Status: marketed in Europe and elsewhere, not U.S.

Organizations involved:

Berna Biotech Ltd. – Manuf.; R&D; Tech.; Europe mark.; Intl. mark.

Crucell N.V. – Parent

Swiss Serum and Vaccine Institute Berne – R&D; Tech.; Former

Cross ref.: See the entry above for Hepatitis A Vaccine Products. See the other hepatitis A virus vaccine entries. See also the entries for other virosomal vaccines --Influenza vaccine, virosomal/Solvay (Invivac) and Influenza vaccine, virosomal/Berna (Inflexal V).

Description: Epaxal is an aqueous virosomal (liposomal) formulation of formalin (formaldehyde)-inactivated whole cell hepatitis A virus (HAV) RG-SB strain cultivated on MRC-5 human diploid cells adsorbed to immuno-potentiating reconstituted influenza virosomes (cell membrane-like phospholipid structures) along with two influenza virus antigens anchored in the virosome membrane – hemagglutinin (HA) and neuraminidase (NA). Each 0.5 mL dose contains at least 500 radioimmunoassay units of HAV antigen along with phospholipids, 350 mg; influenza A virus hemagglutinin, 5-16 µg; formaldehyde, < 25 µg; and sodium chloride, 0.85-0.95% (w/v). The vaccine is stored at 2-8˚C (refrigerated). The vaccine is supplied in packages of one or 10 single-dose, pre-filled syringes.

Epaxal does not contain thiomersal (mercury-based preservative) and is the only aluminum-free hepatitis A vaccine worldwide, i.e., it does not contain any aluminum-based adjuvant. Epaxal also contains no antibiotics and no preservatives.

Although not marketed in the U.S., viro-somal vaccines (without adjuvant) are a proven technology. Besides Expaxal, Berna Biotech (now merged into Crucell N.V.) currently manufactures and markets Inflexal V, an intramuscular injected influenza virus subunit vaccine, primarily marketed in Switzerland and other European countries (see related entry). Sanofi manufactures and markets Inivac, a cell cultured virosomal influenza vaccine (see related entry).

Nomenclature: Hepatitis A Virus Vaccine/Berna [BIO]; Hepatitis A Virus Vaccine Inactivated [FDA, if approved in U.S.]; Epaxal Berna [TR foreign]

Biological.: Virosomes are liposomes, artificial (phos-pho)lipid bilayer membranes resembling the cell membrane, that carry purified two influenza virus antigens anchored in their membrane – hemagglutinin (HA) and neuraminidase (NA) – which enable the virosomes to fuse with cells of the immune system. . Virosomes are composed of a completely biodegradable mixture of synthetic and natural phospholipids forming a liposome membrane. The virosomes, with influenza virus NA and HA, function as adjuvants as well as the delivery system for the hepatitis A antigens. The virosomes form liposomal globules about 150 nm in size with influenza HA and NA on their surface, in addition to membrane-derived phospholipids, which enable the viro-somes to fuse (via the endolysosomal pathway) to immune cells and deliver their contents. After endocytosis uptake into the cell, the viral HA mediates membrane fusion with endosomes, much the same as by influenza virus, releasing the virosome contents into the cytoplasm. The virosomes then degrade within cells. Virosomes mimic the natural method of antigen presentation and uptake of influenza virus, with antigens presented on the surface of lipid-based membranes (like cell membranes). Virosomal vaccines, including Epaxal, induce both T-cell (cellular) and B-cell (humoral) immune responses.

Companies.: Epaxal was was originally developed Swiss Serum and Vaccine Institute Berne, now Berna Biotech Ltd., which was acquired from Acambis by Crucell N.V. in Nov. 2006. The vaccine is manufactured by Berna Biotech and marketed in various European countries by Berna (Crucell).

Indications: [European countries]: active immunization against hepatitis A for adults and children after completion of the first year of age.

Status: Epaxal is approved in various individual European and other countries worldwide, but not in the U.S. It was first launched in 1994, and received European Union approval in 1997. Besides European countries, it is marketed othe countries including Hong-Kong, Pakistan, Singapore, Latin America: Argentina, Chile, and Colombia.

In early 2007, Pediatric Epaxal was licensed in Switzerland.

Trials: After a single injection of Epaxal, 88% of healthy seronegative adults seroconverted (titers > 20 mIU/L) after 14 days and 98% after 1 month. Three to 12 months post-immunization, between 92-94% maintained protective antibody levels. One month after a booster dose, given approximately one year after primary immunization, 99.8% of vaccine recipients had high levels of protective antibody, with a 22-fold increase in geometric mean titer. Mathematical modelling suggests that >90% of vaccine recipients who receive primary immunization and a booster at 1 year will retain protection for at least 10 years.

A post-marketing safety study has shown that the incidence of local adverse reactions with Epaxal is much less than with Havrix.

Medical: The vaccine provides rapid, long lasting protection and exhibits very good tolerability. Since vaccine protection lasts at least 1 year, booster vaccination is only indicated if more than one year has passed since primary immunization. The booster vaccination induces very high antibody titers which presumably will confer protection for 5 to 10 years.

Besides its purity, including lack of thimerosal, aluminum and preservatives, Epaxal offer excellent local tolerability in both adults and children, with minimal allergenic reactions; quick, efficient protection against hepatitis A infection (100 % protection after 10 days), making it useful for last minute travelers; a small injection volume (0.5 ml); and it can also be administered subcutaneously. Booster vaccination may be administered up to 5 years after the primary vaccination. Epaxal can be administered simultaneously with other vaccines.

Tech. transfer: The Swiss Serum and Vaccine Institute Berne, later Berna Biotech (now merged into Crucell N.V.), developed virosomal vaccine technology and has received patents including U.S. 5,879,685, “Immunostimulating and immunopotentiating reconstituted influenza virosomes and vaccines containing them.”

Market: Berna reports, ”Epaxal should reach an 8% to 10% market share in Europe and hence generate sales of approximately CHF 13 million [$10.33 million] in 2006. The chances of posting higher sales are limited given the tough competition. Aventis, GlaxoSmithKline and Merck all sell hepatitis A vaccines and are better positioned than Berna Biotech with their marketing clout, although clinical trials indicate that Epaxal has by far the best tolerability profile.”