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www.cdc.gov/H1N1flu
Nancy J. Cox, Ph.D.Nancy J. Cox, Ph.D.
Director, Influenza DivisionDirector, Influenza Division
Director WHO Collaborating Center for InfluenzaDirector WHO Collaborating Center for Influenza
NCIRD, Centers for Disease Control and PreventionNCIRD, Centers for Disease Control and Prevention
Second WHO Consultation on the GAP for Influenza VaccinesSecond WHO Consultation on the GAP for Influenza Vaccines
1212--14 July 201114 July 2011
Pandemic Influenza Vaccines: Pandemic Influenza Vaccines: Lessons Learned from the H1N1 Lessons Learned from the H1N1
Influenza PandemicInfluenza Pandemic
www.cdc.gov/H1N1flu
GlobalInfluenza Vaccine Strategy
REDUCED DISEASE
VACCINATION POLICY DEVELOPMENT
DATA COMMUNICATED
DATA GENERATED
Capacity Surveillance Research
Laboratory Capacity
Basic Epidemiologic Surveillance
Enhanced Sentinel
Surveillance
Population-based Surveillance
Special studies in selected
countries, i.e., BoD & VE,
www.cdc.gov/H1N1flu
Presentation Themes: Pulling Detection Closer
to Emergence & Vaccine Closer to Disease
� Challenges for early detection of novel viruses with pandemic potential
� Validated diagnostic platforms for detection of novel influenza viruses and other emerging respiratory pathogens
� Build partnerships to identify newly emerging influenza viruses in animals
� Goal: earlier detection of emergence of pandemic influenza viruses suitable as vaccine candidates (H2, H4, H5, H6, H7, H9, H10, etc.)
� Challenges for vaccines - faster development & availability
� Better growing vaccine viruses (focused R&D)
� Library of pre-prepared HG vaccine candidates (clinical trials)
� Stockpile potency testing reagents for library above
� New platforms for streamlining the measurement of vaccine potency and sterility
� Goal: earlier delivery of safe and effective pandemic vaccines
www.cdc.gov/H1N1flu
Preparing for the Pandemic
� Developed New Diagnostic Tests
� Part of national strategy for diagnostic
preparedness
� Two FDA approved devices
� Enhanced surveillance for human
and animal-origin influenza
� Increasing testing over last five years led to more swine flu detected (NEJM
Shinde 2009)
www.cdc.gov/H1N1flu
April 27
CDC Deposits 40
Gene Sequences in
GenBank
May 1
First Diagnostic Kits Shipped to
State Labs Total = 1500 kits to 50 States
May 1
First Diagnostic Kits Shipped to
WHO NetworkTotal = 1400 kits to 153 countries
May 23
Vaccine Virus
Shipment to
Manufacturers
April 28
CDC Posted PCR
Protocol on
WHO website
2009 H1N1
Virus Detected
www.cdc.gov/H1N1flu
AugJulJunMay FebJanOctSepAprMarFebJan DecNov
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www.cdc.gov/H1N1flu
The Greatest Influenza Vaccine Challenge: Gearing up Production
for a Pandemic
www.cdc.gov/H1N1flu
Unique Features of Influenza Vaccines� Current influenza vaccines target a rapidly changing
seasonal viruses & unpredictable pandemic viruses
� Immunity acquired from vaccination is “strain-specific”(e.g., targeted to one antigenic variant per vaccine
component)
� Broadening cross-protection has remained a challenge; oil in water adjuvants : our “best bet” for now
� The “holy grail” of a universal vaccine remains elusive; new targets identified, but unproven
� It remains a race against time to detect the emergence and spread of new influenza variants and to provide
vaccine prior to disease
� Production of influenza vaccines is a high-risk, high-
stress endeavor for manufacturers
www.cdc.gov/H1N1flu
Estimated Timeline of H1N1pdm Vaccine Development and Delivery in the U.S.
CDC ships high growth reassortant viruses to mfrs (X-179A and RG-15) May 26 and 27
Working seed developed by vaccine manufacturers(*) June 20-30
Monovalent concentrate August (§)
Test monovalent concentrate
Pool monovalent concentrate
CBER release Sept 15 & 18 (N/sp)Filling September (at risk)
Final September 30
FDA prepare potency test reagents:
August 12, 2009
CDC/FDA
Manufacturing
Testing
WHO H1N1 vaccine virus recommendation April 27
Vaccine virus reassortment started at CDC and NYMC April 25 and 28
CDC isolates H1N1 April 15
May June July Aug Sept OctApril
(*) Manufacturers were transiently limited in their ability to develop seed viruses due to lack of facilities to grow virus in large volume at the required BSL3 biocontainment
(§) Production of monovalent inactivated vaccine is a continuous process
September 30: Distribution
October 5:Start Vaccination
www.cdc.gov/H1N1flu
www.cdc.gov/H1N1flu
Post Pandemic Blues� After-action Reviews of the 2009 Pandemic Response
� President’s Council of Advisors on Science and Technology met resulting in “Report to the President on Reengineering the Influenza Vaccine Production Enterprise to Meet the Challenges of Pandemic Influenza” – August 2010
� Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Review
� Influenza Manufacturing Improvement – Coordinated by BARDA/HHS (NIH, FDA, CDC and many Academic and Industry
Partners)
� Optimization of Influenza Vaccine Donor and Candidate Viruses
� Potency Assay Improvement
� Rapid Sterility Testing - FDA
www.cdc.gov/H1N1flu
Optimization of Influenza Vaccine Donor and Candidate Viruses
� Aim 1: Analyze Genetics of High Yield A/PR/8/34 Donor Viruses from Different Labs
� Aim 2: Produce and Evaluate High-yield Reassortant Viruses
� Aim 3: Combinatorial Optimization of Vaccine Candidates
� Aim 4: Establish Library of Validated High Growing Vaccine Candidates
www.cdc.gov/H1N1flu
Developing a Risk Assessment Algorithm
� Identify the elements to consider in pandemic risk assessment
� Define each independent element
� Assign weight to each element and use variables for multi-
factorial analysis
� Come up with a composite score
� For high scoring viruses develop “preparedness packages”
(diagnostics and candidate vaccine libraries of high growth reassortants,
clinical trial lots and vaccine trials, if high risk)
� For very high scoring viruses develop pre-pandemic
vaccines
� Candidate vaccine library useful for human and animal health
� Vaccine stockpiles
13
www.cdc.gov/H1N1flu
Risk ProfilingRisk Ranking
Risk Identification
• Political Assessment• Funding Assessment
• Risk Assessment
• Options Assessment• Interventions
• Stakeholder Communication
• Results Monitoring• Process Verification
Prioritization Factors
•Public Health• Political Sensitivity
• Fiscal Considerations
1. RISK EVALUATION
2. MULTIFACTORIAL ASSESSMENT
3. RISK MANAGEMENT
4. MONITOR & REVIEW
RISK PRIORITIZATION FRAMEWORK
www.cdc.gov/H1N1flu
Some Elements of a Risk Assessment Algorithm
� Secondary hosts infected by the novel virus (including poultry, swine and other mammals, especially
humans)
� Transmissibility (using ferret models)
� Susceptibility of the population- seroprevalence
� Geographic spread of the virus in secondary hosts
� Severity of infection in humans and other mammals
� Virus characterization
� Genetic features such as virulence markers
� Genetic and antigenic variation
� Receptor binding properties
� Pathogenesis
15
www.cdc.gov/H1N1flu
Improving Vaccine Antigen Standardization:Potency Testing
� Current methods for measuring the quantity of antigen in the vaccines are decades old and often cause significant delays in the availability of influenza vaccines
� We need faster, more accurate methods for quantitating antigens contained in inactivated influenza vaccines
� Need approaches that could be applied to all protein based influenza vaccines, including new vaccines
� HPLC
� ELISA
� Mass Spectroscopy-Isotope Dilution with
� Antibody mediated pull down of intact HA
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www.cdc.gov/H1N1flu
Vaccine Lessons Learned from the H1N1 Pandemic
� In spite of many successes, once again too little vaccine, too late
� Uneven distribution of influenza vaccines globally
� Having influenza vaccines even 4-6 weeks earlier likely to make big difference in disease reduction and vaccine acceptance
�THE FUTURE
� Set goals: Move detection of novel influenza viruses closer to emergence & the availability of vaccines prior to disease occurrence: What do we need?
� Sustainable multi-use respiratory disease surveillance platforms for identification of novel virus emergence globally
� Library of truly HG reassortants tested and production-ready
� Streamline methods for measuring vax Ag content, suitable for all HA protein (HPLC, ELISA and MSID methods)
� Use of adjuvants to for Ag sparing & more robust immune response
� Improve vaccine capacity globally for vaccine equity (LAIV)
� Enhance partnerships domestically and globally
www.cdc.gov/H1N1flu
Acknowledgements� WHO’s Global Influenza Surveillance Network +
�National Influenza Centers (esp. Mexico and Canada’s NICs)
�WHO CCs�WHO RO and HQ
� Colleagues in Veterinary Health including OIE/FAO and USDA and other MoAg
� State and Local Health Departments and DoD Laboratories in the US
� Other PH Colleagues Around the World
� Influenza Division Staff, CDC
www.cdc.gov/H1N1flu
Questions?
Thanks for you attention.
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