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Acthib

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ActHIB

ActHIB

CLINICAL PHARMACOLOGY

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 (haemophilus b conjugate vaccine) ® is typical of a T-dependent immune response to antigen. The prominent isotype of anticapsular PRP antibody induced by ActHIB (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® has been demonstrated in the United States and worldwide. ActHIB (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ®. 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ®. 19

ActHIB (haemophilus b conjugate vaccine) ® 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 AvP whole-cell DTP vaccine was used to reconstitute lyophilized ActHIB (haemophilus b conjugate vaccine) ® (Table 3). 14,18

TABLE 3 18

ANTI-PRP RESPONSES IN 2-MONTH-OLD INFANTS FOLLOWING IMMUNIZATION WITH

ActHIB (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® combined with AvP DTP by reconstitution was similar when compared to infants who received DTP and ActHIB (haemophilus b conjugate vaccine) ® separately (84% versus 85% and 4.3 µg/mL versus 4.8 µg/mL). 14,18

TriHIBitTM, ActHIB (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ® 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 (haemophilus b conjugate vaccine) ®) 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 (haemophilus b conjugate vaccine) ® AND TRIPEDIA GIVEN CONCOMITANTLY AT SEPARATE SITES

IMMUNOGENICITY

 

Pre- Dose

Post- Dose

 

TriHIBit®

Separate

Injections

TriHIBit®

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.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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