MedImmune’s Flumist™ seasonal flu vaccine differs from the five other seasonal flu vaccines approved for use in the U.S. in two significant ways. First, it is a live attenuated influenza vaccine (LAIV), not an inactivated split or subunit vaccine. Secondly, it is administered intranasally via a special syringe that introduces large-particle aerosol droplets of the vaccine to the nasal mucosa.
The vaccine was approved by FDA in 2003 for active immunization for the prevention of disease caused by influenza A and B viruses in healthy children and adolescents, 5-17 years of age, and healthy adults, 18-49 years of age. In 2008, FDA approved expanding the population to include children between the ages of 2 and 5.
The virus is attenuated, or weakened, by inserting genes that confer the properties of cold adaption (ca) to efficient replication at 25°C, growth-restriction at 37°C (rt) for the Type B and 39°C for the Type A strains, and limited replication in the lungs of ferrets (att). These genes come from the master donor virus strains ca B/Ann Arbor/1/66 and ca A/Ann Arbor/6/60. The seed virus used for annual production of the seasonal vaccine is a 6:2 reassortant produced by reverse genetics. There are 6 internal genes from the attenuated donor virus, and the HA and NA genes from the wild type virus.
When administered intranasally, the LAIV induces both serum and mucosal antibodies, an immune response that closely resembles the body’s natural response to influenza infection, but does not cause illness. The syringe that delivers the intranasal dose is the BD AccuSpray, which is based on the BD Hypak SCF (sterile, clean, ready-to-fill) technology. The total dose is 0.2 mL. The plunger is installed with a dose-divider clip which only permits 0.1ml to be delivered to the first nostril when the plunger is depressed. The clip is then removed so the plunger can be further depressed and deliver the remaining 0.1 mL dose to the second nostril.
In response to the H1N1 pandemic, HHS contracted with Medimmune for 12.8 million doses of the H1N1 strain of Flumist at a cost of $151 million. Apparently Medimmune’s virus strain grew well; 20 million doses have already been produced, and the company projects they could produce up to 200 million doses by March 2010. Unfortunately there are only sufficient Accusprays to fill approximately 40 million of these doses by March 2010. BD has said it will run its sprayer factory around the clock to increase annual production from 20 million sprayers to 70 million. However this would still leave a significant surplus of doses that cannot be filled.
Medimmune is working to define a path for an alternative delivery device, possibly a dropper, to optimize utilization of the additional bulk vaccine capacity. This entails working with FDA’s CBER to gain the regulatory approvals needed for an alternative delivery device. The dropper was used to deliver the vaccine in some of Medimmune’s earlier clinical trials.
Medimmune plans to conduct two concurrent placebo-controlled clinical studiesof the H1N1 candidate in 300 adults 18-49 and 300 children 2-17, using a two-dose schedule one month apart. They expect to have safety data from the first dose by early September and 29-day immunogenicity data by mid-October. They expect to have safety data from the second dose by mid-October and 29-day immunogenicity data by early November.
The Flumist device bottleneck highlights the supply chain challenges that will occur during the response to the pandemic, one that was clearly not anticipated in the case of Flumist. As discussed in this blog on May 20th, 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.
Fortunately, in this case, the decidedly low-tech dropper may save the day. The potential surplus of Flumist can then be used to expand the U.S. supply or provided to other countries.
