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Hibtiter (Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate)) - Description and Clinical Pharmacology



Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) HibTITER is a sterile solution of a conjugate of oligosaccharides of the capsular antigen of Haemophilus influenzae type b (Haemophilus b) and diphtheria CRM197 protein (CRM197) dissolved in 0.9% sodium chloride. The oligosaccharides are derived from highly purified capsular polysaccharide, polyribosylribitol phosphate, isolated from Haemophilus b strain Eagan grown in a chemically defined medium (a mixture of mineral salts, amino acids, and cofactors). The oligosaccharides are purified and sized by diafiltrations through a series of ultrafiltration membranes, and coupled by reductive amination directly to highly purified CRM197.1,2 CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae C7 ((beta)197) grown in a casamino acids and yeast extract-based medium that is ultrafiltered before use. CRM197 is purified through ultrafiltration, ammonium sulfate precipitation, and ion-exchange chromatography to high purity. The conjugate is purified to remove unreacted protein, oligosaccharides, and reagents; sterilized by filtration; and filled into vials. HibTITER is intended for intramuscular use.

The vaccine is a clear, colorless solution. Each single dose of 0.5 mL is formulated to contain 10 µg of purified Haemophilus b saccharide and approximately 25 µg of CRM197 protein. The potency of HibTITER is determined by chemical assay for polyribosylribitol.


For several decades Haemophilus influenzae type b (Haemophilus b) was the most common cause of invasive bacterial disease, including meningitis, in young children in the United States. Although nonencapsulated H. influenzae are common and six capsular polysaccharide types are known, strains with the type b capsule caused most of the invasive Haemophilus diseases. 3

Haemophilus b diseases occurred primarily in children under 5 years of age prior to immunization with Haemophilus influenzae type b vaccines. In the US, the cumulative risk of developing invasive Haemophilus b disease during the first 5 years of life was estimated to be about 1 in 200. Approximately 60% of cases were meningitis. Cellulitis, epiglottitis, pericarditis, pneumonia, sepsis, or septic arthritis made up the remaining 40%. An estimated 12,000 cases of Haemophilus b meningitis occurred annually prior to the routine use of conjugate vaccines in toddlers. 3,4 The mortality rate can be 5%, and neurologic sequelae have been observed in up to 38% of survivors. 5

The incidence of invasive Haemophilus b disease peaks between 6 months and 1 year of age, and approximately 55% of disease occurs between 6 and 18 months of age. 3 Interpersonal transmission of Haemophilus b occurs and risk of invasive disease is increased in children younger than 4 years of age who are exposed in the household to a primary case of disease. Clusters of cases in children in day care have been reported and recent studies suggest that the rate of secondary cases may also be increased among children exposed to a primary case in the daycare setting.3,6

The incidence of invasive Haemophilus b disease is increased in certain children, such as those who are native Americans, black, or from lower socioeconomic status, and those with medical conditions such as asplenia, sickle cell disease, malignancies associated with immunosuppression, and antibody deficiency syndromes. 3,4,6

The protective activity of antibody to Haemophilus b polysaccharide was demonstrated by passive antibody studies in animals and in children with agammaglobulinemia or with Haemophilus b disease7 and confirmed with the efficacy study of Haemophilus b polysaccharide (HbPs) vaccine.8 Data from passive antibody studies indicate that a preexisting titer of antibody to HbPs of 0.15 µg/mL correlates with protection.9 Data from a Finnish field trial in children 18 to 71 months of age indicate that a titer of > 1.0 µg/mL 3 weeks after vaccination is associated with long-term protection.10,11

Linkage of Haemophilus b saccharides to a protein such as CRM197 converts the saccharide (HbO) to a T-dependent (HbOC) antigen, and results in an enhanced antibody response to the saccharide in young infants that primes for an anamnestic response and is predominantly of the IgG class.12 Laboratory evidence indicates that the native state of the CRM197 protein and the use of oligosaccharides in the formulation of HibTITER enhances its immunogenicity.13-15

Prior to licensure, the immunogenicity of HibTITER was evaluated in US infants and children. 15 Infants 1 to 6 months of age at first immunization received three doses at approximately 2-month intervals. 16 Children 7 to 11 and 12 to 14 months of age received 2 doses at the same interval.15 Children 15 to 23 months of age received a single dose.17 HibTITER was highly immunogenic in all age groups studied, with 97% to 100% of 1,232 infants attaining titers of >/= 1 µg/mL and 92% to 100% for bactericidal activity.15-17

Long-term persistence of the antibody response was observed. More than 80% of 235 infants who received three doses of vaccine had an anti-HbPs antibody level >/= 1 µg/mL at 2 years of age. 18

The vaccine generated an immune response characteristic of a protein antigen. IgG anti-HbPs antibodies of IgG1 subclass predominated and the immune system was primed for a booster response to HibTITER. There is some evidence suggesting natural increases in antibody levels over time after vaccination, most probably the result of contact with Haemophilus type b organisms or cross-reactive antigens. 18 These studies were carried out at a time when significant levels of Haemophilus b disease were still present in the community.

Antibody generated by HibTITER has been found to have high avidity, a measure of the functional affinity of antibody to bind to antigen. High-avidity antibody is more potent than low-avidity antibody in serum bactericidal assays. 19 The contribution to clinical protection is unknown.

Immunogenicity of HibTITER was evaluated in 26 children 22 months to 5 years of age who had not responded to earlier vaccination with Haemophilus b polysaccharide vaccine. One dose of HibTITER was immunogenic in all 26 children and generated titers of >/= 1 µg/mL in 25 of the 26 infants. 20 HibTITER has been found to be immunogenic in children with sickle cell disease, a condition that may cause increased susceptibility to Haemophilus b disease.21 HibTITER has also been shown to be immunogenic in native American infants, such as the group of 50 studied in Alaska who received three doses at 2, 4, and 6 months of age. 20 Antibody levels achieved were comparable to those seen in healthy US infants who received their first dose at 1 to 2 months of age and subsequent doses at 4 to 6 months of age. 15,16,20

Postlicensure surveillance of immunogenicity was conducted during the distribution of the first 30 million doses of HibTITER and during the time period over which Haemophilus b disease in children has been decreasing significantly in areas of extensive vaccine usage. 20,22-29 After three doses, titers ranged from 2.37 to 8.45 µg/mL with 67% to 94% attaining >/= 1 µg/mL. 20,24,25

Persistence of antibody was examined in several cohorts of subjects that received either a selected commercial lot or that were part of the initial efficacy trial in northern California. Geometric mean titers for these cohorts were between 0.51 and 1.96 just prior to boosting at 15 to 18 months. These lots not only induced persistent antibody but also provided effective priming for a booster dose with commercial lots, with postboosting titers greater than 1.0 µg/mL in 80% to 97% of subjects. 20

HibTITER (HbOC) was shown to be effective in a large-scale controlled clinical trial in a multiethnic population in northern California carried out between February 1988 and June 1990. 30,31 There were no (0) vaccine failures in infants who received three doses of HibTITER and 12 cases of Haemophilus b disease (6 cases of meningitis) in the control group. The estimate of efficacy is 100% (P =.0002) with 95% confidence intervals of 68% to 100%. Through the end of 1991, with an additional 49,000 person-years of follow-up, there were still no cases of Haemophilus b disease in fully vaccinated infants less than 2 years of age. 22,23 One case of disease has been reported in a 3 1/2-year-old child who did not receive a booster dose as recommended.

A comparative clinical trial was performed in Finland where approximately 53,000 infants received HibTITER at 4 and 6 months of age and a booster dose at 14 months in a trial conducted from January 1988 through December 1990. Only two children developed Haemophilus b disease after receiving the two-dose primary immunization schedule. One child became ill at 15 months of age and the other at 18 months of age; neither child received the scheduled booster at 14 months of age. No vaccine failure has been reported in children who received the two-dose primary series and the booster dose at 14 months of age. Based on more than 32,000 person-years of follow-up time, the estimate of efficacy is about 95% when compared to historical control groups followed between 1985 and 1988. 20 Historical controls were used since all infants received one of two Haemophilus b conjugate vaccines during the period of the trial.

Evidence of efficacy postlicensure includes significant reductions in Haemophilus b disease that are closely associated with increases in the net doses of Haemophilus b Conjugate Vaccine distributed in the US.20,22-29 In the northern California Kaiser Permanente there has been a 94% decrease in Haemophilus disease incidence in 1991 for children younger than 18 months of age, compared to 1984-1988, when HibTITER was not available for this age group.22,23 Furthermore, active surveillance by the Centers for Disease Control and Prevention (CDC) has shown a 71% decrease in Haemophilus b disease in children less than 15 months old, between 1989 and 1991, which corresponds temporally and geographically with increases in net doses of Haemophilus b conjugate vaccine distributed in the US.26 As with all vaccines, this conjugate vaccine cannot be expected to be 100% effective. There have been rare reports to the Vaccine Adverse Event Reporting System (VAERS) of Haemophilus b disease following full primary immunization.

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