Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine - Twinrix
Status - approved; marketed
Organizations involved:
GlaxoSmithKline Biologicals S.A. – R&D; Tech.; Manuf.
GlaxoSmithKline Inc. – USA mark.
GlaxoSmithKline plc – Intl. mark.; Parent
SmithKline Biologicals S.A. – R&D; Tech.; Former.
Cross ref.: See the entries for the two component vaccines – Hepatitis A Inactivated (Havrix) (#463), and Hepatitis B (Recombinant) Vaccine (Engerix-B) (#175).
Description: Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine or Twinrix is an aqueous formulation combining two component hepatitis virus vaccines – Hepatitis A Inactivated (Havrix) and Hepatitis B (Recombinant) Vaccine (Engerix-B). The component hepatitis A virus vaccine, Havrix, is an aqueous formulation of whole inactivated hepatitis A virus (strain HM-175) prepared from virus cultured in MRC-5 human diploid cells, inactivated with formaldehyde and adsorbed onto aluminum hydroxide adjuvant. Engerix-B is an aqueous formulation of recombinant nonglyco-sylated hepatitis B virus surface (s) antigen (HBsAg) from hepatitis B virus subtype adw2 produced by transformed Saccharomyces cerevisiae (yeast) strain DC5 (RT4376) in a synthetic culture medium and adsorbed onto aluminum hydroxide adjuvant.
Twinrix is packaged in 1.0 mL single-dose glass vials and 1.0 mL single-dose pre-filled glass syringes containing at least 720 ELISA units of inactivated hepatitis A virus adsorbed onto aluminum phosphate adjuvant and 20 µg of recombinant HBsAg protein adsorbed onto aluminum hydroxide adjuvant. Each 1.0 mL dose of Twinrix also contains 0.45 mg of aluminum (from the two vaccine adjuvants), amino acids, 5.0 mg 2-phenoxy-ethanol as a preservative, sodium chloride, phosphate buffer, polysorbate 20, Water for Injection, traces of formalin (≤ 0.1 mg), a trace amount of thimerosal (< 1 µg; a mercury based preservative; see #939) residual from the manufacturing process, residual MRC-5 cellular proteins (≤ 2.5 µg), residual yeast protein (≤ 5%), and trace amounts (≤ 20 ng/dose) of neomycin sulfate from cell culture media. The dating period is 36 months when stored at 2-8˚C (refrigerated).
Nomenclature: Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine [FDA]; Hepatitis A/B Vaccine [BIO]; Twinrix [TR]; Ambirix [TR] Europe]; NDC 58160-850-01, NDC 58160-850-11 and NDC 58160-850-46 [NDC]
Companies.: Twinrix was developed and originally manufactured by SmithKline Biologicals S.A. (Rixensart, Belgium), now GlaxoSmithKline Biologicals S.A., CBER/FDA est. no. 1617, now part of GlaxoSmithKline plc (GSK). Twinrix is exclusively marketed in the U.S. by GlaxoSmithKline Inc., and internationally by GlaxoSmithKline Biologicals S.A. and affiliates.
Manufacture: The finished bulk recombinant yeast-expressed hepatitis B virus surface antigen vaccine adsorbed onto aluminum hydroxide adjuvant (Engerix-B) and finished bulk inactivated hepatitis A virus vaccine adsorbed onto aluminum phosphate adjuvant (Havrix) are blended to form Twinrix.
FDA class: Biologic BLA
CBER class: Viral And Rickettsial Vaccines
Approvals: Date = 20010511; first approval, BLA (103850); Indications: = approval for adults over age 18 with a 0, 1, 6-month dosing schedule
Date = 20070119; BLA supplement (STN: 103850/5173); Indications: = changes to the product insert/labeling
Date = 20070328; BLA supplement; Indications: = accelerated adult dosing schedule of 0, 7, 21-30 days followed by a booster at 12 months.
Indications: [partial text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
TWINRIX is indicated for active immunization of persons 18 years of age or older against disease caused by hepatitis A virus and infection by all known subtypes of hepatitis B virus. As with any vaccine, vaccination with TWINRIX may not protect 100% of recipients. As hepatitis D (caused by the delta virus) does not occur in the absence of HBV infection, it can be expected that hepatitis D will also be prevented by vaccination with TWINRIX.
Immunization is recommended for all susceptible persons 18 years of age or older who are, or will be, at risk of exposure to both hepatitis A and hepatitis B viruses, including but not limited to:...[truncated]
Status: FDA approval of Twinrix included waiving of the requirement for new product approvals to include assessment of safety and efficacy in pediatric patients. The company had to commit to conduct a prospective, randomized, 3,300-adult postmarketing study comparing Twinrix with its component monovalent vaccines (despite pediatric approvals for each of the component vaccines).
On Aug. 30, 200, European Union (EU) approval was granted to Ambirix for immunization of aged children and adolescents aged 6-15 (not previously vaccinated).
Twinrix is now available in nearly all countries worldwide.
Tech. transfer: See the entries for each component vaccine.
Trials: Clinical trials have shown Twinrix to be as safe and effective as its two component vaccines administered separately. In eleven clinical trials enrolling over 1,550 health adult volunteers, Twinrix induced protective levels of hepatitis A virus antibodies in 99.9% and protective levels of hepatitis B virus antibodies in 98.5% one month after completion of the three-dose regimen.
The April 2007 approval of an accelerated dosing regimen was based on a study of immune responses to Twinrix given to 250 healthy adults (aged 18 years or older) at a 0-, 7-, and 21- to 30-day schedule, followed by a booster dose at 12 months, compared to separate vaccinations with monovalent one hepatitis A vaccine (Havrix) at 0 and 12 months and monovalent hepatitis B vaccine (Engererix-B) at 0, 1, 2, and 12 months given to 246 healthy adults as a control group. Those who completed the series of Twinrix on the accelerated dosing schedule had an immune response comparable to those who received complete vaccination with separately administered vaccines.
Medical: Twinrix is used for vaccination of adults 18 years of age or older against disease caused by hepatitis A virus and/or hepatitis B virus. The vaccine is administered at 0, 1 and 6 months. It is recommended for persons at high risk for exposure to both viruses. The vaccine is primarily used by travelers visiting areas where there is a high or intermediate rate of both types of hepatitis, e.g., Africa, parts of South America, and most of the Middle East, and South and Southeast Asia. The vaccine is also used by those who, because of their behavior or occupations, are at risk for these infections, e.g., injectable drug users, persons frequently receiving blood products, male homosexuals, laboratory and military personnel, etc.
Market: The 2007 Average Wholesale Price (AWP) is $489.62/five 1 mL 720 el prefilled syringes, and $975.95 for ten (Red Book, 2007).
As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) $78.16 for pediatric single dose vials ($79.42 in 2006) and $78.42 for packages of 5 pediatric prefilled syringes (same in 2006); and 83.10 for packages of adult 10 1-dose vials or adult 5-packs of prefilled syringes. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $37.74 for both for single dose vials and packages of 5 prefilled syringes ($38.68 in 2006; $36.91 in 2005); and $37.64 for packages of adult 10 1-dose vials or adult 5-packs of prefilled syringes. These prices include the $1.50/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. GSKs contract with NIP, CDC, expires on March 31, 2008.
Twinrix is primarily marketed for use by international travelers visiting areas where there is a high or intermediate prevalence rate of both types of hepatitis. Over 11.9 million doses of Twinrix were distributed internationally from its launch in 1996 to U.S. approval.
Competition: Various hepatits A and recombinant hepatitis B vaccines are manufactured and marketed by companies in China, lesser-developed countries and countries lacking relevant granted patents or enforcement of pharmaceutical patents. For example, in Jan. 2005, Sinovac Biotech Ltd. (Beijing, China) received approval in China for Bilive a combination inactivated hepatitis A and recombinant hepatitis B vaccine comparable to Twinrix, which is not currently available in China and sells for a much higher price than Bilive in countries where it is for sale. This may be considered a biogeneric, biosimilar, biocomparable, follow-on or other type of generic biopharmaceutical. The vaccine sells in China for $7-$8/dose.
Companies involvement:
Full monograph
466 Hepatitis A & B, rDNA Vaccine
Nomenclature:
Hepatitis B, rDNA & A Virus Vaccine [BIO]
Twinrix [TR]
Ambirix [TR Europe]
Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine [FDA]
NDC 58160-850-01, NDC 58160-850-11 and NDC 58160-850-46 [NDC]
FDA Class: Biologic BLA
Year of approval (FDA) = 2001
Date of 1st FDA approval = 20010511
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
exempt from CBER lot release requirements
recombinant DNA
vaccines, combination
vaccines, inactivated
vaccines, viral
yeast source materials
yeast source materials
cells, human
fibroblasts, human
hepatitis A virus (HAV) HM-175 strain
hepatitis B virus (HBV)
HM-175, hepatitis A virus strain
mammalian cell culture
Saccharomyces cerevisiae (yeast)
2-phenoxyethanol
aluminum hydroxide
aluminum phosphate
formaldehyde
polysorbate 20 (Tween 20)
thimerosal (mercury derivative)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
bovine source warning, BSE country
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
Copyright© 2020, Biotechnology Information Institute