Global demand for influenza vaccine doses cannot be translated into cell-culture fermentation capacities, because they are
largely dependent on varying productivity levels of different cell-lines and varying yields of different influenza strains.
Moreover, in the case of a pandemic vaccine, the optimum dose required for effective immunity is unknown. These factors, when
combined, pose a tricky proposition for vaccine developers between expanding capacity versus improving efficiency of their
corresponding product platforms. Table 2 provides a summary of the current types of influenza vaccines in development and
current production platforms being used to develop an avian or pandemic vaccine prototype.
Table 2. Current platforms for avian/ pandemic product candidates in development
Although several prototype pandemic candidates are in development based on mammalian cell-culture processes (Madin-Darby canine
kidney [MDCK], Vero, Per.C6, and EBx), other alternative platforms are being developed that offer the potential for improved
productivity per liter and hence, lower capacity requirements. Protein Science's and Novavax's insect-cell-culture–based processes
are novel approaches with the potential to deliver low-cost options. VaxInnate's fusion product expressed in a bacterial system
offers the promise of exceptionally high productivity levels per manufacturing volume. Manufacturing processes based on bacterial
and yeast-based platforms, which are easy to scale up, are cost-efficient and tend to offer better and more consistent yields
over cell-culture–based processes.
DNA-based vaccines in development also hold great potential, as they involve rapidly scalable processes that can produce high
doses per manufacturing volume. Dry formulated DNA vaccines being developed by UK-based PowderMed offer the potential for
a low-dose vaccination using a proprietary needleless epidermal drug delivery. GlobeImmune's yeast-based engineered whole-cell
product, based on a simplified manufacturing process, offers the promise of a highly immunogenic vaccine.
Speed: The Unique Rapid Deployment Challenge
The strain that would cause the next pandemic is uncertain, yet the threat is real. The impact market is global, production
facilities are local, and the time to deliver the vaccine is a window of 24 to 26 weeks. Historical data suggests that pandemic
influenza attacks follow a pattern, with the first wave at time zero and the second wave after a period of about 6 months;
this attack pattern has historically contributed to the biggest percentage of mortalities. A third wave, if it happens, can
be expected within 18 to 24 months from time zero.
These timelines, along with the very limited resources available today, make pandemic influenza vaccine manufacturing unique
in the pharmaceutical industry. Although a combination of several pre-pandemic measures—involving stockpiling of antivirals
and inter-pandemic vaccines—would serve as the first lines of defense, manufacturing for a pandemic vaccine would start only
after a Phase 6 outbreak had been confirmed. Subsequently, the first batches of product that become available 4 to 6 months
post-outbreak would offer hope for immunizations before the fatal second wave erupted (Figure 1). The race to deliver the
vaccine on time would put demands on reducing turnaround times, performing labor-intensive support functions (with concerns
about business continuity issues), and maintaining quality assurance. All of these requirements are achievable by integrating
disposable technologies into the manufacturing process as much as possible.
Although it has been easy to realize the benefits that disposable technologies offer to simple unit operations such as mixing,
buffer and media hold, and aseptic fluid transfer (all of which are carried out in fermentation), applying disposables with
functional groups for separation of biomolecules has been a process challenge downstream. For a pandemic vaccine, reducing
downstream purification steps on a risk-to-benefit basis by simplifying processes developed around single-use filter cartridges
and membrane chromatography technologies could offer significant time- and cost-reduction advantages. Such disposable-based
processes may provide a low-cost manufacturing option, especially in markets where affordability is as important as availability.
However, this situation should be considered with complementing developments in adjuvant technologies that have potential
for dose-sparing strategies that can further improve the cost-per-dose.