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Pandemic influenza vaccine development: Status of preparedness Ruben Donis Influenza Division, NCIRD, CCID, CDC Pandemic influenza vaccine development: Status of preparedness Ruben Donis Influenza Division, NCIRD, CCID, CDC Pandemic Influenza Vaccines: Building a Platform for Global Collaboration Beijing, China; January 28 -30, 2007

Organizers and Sponsors • Chinese Center for Disease Control and Prevention • The National Organizers and Sponsors • Chinese Center for Disease Control and Prevention • The National Bureau of Asian Research • Bill and Melinda Gates Foundation • Wellcome Trust • Other partner organizations

Pandemic Vaccines: challenges and opportunities • Challenges – Insufficient capacity to immunize the world Pandemic Vaccines: challenges and opportunities • Challenges – Insufficient capacity to immunize the world population • Opportunities – – Strengthen virus detection Increase vaccine production capacity by 6 -fold Deliver vaccines to everyone in a timely fashion Develop improved vaccines

Immunization Strategies • Non-replicating vaccines – Inactivated influenza virions • Subviral (split) or whole Immunization Strategies • Non-replicating vaccines – Inactivated influenza virions • Subviral (split) or whole virion • Produced in eggs or (soon) cell culture – Recombinant expression systems • Baculovirus, insect cells, VLP (HA-NA-NP-M) – Nucleic acid vaccines and Adenovirus vectors • Replicating vaccines – Live attenuated cold-adapted strains • Produced in eggs or (soon) cell culture – Viral vectored: alphavirus, flavivirus, paramyxovirus Licensed in USA for use as Seasonal Vaccines

Immunization Challenges • Protective immunity induced by currently licensed vaccines is largely strain specific Immunization Challenges • Protective immunity induced by currently licensed vaccines is largely strain specific – Strain differences reduce vax efficacy – Vaccine stockpiles become obsolete – Prepare many homologous pandemic vaccines • Challenge: • Broaden specificity of protective immunity – Live and inactivated vaccines

Immunization Challenges • Inactivated avian HA subtype vaccines appear to be poorly immunogenic in Immunization Challenges • Inactivated avian HA subtype vaccines appear to be poorly immunogenic in humans – Requiring 2 doses of 90 µg (6 -fold > seasonal flu) – Adjuvants reduce the required dose increase • Challenge: • Increase the immunogenicity of inactivated vaccines – Develop adjuvants – Alternative immunogens or routes of delivery

Pandemic Vaccine Development Challenges Pandemic Influenza (H 5 N 1) Person-to-person Transmission Pandemic Vaccine Pandemic Vaccine Development Challenges Pandemic Influenza (H 5 N 1) Person-to-person Transmission Pandemic Vaccine (H 5 N 1) Immunity to Influenza (H 5 N 1)

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Surveillance Challenges • Virologic surveillance is critical – – Strengthen PH systems and laboratory Surveillance Challenges • Virologic surveillance is critical – – Strengthen PH systems and laboratory support Collaboration with animal health authorities critical Rapid bedside pandemic flu diagnostics needed Lab confirmation of all human cases • Molecular methods: realtime PCR • Virus culture in BSL 3 – Facilities: expand local BSL 3 lab capacity • Opportunities – – Library of viruses for diagnostic and vaccine development Expanded molecular databases International sharing of strains and sequences is essential WHO IHR recommendations in effect June 1 ‘ 07

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Vaccine Strain Selection • Antigenic analysis of viral isolates – Resource intensive process – Vaccine Strain Selection • Antigenic analysis of viral isolates – Resource intensive process – BSL 3 enhanced facilities, personnel, ferrets – Panels of antisera to numerous virus strains • Genetic characterization – Sequence analysis increasing rapidly – Public access to virus sequences is improving • Genbank, LANL, BGI • Challenge – Sharing reagents and sequences is critical – WHO International Health Regulations (IHR) buy-in

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Engineer Safe Vaccine Viruses Reverse Genetics BSL 3 -enhanced virus Virulent Hemagglutinin High Yield Engineer Safe Vaccine Viruses Reverse Genetics BSL 3 -enhanced virus Virulent Hemagglutinin High Yield Attenuated virus (PR 8) 9 days Vero Cells High Yield avirulent vaccine BSL 2 virus

High Yield Reassortants by Reverse Genetics • Work must be done in BSL 3 High Yield Reassortants by Reverse Genetics • Work must be done in BSL 3 • HA modification required for BSL 2 mfg – 6: 2 reassortants (PR 8: H 5 N 1) • RG Technically robust – Applicable to inactivated and LAIV • Challenges – Requires vaccine-certified Vero cells – Commercial use RG process is protected by patents

CDC RG reassortant stocks • 3 H 5 N 1 candidate vaccines distributed by CDC RG reassortant stocks • 3 H 5 N 1 candidate vaccines distributed by CDC • No fees charged to users – A/Vietnam/1203/2004: Clade 1 • 54 recipients – A/Indonesia/5/2005: Clade 2. 1 • 49 recipients – A/Anhui/1/2005: Clade 2. 3 • Collaboration with China National Influenza Center • 14 recipients in 1 st quarter 2007 • MTA for RG required by Medimmune

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics a. Safety testing: permit to transfer from BSL 3 into BSL 2 4. 5. 6. 7. Manufacture vaccine in eggs Potency testing Regulatory approval Distribute vaccine public health & private networks

Transfer virus from BSL 3 to BSL 2 • USA HPAI is restricted to Transfer virus from BSL 3 to BSL 2 • USA HPAI is restricted to BSL 3 by Dep't of Agriculture – “USDA Select Agent” • Apply for permit to use RG vaccine reassortants in BSL 2 – Source of materials (viruses, plasmids, description of modification) – Sequence analysis of the HA gene • amino acid motif at the HA cleavage site – Pathogenicity testing in chickens – Plaque characterization on chicken embryo fibroblast (CEF) cells with or without trypsin – With permit approval, all subsequent work done at BSL-2 level

RG Ressortant: WHO safety evaluation • RG Reassortant Reference Stock – WHO Guidelines: Lack RG Ressortant: WHO safety evaluation • RG Reassortant Reference Stock – WHO Guidelines: Lack of pathogenicity • Ferrets – Intranasal challenge: ≥ 6 logs – Level of virus replication and symptoms ~ PR 8 – No replication in brain tissue • Mouse pathotyping optional • Chickens – Intravenous pathogenicity test

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Egg-based production • Supply of fertile eggs for vaccine – No surge capacity • Egg-based production • Supply of fertile eggs for vaccine – No surge capacity • Production must be scheduled many months in advance • FY 04 HHS-CDC Contract Sanofi-Pasteur – Guaranteed production of fertile eggs for vaccines • Short term fix to secure a minimum of pandemic vax production

Pandemic Vaccine Manufacturers • Australia • Italy – CSL • Austria – Chiron-Novartis • Pandemic Vaccine Manufacturers • Australia • Italy – CSL • Austria – Chiron-Novartis • Japan – Baxter • Canada – ID-GSK • China – Sinovac • France – Sanofi-Pasteur • Germany – GSK – Denka-Seiken, Kaketsuken, Kitasato • Netherlands – Solvay, Nobilon • Switzerland – Berna • UK – Chiron-Novartis • USA Egg production, source (partial listing) – Medimmune, Merck, Sanofi, Novartis

Production Challenge • Current annual total monovalent vaccine production capacity worldwide – 900 -1, Production Challenge • Current annual total monovalent vaccine production capacity worldwide – 900 -1, 000 Million doses @ 15 µg/dose • • • Sufficient for 15% of population (only one dose) >5 years required to immunize everyone Inactivated and live vaccines produced in eggs Fertile egg supplies not likely to increase Challenge – New technologies are needed

Cell-based production • Vertebrate cells used as substrate to propagate virus in large scale Cell-based production • Vertebrate cells used as substrate to propagate virus in large scale • US HHS awarded ~ $1, 000 million in FY 06 – Goal: Production capacity to deliver 600 million doses (@ 15 µg) in 6 months • Awardees: • Baxter • GSK • Med. Immune • Novartis • Sanofi-Pasteur • Solvay

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Potency Evaluation • Determine HA content in bulk vaccine – Required formulation and dispensing Potency Evaluation • Determine HA content in bulk vaccine – Required formulation and dispensing • Single Radial Immunodiffusion (SRID) – Homologous monovalent sheep serum • Several weeks to develop and validate • Requires purified HA to immunize sheep – Calibrated homologous antigen • Challenge – Calibrated antisera and antigen made available quickly – Prevent duplication of effort

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Regulatory Compliance Challenges • Food and Drug Administration, CBER – Licenses vaccines in USA Regulatory Compliance Challenges • Food and Drug Administration, CBER – Licenses vaccines in USA • • • Code of Federal Regulations International Conference on Harmonization (ICH) Guidelines Cell substrates – Vero cells • FDA to view egg-based inactivated pandemic vaccine as strain change for seasonal flu • No discrimination due to reverse genetics

Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at Overview of Inactivated Pandemic Vaccine Production 1. Surveillance: access to viruses from patients at diverse locations a. Knowledge of strains that infect humans 2. Antigenic analysis a. Identify the prevailing antigenic types, select representative strain 3. Produce avirulent high-yield reassortant virus by reverse genetics 4. Manufacture vaccine in eggs 5. Potency testing 6. Regulatory approval 7. Distribute vaccine public health & private networks

Distribution Challenges • Timeliness – Pandemic modeling studies • Speed of vaccine deployment may Distribution Challenges • Timeliness – Pandemic modeling studies • Speed of vaccine deployment may be as important as antigenic match – USA: target capacity of 10 million doses/week • Germann et al. PNAS 103: 5935; 2006

Pandemic Vaccines Development Timeline Week 1 2 3 4 5 6 7 8 9 Pandemic Vaccines Development Timeline Week 1 2 3 4 5 6 7 8 9 x y z • Increase speed and reliability of RG system (Vero cell alternatives) RG reassortant Safety Working seed • Support cell culture-based vaccines • Improve growth of pandemic candidate vaccines Large scale production in eggs Formulate and fill Produce & Standardize Potency Reagents • Improve methods and reagents

Sustainability Challenges • Pandemic preparedness in year 2020 – Political system fatigue – New Sustainability Challenges • Pandemic preparedness in year 2020 – Political system fatigue – New initiatives are more appealing • How to sustain pandemic preparedness? – Strengthen seasonal influenza control – Strengthen links with animal health control – Think beyond H 5 N 1 • H 9 N 2, H 7 N*, H 2 N 2, etc remain a threat • Global Platforms for Collaboration

Acknowledgements • • • • WHO GIP Surveillance Network Catherine Gerdil, Sanofi Pasteur, France Acknowledgements • • • • WHO GIP Surveillance Network Catherine Gerdil, Sanofi Pasteur, France Ervin Fodor, Cambridge, UK Erich Hoffmann, (Med. Immune) St. Jude, Memphis, USA Yumi Matsuoka, ID, CDC Kanta Subbarao, NIH Alexander Klimov, ID, CDC Jacqueline Katz, ID, CDC Tim Uyeki, ID, CDC Robinson, HHS Zhiping Ye, FDA John Wood, NIBSC David Swayne; USDA, ARS, Southeast Poultry Research Laboratory, Athens, GA, USA Nancy Cox, IB, CDC Many more….

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