Haemophilus Influenzae

Haemophilus Influenzae


The HIB vaccine is solely for capsulated Haemophilus B, not non encapsulated Hib.  The HIB vaccine is solely for invasive Hib disease caused by capsular Hib. It has no effect on any other type of Hib disease. You can’t make a Hib vaccine for non-encapsular HIB. Due to the recommended and rountine use of Hib conjugate vaccine, at least half of invasive H influenzae infections are now caused by the nonencapsulated strains.


There are six strains of H. influenzae that have been classified (types a through f) and other non-typeable strains. Type b is responsible for 95 percent of all strains causing invasive disease. Invasive Hib disease usually manifests itself clinically as meningitis, accounting for 50 to 65 percent of all cases.


HIB vaccines are available as a single vaccine or in combination vaccines and four conjugate Hib vaccines are currently available:

Monovalent Hib vaccines:

PedvaxHIB® [Merck] [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] is a highly purified capsular polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilusinfluenzae type b (Haemophilus b, Ross strain) that is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitidis serogroup B. Each 0.5 mL dose of Liquid PedvaxHIB is a sterile product formulated to contain: 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9% sodium chloride, but does not contain lactose or thimerosal.




 ActHib [sanofi pasteur] The vaccine consists of the Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b (HiB) strain 1482 grown in a semi-synthetic medium, covalently bound to tetanus toxoid.1 The lyophilized ActHIB vaccine powder and saline diluent contain no preservative. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium.


Combination vaccines:


COMVAX* [Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine made of the antigenic components used in producing PedvaxHIB* [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] and RECOMBIVAX HB* [Hepatitis B Vaccine (Recombinant)]. These components are the Haemophilus influenzae type b capsular polysaccharide [polyribosylribitol phosphate (PRP)] that is covalently bound to

an outer membrane protein complex (OMPC) of Neisseria meningitidis and hepatitis B surface antigen (HBsAg) from recombinant yeast cultures. Haemophilus influenzae type b and Neisseria meningitidis serogroup B are grown in complex

fermentation media.


The PRP-OMPC conjugate is prepared by the chemical coupling of the highly purified PRP (polyribosylribitol phosphate) of Haemophilus influenzae type b (Haemophilus b, Ross strain) to an OMPC of the B11 strain of Neisseria meningitidis serogroup B. The coupling of the PRP to the OMPC is necessary for enhanced immunogenicity of the PRP. This coupling is confirmed by analysis of the components of the conjugate following chemical treatment which yields a unique amino acid. After conjugation, the aqueous bulk is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant (previously referred to as aluminum hydroxide).

 TriHIBit® (diphtheria and tetanus toxoids and acellular pertussis [DTaP]/Hib vaccine) [sanofi pasteur]

When Tripedia vaccine is used to reconstitute ActHIB® [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)

manufactured by Aventis Pasteur SA] the combination vaccine is TriHIBit®. Each single 0.5 mL dose of TriHIBit vaccine for the

fourth dose only, is formulated to contain 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid (both toxoids induce at least 2 units

of antitoxin per mL in the guinea pig potency test), 46.8 μg of pertussis antigens (approximately 23.4 μg of inactivated PT and

23.4 μg of FHA), 10 μg of purified Haemophilus influenzae type b capsular polysaccharide conjugated to 24 μg of inactivated tetanus toxoid, and 8.5% sucrose. (Refer to ActHIB vaccine package insert.)



HibTITER  HAEMOPHILUS b CONJUGATE VACCINE  (Diphtheria CRM197 Protein Conjugate)


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).


Three conjugate Hib vaccines are licensed for use in infants as young as 6 weeks of age (see below). All three vaccines

utilize different carrier proteins. Two combination vaccines that contain Hib conjugate vaccine are also available.










HIB Vaccine Timeline and History Tidbits:


1970-1st hib vaccine


1980’s Conjugate vaccine for hib


1985-polysaccharide vaccine

Provoked Hib in rats (by causing transient immune suppression for 7 – 14 days) and also in humans.  
The polysaccharide vaccine was quietly swept under the rug. It continued to be used after 1987, but was rapidly replaced with the conjugate vaccine.


In 1985, the first Hib polysaccharide vaccines were licensed for use in the United States. These vaccines contained purified polyribosylribitol phosphate (PRP) capsular material from the type b serovar. Antibody against PRP was shown to be the primary component of serum bactericidal activity against the organism. PRP vaccines were ineffective in children less than 18 months of age because of the T-cell-independent nature of the immune response to PRP polysaccharide.

Conjugation of the PRP polysaccharide with protein carriers confers T-cell-dependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. In 1989, the first Hib conjugate vaccines were licensed for use among children 15 months of age or older. In 1990, two new vaccines were approved for use among infants.

Haemophilus influenzae type b Polysaccharide-Protein Conjugate Vaccines


Conjugation is the process of chemically bonding a polysaccharide (a somewhat ineffective antigen) to a protein “carrier,” which is a more effective antigen. This process changes the polysaccharide from a T-independent to a T-dependent antigen and greatly improves immunogenicity, particularly in young children. In addition, repeat doses of Hib conjugate vaccines elicit booster responses and allow maturation of class-specific immunity with predominance of IgG antibody. The Hib conjugates also cause carrier priming and elicit antibody to “useful” carrier protein. The first Hib conjugate vaccine (PRP-D, ProHIBIT) was licensed in December 1987. This vaccine was not consistently immunogenic in children younger than 18 months of age.


PRP-D is no longer available in the United States.




Haemophilus influenzae is a small, nonmotile Gram-negative bacterium in the family Pasteurellaceae,  on the level with the Vibrionaceae and the Enterobacteriaceae. The family also includes Pasteurella and Actinobacillus, two other genera of bacteria that are parasites of animals.  Encapsulated strains of Haemophilus influenzae isolated from cerebrospinal fluid are coccobacilli, 0.2 to 0.3 to 0.5 to 0.8 um, similar in morphology to Bordetella pertussis, the agent of whooping cough. Non encapsulated organisms from sputum are pleomorphic and often exhibit long threads and filaments. The organism may appear Gram-positive unless the Gram stain procedure is very carefully carried out. Furthermore, elongated forms from sputum may exhibit bipolar staining, leading to an erroneous diagnosis of Streptococcus pneumoniae.









Seven serotypes of the bacterium have been identified on the basis of capsular polysaccharides. Until the implementation of widespread vaccination programs, type b H. influenzae was the most common cause of meningitis in children between the ages of 6 months and 2 years (see Figure 4 below), resulting in 12,000 to 20,000 cases annually in the U.S. It would be interesting to view comparative data since the era of vaccination against H. influenzae meningitis, which began in 1985. Certainly, there are fewer than 100 cases annually of bacterial meningitis caused by H. influenzae type b.


*bloggers note..type g has since been identified.








Two variants among Haemophilus influenzae serotype b strains with distinct bcs4, hcsA and hcsB genes display differences in expression of the polysaccharide capsule



Despite nearly complete vaccine coverage, a small number of fully vaccinated children in the Netherlands have experienced invasive disease caused by Haemophilus influenzae serotype b (Hib). This increase started in 2002, nine years after the introduction of nationwide vaccination in the Netherlands. The capsular polysaccharide of Hib is used as a conjugate vaccine to protect against Hib disease. To evaluate the possible rise of escape variants, explaining the increased number of vaccine failures we analyzed the composition of the capsular genes and the expressed polysaccharide of Dutch Hib strains collected before and after the introduction of Hib vaccination.


Differences in Genetic and Transcriptional Organization of the glpTQ Operons between Haemophilus influenzae Type b and Nontypeable Strains


Haemophilus influenzae is a common pathogen, especially among children, but the clinical manifestations are largely type specific. The encapsulated H. influenzae serotype b (Hib) usually causes invasive infections, such as meningitis and septicemia (2), whereas the much more common nonencapsulated, or nontypeable, H. influenzae (NTHi) is a major cause of otitis media, sinusitis, and pneumonia (8). General vaccination against Hib has reduced the incidence of Hib infection to a near minimum (10), while attempts to construct a vaccine against the costly NTHi infections have as yet been unsuccessful due to a high genetic heterogeneity among NTHi strains.






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