Pandemic influenza vaccine development: Status of preparedness

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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
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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

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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

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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
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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

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Immunization Challenges

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

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Pandemic Vaccine Development Challenges
Pandemic Influenza (H5N1)
Pandemic Vaccine (H5N1)
Immunity to Influenza (H5N1)
Person-to-person Transmission
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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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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 BSL3
• Facilities expand local BSL3 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

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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Vaccine Strain Selection

• Antigenic analysis of viral isolates
• Resource intensive process
• BSL3 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

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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Engineer Safe Vaccine Viruses Reverse Genetics
BSL3-enhanced virus
High Yield Attenuated virus (PR8)
Virulent Hemagglutinin
9 days
High Yield avirulent vaccine
Vero Cells
BSL2 virus
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High Yield Reassortants by Reverse Genetics

• Work must be done in BSL3
• HA modification required for BSL2 mfg
• 62 reassortants (PR8H5N1)
• RG Technically robust
• Applicable to inactivated and LAIV
• Challenges
• Requires vaccine-certified Vero cells
• Commercial use RG process is protected by patents

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CDC RG reassortant stocks

• 3 H5N1 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 1st quarter 2007
• MTA for RG required by Medimmune

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Safety testing permit to transfer from BSL3 into
  BSL2
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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Transfer virus from BSL3 to BSL2

• USA HPAI is restricted to BSL3 by Dep't of
  Agriculture
• USDA Select Agent
• Apply for permit to use RG vaccine reassortants
  in BSL2
• 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

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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 PR8
• No replication in brain tissue
• Mouse pathotyping optional
• Chickens
• Intravenous pathogenicity test

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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Egg-based production

• Supply of fertile eggs for vaccine
• No surge capacity
• Production must be scheduled many months in
  advance
• FY04 HHS-CDC Contract Sanofi-Pasteur
• Guaranteed production of fertile eggs for
  vaccines
• Short term fix to secure a minimum of pandemic
  vax production

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Pandemic Vaccine Manufacturers

• Australia
• CSL
• Austria
• Baxter
• Canada
• ID-GSK
• China
• Sinovac
• France
• Sanofi-Pasteur
• Germany
• GSK

• Italy
• Chiron-Novartis
• Japan
• Denka-Seiken, Kaketsuken, Kitasato
• Netherlands
• Solvay, Nobilon
• Switzerland
• Berna
• UK
• Chiron-Novartis
• USA
• Medimmune, Merck, Sanofi, Novartis

Egg production, source (partial listing)
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Production Challenge

• Current annual total monovalent vaccine
  production capacity worldwide
• 900-1,000 Million doses _at_ 15 µg/dose
• Sufficient for 15 of population (only one dose)
• gt5 years required to immunize everyone
• Inactivated and live vaccines produced in eggs
• Fertile egg supplies not likely to increase
• Challenge
• New technologies are needed

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Cell-based production

• Vertebrate cells used as substrate to propagate
  virus in large scale
• US HHS awarded 1,000 million in FY06
• Goal Production capacity to deliver 600 million
  doses (_at_ 15 µg) in 6 months
• Awardees

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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Potency Evaluation

• Determine HA content in bulk vaccine
• Required for 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

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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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

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Overview of Inactivated Pandemic Vaccine
Production

• Surveillance access to viruses from patients at
  diverse locations
• Knowledge of strains that infect humans
• Antigenic analysis
• Identify the prevailing antigenic types, select
  representative strain
• Produce avirulent high-yield reassortant virus by
  reverse genetics
• Manufacture vaccine in eggs
• Potency testing
• Regulatory approval
• Distribute vaccine public health private
  networks

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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 1035935 2006

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• Pandemic Vaccines Development Timeline

2
1
z
3
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6
7
8
9
x
y
Week
RG reassortant
Safety
Working seed
Large scale production in eggs
Formulate and fill
Produce Standardize Potency Reagents
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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 H5N1
• H9N2, H7N, H2N2, etc remain a threat
• Global Platforms for Collaboration

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Acknowledgements

• WHO GIP Surveillance Network
• Catherine Gerdil, Sanofi Pasteur, France
• Ervin Fodor, Cambridge, UK
• Erich Hoffmann, (MedImmune) St. Jude, Memphis,
  USA
• Yumi Matsuoka, ID, CDC
• Kanta Subbarao, NIH
• Alexander Klimov, ID, CDC
• Jacqueline Katz, ID, CDC
• Tim Uyeki, ID, CDC
• Robin 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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Thanks!