Status: approved; marketed

Organizations involved:

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

Sanofi Pasteur MSD – Europe mark.

Chiron Corp. – Manuf. other; U.K. mark.

Novartis AG – Parent

Evans Vaccines Ltd. – Former

Cross ref: See the Hepatitis A Vaccine Products entry (#461) and the entry for the other U.S.-marketed hepatitis A vaccine (#462).

Description: Hepatitis A Virus Vaccine, Inactivated or Vaqta is an aqueous formulation of inactivated whole hepatitis A virus prepared from attenuated hepatitis A virus cultured in MRC-5 human diploid fibroblasts. The virus is cultured, harvested by physical methods, further purified by high performance liquid chromatography (HPLC), inactivated with formalin (formaldehyde), and adsorbed onto aluminum hydroxide adjuvant. The inactivated virus has a molecular weight of about 5 million (5,000 kDa). The source virus strain was originally derived by serial passage of a proven attenuated strain.

One mL of the vaccine contains approximately 50 units (50 U; a standard adult dosage) of hepatitis A virus antigen adsor-bed onto about 0.45 mg of aluminum hydroxide. Within the limits of current assay variability, the 50 U dose of Vaqta contains less than 0.1 µg of non-viral protein, less than 4 x 10-6 µg of DNA, less than 10-4 µg of bovine albumin, and less than 0.8 µg of formaldehyde. Other process chemical residuals are present at less than 10 parts per billion (ppb). The vaccine contains no preservatives.

Vaqta is packaged in two formulations, with both dosages available in single-dosage vials and prefilled syringes. Pediatric/Adolescent Formulation: each 0.5 mL dose contains approximately 25 U of hepatitis A virus antigen adsorbed onto approximately 0.225 mg of aluminum as aluminum hydroxide, with 35 µg of sodium borate as a pH stabilizer, in 0.9% sodium chloride. Adult Formulation: each 1 mL dose contains approximately 50 U of hepatitis A virus antigen adsorbed onto approximately 0.45 mg of aluminum as aluminum hydroxide, with 70 µg of sodium borate as a pH stabilizer, in 0.9% sodium chloride. The vaccine should be stored at 2-8˚C (refrigerated) and has a dating period (shelf life) of 18 months from the date of manufacture (date of the last valid potency test performed on final container material).

Nomenclature: Hepatitis A Virus Vaccine/Merck [BIO]; VAQTA [TR]; Hepatitis A Virus Vaccine Inactivated [FDA]; HAV [SY CDC]

Companies.: Vaqta was developed and is manufactured by Merck & Co., Inc. (West Point, PA); FDA CBER est. no. 0002. Vaqta is marketed in the U.S. and many other countries by Merck & Co., Inc. The vaccine is also packaged and distributed in the U.K. by Evans Medical Ltd. (Liver-pool, U.K.), which became a subsidiary of PowderJect plc, which merged into Chiron Corp., which merged into Novartis AG in spring 2006.

Sanofi Pasteur MSD (a European joint venture of Merck and Sanofi Aventis), formerly Aventis Pasteur MSD, markets Vaqta in European countries.

Manufacture: As described in “Use of nuclease enzyme in the purification of VAQTA, a hepatitis A vaccine,” Biotechnol Appl Biochem 1996 Jun; 23 (Pt. 3):209-15, the development of the purification process for Vaqta, which results in a highly purified inactivated hepatitis A vaccine, was driven by modifications in the MRC-5 cell culture and harvest methods which enabled hepatitis A virus propagation to support large-scale vaccine manufacture. The starting material for the purification was initially a concentrated MRC-5 cell pellet scraped from roller bottles. However, when this cell culture method was scaled up to use high-surface-area Nunc cell factories or Costar cubes, the early steps in the process had to be modified to handle large volumes of dilute lysate. Membrane concentration was used at first, and a highly purified vaccine was prepared. However, virus-poly(nucleic acid) complexes were formed, which reduced the yields in later processing steps. The use of a nuclease digestion step immediately after harvest, followed by capture chromatography on an anion-exchange column, eliminated the formation of these complexes, and resulted in more consistent performance and higher yields in downstream operations. A seven-step purification process is used.

Prior to final container filling, bulk material may be stored for 33 months at 2-8˚C, including not more than 3 months in the diluted bulk state. The original approval includes export of “bulk [vaccine] to be filled at [redacted or censored by FDA] and import [of] filled syringes to be prepared for sale in the United States.” This presumably refers to Evans Medical Ltd.

Merck Research Labs. received the first Industrial Bio-process Award from the American Chemical Society (ACS) in August 1998 for its development of the innovative process for manufacture of Vaqta.

FDA class: Biologic PLA

CBER class: Viral And Rickettsial Vaccines

Approvals: Date = 19960329, first approval, PLA (95-0001)

Date = 20001117; PLA supplement; Indications: = age range for the pediatric dose was extended from age 2 through 18 years (from prior 2-17), and the timing of the adult booster dose was extended from six to 12 months after the first dose

Date = 20020801; BLA supplement; Indication = added Geriatric Use subsection to Precautions of product insert

Date = 20050811; BLA supplement; Indication = lowered the age indication from two years to 12 months of age

Date = 20100330; BLA supplement; Indication = revisions to the product insert to comply with the Physician’s Labeling Rule format

Indications: [portion of the "INDICATIONS AND USAGE” section from product insert/labeling; 4/3/2006]:

VAQTA is indicated for active immunization against disease caused by hepatitis A virus in persons 12 months of age and older. Primary immunization should be given at least 2 weeks prior to expected exposure to HAV.

The Advisory Committee on Immunization Practices (ACIP) has issued recommendations for hepatitis A vaccination for persons who are at increased risk for infection and for any person wishing to obtain immunity. Please consult the Centers for Disease Control and Prevention for updates to those recommendations (www.cdc.gov).

If passive protection against hepatitis A is required either following exposure to hepatitis A virus or in persons in need of combined immediate and long-term protection, VAQTA may be administered along with immune globulin at a separate site with a separate syringe.

Revaccination: See DOSAGE AND ADMINI-STRA-TION, DOSAGE.

Status: This vaccine is not formally a universally required vaccine in the U.S., e.g., not included in the federal vaccine liability insurance program.

Vaqta received European Union (EU) approval and adult and pediatric formulations were launched in the EU in 1997 and 1998, respectively.

In Dec. 2001, Vaqta stocks were recalled and the vaccine temporarily removed from the U.S., European Union and other markets after the antigen content in some prefilled syringes was found to be below the established minimum specifications.

On Aug. 11, 2005, FDA approved a new pediatric/adolescent formulation of Vaqta for use among persons aged 12 months-18 years. Previously, the pediatric/adolescent formulation was approved for use in persons aged 2-18 years. The labeling change applies only to Vaqta and not to other licensed hepatitis A vaccines. The primary vaccination schedule was not changed and consists of 2 doses, administered on a 0, 6-18 month schedule.

In Aug. 2007, FDA reported a shortage situation for pediatric and adult Vaqta due to production delays. In response, GSK increased its manufacture of Havrix. As of Dec. 2008, the Pediatric/Adolescent formulation was available for ordering, and Merck estimated that the Adult formulation may be available in the second quarter 2009. Tech. transfer: U.S. patent 5,514,376, “Cell Culture of Hepatitis A Virus,” assigned to Merck & Co., covers aspects of the culture of attenuated hepatitis A virus by in vitro passage in susceptible cell cultures, without prior passage in a sub-human primate.

U.S. 5,521,082, “Novel Process for Purification of Hepatitis A Virions,” assigned to Merck, claims processes apparently used for manufacture of Vaqta.

Trials: Clinical trials conducted worldwide with several formulations of the vaccine in 9,181 healthy individuals ranging from 2 to 85 years of age demonstrated that Vaqta is highly immunogenic and generally well tolerated. Trials included a field study (Monroe Efficacy Trial) comparing Vaqta and another inactivated hepatitis A vaccine, Havrix, in a Jewish religious community in Monroe, NY, having experienced hepatitis A outbreaks. In this study in children and adolescents, Vaqta demonstrated 100% onset of protection after the primary dose, with long-term (6 years) protection against illness following a booster dose.

Medical: Vaqta is administered by intramuscular injection with a standard adult dosage of 1.0 mL (50 U) and pediatric dosage of 0.5 mL (25 U), with a booster of the same dosage at 6-18 months.

Market: Vaqta competes in the U.S. directly with Havrix from GlaxoSmithKline. A major advantage for Vaqta vs. Havrix is that only two doses of Vaqta are required for children, while three are required with Havrix.

The 2007 Average Wholesale Price (AWP) for Vaqta Pediatric is $38.56/single-dose vial, with a Direct Price (Manufacturer’s discount) of $303.69; and $364.43/10 single-dose vials, with a Direct Price of $303.69. The 2007 AWP for Vaqta (adult) is $76.51/single-dose vial, with Direct Price of $63.51; and $719.86/10 single-dose vials, with a Direct Price of $599.88 (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) is $30.37 for pediatric five single-dose vials; and $61.50 for 10-packs of adult 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 $12.25 for pediatric five single-dose vials ($12.10 in 2006; $12.15 in 2005); and $61.50 for 10-packs of adult 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.

In April 2005, the U.K. National Health Service (NHS) cost was reported to be £15.65 (~$29.97) for Vaqta Paediatric vaccine

In its April 18, 2006 price list, FFF Enterprises, a major biologics distributor, reported $34.86/single-dose 25 U 0.5 mL vial (same in 2005); $69.73/single-dose 50 U 1.0 mL vial, $329.10/package of 10.