Status: marketed in U.S., EU and most countries worldwide

Organizations involved:

GlaxoSmithKline Biologics S.A. – Manuf.; R&D; Tech.

GlaxoSmithKline Inc. – USA mark.

GlaxoSmithKline plc – Intl. mark.; Parent

Cross ref: See the Haemophilus b Vaccine Products entry (#453).

Description: Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] or Hiberix is a lyophilized (freeze-dried) formulation of Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate [PRP]), prepared from culture of Haemophilus influenzae type b strain 20,752 in a synthetic medium that undergoes heat inactivation and purification chemically conjugated to tetanus toxin from Clostridium tetani grown in a semi-synthetic medium detoxified with formaldehyde and then purified. The capsular polysaccharide is covalently bound to the tetanus toxoid. After activation with cyanogen bromide and derivatization with an adipic hydrazide spacer, the Hib polysaccharide is coupled to tetanus toxoid via carbodiimide condensation. After purification, this conjugate is lyophilized in the presence of lactose as a stabilizer. The vaccine meets the World Health Organization (WHO) requirements for the manufacture of biological substances and Hib conjugate vaccines.

Hiberix is supplied as a white lyophilised pellet in glass vials for reconstitution with sterile saline solution (0.7 mL of 0.9% sodium chloride) supplied in prefilled TIP-LOK syringes . When reconstituted with the accompanying saline diluent, each 0.5-mL dose is formulated to contain 10 µg of purified capsular polysaccharide conjugated to ~25 µg of tetanus toxoid. Each dose also contains 12.6 mg of lactose and ≤0.5 mcg of residual formaldehyde. The shelf-life is three years from the date of manufacture when stored at temperatures between +2°C to +8°C (refrigerated). The manufacture of Hiberix includes exposure to bovine derived materials, presumably culture media components.

Nomenclature: Hiberix [TR]; Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) [FDA]; NDC 58160-806-05 [NDC]

Companies.: Hiberix was developed and is manufactured by GlaxoSmithKline Biologicals S.A. (CBER/FDA est. no. 1617). It is marketed in the U.S. by GlaxoSmithKline Inc. and internationally by GlaxoSmithKline plc.

FDA class: Biologic BLA

Approvals: Date = 20090821, BLA, accelerated approval

Indications: [Full text of the "Indications and USAGE" sectoin of product labeling/insert]:

HIBERIX is indicated for active immunization as a booster dose for the prevention of invasive disease caused by Haemophilus influenzae type b. HIBERIX is approved for use in children 15 months through 4 years of age (prior to fifth birthday).

HIBERIX is to be used as a booster dose in children who have received a primary series with a Haemophilus b Conjugate Vaccine that is licensed for primary immunization. HIBERIX is not approved for primary immunization.

The evaluation of effectiveness of HIBERIX as a booster dose was based on immune responses in children using serological endpoints that predict protection from invasive disease due to H. influenzae type b [see Clinical Pharmacology (12.1) and Clinical Studies (14.1)]. These protective antibody levels have not been evaluated in clinical trials in which a booster dose of HIBERIX is compared to a booster dose of a US-licensed Haemophilus b Conjugate Vaccine in children who previously received a primary series with a US-licensed Haemophilus b Conjugate Vaccine [see Clinical Studies (14.1)].

Status: This monovalent PRP-tetanus toxoid conjugate vaccine that has been available outside the U.S. since 1961.

     Note, Hiberix is approved in the U.S. only as a booster, while it is approved for both primary and booster inoculations in most every other territory. Hiberix received accelearated FDA approval after a shortage of Hib vaccines developed in the U.S. A nationwide shortage of Hib vaccine began in Dec. 2007 due to a voluntary recall by Merck & Co. and subsequent production suspension of PedvaxHIB and COMVAX, two of four vaccines licensed in the U.S. for primary and booster immunization against invasive disease due to Hib. This led the CDC (Centers for Disease Control and Prevention) to recommend temporary deferral of the booster dose for healthy children not at increased risk for Hib disease. In summer 2009, the CDC reinstated the routine Hib booster dose due to an increase in supply. However, supply was not sufficient to support a mass catch-up effort for the millions of children who did not receive the booster dose during the shortage. Hiberix was expected to help restore supply so children who missed the booster dose can get caught-up. Additionally, children coming in for routine visits can receive the Hib booster shot on time.

Trials: In its BLA, GSK submitted safety and efficacy information from clinical studies conducted outside the U.S. In those studies, a booster dose of Hiberix following primary series vaccination provided protective levels of antibodies against Hib bacteria, regardless of the priming vaccine that was used.

Based on data from passive antibody studies and a clinical efficacy study with unconjugated Haemophilus b polysaccharide vaccine, an anti-PRP concentration of 0.15 mcg/mL has been accepted as a minimal protective level. Data from an efficacy study with unconjugated Haemophilus b polysaccharide vaccine indicate that an anti-PRP concentration of ≥1.0 mcg/mL predicts protection through at least a 1-year period. These antibody levels were used to evaluate the effectiveness of Haemophilus b Conjugate Vaccines, including Hiberix.

The protective efficacy of Hiberix has not been studied in field trials. Hiberix has however been shown to induce anti-PRP antibodies above the level known to be protective against invasive disease due to Haemophilus influenzae type b. An anti-PRP antibody titre ≥ 0.15 mcg/mL correlates w ith immediate protection against Hib infection and ≥ 1.0 mcg/mL correlates with long term protection.

In booster trials, a boosting dose was given either separately (n=19) or in combination with DTPa (n=56) to infants aged between 15 and 18 months who had previously received Hiberix and DTPa given at separate sites. One month after administration of this booster dose, an anamnestic response was observed with anti-PRP antibody titres of ≥ 0.15 mcg/mL and ≥ 1.0 mcg/mL being obtained in 100% and greater than 94% of infants respectively.

Medical: Hiberix is administered as a 0.5-mL dose by intramuscular injection into the anterolateral aspect of the thigh or deltoid.

Market: More than 54 million doses of Hiberix have been distributed outside the U.S. since the 1996 launch in Germany, and upon FDA approval the vaccine was registered in nearly 100 countries.