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
Acthib Pharmacology, Pharmacokinetics, Studies, Metabolism - Haemophilus b Conjugate Vaccine
Acthib Pharmacology, Pharmacokinetics, Studies, Metabolism - Haemophilus b Conjugate Vaccine
PHARMACOLOGY
NOTE: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)
- ActHIB® is identical
to Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) - OmniHIB®
(distributed by SmithKline Beecham Pharmaceuticals); and is manufactured
by Pasteur Mérieux Sérums Vaccins S.A.
H influenzae type b was
the leading cause of invasive
bacterial disease among children in the United States prior to licensing
of Haemophilus b conjugate
vaccines. Based on its active surveillance
areas, the Centers for Disease Control and Prevention (CDC) now estimate
that H influenzae type b disease
in children under the age of 5
years has been reduced by 95%. 3 Before
effective vaccines were introduced,it was estimated that one in 200 children
developed invasive H influenzae type
b disease by the age
of 5 years. In children less than
5 years of age, the mortality
rate for invasive
H influenzae type b disease
ranged between 3% and 6%. 3 In more than
60% of these children, meningitis
was the clinical syndrome
and permanent sequelae ranging from mild hearing
loss to mental
retardation affecting 20% to 30% of all survivors. 3
Ninety-five percent of the
cases of invasive H influenzae
disease among children <5 years of age
were caused by organisms with the type b polysaccharide
capsule. Approximately two-thirds of all cases of invasive H influenzae
type b disease
affected infants and children <15 months of age, a group
for which a vaccine was not
available until late 1990. 4,5
Incidence rates of invasive
H influenzae type b disease
have been shown to be increased in certain high-risk groups, such as native
Americans (both American Indians and Eskimos), blacks, individuals of
lower socioeconomic status, and patients with asplenia, sickle cell
disease, Hodgkin's disease,
and antibody deficiency
syndromes. 5,6 Studies also have suggested
that the risk of acquiring primary
invasive H influenzaetype b disease
for children under 5 years of age
appears to be greater for those who attend day care facilities. 7,8,9,10
The potential for person
to person transmission
of the organism among susceptible
individuals has been recognized. Studies of secondary
spread of disease in household
contacts of index patients have
shown a substantially increased risk
among exposed household contacts under 4 years of age. 11
Adults can be colonized with H influenzae type b from children
infected with the organism. 12
The response to ActHIB®
is typical of a T-dependent immune
response to antigen. The
prominent isotype of anticapsular
PRP antibody induced
by ActHIB® is IgG. 13
A substantial booster
response has been demonstrated in children 12 months of age
or older who previously received two or three doses. Bactericidal activity
against H influenzae type b is demonstrated in serum
after immunization and
statistically correlates with the anti-PRP antibody
response induced
by ActHIB® 14
Antibody to H influenzae capsular
polysaccharide (anti-PRP)
titers of >1.0 µg/mL following vaccination
with unconjugated PRP vaccine correlated with long-term protection against
invasive H influenzae
type b disease in children
older than 24 months of age. 15 Although
the relevance of this threshold
to clinical protection after
immunization with conjugate
vaccines is not known, particularly in light
of the induced, immunologic memory, this level continues to be considered
as indicative of long-term protection. 4
The immunogenicity and safety of ActHIB®
has been demonstrated in the United States and worldwide. ActHIB®
induced, on average anti-
PRP levels >1.0 µg/mL in 90% of infants after the primary
series and in more than 98%
of infants after a booster
dose. 14
Two clinical trials supported
by the National Institutes of Health (NIH) have compared the anti-PRP
antibody responses to three
Haemophilus b conjugate
vaccines in racially mixed populations
of children. These studies were done in Tennessee 16
(Table 1) and in Minnesota, Missouri and Texas 17
(Table 2) in infants immunized with ActHIB®
and other Haemophilus b conjugate
vaccines at 2, 4 and 6 months of age. All Haemophilus
b conjugate vaccines were administered concomitantly with Poliovirus Vaccine
Live Oral and DTP vaccines at separate sites.
TABLE 1 16
|
ANTI-PRP
ANTIBODY RESPONSES IN 2-MONTH-OLD INFANTS NIH
TRIAL IN TENNESSEE
|
|
GEOMETRIC
MEAN TITER (GMT)
(µg/
mL)
|
|
VACCINE
|
N*
|
Pre-Immunization
|
Post Second
Immunization
|
Post Third
Immunization
|
Post Third
Immunization %>1.0µg/mL
|
| PRP-T†
(ActHIB® ) |
65
|
0.10
|
0.30
|
3.64
|
83%
|
| PRP-OMP
(PedvaxHIB®) |
64
|
0.11
|
0.84
|
N/A
|
50%**
|
| HbOC‡
(HibTITER® ) |
61
|
0.07
|
0.13
|
3.08
|
75%
|
TABLE 217
|
ANTI-PRP
ANTIBODY RESPONSES IN 2- MONTH- OLD INFANTS
NIH TRIAL
IN MINNESOTA, MISSOURI AND TEXAS
|
|
GEOMETRIC
MEAN TITER (GMT)
(µg/
mL)
|
|
VACCINE
|
N*
|
Pre- Immunization
|
Post Second
Immunization
|
Post Third
§ Immunization
|
Post Third
§ Immunization %>1.0µg/mL
|
| PRP-T†
(ActHIB® ) |
142
|
0.25
|
1.25
|
6.37
|
97%
|
| PRP-OMP
(PedvaxHIB® ) |
149
|
0.18
|
4.00
|
N/A
|
85%**
|
| HbOC‡
(HibTITER®) |
167
|
0.17
|
0.45
|
6.31
|
90%
|
* N= Number of Children
§ Sera
were obtained after the third dose
from 86 and 110 infants, in PRP-T and HbOC vaccine
groups, respectively.
† Haemophilus
b Conjugate Vaccine (Tetanus Toxoid Conjugate)
*** Haemophilus
b Conjugate Vaccine (Meningococcal Protein Conjugate)
** Seroconversion after the recommended 2-dose primary
immunization series is shown.
‡ Haemophilus
b Conjugate Vaccine (Diphtheria CRM
197 Protein Conjugate)
N/A Not applicable in this comparison trial although third
dose data have been published. 16,17
Native American populations have had high rates of H influenzae type
b disease and have been observed
to have low immune responses
to Haemophilus b conjugate
vaccines. Following three doses of ActHIB®
at six weeks, four and six months of age, 75% of Native Americans in Alaska
showed an anti-PRP antibody
titer of >1.0 µg/mL.
18
Children 12 to 24 months of age
who had not previously received Haemophilus b conjugate
vaccination were immunized
with a single dose of ActHIB®.
GMT anti-PRP antibody
responses were 5.12 µg/mL (90% responding with >1.0 µg/mL)
for children 12 to 15 months of age
and 4.4 µg/mL (82% responding with <1.0 µg/mL) for
children 17 to 24 months of age. 18
These trials demonstrated that ActHIB®
consistently conferred an anti-PRP antibody
response previously shown
to correlate with protection, when administered either as a regimen
of three doses at least four to eight weeks apart in infants 2 to 6 months
of age or as a single dose in
children 12 months of age and
older. 18
ActHIB® has
been found to be immunogenic
in children with sickle cell
anemia, a condition which may
cause increased susceptibility
to Haemophilus b disease.
Two doses of ActHIB®
given at two-month intervals induced
anti-PRP antibody titers
of >1.0 µg/mL in 89% of these children with a mean
age of 11 months. This is comparable
to anti-PRP antibody levels
demonstrated in normal children
of similar age following two doses
of ActHIB®.
19
ActHIB® COMBINED
WITH WHOLE-CELL PERTUSSIS VACCINE (DTP) BY RECONSTITUTION FOR PRIMARY
IMMUNIZATION
Comparative clinical trials
demonstrated that a similar anti-PRP response was achieved in infants
as young as 2 months old when one dose
of CLI whole-cell DTP vaccine
was used to reconstitute lyophilized ActHIB®
(Table 3). 14,18
TABLE 3 18
|
ANTI-PRP
RESPONSES IN 2-MONTH-OLD INFANTS FOLLOWING IMMUNIZATION WITH
ActHIB
® COMBINED WITH CONNAUGHT LABORATORIES, INC.
DTP BY RECONSTITUTION
|
|
GEOMETRIC
MEAN TITER (GMT)
(µg/mL)
|
|
STUDY
SITE
|
N*
|
Pre-Immunization
|
Post Second
Immunization
|
Post Third
Immunization
|
Post Third
Immunization%>1.0 µg/ mL
|
|
US
|
45
|
0.13
|
0.55
|
4.49
|
91
|
|
US
|
135
|
0.12
|
0.43
|
4.46
|
85
|
|
Chile
|
94
|
0.09
|
4.31
|
6.94
|
96
|
* N=Number of Children
Antibody responses to diphtheria, tetanus
and pertussis antigens were
also measured in this trial. Post dose
three antibody responses
to all measured vaccine antigens
were similar, within each study, when infants who received the combined
vaccine were compared to infants
who received whole-cell DTP and ActHIB®
separately. Interference with the antibody
response to the pertussis
component has been suggested with a DTP vaccine
unlicensed in the US. 20 Percentages of
subjects achieving antibody
titers over 1 µg/mL and GMT to PRP in 2-month-old infants following
immunization with ActHIB®
combined with CLI DTP by reconstitution
was similar when compared to infants who received DTP and ActHIB®
separately (84% versus 85% and 4.3 µg/mL versus 4.8 µg/mL).
14,18
TriHIBitTM, ActHIB®
COMBINED WITH TRIPEDIA®
VACCINE BY RECONSTITUTION FOR BOOSTER DOSE Randomized comparative clinical
trials demonstrated that the anti-PRP response
achieved in 15 to 20 month old children after one dose
of TriHIBitTM, Tripedia®
and ActHIB®
combination vaccine, was similar to that achieved when the two vaccines
were given concomitantly at different sites with separate needles and
syringes (Table 4). 18 All children had
received three doses of a Haemophilus
b conjugate vaccine
(HibTITER®
or ActHIB®)
and three doses of a whole-cell DTP vaccine
prior to entry into this clinical trial.
TABLE 4 18
|
ANTI-PRP
RESPONSES IN 15 TO 20-MONTH-OLD
CHILDREN FOLLOWING IMMUNIZATION
With TriHIBitTM
COMPARED TO ActHIB®
AND TRIPEDIA GIVEN CONCOMITANTLY AT SEPARATE SITES
|
|
IMMUNOGENICITY
|
| |
Pre- Dose
|
Post-
Dose
|
| |
TriHIBitTM
|
Separate
Injections
|
TriHIBitTM
|
Separate
Injections
|
|
N*
|
88
|
94
|
93
|
98
|
|
Anti- PRP
(µg/mL)
|
0.89
|
1.15
|
90.30
|
80.90
|
|
%>1 µg/mL
|
45.50
|
53.20
|
100.00
|
100.00
|
* N=Number of Children
Geometric mean titers in response
to diphtheria, tetanus and
pertussis (PT and FHA) were also similar between groups. (Refer
to product insert for Tripedia®).
A difference in four-fold antibody
response to FHA was noted
in this trial. However, the clinical
significance of this difference is not known at present.
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