Status: approved; marketed

Organizations involved:

Sanofi Pasteur S.A. – Manuf.; R&D; Tech.; Intl. mark.; Parent

Sanofi Pasteur Inc. – USA mark.

Cross ref: See the Haemophilus b Vaccine Products entry (#399). See also the entry for an identical vaccine, OmniHIB (#459), relabeled and marketed by Glaxo-SmithKline Inc. See also the entry (#454) for an earlier generation Haemophilus conjugate vaccine, Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) or ProHIBiT, from Sanofi Pasteur.

Description: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) or ActHIB is a lyophilized (freeze-dried) formulation of bacterial polysaccharide-protein conjugate vaccine formed from purified Haemophilus influenzae type b strain 1482 capsular polysaccharide (PRP) linked covalently via carbo-diimide (EDAC), a six-carbon chain spacer group, to deri-vatized tetanus toxoid (T) protein (inactivated C. diph-theriae bacterial toxin; comparable to unadsorbed tetanus toxoid vaccine from Sanofi Pasteur). The H. influenzae polysaccharide is a bacterial outer capsule-derived polymer composed of polyribosylribitol phosphate (a polymer of ribose, ribitol and phosphate or PRP) obtained from the cell membranes of cultured H. influenzae type b (Hib). The polysaccharide-protein conjugate molecule is referred to as PRP-T.

ActHIB is packaged in 0.6 mL vials containing lyophilized powder with no preservative for reconstitution with diluent (0.4% sodium chloride) or a DTaP or DTP vaccine manufactured by Sanofi Pasteur Inc. ActHIB is sold in kits along with either saline (0.4% sodium chloride) for reconstitution and use as a monovalent vaccine; or in kits with whole cell DTP vaccine from Sanofi Pasteur Inc. for reconstitution (dissolution of ActHIB to form Tripedia, a quadravalent DTP-Hib vaccine). Sanofi Pasteur Inc. packages ActHIB with its Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) vaccine (Tripedia), but physicians are free to purchased these separately and use Tripedia for reconstitution of ActHIB to form TriHIBit (DTaP-Hib; see #443).

ActHIB powder contains 8.5% sucrose, ammonium sulfate, and formalin as excipients. After reconstitution, the vaccine contains 10 µg of Hib PRP conjugated to 24 µg of tetanus toxoid per 0.5 mL dose. The vaccine is available as a box of five single-dose packages containing a powder vial and a disposable syringe containing 0.6 mL of diluent with a 5/8 inch, 23 gauge needle. The lyophilized ActHIB powder and saline diluent contain no preservatives. The vaccine is stored at 2-8˚C (refrigerated). ActHIB is sold in packages of 5 vials each containing one 7.5 mL vial along with 0.6 mL vials containing saline diluent, and as TriHIBit kits containing 10 one-dose vials with a 7.5 mL vial of Tripedia (DTaP vaccine) as diluent.

Nomenclature: Haemophilus b Vaccine (PRP-T) [BIO]; ActHIB [TR]; Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) [FDA]; Hib vaccine [SY]; HIB [CDC]; NDC 49281-545-05; NDC 49281-549-10 [NDC]

Companies.: ActHIB is manufactured by Sanofi Pasteur S.A. (Lyon, France); FDA CBER est. no. 0384, formerly Aventis Pasteur S.A. It is marketed in the U.S. by Sanofi Pasteur Inc., formerly Aventis Pasteur Inc., and internationally by Sanofi Pasteur S.A. and affiliates. Aventis merged into Sanofi Aventis S.A. in late 2004.

Manufacture: The manufacturing process for ActHIB is very similar to that of Haemophilus b Conjugate Vaccine (Diphtheria Toxoid Conjugate) or ProHIBiT (#454), except a different Hib strain is used as the source for PRP and tetanus toxoid, rather than diphtheria toxoid, is used for conjugation. Haemophilus influenzae type b strain 1482 is cultured in a semi-synthetic medium, and the outer membrane polysaccharide (PRP) is purified. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin (formaldehyde) inactivation of the toxin obtained from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. The toxoid is filtration sterilized prior to the conjugation process. Purified activated H. influenzae PRP and derivatized tetanus toxoid are covalently linked via car-bo-diimide (EDAC). Quality control includes specification of the content of PRP polysaccharide and protein, and the percentage of conjugated polysaccharide and protein as high molecular weight conjugate.

FDA class: Biologic PLA

CBER class: Bacterial Antigens and Vaccines

Approvals: Date = 199333; PLA; granted to Connaught Labs., Inc.; Indication = prevention of Hib disease

Date = 1996927; PLA supplement; Indication = for reconstitution with Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed manufactured by Connaught Labs. for immunization of 15-18 month old children

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

Indications: [portion of the "INDICATIONS AND USAGE” section from product insert/labeling, 8/2004; ‘AvP’ refers to Aventis Pasteur Inc.]:

ActHIB or ActHIB combined with AvP DTP vaccine by reconstitution is indicated for the active immunization of infants and children 2 through 18 months of age for the prevention of invasive disease caused by H. influenzae type b and/or diphtheria, tetanus and pertussis. TriHIBit, ActHIB combined with Tripedia by reconstitution, is indicated for the active immunization of children 15 to 18 months of age for prevention of invasive disease caused by H. influenzae type b and diphtheria, tetanus and pertussis. Antibody levels associated with protection may not be achieved earlier than two weeks following the last recommended dose. Only AvP whole-cell DTP, Tripedia or 0.4% Sodium Chloride diluent may be used for reconstitution of lyophilized ActHIB. TroHIBit, ActHIB combined with Tripedia by reconstitution, should not be administered to infants younger than 15 months of age.

Status: CBER/FDA reported in December 2000 that ActHIB was being manufactured using bovine-derived materials from countries on the official USDA list of countries known to have cattle with BSE. See the Vaccine Products entry (#400) for further information about bovine source materials and BSE. In March 2004, CBER/FDA again listed ActHIB as being on the “Current list of vaccines using bovine-derived materials from countries on the USDA’s BSE list.”

ActHIB is marketed in some European countries, but has not received centralized European Union approval.

Trials: In clinical trials in the U.S. and worldwide. ActHIB induced average PRP antibody levels ≥ 1.0 µg/mL in 90% of infants after the primary series and in more than 98% of infants after a booster dose.

Medical: In considering use of ActHIB combined with Tripedia (DTaP), the benefits and risks of combined diphtheria, pertussis, tetanus and Hib vaccination (fewer injections, physician/clinic visits, lower costs, better compliance) must be weighed against the known slight decrease in efficacy of the combined vs. separately administered component vaccines.

Market: ActHIB is considered a second-generation Haemophilus B vaccine and has replaced ProHIBiT, a first generation vaccine (see related entry). ActHIB has advantages over ProHI-BiT including improved efficacy in infants down to two months of age, and formulation without thimerosal.

ActHIB is reported to have about half the U.S. market for Hib vaccines, providing about 7 million doses. Presuming a wholesale price of about $25/dose, the U.S. market is ~$175 million.

As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $21.88 ($22.53 in 2006 and 2005) for package sof 5 single dose vials.. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $8.28 for packages of 5 single dose vials ($7.92 in 2006; $7.86 in 2005). 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. Sanofi Pasteur’s contract with NIP, CDC, expires on March 31, 2008.

The 2007 Average Wholesale Price (AWP) is $135.20 for five 10 µg vials, with a Direct Price (Manufacturer’s discount) of $108.91 (Red Book, 2007).

The Sanofi Pasteur list price in Jan. 2006 for ActHIB was $105.16/package of five 1-dose vials ($21.03/dose) (same in 2002 and 2004). A federal excise tax of $0.75/dose is added to the sale price charged by the manufacturer to fund the federal vaccine injury compensation program.

In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported is price as $118.92/package of five single-dose vials plus diluent ($118.92 in 2005; $121.01 in 2004).