Influenza A (H1N1) 2009 Monovalent Vaccine - Pandermix H1N1; swine flu vaccine

Cross ref.: See the Influenza H1N1 Vaccine Products and Influenza Vaccine Products entries.

Status: "mock approval" in European Union in 2008; being distributed for the 2009/10 flu season by various European and other countries; not approved in the U.S.

Organizations involved:

GlaxoSmithKline Biologicals S.A. (GSK) – Manuf; R&D; Tech.;World mark. [sales to governments]

GlaxoSmithKline Inc. (GSK) – USA mark.

GlaxoSmithKline Inc. (GSK) – Parent

Cross ref.: See the Influenza H1N1 Vaccine Products and Influenza Vaccine Products entries. See also the Influenza Vaccine, H5N1/GSK entry for the analogous H5N1 vaccine.

Description: Pandemrix is an aqueous formulation of a sodium deoxycholate-split formaldehyde-inactivated influenza H1N1 vaccine containing inactivated split reassortment pandemic strain A/California/07/2009 (H1N1)v-like strain (X-179A), the "reference strain," based on original mock-up approval of a comparable vaccine containing influenza A/Vietnam/1194/2004 NIBRG-14 (H5N1) strain. The vaccine contains thimerosal (mercury derivative; see related entry) as an antimicrobial preservative. AS03 adjuvant, which is mixed with the vaccine prior to injection, is composed of squalene, DL--tocopherol (vitamin E) and polysorbate 80 (Tween 80).

Pandemrix is supplied as glass vials containing vacine and glas vials containing adjuvant, with adjuvant to be mixed with the vaccine within 24 hours of use.

Each 0.5 ml dose of vaccine contains A/California/07/2009 (H1N1)v-like strain (X-179A), based on original mock-up approval, 3.75 µg hemagglutinin (HA; antigen); adjuvant containing squalene 10.69 mg, DL-alpha-tocopherol (vitamin E) 11.86 mg and polysorbate 80 (Tween 80) 4.86 mg. Other ingredients in the vaccine vial are octoxynol 10; sodium chloride; disodium phosphate; potassium dihydrogen phosphate; potassium chloride; magnesium chloride; thiomersal (mercury derivative; see related entry) 5 µg and; Water for injections. The emulsion vial contains sodium chloride; disodium hydrogen phosphate; potassium dihydrogen phosphate; potassium chloride (KCl) and; Water for injections. Pandemrix has a shelf-life of 18 months when stored at 2-8˚C (refrigerated).

Companies.: Pandermix was developed and is manufactured by GlaxoSmithKline Biologicals S.A., CBER/FDAS est. no. 1617 (Rixensart, Belgium). Pandemrix is marketed internationally by GlaxoSmithKline Biologicals S.A. GlaxoSmithKline Inc. handles marketing and distribution in the U.S.

For the 2009/10 flu season, GSK received an order from the U.S. government (BARDA/NIAID/NIH/HS) for about $250 million worth of bulk-vaccine ingredients and "pandemic product."

The UK has purchased 60 million doses of the vaccine for the 2009/2010 flu season.

Manufacture: For the mock-up approval (based on a H5N1 strain), a master and working seed were prepared from the NIBRG-14 reference virus, received from the WHO Reference centre (NIBSC, UK), derived from the A/Viet Nam/1194/2004 (H5N1) NIBRG-14 vaccine virus strain. The reference virus is A/California/7/2009 (H1N1)v NYMC X-179A. This strain wasdeveloped by the New York Medical College (NYMC) using classical genetic reassortion (non-recombinant, not genetically engineered). The reassortant strain combines the HA, NA and PB1 genes of A/California/7/2009 (H1N1)v, to the PR8 strain backbone. Thus, unlike for H5N1 A/Indonesia and A/Vietnam, the A(H1N1)v strain (see Pandemrix entry), the reference viral strain, that being used in Europe for the 2009/10 flu season, is produced using classical reassortment on eggs rather than being attenuated by reverse genetics.

The manufacturing process for the monovalent bulks is similar to the manufacturing process for the monovalent bulks of the licensed product Fluarix (seasonal influenza virus) and can be divided into four main parts:

Propagation of the working seed in fertilised hen’s eggs, harvesting and pooling of infected allantoic fluids; Purification of the whole virus bulk Splitting of the monovalent with sodium deoxycholate and; Inactivation of the monovalent split virus using sodium deoxycholate and formaldehyde, followed by ultrafiltration and sterile filtration. The process parameters are generally derived from those used for manufacture of Fluarix, a GSK seasonal vaccine (see related entry). The testing of the virus and the eggs are the same as for Fluarix.

The sodium deoxycholate used to split or dsirupt the virus is derived from bovine bile.

An overage of 10 % HA is applied at formulation of commercials lots.

Formulation of the AS03 adjuvant consists of the preparation of the bulk (formation of oil/water emulsion using high shear and pressure homogenization) followed by filling into glass vials. With the exception of squalene, all excipients are described and controlled in line with the Ph.Eur. Quality control of squalene is performed by the supplier and GSK (according to an internal GSK monograph which is in line with the Ph.Eur. monograph for squalane). Emulsion bulk and AS03 final containers are tested at release for Description, Identity and Content of adjuvant components (polysorbate 80, -tocopherol and squalene), pH, Endotoxin content, Sterility, Particle size, Polydispersity index and Volume (final containers only). Tests for sterility and bacterial endotoxins are performed in line with the Ph.Eur. and tests for polysorbate 80, -tocopherol and squalene are validated. Particle size and associated system suitability are also measured.

The A/California/7/2009 (H1N1)v like strain (X-179A) final bulks and final containers are respectively formulated and filled as approved for the H5N1 final bulks and final containers of Pandemrix H5N1.

Status: On Feb. 7, 2007, GSK filed an application for Marketing Authorisation to the European Medicines Agency (EMEA), European Union (EU), for Pandemrix as an H5N1 mock-up vaccine, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. In simplistic terms, this vaccine was approved comparable to an FDA suppplemental approval, with the approved/marketed product being a modified version of GSK's H5N1 (Pandemrix) vaccine (which can be simplistically viewed as a biosimilar version of GSK's Fluarix seasonal vaccine).

On May 20, 2008, the mock-up vaccine received MAA approval.

On Sept. 22, 2009, GSK applied for a variation according to Article 8 of the Commission Regulation (EC) No. 1085/2003 in order to update to the composition of the strain of Pandemrix to that officially recommended by WHO and CHMP/EU for the Pandemic Influenza A (H1N1)v, designated A/California/07/2009 (H1N1)v like strain (X-179A). On Sept. 24, 2009, approval was granted.

EU approval of Pandemrix was based on a “mock-up” registration file using the H5N1 antigen that had earlier received approval. The submission also included early results from clinical studies using the current H1N1 strain, including data showing that just one dose of the vaccine provided a strong immune response “which exceeds the immunogenicity criteria as defined by international licensing authorities for a pandemic influenza vaccine.” Initial evidence suggested that the new H1N1 vaccine has a similar safety and tolerability profile as the already approved Pandemrix H5N1 version.

Trials: As of Oct. 2009, more than 9,000 patients across Europe, Canada and US. were taking part in 16 clinical trials designed to further assess the efficiency and safety of Pandemrix.

The first clinical data on the final formulation of Pandemrix A(H1N1)v (i.e. with the antigen content as specified for the mock-up vaccine and in the strain change variation) was expected to be available by mid-Oct. 2009 and will come from adults aged 18-60 years. Data from subjects aged > 60 years and from children and adolescents will follow at intervals.

Medical: Adults and persons over age 10 receive two 0.5 mL doses and children ages 6 months to 10 receive two doses or 0.25 mL.

Marketing: As of Oct. 2009, GSK reported having received orders for 440 million doses of Pandemrix. Presuming this was conservatively sold for ~$9/dose (with $10/dose the amount reported as paid by the U.K. government), this represents ~$4 billion in sales. The company had reported orders for 291 million doses in July 2009 and subsequently received orders for an additional 149 million doses. Orders were received from 22 governments. Media sources have reported GSK will make a profit of $3.5 billion from these sales.