• Vaccine Name: HIBTITER
• Target Pathogen: Haemophilus influenzae
• Target Disease: Meningitis
• Product Name: H. influenzae type b conjugate vaccine (Hb-OC)
• Tradename: HIBTITER
• Vaccine Ontology ID: VO_0000659
• Type: conjugate vaccines
• Antigen: Haemophilus influenzae type b capsular polyribosyl-ribitol-phosphate(PRP)-Diphtheria CRM197 Protein (HibTITER 2007).
• Preparation: 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. CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae C7 (β197) 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 2007). 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 (HibTITER 2007).
• Description: 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 (Weinberg et al., 1988).
  In most cases HibTITER was administered concomitantly with other vaccines including DTP, DTaP, hepatitis B vaccine, IPV, OPV, pneumococcal 7-valent conjugate vaccine, MMR, and/or meningococcal group C conjugate vaccine (not licensed in the US).

Human Response

• Vaccination Protocol: Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) HibTITER is indicated for the immunization of children 2 months to 71 months of age against invasive diseases caused by H. influenzae type b. HibTITER is for intramuscular use only.
  
  For infants 2 to 6 months of age, the immunizing dose is three separate injections of 0.5 mL given at approximately 2-month intervals. Previously unvaccinated infants 12 from 7 through 11 months of age should receive two separate injections approximately 2 months apart. Children from 12 through 14 months of age who have not been vaccinated previously receive one injection. All vaccinated children receive a single booster dose at 15 months of age or older, but not less than 2 months after the previous dose. Previously unvaccinated children 15 to 71 months of age receive a single injection of HibTITER. Preterm infants should be vaccinated with HibTITER according to their chronological age, from birth (AAPC 1991).
  
  Data support that HibTITER may be interchanged with other Haemophilus influenzae type b conjugate vaccines for the primary immunization series and booster dose.
  Each dose of 0.5 mL is formulated to contain 10 μg of purified Haemophilus b saccharide and approximately 25 μg of CRM197 protein.
• Persistence: 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 (Reinholdt et al., 1997).
• Side Effects: Side effects associated with a single vaccination of HibTITER include fever, local reactions, rash, diarrhea , vomiting , prolonged crying.
• Efficacy: The immunogenicity of HibTITER was evaluated in US infants and children.Infants 1 to 6 months of age at first immunization received three doses at approximately 2-month intervals. Children 7 to 11 and 12 to 14 months of age received 2 doses at the same interval.Children 15 to 23 months of age received a single dose. 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 (HibTITER 2007).
  
  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.After three doses, titers ranged from 2.37 to 8.45 μg/mL with 67% to 94% attaining ≥ 1 μg/mL (HibTITER 2007).
  
  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 (HibTITER 2007).