1. Vaccine Manufacturing Joe Bielitzki NanoScience Technology Center University of Central Florida Orlando, Florida jbielitz@mail.ucf.edu

2. Vaccine need Infectious diseases of public health interest Rotavirus Measles, mumps, rubella Diphtheria, pertussis, tetanus Polio Emerging diseases HIV SARS WNV Bio-threat agents Smallpox Anthrax Plague Infectious diseases of regional concern Tick borne encephalitis Japanese encephalitis Infectious diseases of concern to the military Dengue Malaria Adenovirus Agriculture (animal vaccines) And some live in all categories

3. Current status For the usual products- supply and demand For the others – wait and see Discovery through Commercialization Not linked Production is limited Single or limited methodology cGMP Little innovation Market forces restrict change Intellectual property law Regulatory process

4. What’s needed New technology? New science? Incorporation of existing methods? Flexibility? Modularity? Surge capacity? Interdisciplinary approach? Research?

5. Vaccine shortages 2000-2002 DTaP Two producers stop Thimerosal removal Td One producer stops MMR Sole producer has GMP issues Varicella Alteration to production facilities Pneumococcus Demand exceeds supply Influenza Difficulty growing virus Increased demand due to change in target population age -65 to 50 QC issues at one producer

6. Barriers to vaccine supplies Exit and concentration (multinationals) Loss of current producers mergers Research and development Return on investment IP Barriers to entry Cost of trials Discovery firms are small Regulation Need updating Cost benefit is questioned Undervaluation of vaccines Return on investment Capacity prior to license Prophylaxis vs therapy

7. Vaccine production: an interdisciplinary problem Bringing new science to the table Adjuvants Protein stability Linked development schemes Pathways to immunity Looking at production Immunogen production Permissive cells Contamination/cross contamination Protein stabilization A systems problem without a systems approach Entrenched production methods Shelf life – wet vs dry – refrigerated vs ambient Benefits for the future Improved immunity Increased surge capacity Ability to deal with novel and new threats Changing paradigms for an uncertain future

8. Engineering and Science join forces Science needs in vaccine production Science needs in vaccine production Pathways to immunity Pathways to immunity Rapid id of immunogenic areas Rapid id of immunogenic areas Adjuvants (MyD88, IMD, RIP/FADD) Adjuvants (MyD88, IMD, RIP/FADD) Selective T and B cell responses Selective T and B cell responses Rate limiting factors in vaccine utility Rate limiting factors in vaccine utility New production tools and methods New production tools and methods Immunogen production Immunogen production Protein stability Protein stability Shelf life Shelf life Storage requirements Storage requirements

9. The problem Vaccine production is slow Vaccine production is slow Vaccine manufacturing facilities deal with one familiar agent Vaccine manufacturing facilities deal with one familiar agent Lack modularity and flexibility Lack modularity and flexibility Methods are validated and approved Methods are validated and approved Economics limits new methodology Economics limits new methodology

10. A systems approach Identify rate limiting steps in process Identify rate limiting steps in process Technology bottlenecks Technology bottlenecks Science bottlenecks Science bottlenecks Define an ideal vaccine response Define an ideal vaccine response Reverse engineer the process Reverse engineer the process Immunology Immunology Host and agent needs Host and agent needs Manufacturing needs Manufacturing needs Storage and shelf life Storage and shelf life Time to product Time to product What do we know and what do we need to know What do we know and what do we need to know Who knows what now Who knows what now

11. A team of scientists a fresh look Immunologist Immunologist Microbiologist Microbiologist Vaccinologist Vaccinologist Systems engineer Systems engineer Bio Process engineer Bio Process engineer Generalist Generalist

12. Study concepts Report on the status of research for advancing the vaccine manufacturing Report on the status of research for advancing the vaccine manufacturing Current production methods and needs Current production methods and needs Innovative concepts Innovative concepts Research needs to facilitate flexibility Research needs to facilitate flexibility Research needs to increase surge capacity Research needs to increase surge capacity Research needs for modularity (plug and play) Research needs for modularity (plug and play) Vaccine short comings (as a Product) Vaccine short comings (as a Product) Race to find new vaccine production techniques in fight against influenza The Pharmaceutical Journal Vol 275 No 7373 p543-544 29 October 2005 29 October 2005

13. Recent IOM Publications Financing Vaccines in the 21 st Century (2003) Financing Vaccines in the 21 st Century (2003) Assuring Access and Availability Assuring Access and Availability Orphans and Incentives (1997) Orphans and Incentives (1997) Developing Technologies to Address Emerging Infections Developing Technologies to Address Emerging Infections Biological Threats and Terrorism (2002) Biological Threats and Terrorism (2002) Assessing the Science and Response Capabilities Assessing the Science and Response Capabilities there are more there are more Recent Non-IOM publication Vaccines: Frontiers in Design and Development (2005) Moingeon, P.