Status: marketed in Europe

Organizations involved:

Istituto Sieroterapic Berna S.r.l – Manuf.

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

Crucell N.V. – Parent

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

Cross ref.: See also other virosomal vaccines, Influenza vaccine, virosomal/Solvay (Invivax) and Hepatitis A Virus Vaccine/Berna (Epaxal Berna). See the Influenza Vaccine Products entry.

Description: Inflexal V is an aqueous trivalent formulation of conventionally egg-cultured beta-propiolactone-inactivated influenza viruses adsorbed onto the surface of liposomal virosomes – immunopotentiating phospholipid membrane structures having two influenza virus antigens anchored in the membrane, hemagglutinin (HA) and neuraminidase (NA), with the structure essentially mimicing the influenza virus outer coat. Inflexal V is conventionally cultivated on the allantoic fluid of chicken eggs. Viruses are inactivated with beta-propiolactone and purified.

Through the presence of the lecithin and the hemagglutinins, Immunopotentiating Reconstituted Influenza Virosomes (IRIVs) are formed. Inflexal is the only adjuvanted influenza vaccine licensed in a major market (EU) for all age groups. It uses a fully biodegradable adjuvant (virosomes) that mimics natural virus infection, and is free of thimerosal and formaldehyde.

Inflexal V is packaged in single-use syringes for intramuscular injection. Each dose (0.5 ml) of the vaccine contains 15 µg hemagglutinin of each of the influenza virus strains recommended for use in each year’s influenza vaccine formulation. Each dose also contains 117 µg lecithin, 3.8 mg disodium hydrogen phosphate dihydrate, 0.7 mg potassium dihydrogen phosphate, 2.4 mg sodium chloride, and 0.5 ml water for injection.

Nomenclature: Influenza vaccine, virosomal/Berna [BIO]; Inflexal V [TR]; influenza virus vaccine, inactivated, virosomal [SY]

Biological.: Virosomes are liposomes or artificial (phospho)lipid bilayer membranes resembling the cell membrane that present two influenza virus antigens anchored in their membrane – influenza hemagglutinin (HA) and neuraminidase (NA) – which, as they do with the live influenza virus, enable the virosomes to fuse with cells of the immune system. The virosomes form liposomal globules about 150 nm in size with influenza HA and NA on their surface, which in addition to membrane-derived phospholipids, enable the virosomes to fuse (via the endolysosomal pathway) to immune cells and deliver their contents. Virosomes mimic the natural method of antigen presentation and uptake of influenza virus, with antigens presented on the surface of lipid-based membranes (resembling cell membranes). Virosomal vaccines, including Inflexal V, Invivac, and Epaxal (a virosomal hepatitis A vaccine; see related entry), induce both humoral (IgG antibody) and cellular (cytoxic T-cell) immunity.

Virosomes are composed of a biodegradable mixture of synthetic and natural lecithin and (phospho)lipids forming a liposome membrane. Hemagglutinin surface molecules of the influenza viruses are anchored on the double membrane of lecithin-phospholipid liposomes. The exposed HA of the virosomes binds to cellular receptors of macrophages, B-cells and other immune cells, and the virosomes are phagocytized. After endocytosis uptake into the cell, the viral HA mediates membrane fusion with endosomes, much the same as with influenza virus infection, releasing the virosome contents into the cytoplasm of the cell. In the endosome of target macrophages, at a pH of 5, influenza hemagglutinin is activated and the phagocytized liposome immediately fuses with the endosomal membrane. The virosomes then degrade within cells. The virosomes, themselves, do not trigger any immune reaction, but their delivery of inactivated whole influenza viruses into immune system cells induces potent humoral and cellular immune responses. The virosomes function as adjuvants, boosting HA and NA immune responses, as well as the delivery system for the influenza antigens.

Besides antibodies from B-cells attacking infecting influenza viruses, T-cells recognize and eliminate infected cells, and are important for the recovery process after an influenza infection. Elderly people may have a weakened immune system, and T-cell stimulation by a virosomal vaccine may be beneficial for this group.

Companies.: Inflexal V was developed by Berna Biotech Ltd. (originally Swiss Serum and Vaccine Institute Berne), which merged into Crucell N.V. in Oct. 2006. The vaccine is manufactured at Istituto Sieroterapic Berna S.r.l. (Como, Italy), a subsidiary of Berna Biotech/Crucell.

Indications: [European]:

Active immunization against influenza in adults and children from the age of 2 years

Status: Inflexal V received European Union (EU) approval in Oct. 2001, and was first launched in various EU countries for the 2001/2 flu season. Inflexal V received its first approval in Switzerland in 1997, where it was first launched for the 1997/8 flu season.

In June 2008, Crucell reported Dukoral was being marketed in 43 countries and that 27 million doses had been sold since 1997.

Medical: Inflexal V, through clinical trials and use for several years, has proven to be safe and well tolerated, and to perform particularly well in the elderly and others with less than optimal immune systems, and in persons with low pre-vaccination titers of influenza virus antibodies (i.e., not vaccinated or not experiencing influenza infections in recent years and/or having compromised immune systems).

Tech. transfer: The Swiss Serum and Vaccine Institute Berne, now Berna Biotech (merged into Crucell N.V. in Jan. 2006), 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: With the end of the 2004/5 flu season, more than 17 million doses had been sold, and the vaccine is approved in 38 countries (but not in the U.S.).