A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rabavert Pharmacology, Pharmacokinetics, Studies, Metabolism - Rabies Vaccine
Rabavert Pharmacology, Pharmacokinetics, Studies, Metabolism - Rabies Vaccine
CLINICAL PHARMACOLOGY
Rabies in the United States
Over the last 100 years, the epidemiology
of rabies in animals
in the United States has changed dramatically. More than 90% of
all animal rabies cases
reported annually to the Centers for Disease Control and Prevention
(CDC) now occur in wildlife, whereas before 1960 the majority were
in domestic animals. The principal
rabies hosts today are
wild carnivores and bats. Annual human
deaths have fallen from more than a hundred at the turn of the century
to one to two per year despite
major outbreaks of animal
rabies in several geographic areas. Within the United States, only
Hawaii has remained rabies
free. Although rabies
among humans is rare in the United States, every year tens of thousands
of people receive rabies
vaccine for post-exposure
prophylaxis. Rabies is almost invariably fatal
due to encephalomyelitis. Modern day prophylaxis
has proven nearly 100% successful; most human
fatalities now occur in people who fail to seek medical
treatment, usually
because they do not recognize a risk
in the animal contact
leading to the infection. Inappropriate post-exposure prophylaxis
may also result in clinical
rabies. Survival after clinical
rabies is extremely rare,
and is associated with severe brain
damage and permanent
disability. RabAvert (in combination with passive
immunization with
Human Rabies Immune Globulin (HRIG) and local wound
treatment) in post-exposure immunization
against rabies has been
shown to protect, patients of all age
groups from rabies, when the vaccine was administered according
to the World Health Organization (WHO) guidelines and as soon as
possible after rabid animal
contact. Anti-rabies antibody titers after immunization
have been shown to reach levels well above the minimal
protective level
of 0.5 IU/mL within 14 days after initiating the immunization
series. The minimal
antibody titer
accepted as seroconversion is 0.5 IU, measured by the rapid fluorescent
inhibition test
(RFFIT) as specified by the WHO
(1, 2) or a 1:5 titer
(complete inhibition
in RFFIT at 1:5 dilution) as specified by the C.C.
Vaccine failure has
only been reported when key elements of rabies
post-exposure regimens were omitted or when the vaccine
has been incorrectly administered.
Pre-exposure Immunization
The immunogenicity
of RabAvert has been demonstrated in clinical
trials conducted in different countries such
as the USA (3, 4), UK (5), Croatia (6), and Thailand (7,8,9). When
administered according to the recommended immunization schedule
(days 0, 7, 21), 100% of subjects attained a protective titer. Two
studies carried out in the USA in 101 subjects antibody
titers >0.5 IU/mL were obtained by day 28 in all subjects. In
studies carried out in Thailand in 22 subjects, and in Croatia in
25 subjects, antibody titers of >0.5 IU/mL were obtained by day
14 (injections on days 0, 7, 21) in all subjects.
The ability of RabAvert
to boost previously immunized subjects was evaluated in three clinical
trials. In the Thailand study,
pre-exposure booster
doses were administered to 10 individuals. Antibody titers of >0.5
IU/mL were present at baseline
on day 0 in all subjects (8). Titers after a booster dose were enhanced
from geometric mean titers
(GMT) of 1.91 IU/mL to 23.66 IU/mL on day 30. In
an additional booster
study, individuals known to have been immunized with Human Diploid
Cell Vaccine (HDCV) were boosted with RabAvert. In
this study, a booster
response was observed
on day 14 for all (22/22) individuals (10). In
a trial carried out in the USA (3), a RabAvert IM booster
dose resulted in a significant
increase in titers in all (35/35) subjects, regardless of whether
they had received RabAvert or HDCV
as the primary vaccine.
Persistence of antibody
after immunization
with RabAvert has been evaluated. In a trial performed i n the UK,
neutralizing antibody
titers >0.5 IU/mL were present
2 years after immunization
in all sera (6/6) tested.
Post-exposure Immunization
RabAvert, when used in the recommended post-exposure WHO
program of 5 to 6 IM
injections of 1 mL (days 0, 3, 7, 14, 30, and one optionally on
day 90) provided protective
titers of neutralizing antibody
(> 0.5 IU/mL) in 158/160 patients (7, 8, 11-14) within 14 days
and in 215/216 patients by day 28-38. Of these, 203 were followed
for at least 10 months. No case
of rabies was observed
(7,8,11-18). Some patients received HRIG, 20 - 30 IU per
kg body
weight, or Equine Rabies Immune Globulin (ERIG), 40 IU per
kg body
weight, at the time of
the first dose. In most studies
(7, 8, 11, 15), the addition
of either HRIG or ERIG caused a slight decrease in GMTs which was
neither clinically relevant nor statistically significant. In one
study (14), patients receiving HRIG had significantly lower (p<0.05)
GMTs on day 14; however, again this was not clinically relevant.
After day 14 there was no
statistical significance.
The results of several studies of normal
volunteers who have been given the WHO
regimen of vaccine
for post-exposure use (10,19-22), i.e., "simulated" post-exposure
use, show that with sampling
by day 28-30, 205/208 vaccinees had protective
titers > 0.5 IU/mL.
Over a 10 year (7/85-6/95) period, 46 reports of suspected post-exposure
vaccine failure have
been evaluated (11.8 million doses distributed). In each case, post-exposure
treatment had not
been i n compliance
with WHO recommendations.
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