An Alternative to the Scale-up and Distribution of Pandemic Influenza Vaccine - With baculovirus-based production in disposable equipment, vaccine can be available 10 to 12 weeks after an outbreak. -

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An Alternative to the Scale-up and Distribution of Pandemic Influenza Vaccine
With baculovirus-based production in disposable equipment, vaccine can be available 10 to 12 weeks after an outbreak.


BioPharm International Supplements


An Alternative Approach: Baculovirus Production in Disposable Equipment

Novavax, Inc. (Rockville, MD), is developing a novel, recombinant vaccine using cell culture to rapidly produce three proteins specific to an emerging influenza strain that self-assemble into an enveloped, non-infectious particle (virus-like particle or VLP) resembling the influenza virus. The approach provides vaccine within 10 to 12 weeks of identification of the new strain and provides an exact match to the wild-type influenza strain. Yields are significantly higher than egg and mammalian cell culture production. The high yields and use of a nonpathogenic baculovirus allows production in disposable manufacturing equipment. The use of disposables radically lowers facility costs, making the solution affordable to many governments. These advantages are explained below.


Figure 1. The insect-cell based vaccine can be ready in 10–12 weeks, compared to 24 for a traditional method. Part of the time savings is achieved by preparing the reagants for lot-release testing while the vaccine is in production.
The time required to manufacture this insect-cell based vaccine is 10–12 weeks, as shown in Figure 1. This time includes four weeks to make recombinant baculovirus production seed stock from the native influenza virus DNA or from the DNA sequence identified by the relevant health agencies, such as the Centers for Disease Control or the World Health Organization. These seed stocks are used to make manufacturing lots starting in week 5. In parallel, recombinant hemagglutinin (HA), neuraminidase (NA), and matrix (M1) protein are made for the generation of reagents needed for lot-release testing. During weeks 8 to 10, vaccine lots, which have been in production since week 5, are formulated, filled, and packaged for distribution, with release expected in weeks 10 to 12. This is approximately the same time that the first pandemic wave of disease will peak, so having vaccine available this quickly offers the potential to halt the pandemic in its tracks. Traditional manufacturing processes, in contrast, require preparation of a nonpathogenic virus (because an avian virus would kill the fertile egg used in production), and then production of materials used to make reagents. Only when these reagents are available can vaccine be released. The traditional process in this case takes at least 20 to 24 weeks, which means that vaccine is not available until the second wave of pandemic disease, after much of the damage has been done.


Figure 2. Relative yield from traditional vaccine production compared to baculovirus production of a virus-like particle (VLP) based vaccine. Because the VLP vaccine is effective at a much lower dose, the effective yield of the baculovirus production system is 42 times higher.
The insect-cell production system also has a very high productivity compared to traditional approaches (Figure 2). Yields in the production of HA are 7–10 times higher (in grams of protein per volume of production lot) than with traditional methods. These high yields make it possible to use small disposable reactors (1,000–2,000 L) instead of 20,000-L reactors needed for mammalian cell culture production. The system developed for making Phase 1 and Phase 2 clinical lots uses 200-L Wave reactors (GE Healthcare, Uppsala, Sweden) for the production of VLPs, followed by a series of purification steps that are also executed in disposable equipment. The current high yields are expected to increase as high-performance disposable stirred reactors (Xcellerex Inc., Waltham, MA) are used to scale up the process to 1,000 L for commercial production. Higher gas transfer rates are expected to support higher insect cell culture densities, thus providing higher volumetric productivity. Further, clinical testing to date has shown that much smaller doses of the VLP vaccine are needed to match the effectiveness of licensed pandemic vaccines (without the use of adjuvants). This means that the yield advantage is further magnified to >40-fold higher productivity in terms of doses of vaccine per liter of cell culture.


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