After a ‘positive opinion’ by EMEA’s CHMP, the European Commission (EC) has granted marketing authorization for Baxter’s Celvapan H1N1 pandemic vaccine. Celvapan H1N1 is the first cell culture-based, non-adjuvanted, pandemic influenza vaccine to receive marketing authorization in the European Union. The other two approved H1N1 vaccines are Pandemrix and Focetria, both of which are produced in eggs and contain oil-in-water emulsion adjuvants. GSK’s Daronrix is the remaining vaccine that has been authorised as a ‘mock up’ vaccine for potential use during an influenza pandemic, but has not yet been approved in the EU for use in the current H1N1 pandemic.
Celvapan H1N1 is an inactivated whole virion vaccine that contains 7.5 mcg of antigen in a 0.5 ml dose. Whole virion vaccines contain a complete virus that has been purified from the production matrix by centrifugation. For Celvapan, 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. Pandemrix and Focetria differ from Celvapan in that they have had the viral surface antigens dissociated and purified from the virus by detergent treatment and centrifugation, so they are termed split virus vaccines.
A careful reading of the EPAR for Celvapan H1N1 reveals that a major objection was raised during the review process. Baxter had not provided validation data from commercial-scale production batches for virus inactivation by formaldehyde. This objection was finally resolved after Baxter provided a scientific justification that supported the high capacity of the process to effectively inactivate H1N1 virus within a short time frame. CHMP concluded that a sufficient safety margin existed for vaccine production at an industrial scale. In addition, Baxter committed to provide additional inactivation data on three industrial scale batches to confirm the existing results.
The review process also identified problematic bacterial contamination of cell culture medium; 3 out of 16 commercial fermentation batches were contaminated (through 23rd September 2009). The three batches were consecutive and kept in quarantine. A root cause for the contamination was ultimately identified and corrective measures were put into place to prevent future contaminations. A product related inspection at the manufacturing site confirmed the conclusions that the root cause for the bacterial contamination during the fermentation was identified and corrective actions were effective.
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 world’s current manufacturing capacity is cell-culture based. Baxter produces Celvapan in Bohumil, Czech Republic.
Celvapan is the first approved cell-culture-based pandemic influenza vaccine, but not the first approved cell-culture-based influenza vaccine. Novartis’ Optaflu is a seasonal trivalent inactivated influenza vaccine produced in cell culture and granted marketing authorisation in the European Union in June 2007. Optaflu is also an inactivated, detergent disrupted and purified product. It is produced in Madin Derby Canine Kidney (MDCK) cells. The MDCK cell line was originally established from the kidney of an adult male cocker spaniel in 1958 by Madin and Derby at UC Berkeley, California. No cell-culture based influenza vaccines have been approved to-date in the US, although capacity is currently being created by companies like Novartis and GSK through HHS funding.
Now that marketing authorisation of the pandemic vaccines Celvapan, Focetria and Pandemrix has diversified the approved technologies for influenza vaccines, it seems likely that Baxter, Novartis, and GSK will shoot for approval of lower doses, Vero cell technology, and ASO3 and MF59 adjuvants in their seasonal influenza vaccines. I anticipate a glimpse of this in 2010, although it seems unlikely that there will be any changes for the 2010-2011 season vaccines themselves given the timeline for manufacture. Of course, if the decision is made to include the A/California/07/2009 (H1N1)v strain in the 2010-2011 seasonal vaccine, things could get very interesting.
