The global vaccine industry has undergone a dramatic and well publicized rebirth. Near the end of the 20th century, it faced an uncertain future with increased pricing pressures and liability challenges for marketed vaccines. Many long-standing members of the industry chose to scale back their R&D efforts or abandon them altogether. Today, however, the landscape has changed. Because of a confluence of positive factors (advancements in science and technology, greater appreciation for the role of vaccines as antibiotic resistance increased, and documentation of the true public health benefits of vaccines), major pharmaceutical and start-up companies are reinvesting significant resources into vaccine discovery.

Perhaps just as significant has been the demonstration of the commercial possibilities of newly introduced vaccines such as Wyeth’s Prevnar pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein), the first to achieve “blockbuster” status in the industry. Through routine use, annual sales of this vaccine should reach >$3 billion by 2009. Merck’s Gardasil human papillomavirus (HPV) vaccine has also achieved significant commercial success.

Based on the success of marketed products and the commercial potential of those in the pipeline, it is projected that the overall market opportunity for pediatric and adolescent vaccines alone in the seven major markets will grow from ∼$4.3 billion in 2006 to >$16 billion by 2016 (1).

This environment provides an exciting opportunity for growth, but it also poses a fundamental challenge: How does the industry go about ensuring that vaccines can be produced at levels required to meet increased global demand and continue to develop new products that provide solutions to unmet medical needs?

New Challenges, New Technology

To understand the challenges today, it is instructive to consider recent evolutionary changes. Wyeth’s Prevnar introduction exemplified a progression in the science of vaccine development and manufacture. Production once typically focused on growing, then chemically killing or weakening pathogens, and filtering and bottling the resulting immunogenic material. New vaccines are made by expressing the components of viruses or bacteria, followed by biochemical rearrangements or restructuring. Wyeth pioneered conjugate technology, used in Prevnar manufacture, for example. The manufacturing process is highly complex because the vaccine is equivalent to seven different polysaccharide vaccines in one. It combines seven different polysaccharides found on the cell coats of seven different pneumococcal bacterial serotypes with a carrier protein that helps enhance immunologic response to the pathogen.

To meet market demand, Wyeth undertook major changes in both its processes and facilities: improvements in vaccine manufacturing processes, increases in manufacturing capability and operational efficiency, and investment in existing and new facilities. End-to-end cycle times were dramatically reduced, and output from the manufacturing facilities tripled over the past four years.

A well-worn axiom in the biotech industry is that “The process is the product.” That is true for vaccines more than ever as the principles of biotechnology are applied to vaccine production. Important progress has been made in advancing into new platforms and gaining deeper understanding of protein expression, modification, and immunogenicity. The industry continues to learn more about vaccine manufacturing and the impacts of process changes.

Wyeth is currently applying quality by design (QbD) principles to its vaccine manufacturing operations at pilot scale. This program uses in-depth analytics coupled with in vitro and in vivo preclinical measures of immunogenicity. Improvements in analytics and the enhanced ability to correlate biochemical characterization and pharmacologic effects will further advance vaccine manufacturing. QbD provides a model for gaining deeper knowledge and controlling processes.

Greater process harmonization is critical as biomanufacturing becomes increasingly global and the need for maximum use of existing assets becomes greater. Manufacturing facilities typically take up to five years to build and validate, with ≤$800 million in capital investment. About half of those currently online are manufacturing products different from those for which they were constructed. Increased understanding of the processes behind vaccine production will help enable the industry to take better advantage of unexpected capacity excesses through such means as contract manufacturing and partnering arrangements.

Perhaps the most pressing need is the ability to keep pace with the growing complexity of vaccines in development. When combined with multipurpose platforms, greater process understanding will enable companies to adapt to opportunities for developing vaccines intended for global use in a general population while improving the economic viability of “boutique” vaccines targeted at smaller patient populations.

It’s an exciting time for the vaccine industry. Continued growth in our understanding of what stimulates the immune system is leading to development of increasingly effective vaccines. With technologies at our disposal, the industry can achieve dramatic improvements in product yields and consistency, react more nimbly to shifts in demand and development cycles, and reduce investment in manufacturing infrastructure.

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