A recent private grant of US$10 billion for human vaccine applications illustrates the revival of interest in vaccine science (1). The 2009 response by vaccine manufacturers to the H1N1 pandemic revealed the convergence of three technological developments. First is a revolution in technology: Vaccines are being developed for diverse and unprecedented applications through a number of entirely new approaches. Second is the recent adoption of cultured cell-based production for a growing number of vaccines, such as influenza. And third is the rapid acceptance of single-use technology in bioproduction overall.

The Revolution in Vaccine Technology

Because of remarkable technological innovations in both prophylactic and therapeutic vaccine science, it's important to establish the exact scope of this topic. From novel and unique vaccine types (e.g., DNA plasmid vaccines) to their unprecedented indications (such as cancer and diabetes treatment) to innovative means of delivery (e.g., inhaled nanoparticles) to entirely new production approaches (such as in genetically engineered plants), it has become a challenge just to stay on top of this field (2). Here, I address the use of higher-animal cell culture such as Madin-Darby canine kidney (MDCK) cells in production of a vaccine biological component (such as a viral vector) using disposable systems (such as single-use bioreactors).

Keep in mind that although much has been made of the recent move to human H1N1 flu vaccine production in cultured cell and disposable systems, these technologies also support a wide range of vaccine types against a number of pathologies in human and veterinary applications. This new world of vaccine design includes such diverse new approaches as recombinant vectors, virus-like particles (VLPs), and new adjuvants. Some related vaccine designs are not only facilitated by these newer manufacturing methods, they in fact depend on those advances.

Vaccine Production Through Cell Culture

The transition of vaccine production from primary animal tissues to cell culture began >50 years ago with the famous establishment of polio vaccine production in primary monkey kidney cells. A significant development occurred in 1987 with establishment of a World Health Organization guidance for using immortalized (continuous) cell lines for vaccine manufacturing (3). Since then, a large number of approved human and veterinary vaccines against a number of pathogens have been made using cell culture methods. For example, the ACAM2000 smallpox vaccine from Acambis, Inc. (www.acambis.com) is produced in Vero cell culture.

On the other hand, the transition to cell culture from flu vaccine production based on chicken eggs began only recently. Although it was heavily supported by >$1 billion in government funding in 2005–2006, it is not yet complete (4,5,6). In general, cell culture offers many advantages over animal tissue and egg-based manufacturing approaches, as listed in the “Features” box. A more specific concern is identification of the best from the many available cell-based production platforms, which range from human kidney cells cultured in serum-based media on microcarriers to immortalized duck embryonic stem cells in serum-free suspension culture.

FEATURES OF VACCINE PRODUCTION BY CELL CULTURE
Advantages
Eliminates expense of obtaining animal tissue or chicken eggs from biosecure flocks
Eliminates four- to six-month lead times for embryonated eggs
Eliminates time required to adapt new seed stocks to egg production
Facilitates use of nonadapted, wild-type strains in actual manufacturing
Eliminates risk of egg-adaptation- induced immunogenic changes in viruses
Generally supports greatly reduced high- volume production start-up times
Greatly supports rapid pandemic vaccine response
Frozen cell stocks greatly facilitate warm and surge capacity
Facilitates supplemental production when strain changes are necessary
Reduces extent/level of production facility classification (biosafety level)
Supports the linkage, automation, and closure of up- and downstream processes
Provides for a more reliable, expandable, and flexible process
Provides higher initial product purity in downstream operations
Reduces the potential of viable and nonviable contamination
Expands the population of potential vaccine recipients

Reported Concerns
Regulatory hurdles
Product comparability costs and challenges
New process development costs/delays
Multiple costs of implementing entirely new operations/equipment