Tuesday’s FDA approval of GSK’s H1N1 vaccine means all five of the manufacturers approved to manufacture and distribute the 2009-10 seasonal influenza vaccine (CSL, GSK, MedImmune, Sanofi-Pasteur, and Novartis) are now approved to manufacture and distribute H1N1 vaccines .
The unadjuvanted GSK H1N1 vaccine is actually manufactured in Canada by ID Biomedical Corporation of Quebec, which is owned by GSK. The process used to produce the hemaggluttinin antigen (HA) is the same as that used for production of the antigen in the seasonal influenza vaccine Fluviral, which has been approved in Canada since 1992 and in the US as Flulaval since October of 2006.
The United States Department of Health and Human Services has placed an order to fill 7.6 million doses of H1N1 pandemic vaccine from GSK, which will contribute to the approximately 250 million doses secured by the US government. The vaccine will be produced in multi-dose vials from bulk vaccine manufactured at GSK’s facility in Quebec, Canada. GSK expects to begin shipping vaccine in December and to provide all 7.6 million doses by the end of the year.
The HHS order was for $38 million of vaccine, suggesting a cost of $5 for each of the 7.6 million doses. As discussed in this blog on September 21st, this is in line with the $5.30 per dose paid for the 75.3 million doses contracted from Sanofi, but still a considerable discount to the price of $10.65 a dose for the 42 million doses contracted from MedImmune.
The GSK H1N1 vaccine is an inactivated split virus influenza vaccine that will be administered as a single 0.5 ml dose containing 15 mcg of antigen. The multi-dose format of the vaccine packaging necessitates the inclusion of the preservative thimerosal, which is an organo mercury compound with antibacterial properties, included to allow multiple withdrawals to be made from the vial up to a prespecified period of time after the first entry.
In contrast to the unadjuvanted GSK H1N1 vaccine approved in the US, Canadians will get an oil-in-water AS03 adjuvanted version of the same vaccine, called Arepanrix.
After review of the available data on quality, safety, and immunogenicity, Health Canada have concluded that the benefit/risk profile of the Arepanrix H1N1 vaccine is favourable for active immunization against the H1N1 2009 influenza strain and issued a Notice of Decision for the vaccine. The Minister of Health authorized the sale of Arepanrix on October 21st, 2009 based on the limited clinical testing in humans under the provision of an interim order issued by request of the Public Health Agency of Canada on October 13th.
As described here in earlier blogs about the European pandemic vaccine approval process, Canada employed the mock vaccine approach, developing an H5N1 vaccine in the pre-pandemic period. Health Canadainspected the antigen manufacturing facilities, evaluated data from the process, and reviewed both animal and human data from studies performed with the mock vaccine. Safety and effectiveness of the AS03 adjuvant was also evaluated and deemed acceptable.
Arepanrix H1N1 vaccine is given as a single 0.5 ml intramuscular dose containing 3.75 mcg of hemagglutinin (HA) in the AS03 adjuvant. As noted above, the HA antigen is manufactured in Quebec by ID Biomedical Corporation of Quebec.
Arepanrix is provided as a two-component vaccine. One multidose vial contains the antigen and a second multidose vial contains the AS03 adjuvant. The 10 ml H1N1 antigen vial contains 2.5ml of antigen. The 3 ml AS03 adjuvant vial contains 2.5 ml of adjuvant. Prior to injection the entire content of the AS03 vial is withdrawn, added to the H1N1 antigen vial, and mixed. The mixed final product for injection is an emulsion containing enough vaccine for 10 doses, and contains 50 mcg of thimerosal, which is the equivalent of 2.5 mcg of organic mercury per 0.5ml dose. This is ten fold less mercury as found in other multidose flu vaccines, probably because the final vaccine vial must be discarded within 24 hours of addition of the adjuvant. Non adjuvanted multi-dose influenza vaccine vials, such as Flulaval, can be used for up to 28 days after the first entry, therefore typically include 25mcg of mercury per dose.
Now that the H1N1 vaccines produced by the major manufacturers have all been approved, it’s a good time to survey the regulatory landscape. As highlighted in this Blog entry, Health Canada has approved an adjuvanted H1N1 vaccine (Arepanrix). Europe’s EMEA has approved both adjuvanted (Focetria and Pandemrix) and unadjuvanted (Celvapan) H1N1 vaccines. Finally, FDA has only approved unadjuvanted H1N1 vaccines (GSK, Novartis, CSL, Sanofi, MedImmune), despite the fact that it’s parent organization, HHS purchased nearly $700 million worth of AS03 adjuvant from GSK and MF59 adjuvant from Novartis.
It is not clear why FDA has failed to join other regions in approving the adjuvanted vaccines, especially in the face of the more difficult production of the H1N1 antigen compared to the seasonal antigen. The AS03-adjuvanted GSK Arepanrix vaccine approved in Canada requires four-fold less antigen than the corresponding unadjuvanted GSK vaccine approved in the US. A split personality indeed.
