Status: approved; marketed

Organizations involved:

Merck & Co., Inc. – Manuf.; R&D; Tech.; USA mark.; Intl. mark.

Sanofi Pasteur MSD – Europe mark.

Behringwerke AG – Tech.

Cross ref: See the Haemophilus b Vaccine Products entry (#453). See also a combination vaccine (#460) containing this vaccine as a component – Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine or COMVAX.

Description: Haemophilus b Conjugate (Meningococcal Protein Conjugate) or PedvaxHIB refers to aqueous and lyophilized (freeze-dried) formulations of capsular polysaccharide (polyri-bosyl-ribitol-phosphate or PRP) antigen of Haemophilus influenzae type b (Haemophilus B) Ross strain chemically conjugated to meningococcal protein (OMP complex; OPMC) from Neisseria meningitidis group B strain B11 bacterium, adsorbed onto aluminum hydroxide adjuvant. Conjugation of the N. meningitidis capsular polysaccharide PRP to the Hib OMPC protein substantially increases the immunogenicity of the Hib OMPC antigen, enabling its the vaccine’s use in infants who otherwise would not develop adequate immune responses to unconjugated Hib PRP.

PedvaxHIB is packaged as a powder for reconstitution and as liquid, both for intramuscular injection. The solvent in the liquid formulation is 0.9% sodium chloride with thimerosal (mer-cury derivative; 0.005%) as an antimicrobial preserva-tive (see #939). The powder contains 2 mg lactose as an excipient with no thimerosal or other preservative. After reconstitution (aqueous dilution) for injection, the powder provides 15 µg of Hib polysaccharide, 250 µg of Neisseria menin-gitidis OMPC, and 225 µg of aluminum (as aluminum hydroxide) per 0.5 mL dose. The liquid solution provides 7.5 µg of Hib polysaccharide, 125 µg of N. meningitidis OMPC, and 225 µg of aluminum (as aluminum hydroxide) per 0.5 mL dose. The powder is available as a single dose package with diluent and as a box of five single dose packages. The liquid formulation is available in single dose vials and as a box of five single dose vials.

Nomenclature: Haemophilus b Vaccine/Merck [BIO]; PedvaxHIB [TR]; Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) [FDA]; PRP-OMP [SY]; HIB [CDC]; NDC 00006-4792-00; NDC 00006-4797-00; NDC 00006-4877-00; NDC 00006-4897-00 [NDC]

Companies.: This vaccine was developed and is manufactured by Merck & Co., Inc. (West Point, PA), FDA CBER est. no. 0002. It is marketed in the U.S. by Merck & Co., and internationally by Merck affiliates. The vaccine is marketed in Europe by Sanofi Pasteur MSD, a joint venture of Merck and Sanofi Pasteur S.A.

Manufacture: Haemophilus influenzae type b (Hib) Ross strain and Neisseria meningitidis serogroup B are separately cultured in complex fermentation media. The PRP is purified from the H. influenzae type b culture broth by purification procedures including ethanol fractionation, enzyme digestion, phenol extraction, and diafiltration. The OMPC is purified from the culture broth of N. meningitidis by detergent extraction, ultracentrifugation, diafiltration and sterile filtration.

The PRP-OMPC conjugate is prepared by the chemical conjugation of the highly purified PRP to OMPC. The coupling of the PRP to the OMPC is confirmed by analysis of the conjugate’s components following chemical treatment which yields a unique amino acid (facilitating confirmation of conjugation). After conjugation, the aqueous bulk is adsorbed onto aluminum hydroxide adjuvant. The potency of PedvaxHIB is determined by assay of PRP. Conjugation can be confirmed by intensional degradation of the conjugate, resulting in a unique amino acid that results only from proper conjugation.

FDA class: Biologic PLA

CBER class: Bacterial Antigens and Vaccines

Approvals: Date = 19891220; first approval, PLA; Indication = for use in infants 18 months or older

Date = 19900000; PLA supplement; Indication = use extended to include infants two months or older

Date = 19960800; PLA supplement; Indication = liquid formulation approved

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

Liquid PedvaxHIB is indicated for routine vaccination against invasive disease caused by Haemophilus influenzae type b in infants and children 2 to 71 months of age.

Status: The vaccine is marketed Sweden and, perhaps, other individual European countries; and has not received centralized European Union approval.

Status: In Nov. 2007, a shortage of PediavaxHIB was declared in the U.S., with the vaccine unavailable due to manufacturing problems. A total of 1.2 million doses were recalled after Merck found the equipment used to make the vaccine to be contaminated with bacteria. The recall involved vaccine shipped starting in April 2007. The recall involved 11 lots of Pedvaxhib, and two lots of a combination vaccine for both Hib and hepatitis B -- Comvax. The vaccines were manufacture at Merck's plant in West Point, PA. Merck issued this voluntary recall as a precautionary measure because the company could not assure the sterility of equipment used during manufacture of these lots. However, the potency of the vaccine in the recalled lots was not affected, and no contamination of vaccine was detected. Children who received Hib conjugate vaccine from the recalled lots did not need revaccination or any special follow-up. Merck was expected to resolve its problems and resume full manufacture in mid-to-late 2009. Until then there were shortages of pneumococcal vaccine, and CDC reported seeing an increase in pediatric pneumococcal disease.

Tech. transfer: The meningococcal protein used for conjugation was developed and patented by Beh-ring-werke AG. Merck developed the methods for covalent conjugation.

Market: PedvaxHIB is reported to have about half the U.S. market for Hib vaccines, providing about 7 million doses. Presuming a wholesale price price of $25/dose, the U.S. market would be about $185 million/year.

The 2007 Average Wholesale Price (AWP) is 272.23/10 single-dose vials (Red Book, 2007; $289.73 in 2005; $267.16 in 2004), with a Direct Price (Manufacturer’s discounted price) of $227.69 ($235.19 in 2005).

As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) $22,77 for packages of 10 single dose vials (no change since 2005). The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $10.83 ($10.62/dose in 2006; $10.22 in 2005) for packages of 10 single dose vials. These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Merck’s contract with NIP, CDC, expires on March 31, 2008.