post-exposure
with 0.1 mL of Verorabs administered intra-
dermally, with simultaneous injections to 4 differ-
ent sites.60 The 4-site single visit intradermal
regimen yielded significantly higher titers post-
boosting than the standard 2 dose intramuscular
regimen.
Intradermal post-exposure prophylaxis is as effi-
cacious, and at least as immunogenic as intramus-
cular administration. Intradermal immunization
337
reduces costs and extends the availability of cell
culture vaccines, and is now accepted practice.
Khawplod et al. showed that reconstituted vaccine
could be refrigerated for 1 week without losing
potency,61 reducing costs even further and facil-
itating usage in resource poor settings.
5.2.4. Subcutaneous administration and
immunogenicity
Much has been made of the need to ensure that
intradermal rabies immunizations are administered
into the dermis, and not given subcutaneously.27
A Thai study examined the effect of subcuta-
neous administration,62 comparing neutralizing
antibody titers between subjects given a solely
intradermal series (N ¼ 15), a solely subcutaneous
series (N ¼ 15), and a series comprising 50%
subcutaneous and 50% intradermal injections
(N ¼ 14). All subjects were seronegative on study
entry, and all were immunized following the same
regimen: 2 injections of 0.1 mL Verorabs on days 0,
3, and 7.
Neutralizing antibody titers were measured on
day 14 and found to be above the WHO minimum in
all subjects. There was no statistically significant
difference in GMT between the groups that
received vaccine intradermal only (15.5 IU/mL)
and subcutaneous only (18.5 IU/mL). The group
which received 50% subcutaneous and 50% intra-
dermal vaccine showed a significantly higher
GMT (26.4 IU/mL). Chadli et al. used Verorabs
subcutaneously, at 0.5 mL/dose for post-exposure
prophylaxis and achieved satisfactory neutralizing
titers.46 Favi et al.’s study also demonstrated
adequate titers following subcutaneous Verorabs
administration.14
Verorabs appears superior to HDCV following
subcutaneous administration: HDCV in subcuta-
neous usage generates lower, but still adequate,
levels of neutralizing antibody.63 Fournier et al.
reported 64 subjects given 0.5 mL of Verorabs
subcutaneously on days 0,7, and 21; all were
seroprotected by day 14.6 A Tunisian post-exposure
study achieved 100% seroprotection by day 14 with
subcutaneous Verorabs.46 Thongcharoen et al.
successfully used subcutaneous Verorabs in 27 Thai
children, 7 of whom received human RIG.32
In Dureux et al.’s study, a number of subjects
were intentionally administered Verorabs subcu-
taneously.38 Although titers in subjects adminis-
tered subcutaneous vaccine were not reported
separately in the study, no subject failed to achieve
seroprotective levels of neutralizing antibody.
Inadvertent subcutaneous Verorabs administration
should not to be cause for concern.
 ARTICLE IN PRESS
338
5.3. Post-exposure prophylaxis with
Verorabs and RIG
Studies that examined the co-administration of RIG
with Verorabs are summarized in Table 4.
Suntharasamai et al. directly assessed the effect
of RIG on neutralizing antibody development,
comparing titers in Thai students administered
Verorabs with (N ¼ 14), and without (N ¼ 15)
human RIG.34 Verorabs was administered in a 6
dose Essen regimen. The authors found human RIG
administration did not affect neutralizing antibody
titers when measured on days 7, 14, 28, and 91.
When HDCV was substituted for Verorabs and co-
administered with human RIG, some suppression of
antibody development was observed, although this
was probably not clinically significant.
Suntharasamai et al. also compared the neutraliz-
ing antibody responses in Thai patients administered
intramuscular Verorabs following a 6 dose Essen
regimen with human RIG (N ¼ 47), and subjects
administered Verorabs without human RIG (N ¼
59).7 No significant differences in seroconversion rates
or GMT were found between the two groups: GMTs in
the group that received RIG were 22.6 IU/mL on day
14 and 2.5 IU/mL on day 365. All subjects survived.
Chutivongse et al. administered TRC-ID Verorabs
with equine RIG to 100 Thai patients severely bitten
by confirmed rabid animals58; 96 received equine
and 4 human RIG. Serological assessment of 10
subjects revealed adequate titers, and all subjects
survived. If the administration of RIG did interfere
with antibody development, the effect was not
clinically relevant.
Chutivongse et al. also reported results from the
co-administration of RIG with Zagreb regimen Veror-
abs.55 Seroprotection fell from 100% at 14 days to
80% at day 90, and to just 50% at day 365. The authors
concluded that the Zagreb regimen was not suitable
for administration with RIG. The same vaccine batch
(lot A0254 with potency 3.17 IU/mL) was used in
Chutivongse’s TRC-ID study detailed above.
Lang et al. also found RIG-suppressed neutraliz-
ing antibody development when used with Zagreb
regimen Verorabs.56 This study compared neutra-
lizing antibody titers between three groups: one
given Verorabs alone (N ¼ 58), one given Verorabs
and equine RIG (N ¼ 33), and one given Verorabs
and human RIG (N ¼ 45). Significant differences in
seroconversion rates were found between the three
groups on day 28. While the Verorabs only group
achieved 100% seroprotection, the rate fell to
94.4% in the Verorabs and equine RIG group, and
90.7% in the Verorabs and human RIG group.
In contrast, Lang et al. found no suppres-
sion when the Essen regimen was followed.49
S. Toovey
Neutralizing antibody titers were measured in 71
volunteers: 36 received standard equine RIG, and
35 received a purified, heat treated equine RIG
fragment, F(ab0 )2. By day 7, protective antibody
levels were seen in 48.6% of F(ab0 )2 recipients, and
58.3% of standard equine RIG recipients. All
subjects had seroprotective neutralizing antibody
titers on days 14 and 28, with the day 28 GMT
430 IU/mL.
Chutivongse et al. administered Verorabs, using
both TRC-ID and intramuscular Essen regimens, to
68 pregnant Thai women1; 65 received equine RIG,
and 3 human RIG. Serological response was not
measured, but efficacy was demonstrated by all
women being alive 1 year after treatment.
Thongcharoen reported no differences in the
neutralizing antibody titers of Thai children given
Verorabs either with (N ¼ 7) or without human RIG
(N ¼ 20), when measured on day 14 and 1 year
after immunization.32
Seghal reported the use of Verorabs according to
the Essen regimen with RIG in 22 patients with
severe bites.50 This report does not provide
separate data on patients administered RIG, but
all subjects achieved satisfactory antibody levels
and no deaths occurred.
Jaiiaroensup et al. administered intramuscular or
intradermal Verorabs with either equine or human
RIG to 84 victims of severe bites from rabid animals
without treatment failure,47 while a Chinese study
(N ¼ 163) showed that equine RIG did not interfere
with seroprotection from Essen regimen Veror-
abs.48 All subjects developed high titers of neutra-
lizing antibody.
The available evidence suggests that the immu-
nogenicity of Verorabs is not compromised to any
significant extent by the simultaneous administra-
tion of RIG,7,32,34,49,50 except when the Zagreb
regimen is followed,55,56 even though the evidence
suggests that Verorabs is less susceptible than
HDCV to RIG interference.34
Encouragingly for developing countries, the less
expensive equine RIG appears less prone to interfere
with antibody development.49,56 Equally encouraging
for developing countries is that RIG appears not to
interfere with intradermal Verorabs.58 Overall, the
studies show human and equine RIG as not impeding
in any significant way the development of seropro-
tection by intradermal or Essen regimen Verorabs.
5.4. Post-exposure prophylaxis in special
situations
5.4.1. Severe injuries
Studies reporting experience with post-exposure
prophylaxis for severe wounds, and those inflicted
Table 4 Studies reporting experience of post-exposure prophylaxis with RIG.

Study Routea Regimen N Severe Rabid RIGc Results & conclusions

injury injury

Chutivongse 1991 im Zagreb 96 96 96 ERIG 100% protection on day 14; no human rabies Essen
titer4Zagreb
Chutivongse 1991 im Zagreb 4 400 4 HRIG 100% protection on day 14; no human rabies Essen
titer4Zagreb
Chutivongse 1990 id TRC-IDb 96 19 96 ERIG 100% protection on day 14; no human rabies
Chutivongse 1990 id TRC-ID 4 4 HRIG 100% protection on day 14; no human rabies.
Chutivongse 1995 id/im TRC-ID/ 65 65 ERIG No human rabies; no increase in pregnancy/fetal
Essen abnormalities
Chutivongse 1995 id/im TRC-ID/ 3 3 HRIG No human rabies; no increase in pregnancy/fetal
Essen abnormalities
Jaiiroensup id TRC-ID 40 40 E/HRIG No human rabies
Jaiiroensup im Essen 44 44 E/HRIG No human rabies
Jaiiroensup id TRC-ID 259 E/HRIGd No human rabies
Preventing rabies with the Verorabs vaccine: 1985–2005

Jaiiroensup im Essen 255 E/HRIGd No human rabies

Lang, Attanah im Essen 36 ERIG 100% protection on day 14
Lang, Attanah im Essen 35 PERIG 100% protection on day 14
Lang, Simanjuntak im Zagreb 33 ERIG 94.4% protection on day 28
ARTICLE IN PRESS

Lang, Simanjuntak im Zagreb 45 HRIG 90.7% protection on day 28

Seghal ? Essen 22 22 RIGe 100% protection on day 10–15. No human rabies
Suntharasamai 1986 im Essen 47 47 HRIG 100% protection on day 14. No human rabies
Suntharasamai 1986 im Essen 15 HRIG 100% protection on day 14. Equivalent to HDCV
Thangcharoen sc Essen 7 7 7 HRIG 100% protection on day 14. No human rabies
Wang im Essen 163 163 ERIG 100% protection on day 14. No human rabies
a
id, intradermal; im, intramuscular; ‘?’, unspecified.
b
Thai Red Cross intradermal regimen.
c
ERIG, equine RIG; HRIG, human RIG; PERIG, highly purified equine F(ab0 )2 fragment RIG.
d
not all subjects received RIG.
e
RIG-type unspecified.
339
 ARTICLE IN PRESS
340
by confirmed rabid animals, are summarized in
Table 5.
Severe injuries are more likely to inoculate
greater virus numbers into victims, expose more
nerves, and offer more rapid access to the nervous
system. It may also be more difficult to administer
sufficient RIG in an even way to multiple or severe
wounds.27,33 All of these factors increase the risk of
clinical rabies and provide more demanding tests of
post-exposure prophylaxis.
Chutivongse et al. reported on 12 pregnant
subjects severely bitten by animals confirmed to
be rabid64; 8 subjects received intradermal, and
4 intramuscular vaccine. All subjects were pas-
sively immunized with equine RIG. No cases of
clinical rabies occurred, and all women were alive
and well twelve months later. Sudarshan et al.
treated 6 severely injured, pregnant women using
the Essen regimen without RIG51; all women
mounted satisfactory antibody responses to vacci-
nation and survived.
Jaiiaroensup et al treated 84 victims with severe
bites inflicted by confirmed rabid animals47: 50% of
bites were to the head or the hands. Forty-four
patients received intramuscular vaccine, and 40
intradermal; human or equine RIG was adminis-
tered to all victims. All victims were alive and well
3 years later.
Wang et al.’s series of 163 Chinese patients
included only severe injuries.48 All subjects were
administered Verorabs according to the Essen
regimen, and received equine RIG. All were alive
and well 6 months after treatment.
Suntharasamai et al. treated 47 patients with
severe injuries from known rabid animals.7 Victims
all received 6 dose Essen regimen Verorabs and
human RIG; all were alive and well at 6 months.
Seghal et al.’s Indian series reported 67 potential
exposures with severe injury. All received Veror-
abs, and 22 were co-administered RIG.50 All
subjects were alive 6 months post-treatment.
Chutivongse et al. reported a series of 100 Thai
patients with severe exposures from confirmed
rabid animals.55 Zagreb regimen Verorabs was
administered, with either human or equine RIG.
All patients were alive 12 months post-treatment.
All 19 Thai patients severely bitten by rabid animals
and administered TRC-ID Verorabs, with equine or
human RIG in the report by Chutivongse et al.58
were alive 1 year later.
Studies of Verorabs have proven it to be effective
in severe injuries when given either intramuscularly
or intradermally. This was also the case when RIG
was omitted, although this practice does not accord
with WHO recommendations nor the rationale
underlying post-exposure prophylaxis.27 No Zagreb
S. Toovey
regimen failures were recorded in severely injured
patients, but this regimen is probably best avoided
in severe cases.15,55,56
5.4.2. Pregnancy
Table 6 summarizes experience with post-exposure
prophylaxis in pregnancy.
Chutivongse et al. conducted a prospective study
of Verorabs post- exposure prophylaxis in 202
pregnant Thai women1: 59 were in their first
trimester, 91 in their second, and 52 in their third.
Sixty-two patients were primigravadas and 140
multigravadas. All had suffered potential rabies
exposure, with 68 classified as severe (category III).
All category III exposures received RIG. In 21 cases
the attacking animal was confirmed to be rabid.64
The Essen regimen was applied in 109 cases, and
the TRC-ID regimen in 93. The study did not report
any serological findings, relying upon outcomes as a
measure of treatment efficacy. No rabies deaths
were reported, and the incidence of pregnancy
complications did not differ from the background
rate. Adverse effects reported were minor and of
no clinical significance. Eight spontaneous abor-
tions occurred in treated subjects, all following
severe injuries: 3 within 24 h of being attacked, 4
between days 3 and 7, and 1 on day 14; the
spontaneous abortion rate was not significantly
different from the Thai background rate. Addition-
ally, obstetric histories were available for 140
subjects, of whom 6 had spontaneously aborted in
a previous pregnancy, a rate identical to that
reported in treated subjects. From the 190 subjects
available for follow up over 1 year, 185 live births
were recorded, with 1 minor congenital abnorm-
ality. Again, this rate was not more than the Thai
background rate. Five (2.7%) infants with low birth
weights were recorded, also in keeping with the
background rate.
Sudarshan et al. reported from India on Essen
regimen administration of Verorabs to 29 pregnant
women, between 4 and 35 weeks gestation.51
Despite 6 women rated as having suffered category
III exposures, no subject received RIG. A total of
105 vaccine doses were administered; immuniza-
tion was halted if the offending animal remained
well after 10 days’ of observation. Baseline ultra-
sonography was undertaken to rule out pre-existing
fetal abnormality; serology was taken on days 0,
14, 30, 90, 180, and 365. Serology was available
from 13 infants, with neutralizing antibody deter-
minations on the day of birth, and days 14, 30, and
90 post-partum. Twenty-seven women had not
been previously vaccinated. All mounted adequate
neutralizing antibody responses, with GMT of
12.2 IU/mL at day 14, and GMT of 1.8 IU/mL at
Table 5 Studies reporting post-exposure prophylaxis experience in patients with severe injuries, or injuries from animals proven rabid.

Study Routea Regimen N Children Severe Rabid RIG

Chutivongse et al., 1991 im Zagreb 96 40 96 96 ERIG 100% protection on day 14; no human rabies
but Essen titer4 Zagreb
Chutivongse et al., 1991 im Zagreb 4 4 4 HRIG 100% protection on day 14; O human rabies
but Essen titer4Zagreb
Chutivongse et al., 1990 id TRC-IDb 96 19 96 ERIG 100% protection on day 14; no human rabies
Chutivongse et al., 1990 id TRC-ID 4 4 HRIG 100% protection on day 14; no human rabies
(May have included severe cases)
Chutivongse et al., 1995 id/im TRC-ID/ 65 65 ERIG No human rabies; no increase in pregnancy or
Essen fetal abnormalities
Chutivongse et al., 1995 id/im TRC-ID/ 3 3 HRIG No human rabies; no increase in pregnancy or
Essen fetal abnormalities
Dureux et al. sc/im Essen 90 27 100% protection on day 30; no human rabies
Jaiiroensup et al. id TRC-ID 40 40 E/HRIG No human rabies
Jaiiroensup et al. im Essen 44 44 E/HRIG No human rabies
Preventing rabies with the Verorabs vaccine: 1985–2005

Seghal et al. ? Essen 184 125 45 100% protection on day 10–15; no human
rabies
Seghal et al. ? Essen 22 22 RIGc 100% protection on day 10–15; no human
rabies
ARTICLE IN PRESS

Suntharasamai et al., im Essen 59 59 100% protection on day 14; no human rabies

1986
Suntharasamai et al., im Essen 47 47 HRIG 100% protection on day 14; no human rabies
1986
Thangcharoen et al. sc Essen 20 20 20 100% protection on day 14; no human rabies
Thangcharoen et al. sc Essen 7 7 7 7 HRIG 100% protection on day 14; no human rabies
a
im, intramuscular; id, intradermal; sc, subcutaneous; ‘?’, unspecified.
b
Thai Red Cross intradermal regimen.
c
type of RIG unspecified.
341
 ARTICLE IN PRESS
342 S. Toovey

day 365. All infant titers were X0.5 IU/mL at birth

100% protection on day 14; no human rabies;

and at subsequent measurements.

100% protection on day 14; no human rabies

No human rabies; no increase in pregnancy/

No human rabies; no increase in pregnancy/

No human rabies; no increase in pregnancy/

no human rabies; no increase in pregnancy/

No cases of clinical rabies developed despite
the non-administration of RIG. Although adverse

100% protection on day 14 and 365; no

events were sought, none was reported. Twenty-

immunosuppression by pregnancy
five women were followed to delivery, with 26 live
infants born. No notable delivery events or com-
plications were reported, and all infants were free
of abnormalities. Birth weights and measurements

Results and conclusions

were within the local norms. All infants were alive

fetal Abnormalities
fetal abnormalities

fetal abnormalities

fetal abnormalities
and well at 1 year of age.
In a separate study, Sudarshan et al. compared
titers in 17 pregnant women administered Essen
regimen prophylaxis with 17 non-gravid women.65
Titers were slightly higher in pregnant subjects, but
not significantly so.
Sudarshan et al.’s work shows Verorabs is
effective and safe in pregnancy, with no immuno-
suppressive effect of pregnancy evident. Despite 42
of 105 doses having been administered prior to

HRIG
ERIG
RIGc
week 14 of gestation, no teratogenic effect was
observed.
Suntharasamai et al.’s series of patients treated
following bites from rabid animals included 2
injury
Rabid
pregnant women, 1 of whom delivered a normal

59
infant, the other of whom spontaneously aborted 4
months after post-exposure prophylaxis.7 An addi-
tional case report from Mexico relates successful
treatment without significant adverse effects.66
Severe
injury

Experience with 251 pregnant vaccine recipients

65

6
is reported, with no increase in complications of
pregnancy, spontaneous abortion, or fetal abnorm-
alities evident, and with no treatment failures. The
Experience with post-exposure prophylaxis in pregnancy.

134
65

29

17

59
N

experience reported supports rabies immunization,

including the co-administration of RIG, as effective
and safe for both mother and child during preg-
TRC-ID/Essen

TRC-ID/Essen

TRC-ID/Essen

nancy. Neither rabies vaccine nor RIG should be

Regimenb

withheld on account of pregnancy.

Essen

Essen

Essen

5.4.3. Children
Post-exposure prophylaxis experience with children
TRC-ID, Thai Red Cross intradermal regimen.

is listed within Table 1.

Routea

id/im

id/im

id/im

While a number of studies have included children

im

im

im

ERIG, equine RIG; HRIG, human RIG.

amongst their subjects, only a few have reported

id, intradermal; im, intramuscular.

their results separately. Lang et al. immunized at

Sudarshan, Gangaboriah et al.

total of 276 children,36,37 Sabchareon et al. 190,40

Suntharasamai et al., 1986

Seghal et al. 125,40 and Chutivongse et al. 40.55

Chutivongse et al., 1995

Chutivongse et al., 1995

Chutivongse et al., 1995

Children were successfully immunized from as

young as 2 months of age.36,37 Chadli et al.
administered Verorabs subcutaneously to 22 chil-
Sudarshan et al.

dren aged o15 years in a post-exposure setting; all

achieved adequate levels of protective antibody.46
No significant adverse events or vaccine failures
Table 6

Study

were reported in any study.

b
a

Chanthavanich et al. studied the relationship

between PVRV dose and neutralizing antibody titer
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005
in Thai children aged 7–13 years.67 Children were
immunized according to the Zagreb regimen and
received either a full 0.5 mL dose (N ¼ 29), a half
dose (N ¼ 26), or one third of a dose (N ¼ 27).
Serological assessment confirmed the GMT of
neutralizing antibody titer above the WHO thresh-
old on days 14, 28, 91, and 182 in the groups which
received full and half doses. Children who received
just one third of the normal dose had a significantly
lower GMT on days 14 and 28, although not on days
91 and 182.
The authors report antibody titer as being dose
related, confirming that children should receive the
same dose as adults.
The reported pediatric experience with Verorabs,
with subjects as young as 2 months, has shown the
vaccine to be safe, immunogenic, and effective at
preventing rabies in children.
5.4.4. Immunodeficient patients
Failure by HDCV to elicit a seroprotective response
in severely immunocompromised individuals has
been reported in a handful of cases.30,68,69 Reports
of Verorabs use in this setting could not be found.
Extrapolating from the experience with HDCV, an
argument can be made for the immunization of
HIV-positive individuals early in the course of their
infection, while they are able to mount an
adequate immune response, in the hope that some
immune memory will persist.33 The monitoring
post-vaccination of antibody levels on days 14 and
28 has been suggested.15,68 Evidence has yet to
accumulate that administration of double doses is
helpful when immunizing the severely immunocom-
promised.33
6. Treatment failures
Hemachudha et al. report the case of a 72 year-old
Thai woman bitten by a dog on her face.70 She was
treated with RIG and given 1 injection of Verorabs
followed by purified chick embryo rabies vaccine.
The authors speculate that virus was directly
introduced into a nerve during the offending dog
bite. A second case of treatment failure, in an
alcoholic, is attributed by Chutivongse et al. to
delayed presentation.58
Wilde et al analyzed reports of Verorabs failure
in children.71 Failure to adhere to standard proto-
cols explained all but 1 failure: a Thai child with
severe facial bites. Although RIG was infiltrated
into the wounds, there was insufficient RIG volume
at the calculated dose to infiltrate all wounds.
Wilde’s group now recommend dilution of the
343
calculated weight-based RIG dose in saline to
enable infiltration of all wounds.33,71
Plotkin’s comment on failures of post-exposure
prophylaxis identified ‘‘in nearly all cases’’ an
aspect of the treatment which did not follow
accepted protocols, with delayed treatment, fail-
ure to use RIG, improper administration of RIG, and
inadequate wound toilet being common and fatal
management errors.57 Although no treatment fail-
ures occurred, Kreindel et al.’s study of post-
exposure prophylaxis in Massachusetts demon-
strated inadequacies in post-exposure management
in the USA.72
7. Verorabs safety and adverse event
profile
Chutivongse et al. reported mild lymphadenopathy
in 10 of 100 patients administered TRC-ID Veror-
abs58; 3 of 100 patients suffered malaise, fever, and
headache, although it was not possible to attribute
these specifically to the vaccine, as tetanus toxoid,
RIG, and antibiotics were also administered. A case
of delayed but mild serum sickness attributed to
vaccine occurred in 1 subject; symptoms recurred
with subsequent vaccine doses. No adverse event
interfered with treatment.
Chutivongse et al. also studied 93 pregnant Thai
women administered TRC-ID Verorabs.1 The inci-
dence of adverse events, complications of preg-
nancy, spontaneous abortion, and still birth rates
did not differ from the natural background rates.
The authors were able to compare the incidence
of vaccine attributed minor adverse events with 93
pregnant subjects administered intramuscular post-
exposure prophylaxis: injection site pruritis was
significantly more common in recipients of intra-
dermal Verorabs (w2, p ¼ 0.176). No significant
differences were noted in the incidence of other
vaccine attributable adverse events.
Jaiiaroensup et al.’s post-exposure prophylaxis
study compared 299 subjects who received TRC-ID
Verorabs with 299 who received Essen regimen
Verorabs.47 The reported adverse event rates are
confounded to some extent by 50 subjects having
been administered human RIG, and 155 equine RIG.
Pruritis was significantly more common in the
intradermal group (107 [365] versus 835; w2,
po0.0001), as was erythema (26 [9%] versus 1
[0.3%]; w2, po0.0001). Injection site pain was more
common in the intramuscular group (65 [22%]
versus 12 [4%]; w2, po0.0001). Although minor
adverse events were statistically more significant
following intradermal administration, the authors
concluded they were not of clinical significance.
 ARTICLE IN PRESS
344
Wang et al.’s Chinese study reported a 7%
incidence of local reactions to intramuscular
Verorabs, comprising mainly pain, erythema, and
pruritis.48 Systemic reactions comprising pruritis,
rash, and vertigo were observed in 7% of sub-
jects, although the concurrent use of equine RIG
may have confounded the reporting of systemic
reactions.
Lang et al.’s study of Verorabs in association
with either commercially available equine RIG or
heat-treated purified equine RIG [F(ab’)2] failed to
find any serious adverse events.49 Less severe
events, including one instance of moderate dizzi-
ness and one of a ‘‘moderate rash’’ may have been
attributable to either RIG or vaccine.
Chutivongse followed 100 severely exposed Thai
patients for 1 year, noting only minor side effects
attributable to vaccine administration.55 Subjects
received Verorabs according to the Zagreb regi-
men, plus RIG. Chutivongse also studied 109
pregnant Thai women administered Verorabs ac-
cording to the Essen regimen.1 The incidence of
adverse events, complications of pregnancy, spon-
taneous abortion, and still birth did not differ from
the observed natural background rates. No major
adverse events attributable to the vaccine were
recorded.
Seghal et al. followed the Essen regimen in their
series of 309 Indian patients.50 No serious adverse
events were reported. The overall adverse event
rate was 23/309 (7.4%), with injection site pain in
11/309 (3.5%); injection site induration in 6/309
(1.9%), and fever o37.8 1C in 6/309 (1.9%).
Svjetlicic reported local pain in just 18 of 100
subjects administered intramuscular Verorabs, of
whom 40 received an Essen post-exposure regi-
men.5 No systemic adverse events were found,
despite daily observation by a physician for 3 days
following each injection.
Jaiiaroensup et al.’s study compared the inci-
dence of adverse effects of intradermal and
intramuscular Verorabs for pre- and post-exposure
prophylaxis regimens.47 Three hundred subjects
received intramuscular Verorabs and 300 intrader-
mal Verorabs on days 0, 7, and 28, simulating pre-
exposure prophylaxis. No serious adverse events
were reported in either group. Overall, the report-
ing of at least one minor adverse event was
significantly more common in the intradermal
group (80/300 versus 58/300; w2, po0.05), with
pruritis (60/300 versus 8/300; w2, po0.0001) and
erythema (18/300 versus 0/300; w2, po0.0001)
being significantly more common in the intradermal
group. Conversely, pain at the injection site was
more common in the intramuscular group (52/300
versus 6/300; w2, po0.0001).
S. Toovey
Lang et al.’s study of Vietnamese infants failed to
detect any serious adverse events from intramus-
cular administration.36 A later study of Vietnamese
infants did not detect any serious adverse events,
but did show intradermal administration to be
associated with a higher incidence of minor
adverse events, although these were not of clinical
significance.37
Hacibektasoglu et al. administered intramuscular
Verorabs to 30 subjects on days 0, 7, and 21
without any serious adverse event.42 Reported
adverse events were mild and consisted mainly of
injection site pain, erythema, or induration.
Sabchareon’s comparison of intradermal with
intramuscular Verorabs in 190 Thai children aged
7–9 years failed to reveal any serious adverse
events,40 finding only mild local reactions. These
reactions were significantly more common in the
intradermal group. Systemic adverse events were
noted in just a few children of each group and were
self-limiting, comprising low grade fever, head-
ache, and rash. Following a booster vaccination at 1
year, a similar pattern of mild local and systemic
adverse events was observed.
Svjetlicic reported local pain in just 18 of 100
subjects administered intramuscular Verorabs, of
whom 30 received a 3 dose pre-exposure regimen.5
No systemic adverse events were reported. An early
French study (N ¼ 174) reported the following mild
adverse event rates: erythema 4%, induration 3.3%,
slight local pain 6.7%6; 1 subject reported fever
438 1C and 1 mild asthenia, both lasting o48 h.
Dureux et al. reported combined adverse event
rates for subjects who had received pre- or post-
exposure prophylaxis, by subcutaneous or intra-
muscular injection, without differentiation.38 No
major adverse events were reported.
Mild adverse events reported comprised erythe-
ma (13%), pain (13%), and induration (4%) at
injection sites; fever was noted in 0.4% of subjects.
Chadli et al. reported only mild local adverse
reactions in 2 of 75 (3%) subjects administered a
course of subcutaneous Verorabs, at 0.5 mL/
dose.46 Thongcharoen et al.’s study of 27 Thai
children administered subcutaneous Verorabs
failed to find any serious adverse effects, with only
6 (22%) children exhibiting mild local reactions.73
Suntharasamai et al. found no significant differ-
ence in adverse events in subjects administered
Verorabs (N ¼ 30) and subjects administered HDCV
(N ¼ 30).34 Half of the subjects in each group also
received human RIG. Adverse events were mild and
mostly local. Another study by Suntharasamai et al.
compared intradermal and intramuscular HDCV
against intramuscular Verorabs in a variety
of regimens.45 Only mild adverse effects were
 ARTICLE IN PRESS
Preventing rabies with the Verorabs vaccine: 1985–2005
reported, with intramuscular Verorabs better
tolerated than intradermal HDCV.
A detailed direct comparison of the adverse
event incidence of Verorabs (N ¼ 72) and HDCV
(N ¼ 74) was made by Aijan et al.4 The local
adverse event rate was significantly higher in the
HDCV group for pain (w2, p ¼ 0.029), induration
(w2, p ¼ 0.007), and erythema (w2, p ¼ 0.002).
Interestingly, the incidence of erythema increased
as HDCV recipients progressed through the 3
injection series, from 29% to 42% (p ¼ 0.015).
Verorabs appears better tolerated than HDCV.
The latter has been associated with pruritis,
urticaria, and angioedema in about 6% of subjects
given booster doses57,74; Dreesen et al. reported a
10% incidence of serum sickness in recipients of
HDCV boosters.75,76 Type I and III reactions seen
with HDCV are attributed to an allergen generated
from HDCV’s albumin stabilizer by the contained
b-propiolactone on77; Verorabs appears free of
these allergic-type reactions.40
The superior injection site comfort of Verorabs
is likely due to a combination of its reduced
reactogenicity and smaller injection volume.
Sabchareon et al.40 specifically noted that
adverse event rates observed with Verorabs
boosting were not significantly different to those
observed with primary Verorabs courses. These
findings might explain why Verorabs adverse
events do not increase in severity as an immuniza-
tion course progress, while they do for HDCV. The
smaller volume of intramuscular injection, 0.5 mL
for Verorabs, versus 1.0 mL for HDCV may partly
explain the significantly lower incidence of injec-
tion site pain seen with Verorabs. A survey of
rabies experts by Sriaroon et al. found that those
who preferred Verorabs to other cell culture
vaccines cited a better adverse effect profile as a
reason for their preference; the lower volume of
injection was cited by 25% of these experts as
reducing pain on intramuscular injection.33
Overall, reported adverse events associated with
Verorabs are mild and mostly non-systemic in
nature. No serious adverse events have been
reported.
8. Conclusion
Extensive experience over 20 years has demonstrated
the immunogenicity, efficacy and safety of Verorabs
for pre- and post-exposure prophylaxis of rabies, with
the vaccine reliably inducing rapid seroconversion
and protective levels of neutralizing antibody. Veror-
abs is at least as immunogenic as HDCV, the
reference vaccine. Faster rises in antibody titers,
345
higher titers and greater duration of seroprotection
have been observed with Verorabs in a number of
studies.4,34,41–45 Studies also confirm the persistence
of antibody, with booster doses provoking a rapid
and brisk anamnestic response. The findings extend
to and support use in pregnancy,1,7,51,64 child-
hood,32,36,37,40,50,67 and individuals with severe and
high risk injuries.1,32,38,47,48,50,51,55,64,78
The literature supports use by both intramuscular
and intradermal routes for pre- and post-exposure
prophylaxis by a number of different regimens. The
vaccine is approved by WHO for pre- and post-
exposure prophylaxis, and for administration by the
Essen, Zagreb, and TRC-ID regimens27; the latter is
a dependable and cost-effective option for devel-
oping countries. The Zagreb regimen is best
avoided when RIG is administered, as RIG may
suppress antibody development.
Verorabs has a better safety profile than HDCV
with the lower volume for intramuscular injection
possibly accounting for good tolerability. Unlike
HDCV, Verorabs is not associated with type I and III
reactions.74,79 No serious adverse events have been
documented with Verorabs, and most adverse
events that do occur are local rather than systemic
in nature.
Extensive clinical experience and numerous
publications support the use of Verorabs, confirm-
ing it as safe, immunogenic, and efficacious.
Acknowledgments
Linda Stephen is thanked for her patient assistance
with this manuscript. Keith Veitch of sanofipasteur
is thanked for his assistance with finding and
obtaining less readily available references.
Conflict of interest statement
This review was funded by sanofipasteur. The
author has been reimbursed by a number of vaccine
companies for speaking, consulting, and attending
conferences.
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