Dr. David Salisbury, the Head of Immunisation for the UK’s Department of Health has just issued a ‘Dear Colleague’ letter. The letter describes the UK’s decisions on use of the H1N1 vaccine, and is directed to local health authority immunisation coordinators and leads.
The Department of Health is recommending vaccines from both Baxter Healthcare and GlaxoSmithKline, and expects to have the first doses available in August, with the supply continuing for about 12 months. A two-dose schedule (0 and 21 days) is recommended, suggesting the clinical studies of these two vaccines have been completed and that two doses of vaccine are indeed required for seroprotection.
Regulatory approval will be required for both the Baxter and GSK vaccines prior to distribution, but this should be straightforward since both companies have received European Medicines Agency (EMEA) approval for their respective mock-up pandemic vaccines. In January of 2009 the EMEA established a fast-track assessment procedure for pandemic influenza vaccines, as described in the Guideline on Submission of Marketing Authorization Applications for Pandemic Influenza Vaccines through the Centralized Procedure. The guideline outlines a process for building a core MAA dossier to support approval of a mock-up vaccine during an interpandemic period; when a pandemic then arrives, the marketing authorization holder (MAH) need only submit a variation to the MAA for fast-track approval of the final pandemic strain influenza vaccine. Baxter’s mock up vaccine is Celvapan. GSK has received approval for two mock-up vaccines, Pandemrix and Daronrix. All three mock-up vaccines were approved with antigens from various H5N1 flu strains, the contents of which are now being changed to the H1N1 pandemic strain for the expected August distribution
Although there is no mention of the recommended dose of pandemic vaccine in Salisbury’s letter, the European Public Assessment Reports (EPARS) for the mock-up pandemic vaccines that were submitted to the dossier reveal the Celvapan dose is 7.5 micrograms, the Pandemrix dose is 3.75 micrograms, and the Daronrix dose is 15 micrograms. There is no evidence that the recently developed H1N1 vaccine will have comparable immunogenicity to the H5N1mock-up vaccine, so it remains to be seen what dose will recommended for the H1N1 vaccine.
The three mock-up vaccines described in the EPARS differ fundamentally from each other in several ways.
Celvapan is a whole virion inactivated vaccine. Whole virion vaccines contain a complete virus that has been purified from the production matrix by centrifugation. The virus is inactivated with formaldehyde and UV irradiation. Inactivation makes the virus incapable of replication and infection, rendering it safe for use as a vaccine. Probably the most unique element of Celvapan is that it is produced using cell-culture technology, the wave of the future for flu vaccine manufacturing. Specifically, the virus is grown in Vero cells, a mammalian cell-line derived from the kidney epithelial cells of African green monkeys. As described in this Blog on June 12th, only about 5% of the worlds current manufacturing capacity is cell-culture based. Baxter produces Celvapan in Bohumil, Czech Republic.
GSK’s Pandemrix is a split-virion inactivated vaccine, produced in embryonated hens eggs. Split-virion vaccines contain virus that has been disrupted with detergent, and purified by centrifugation and diafiltration. The virus is inactivated with formaldehyde and sodium deoxycholate. In contrast to Celvapan, which contains no adjuvant, Pandemrix contains the adjuvant AS03, a squalene based oil-in-water emulsion. The vaccine is supplied in a two-vial format, one containing the antigen, the other the adjuvant. The adjuvant is added to the antigen vial at the time of dispensing for immunisation. The vaccine antigen is produced in Dresden, Germany.
GSK’s second mock-up pandemic vaccine, Daronrix, is a whole virion inactivated vaccine like Baxter’s Celvapan, but it is produced by conventional methods in eggs. Alum is used as an adjuvant. The antigen is adsorbed to the alum prior to the final fill, so this vaccine is supplied in a single-vial format. GSK also produces the Daronrix antigen in Dresden, Germany.
In a June 6th 2009 press release GSK described their candidate H1N1 vaccine as being adjuvanted with AS03, so I am assuming that alum-adjuvanted Daronrix is not being pursued by GSK and the UK Department of Health will be purchasing the H1N1 strain of Pandemrix. If so, and vaccine production remains on schedule, then August may mark the first use of the H1N1 vaccine and immunisation with the first commercial dose of the AS03 adjuvant.
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