Status - approved; marketed

Organizations involved:

GlaxoSmithKline Biologicals S.A. – Manuf.

GlaxoSmithKline Inc. – USA mark.

GlaxoSmithKline plc – Parent; Intl. mark.

SmithKline Beecham plc – R&D; Tech.; Former

Biogen Idec, Inc. – Tech.

Biogen Corp. – Former

University of Edinburgh – R&D; Tech.

Genentech, Inc. – Tech.

University of Washington – Tech.

University of California – Tech.

Washington Research Foundation – Tech.

Chiron Corp. – Patent dispute; Tech.

Novartis AG – Parent

City of Hope Medical Center – R&D; Tech; Patent dispute

Cross ref.: See the Hepatitis B Virus Vaccine Products entry in the Vaccines section, and the other hepatitis B virus vaccine entries above. See also a double combination vaccine incorporating Engerix-B – Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine or Twinrix).

Description: Hepatitis B Vaccine (Recombinant) or Engerix-B refers to aqueous formulations of a recombinant nonglycosylated hepatitis B virus surface (s) antigen (HBsAg) from hepatitis B virus subtype adw2 produced by transformed Saccharomyces cerevisiae (yeast) strain DC5 (RT4376) as a suspension adsorbed onto aluminum hydroxide adjuvant. The recombinant HBsAg polypeptide is composed of 226-amino acids with a molecular weight of 24 kDa. Recombinant HBsAg, like native human HBsAg, readily self-assembles in solution to form 22 nm liposome-like particles presenting immunogenic HBsAg epitopes on their surface. Although not glycosylated (as is native human HBsAg), the polypeptide is immunogenically and physically similar to HBsAg antigen isolated from the plasma of chronic hepatitis B virus-infected carriers (see the Heptavax-B entry in the Vaccines section). The surface (s) protein of hepatitis B virus (HBsAg) is the primary viral envelope protein responsible for antigenicity and immunity from infection.

Engerix-B is supplied as a sterile suspension ready for intramuscular injection, generally into the deltoid muscle of the arm, without need for reconstitution or dilution. Two different formulations are available – a relatively new, substantially preservative-free, pediatric/adolescent formulation; and the traditional, now termed adult, formulation containing thimerosal, a mercury derivative preservative. Each 1 mL of adult vaccine contains 20 µg of rHBsAg adsorbed on 0.5 mg aluminum (as aluminum hydroxide), 25 µg of mercury (1:20,000 thimerosal), sodium chloride (9 mg/ml), and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/ml and sodium dihydrogen phosphate dihydrate, 0.71 mg/ml). The adult formulation is packaged as 20 µg/mL in single-dose vials in packages of 1 and 25 vials; 20 µg/mL in single-dose prefilled disposable syringes; and 20 µg/mL in single-dose prefilled disposable Tip-Lok syringes with 1-inch 23-guage needles.

The pediatric/adolescent vaccine is formulated without addition of preservative (thimerosal). Each 1 mL of vaccine contains 20 µg of HBsAg adsorbed on 0.5 mg aluminum (as aluminum hydroxide), plus sodium chloride (9 mg/ml) and phosphate buffers (disodium phosphate dihydrate, 0.98 mg/ml and sodium dihydrogen phosphate dihydrate, 0.71 mg/ml). The pediatric/adolescent formulation is packaged as 10 µg/0.5 mL in single-dose vials in packages of 1 and 25 vials, and as a 10 µg/0.5 single-dose prefilled disposable Tip-Lok syringe with either 1-inch 23-guage needles or 5/8 inch 25-guage needle. This formulation still contains a trace of mercury (less than 1 µg of thimerosal/0.5 mL dose of vaccine) residual from the manufacturing process, apparently from antimicrobial use of thimerosal in culture media or media components. The pediatric/adolescent formulation is a 96% reduction of mercury content relative to the 12.5 µg/dose (1:20,000 thimerosal concentration) of the adult dose, and contains an amount of mercury considered clinically insignificant. In Oct. 2009, a 10 pack carton of Engerix-B 10 µg Pre-Filled Syringes for Pediatric/Adolescent use received FDA approval.

With its 2001 approval, Engerix-B is also packaged in Safety Tip-Lok syringes incorporating BD SafetyGlide Needles from BD Pharmaceutical Systems, Becton Dickinson and Co. [to be in compliance with revised Occupational Safety and Health Administration (OHSA) standards for bloodborne pathogen exposure].

The dating period for the vaccine is 24 months from the date of manufacture when stored continuously at 2-8˚C. The date of manufacture is the date of initiation of the last valid potency test on the final container product.

Nomenclature: Hepatitis. B Vaccine, rDNA/GSK [BIO]; Engerix-B [TR]; Hepatitis B Vaccine (Recombinant) [FDA]; Tecnoquim [TR non-US]; hepatitis B virus surface antigen, recombinant [SY]; HBsAg, rDNA [SY]

Companies.: The vaccine was developed by SmithKline Biologicals S.A., now GlaxoSmithKline Biologicals S.A. It is manufactured by GlaxoSmithKline Biologicals S.A. (Rixensart, Belgium), CBER/FDA est. no. 1617. Engerix-B is marketed in the U.S. by GlaxoSmithKline Inc. and internationally by GlaxoSmithKline (GSK) affiliates

In Jan. 2009, GSK opened a new vaccine manufacturing facility in Marietta, PA. Engerix-B will be finished at this site. The facility will assemble, label and pack syringes containing the vaccine, using bulk material produced at the company's vaccine headquarters in Rixensart, Belgium. GSK bought the 90-acre Marietta site from Wyeth in 2005. Wyeth had earmarked the facility as the production unit for Flumist, an inhaled flu vaccine that largely failed (see related entry). Eventually, the new plant will handle all GSK's U.S. vaccines packaging and distribution operations. The plant is expected to be fully operational in 2013.

Manufacture: The gene for hepatitis B virus (HBV) surface (s) antigen (HBsAg; p24 protein) from a strain of HBV adw2 subtype was cloned using pRIT12363, a functional expression plasmid vector (derived from E. coli clone pACYC 184) for insertion into Saccharomyces cerevisiae (yeast) strain DC5 [also reported as RT4376]. Plasmid pRIT 12363 contains the HBsAg gene flanked by promoter sequences for a glycolytic gene and an ARG3 gene termination sequence. Fermentation is monitored for temperature, pH and dissolved oxygen. After fermentation, yeast cells are disrupted, residual solids are precipitated, soluble contaminants are removed by diafiltration, and diafiltered medium is concentrated. HBsAg is purified by gel permeation chromatography (GPC), ion exchange chromatography, and cesium chloride (CsCl) ultracentrifugation. CsCl is removed by gel filtration. For the thimerosal-reduced pediatric formulation, purified HBsAg undergoes dialysis with cysteine to remove residual thimerosal. The product is adsorbed onto aluminum hydroxide and filled into vials.

Fermentation product is assayed for plasmid retention, microbial purity, and consistency of yield (dry cell weight and antigen content). Bulk, non-adsorbed vaccine is tested for HBsAg identification and protein contaminants by sodium dodecyl sulfate-poly acrylamide gel electrophoresis (SDS-PAGE). Assays for cesium, polysaccharides, DNA, pyrogens and sterility are performed. The adsorbed vaccine (finished product) is tested for HBsAg identification by SDS-PAGE (silver stained), pH, volume, aluminum content, thimerosal, sterility, general safety, endotoxin, and potency in mice.

No substances of human origin are used in the manufacture or formulation of Engerix-B.

It has reported that the ultracentrifugation steps, in which samples are subjected to 100,000 times gravity to separate the protein from DNA, only recovered 15 per cent of the protein and the cesium chloride used is expensive and has to be completely removed from the final product because it is toxic, adding further processing, time and costs. Use of alternative purification methods is one way that biosmilar/biobetter/biogeneric manufacturers can make HBsAg vaccine for less than that of GSK, e.g., Bharat Biotech's HNVAC vaccine uses the Himax technique to purify on the basis of molecular charge.

FDA class: Biologic PLA BLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = 19890828; first approval, PLA 87-0556; Indication = prophylaxis against hepatitis B virus infection

Date = 19980707; PLA supplement; Indication = prophylaxis against hepatitis B virus infection in persons with chronic hepatitis C virus (HCV) infection

Date = 19991214; PLA supplement; Indication = added a statement in the Clinical Pharmacology section of the product insert/labeling accepting CDC’s description of hepatitis B virus vaccines as effective for prophylaxis against liver cancer

Date = 20000328; PLA supplement; Indication = preservative-(thimerosal)-free pediatric/adolescent monodose formulation

Date = 20010700 (est.); BLA supplement (PLA now a BLA; STN: BL 103239); Indication = approval of prefilled Safety Tip-Lok syringes from BD Pharmaceutical Systems, Becton Dickinson and Co.

Date = 20070130; BLA supplement; Indication = approval of a thimerosal-free formulation and use of new a hepatitis B virus working seed

Date = 20091015; BLA supplement; Indications: = approval of a 10 pack carton of Engerix-B 10 µg Pre-Filled Syringes for Pediatric/Adolescent use and accompanying Package Insert.

Date = 20091223; BLA supplement; Indications: = update the Package Insert to include the addition of text to visually inspect vials or syringes for cracks prior to administration

Date = 20100823; BLA supplement; Indication = revised the Package Insert and pre-filled syringe carton to include the appropriate warnings regarding latex containing components (with a Dear Health Care Provider mailed on August 13, 2010)

Indications: [portions of the “INDICATION AND USAGE” section from product insert/labeling]:

Engerix-B is indicated for immunization against infection caused by all known subtypes of hepatitis B virus. As hepatitis D (caused by the delta virus) does not occur in the absence of hepatitis B infection, it can be expected that hepatitis D will also be prevented by Engerix-B vaccination.

Immunization is recommended for persons of all ages, especially those who are, or will be, at increased risk of exposure to hepatitis B virus, for example...Health Care Personnel...Selected Patients and Patient Contacts... Adolescents...[truncated; See the Recombivax HB entry for more].

Status: Engerix-B is marketed in most countries worldwide. In August 1998, Merck discontinued production of the 2.5 µg dosage to simplify its product line (leaving the 5 µg dosage).

Engerix-B is generally subject to FDA CBER lot release requirements. However, as stipulated (but not explained) in the approval letter of January 12, 1994, “Alternatives to Lot Release will remain in effect for the preservative-free presentation,” indicating that this formulation may be exempt from some lot release requirements.

No centralized EU approvals granted - country-by-country in Europe.

Tech. transfer: SmithKlineBeecham (SKB) now GlaxoSmithKline (SKB), and Merck & Co. have cross-licensed various hepatitis B virus vaccine-related patents and licensing rights (and each may hold licenses to the various technologies cited in both this and the Recombivax HB entry). See the entry for Recombivax HB above.

SmithKlineBeecham (SKB), now GlaxoSmithKline (GSK) (and also Merck & Co.) licensed key recombinant hepatitis B virus surface antigen (HBsAg) patents from Biogen Corp. (now Biogen Idec) in mid-1988 and pays unspecified royalties on U.S. sales until patent expiration in 2004. University of Edinburgh scientists collaborated with Biogen in sequencing and producing recombinant hepatitis B surface antigens, and the university likely receives a share of Biogen’s licening income. Licensing included U.S. patent 4,710,463, “Recombinant DNA molecules capable of expressing HBV core and surface antigens,” covering aspects of recombinant hepatitis B virus surface and core antigens. Biogen has claimed that this patent covers production of all recombinant HBsAg products. It was reported in 1990 that Biogen Corp. receives a 6% royalty on sales of Recombivax HB. Biogen’s European patents expired at the end of 1999, except in countries where the company has supplemental protection (patent extension) certificates. The additional coverage these provide ranges from 2-6 years.

Yeast expression system technology used for manufacture was also developed by and licensed from the University of Washington and Genentech, Inc. Washington Research Foundation (WRF) is the exclusive licensing agent for this family of yeast expression patents. The issued patents, particularly the more recently issued patents, broadly claim processes and materials for expression of proteins in yeast. Patents include U.S. 5,854,018 (issued April 8, 1997) and 5,856,123 (continuations of 5,618,676) concerning recombinant production of proteins in yeast expression systems including Saccharomyces, Kluyveromyces, Pichia and Hansenula. All three U.S. patents will expire in 2014. The new patents are broader, as they claim processes and materials for expression of proteins in recombinant yeast systems generally. Other licensed patents include also U.S. 4,769,238 and 5,196,194.

SKB (GSK) also licensed recombinant hepatitis B virus surface antigen (HbSAg) yeast expression technology from Genentech, Inc. (S. San Francisco, CA). See the Recombivax HB entry for further information. As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech, including involvement in hepatitis B vaccine development. Genentech is appealing to the California State Supreme Court.

SKB (GSK) in September 1998 settled long-running patent litigation over its use of certain glyceraldehyde-3-phosphate dehydrogenase (GAPDH) promoters, claimed in patents held by Chiron Corp. regarding yeast expression of recombinant antigens. SKB received a nonexclusive worldwide license from Chiron to use the promoters for production of human vaccines. Chiron was paid a license issuance fee and receives unspecified royalties on sales of vaccines manufactured using the promoters. Novartis AG acquired Chiron Corp. in late 2005. Exemplary Chiron patents include U.S. 5,089,398, Rosenberg, et al. Exemplary yeast strains 2150-2-3 (GAP5), 2150-2-3 (Pyk5) and 2150-2-3 (PHO5GAP1) expressing hepatitis B surface antigen were deposited as ATCC nos. 20705, 20706 and 20707, respectively.

As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent dispute involving COH cloning DNA for Genentech, including involvement in hepatitis B vaccine development. Genentech is appealing to the Supreme Court of California.

Medical: The usual dosage for adults and children over age 10 is 20 µg or 1 mL of adult vaccine. The dosage for those under age 10 is 10 µg, e.g., 0.5 mL of pediatric vaccine. Injections are administered at 0, 1 and six months. In certain patients, such as neonates born to infected mothers, persons recently exposed to hepatitis B virus, and persons traveling to high risk areas, etc.), an additional dose at 12 months is recommended. The recommended regimen for hemodialysis patients is 40 mg at 0, 1, 2 and six months. Other alternative regimens are available for specialized patients/situations.

In its over 10 years on the world market, well over 500 million doses have been administered and over 250 clinical trials have been conducted with Engerix-B. Experience with the vaccine is reviewed in “Over a Decade of Experience with a Yeast Recombinant Hepatitis B Vaccine,” Vaccine, vol. 18, no. 2000, p. 57-67.

The minimum HBsAg-specific antibody titer considered as needed to provide protection against active viral infection is 10 mIU/mL. Seroconversion is defined as HBsAg-specific antibody titers ≥ 1 mIU/mL. In clinical trials, healthy adults administered a normal Engerix-B vaccination regimen (0, 1 and 6 months) resulted in 96% seroconversion, with a geometric mean antibody titer (GMT) of about 2,200 mIU/mL at month seven.

Clinical studies with Engerix-B began in February 1984. By July 1988 (FDA submission), over 10,000 persons had received the vaccine in 87 studies. Overall, 96-99% of healthy adults achieved protective levels of antibody (> 10 mIU/ml). The 0, 1, 6 month dosing schedule provided protective antibody titers in 99% of subjects by one month after the third vaccine dose. A fourth dose at month 12 was shown to substantially increase the geometric mean titer (GMT) of antibody. Protective efficacy was demonstrated in high risk groups including neonates born to HBV carriers (infected mothers). In a study in 58 neonates born to infected mothers and vaccinated at 0, 1, 2 and 12 months, only 2 (3%) of vaccinated infants became chronic carriers, compared to historical rate of 60-90%.

Market: The total monovalent hepatitis B vaccine market has been reported in 2011 to be ≥$400 million. In this context, Engerix-B may have sales of about $200 million.

Based on reported first-half 2013 sales of about $500 million for all GSK hepatitis B component-containing vaccines, 2012 sales of these products, including combination vaccines, are estimated to be about $950 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) for the pediatric-adolescent dose is $21.37 for 5- and 10-pack vials and prefilled syringes (unchanged 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 $9.10 for pediatric-adolescent 5- and 10-pack vials and prefilled syringes. 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. GSK’s contract with NIP, CDC, expires on March 31, 2008. The Private Sector Cost/Dose for the adult dosage is $50.35 for 5- and 10-pack vials and prefilled syringes. The CDC Cost/Dose for adult dosage is $24.73 for 5- and 10-pack vials and prefilled syringes, The contract with GSK for pediatric-adolescent Engerix-B expires on March 31, 2008, and the contract for the adult formulation expires on June 30, 2008. These prices include the $.75/dose ($75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program.

With three inoculations needed for long-term immunity, the cost paid by the consumer for a course of inoculations can easily run over $100.

In early 2005, GSK reported that over one billion doses had cumulatively been distributed worldwide. SKB, now GSK, reported that 1997 worldwide sales of Engerix-B were $584 million, an increase of 9% from 1996. U.S. sales were $264 million (45% of total), an increase of 22% from 1996.