In the biopharmaceutical timescale the influenza vaccine manufacturing process is back there in the Devonian period; pretty old. The influenza virus was successfully propagated in eggs back in 1937, paving the way for the first influenza vaccines in 1945. The vast majority of flu vaccine doses are still produced from virus propagated in embryonated eggs, making egg supply a critical link in the supply chain. Manufacturers estimate vaccine demand and contract with farmers to provide the embryonic eggs for vaccine production. The egg producing chickens are usually hatched in the summer so as to reach maturity and begin laying eggs by December/January when seasonal production begins. Eggs from new laying hens are most suited to vaccine production based on size, shell thickness, bioburden and embryonic viability. Aged flocks are sacrificed at the end of production in the summer, however the lifespan of the flock can be extended if additional vaccine production is warranted
A rule of thumb is that one egg can produce sufficient virus for a 15mcg hemagglutinin (HA) dose of that flu strain. A pandemic vaccine such as H1N1 will include only one strain; however it is unclear at this time how much H1N1HA will be required in a dose, and how many immunizations will be required to seroprotect an individual. H5N1 studies suggest the HA content could need to be as high as 90mcg and two immunizations may be required.
For the 2008-2009 flu season the six manufacturers estimated 146 million doses of vaccine would be available. Sanofi Pasteur have just brought on line capacity for another 100 million doses, putting US FDA approved capacity at about 250 million doses of seasonal vaccine. So if all of the capacity is dedicated to H1N1, 750 million doses could be produced at 15mcg, or 180 million doses at 90mcg – 90 million doses if a two dose regimen is required. Going back to the rule of thumb, whatever the final dose and regimen, nearly a billion eggs will be required to produce sufficient virus to utilise the available capacity.
In 2005 the Department of Health and Human Services had the foresight to recognize the criticality of the egg supply and awarded a contract to Sanofi Aventis to ensure there are enough eggs on hand to manufacture flu vaccines in the event of a pandemic flu outbreak or future vaccine shortages. I assume this means that Sanofi Pasteur now has the egg supply to go straight into H1N1 manufacturing on the back of the 2009-2010 seasonal vaccine campaign. It is not clear to me, given the nature of supply chains, especially for critical raw materials, that sufficient eggs would be available to all manufacturers in time to initiate H1N1 manufacturing in the summer of 2009. Maybe this will become clearer as the manufacturer’s and WHO’s plans unfold and become public. As described above the manufacturers may decide not to sacrifice the old flocks in order to meet the egg demand.
Flu vaccine manufacturing has always been challenging; this is partly because of the dependence on eggs. Fortunately several manufacturers have now developed cell culture techniques for producing the virus, ridding the process of eggs. Unfortunately the cell culture-based capacity will be relatively insignificant for H1N1 production, at least in the 2009-2010 timeframe. So lay chicken lay.
Tags: cell culture, flu, H1N1, Manufacturing, swine flu, Vaccine
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