Status: withdrawn from market

Organizations involved:

Sanofi Pasteur Inc. – Former

Sanofi Pasteur S.A. – Parent; Former

Rohm Pharma – Former

Cheil Jedang Corp. – Former

Cross ref: See the Haemophilus b Vaccine Products entry (#453) above. Sanofi Pasteur also manufactures and markets Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), trade name ActHIB (entry #455).

Description: Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) or ProHIBiT was an aqueous formulation of bacterial polysaccharide-protein conjugate vaccine formed from purified Haemophilus influenzae type B Eagan strain capsular polysaccharide covalently linked via a spacer to diphtheria toxoid protein (D; inactivated Corynebacterium diph-theriae bacterial toxin; equivalent to the unadsorbed diphtheria toxoid component of Aventis Pasteur (Sanofi Pasteur) combination vaccines containing a diphtheria toxoid component). The H. influenzae poly-saccharide is composed of polyribosylribitol phosphate (PRP), a polymer of ribose, ribitol and phosphate, obtained from the outer bacterial capsule cell membranes of cultured H. influenzae. The polysaccharide-protein conjugate molecule is referred to as PRP-D.

Purified activated H. influenzae polysaccharide and deri-vatized diphtheria toxoid are covalently linked via carbodi-imide (EDAC), and dissolved in sodium phosphate buffered isotonic sodium chloride solution. A six-carbon chain forms a linker group or spacer between the polysaccharide and protein. Linkage of the toxoid molecule to the bacterial polysaccharide substantially increases the immunogenicity of the polysaccharide.

The vaccine is packaged in single 2.5 mL (five 0.5 mL dose) vials, in single 5 mL (10 dose) vials, and in packages of six 0.5 mL single dose disposable syringes each with a 5/8 inch 25 gauge needle. Each single dose of 0.5 mL contains 25 µg of capsular polysaccharide and 18 µg of diphtheria toxoid protein. Thimerosal, a mercury-based antimicrobial preservative is added at a concentration of 0.01% or 1:10,000.

Nomenclature: Haemophilus b Vaccine (PRP-D) [BIO]; ProHIBiT [TR]; Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) [FDA]; Hib-Vaccinol [SY]; PRP-D [SY]; HIB [CDC]; NDC 49281-0541-10 and 49281-0541-61 [NDC]

Companies.: ProHIBiT was developed and manufactured by Aventis Pasteur Inc. (Switftwater, PA), CBER/FDA est. no. 0711, now Sanofi Aventis Inc. It was marketed in the U.S. by Aventis Pasteur Inc., and internationally by Aventis Pasteur S.A. (now Sanofi Pasteur S.A.) affiliates. Marketing rights in Germany were licensed to Rohm Pharma. Marketing rights in S. Korea were licensed to Cheil Jedang Corp.

Manufacture: The conjugate is prepared by reacting cyanogen bromide-activated capsular H. influenzae b polysaccharide hapten (consisting of approximately equal parts of ribose, ribitol and phosphate) with derivatized diphtheria toxoid (D-AH).

The PRP polysaccharide component is first “heat sized.” The molecular size/mass of the Haemophilus influenzae B polysaccharide is adjusted by heating until the desired dimension for the hapten is obtained. Typically, heating of the liquid polysaccharide for 15 minutes at 100˚C assures that less than 20% of the molecules are less than 200 kDa and less than 20% are greater than 2,000 kDa. This sizing operation is important to obtain a proper PRP-D from unreacted protein. The sized polysaccharide is reacted (activated) with cyanogen bromide, forming an electrophilic group on the polysaccharide. Unreacted cyanogen halide is exhaustively removed, because residue causes undesired cross-linking of the toxoid protein, trapping the polysaccharide and forming PRP-D with undesired structure.

The purified diphtheria toxoid (D) used as carrier is a commercial Diphtheria Toxoid chemically modified (derivatized) by the attachment of a spacer molecule, e.g., adipic acid dihydrazide (ADH), using the water-soluble carbo-diimide condensation method. The adipic hydrazide derivative, D-AH, is then freed from unreacted ADH.

The activated PRP and D-AH are then combined and allowed to react in the cold. Some of the hydrazide groups on the derivatized diphtheria toxoid react with the activated sites on PRP to form covalent bonds. The product is PRP covalently bound to derivatized D through a six carbon chain (PRP-D). This desired reaction product is purified by gel permeation chromatography to remove any unreacted protein and low molecular weight contaminants (lower than 140 kDa). The typical molecular weight of the principal fraction is about 675,000 Dalton (675 kDa) relative to a dextran standard. A typical range for relative molecular size is 140 kDa to 4,500 kDa. Thimerosal is added to a final concentration of 1:10,000. The bulk concentrate (PRP-D) is sterile filtered through a 0.2 micron Durapore membrane and stored in the cold. The product is diluted to 50 µg of polysaccharide/mL and filled into final containers (vials or disposable syringes).

FDA class: Biologic PLA

CBER class: Bacterial Antigens and Vaccines

Approvals: Date = 19871222; first approval, PLA; Indication = for immunization of infants of age 18 to 59 months against Haemophilus influenzae infection

Date = 19920917; PLA supplement; Indication = use as a booster dosage in children 12-15 months of age or older

Date = 19991209; approval revoked from Connaught Labs., Inc. and granted (reissued) to new owner, Aventis Pasteur Inc.

Indications: [truncated text of the "INDICATIONS AND USAGE” section from recent product insert/labeling]:

ProHIBiT is indicated for immunization against invasive diseases caused by Haemophilus influenzae type b. ProHIBiT may be administered as a booster vaccination at 12 to 15 months of age in children who received primary immunization with Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) or Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate) as illustrated in Tables 2, 3, 4 and 5. This vaccine also may be administered as primary immunization at 15 months of age in children who have not received primary immunization with any licensed Haemophilus b Conjugate Vaccine.

Status: The BLA for ProHIBit was recently voluntarily withdrawn. It is no longer manufactured or marketed.

Market: ProHIBiT was considered a first-generation Hib vaccine and has been replaced in the company’s product line by ActHIB (also marketed by Sanofi Pasteur Inc.; see related entry). ActHIB has advantages including improved immunogenicity and efficacy in younger persons, down to two months of age. Also, ActHIB (and equivalent OmniHIB) is formulated without thimerosal (mercury-based preservative).