View
7
Download
0
Category
Preview:
Citation preview
1
United States Department of
Health & Human Services Office of the Assistant Secretary for Preparedness and Response
Rick A. Bright, Ph.D.
Deputy Director, Influenza Division
Biomedical Advanced Research and
Development Authority (BARDA)
Influenza Vaccine Innovation
New Vaccines Approved and on the Way
2013 National Adult and Influenza Immunization Summit May 14 – 16, 2013 Atlanta, GA USA
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 2
The Biomedical Advanced Research and Development Authority
Develop and provide countermeasures for CBRN threats, pandemic influenza, and emerging infectious diseases through product development, stockpile acquisition/building, manufacturing
infrastructure building, and product innovation.
Vaccines Therapeutics Diagnostics Infrastructure Devices
2
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 3
Requirements
• Requirements addressed by the BARDA Influenza Portfolio are derived from a number of documents that guide the US Government efforts to prepare for pandemics • National Strategy for Pandemic Influenza (Nov 2005)
• HHS Pandemic Influenza Plan (Nov 2005)
• Nation Strategy for Pandemic Influenza Implementation Plan (May 2006)
• Public Health Emergency Medical Countermeasures Review (Aug 2010)
• PCAST report on Reengineering the Influenza Vaccine Production Enterprise (Aug 2010)
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 4
National Research Council, "Vaccine Supply." The 2009 H1N1 Influenza Vaccination Campaign: Summary of a
Workshop Series. Washington, DC: The National Academies Press, 2010.
Vaccine Challenges Pandemic Response
3
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 5
3-7 yr 0.5-2 yr 1-2 yr 2-3.5 yr 2.5 -4 yr 1-2 yrs
Discovery Phase I Phase II Licensure Phase III Preclinical
Development
Production
& Delivery
PROBABILITY OF SUCCESS TO LICENSURE
PR
OD
UC
T P
IPE
LIN
E
Licensed Product
1-3% 5-17% 10-25% 18-35% 45-70% 90%
TIME
IND NDA/BLA
PHASE
1 2 3 4 5 6 7 8 9 TRLs
5 candidates here… …yield 1 product here
Sources: PRTM & Industry Data
$100M -130M $60-70M $70M-100M $130M-160M $190M-220M $18M-20M COST
PER
PHASE
Vaccine Challenges The Development Process
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Trends
• Budget austerity across all levels of government
• Industry economic pressures towards reliable opportunities and faster return on investment
• Smaller amounts of available venture capital funding
Approximate scale of total investments: ~$100M ~$10B ~$1B
Pre-2004
2005-2009 Post-2009
Vaccine Challenges Financial Outlook
INDUSTRY
NGO
GOV’T
VC
INDUSTRY INDUSTRY
GOV’T GOV’T
NGO NGO VC
VC
6
4
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 7
Egg-based
inactivated
Cell-culture
inactivated
LAIV
Recombinant
(VLPs)
Universal
Vectors/
Adjuvant
SERUM INSTITUTE OF
INDIA LTD
WIV
WIV Egg inactivated
H5N1 WIV +Alum
Split
H5N1 Surface
antigen w/ AlPO4 Split Split
H5N1 AS03
Fill/Finish sp Split
WIV H9N2 virosomal & whole
H5N1 WIV w/ Adjuvant Proteosome intranasal
Split
Adimmune- Taiwan
H5N1, WIV
WIV
Flu – intradermal;
improved seasonal
H5N1 Monkey Kidney Cell MDCK subunit (EU) US
2009/2010
Vero, Influject/
Cevapan(EU)
SIIL
Egg MDCK H5N1 dNS1 - Vero Egg H5N1/H9N2 Egg, H5N2
H5 Egg, Thailand
Serum Institute
of India Ltd
Egg Egg QIV Egg (Russia)
dNS1- Vero
VLP / HA VLP, Insect cells VLP, 293 cells rHA, Plants rHA Insect cells VLP, Plants rHA, Insect cells VLP, Insect Cells
Salmonella, Oral VLP, Fungus Yeast, IN - Oral
Salmonella, Oral Chimeric VLP +
microneedles VLP, insect cells
Molecular HAs
NYU / MSSM HA stalk
Novel peptides
NP & ISS Tech Peptide based
HA, Flagellin, e coli
MVA Based Adenovirus M & NP Adenovirus Adenovirus, Oral Split MVA
MVA Based
DNA DNA / Vaxfectin
Seasonal
Pandemic
Seasonal &
Pandemic
US License
Influenza Vaccine Landscape
Updated: 6MAR2013
M2e Liposome
rHA, Plants rHA, Plants
DNA / SnyCon w/
Electroporation
rHA Insect Cells
Mass Gen
Hospital
Listeria
Pre Clinical Phase 1 Phase 2 Phase 3 Market Approval
HuaLan
Pandemic
Seasonal
H1N1 Cell; HN-VAC (India)
Seasonal
Seasonal Seasonal
Fil / Finish
Institutul Cantacuzino
Split sp H5N1 + GSK AS03
Egg, Thailand
Egg, Thailand
H9N2 virosomal & whole
H1 Egg, Thailand
Egg inactivated SynBio LAIV
QIV
EB 66 Cells
M2e flagellin
Seasonal Dormant
COBRA HA VLP
M2e
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 8
•Safe and efficacious, decades of experience
•Vulnerable to antigenic drifts and shifts
─ Antibodies target highly variable regions of HA and NA
─ Protection following vaccination or infection is limited to specific strains
─ Single site mutations can reduce efficacy
─ Host variations in immune response can reduce efficacy
•Non-adjuvanted vaccines provide minimal cross-protection within subtypes or against other subtypes
•Short duration of immunity, particularly in at-risk populations (e.g., pediatric, geriatric)
Current Influenza Vaccines
5
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Effective in general and at-risk populations
Safe for use in all populations
Rapid, scalable production
Low cost per dose
Broadly reactive against multiple strains
Long-lasting immunity
Ideal Attributes of Next-Generation Vaccines
9
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 10
•More
─Maximizing vaccine supply
•Faster
─Minimizing the timeframe from pandemic virus identification to first vaccine dose
•Better
─Driving generational improvements in manufacturability, speed, and effectiveness
BARDA’s Approach to Vaccine Innovation
6
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 11
•Egg-based vaccines
─Contracts to ensure year-round egg supply
─Licensure of first H5N1 vaccine
─Adjuvanted vaccines
•Cell-based vaccines
─Advanced development of multiple technologies
─Establish infrastructure for U.S.-based manufacturing
• International vaccine programs
Maximizing Near-Term Technologies
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
12
First U.S. Cell-Based Facility Landmark Public-Private Partnership
7
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Licensed Influenza Vaccine Producers
13
Global Influenza Vaccine Production circa 2006
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Licensed/Active Influenza Vaccine Producers
BARDA/WHO Cooperative Agreement Grantees
14
Global Influenza Vaccine Production circa 2012
Romania
Cantacuzino
Institute
Mexico
Birmex
Brazil
Instituto
Butantan South
Africa
Biovac
India
Serum
Institute
Vietnam
IVAC
VABIOTECH
PATH
Thailand
GPO
Indonesia
Bio Farma
Egypt
VACSERA
South Korea
Green Cross Serbia
Torlak
Institute
Kazakhstan
RIBSP
8
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 15
•More
─Maximizing vaccine supply
•Faster
─Minimizing the timeframe from pandemic virus identification to first vaccine dose
•Better
─Driving generational improvements in manufacturability, speed, and effectiveness
BARDA’s Approach to Vaccine Innovation
ASPR: Resilient People. Healthy Communities. A Nation Prepared. www.who.int/influenza/resources/documents/influenza_vaccine-virus_selection 16
Influenza Vaccine Virus Selection and Development Process
9
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 17
Traditional Egg-based Vaccine Manufacturing Processes
Virus
Isolate &
Re-assort
Amplify
Egg Production Filling
Packaging Distribution
Testing
Egg Based
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Influenza Vaccine Manufacturing Improvement Initiative
WT Reassortment
17 days Seed
•Faster sterility assays
•Reagent calibration and potency assays
•Novel set of optimized donor viruses
10
ASPR: Resilient People. Healthy Communities. A Nation Prepared. IVMI Program Workshop | Dormitzer | August 28, 2012 | Synthetic Influenza Vaccine Seeds
Total = 10-13 hours
Final product is uncloned, synthetic linear HA
or NA gene segment with regulatory control
elements (promoters & terminators).
Pool overlapping oligos for HA or NA
Assemble and amplify oligos
Error-correct & reamplify
Assemble oligos into linearized pKS10 vector
to add essential reverse genetics promoter and
terminator elements
Amplify to get linear synthetic HA or NA
segments
0.5 hr
2.5 hr
3.0 hr
1.0 hr
2.0 hr
1.0 hr Precipitate DNA and clean up reactions
x x
x x
x x
Rapid synthesis process to assemble oligos into flu HA and NA segments in <1 day
Synthetic Biology Vaccine Seed Production
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Robust process to rescue influenza virus using synthetic gene segments
in vaccine-approved MDCK cells
IVMI Program Workshop | Dormitzer | August 28, 2012 | Synthetic Influenza Vaccine Seeds
Seed MDCK cells
Transfect cells with DNA
Remove serum, add
feeder cells and trypsin *
Monitor virus rescue
daily by FFA**
* Replenish trypsin concentration every 48h if
rescues take longer than 3 days.
** focus-formation assay; based on immunological
staining of viral nucleoprotein in infected cells
Day 0
Day 1
Day 2
Days 3-6
Confirmed viruses = 4 - 7 days
FFA
Synthetic Biology Vaccine Seed Production
11
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 21
•More
─Maximizing vaccine supply
•Faster
─Minimizing the timeframe from pandemic virus identification to first vaccine dose
•Better
─Driving generational improvements in manufacturability, speed, and effectiveness
BARDA’s Approach to Vaccine Innovation
ASPR: Resilient People. Healthy Communities. A Nation Prepared.
Recombinant Vaccine Production
22
Recombinant technologies provide
vaccine sooner with less dependence
on influenza virus strain properties
12
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 23
New Vaccine Production Paradigm
Virus
Sequence
Isolate &
Re-assort
or
Expression Vector Synthetic Seed
Amplify
Egg Production Filling
Packaging Distribution
Testing
Cell Based Egg Based
Cell Production
Recombinant Production
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 24
Other Novel Approaches
• DNA vaccines
• Live-viral vectors (adenovirus, modified vaccinia)
• Other expression systems (E. coli, Neurospora)
• Synthetic vaccinology – from sequence to vaccine
13
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 25
The Influenza Crystal Ball
Adapted from: Paul Lewis, MD Oregon State Public Health
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 26
• Many definitions for a universal influenza vaccine
─ A single influenza vaccine that would provide “protection” against any given subtype of influenza A and/or B
─ Could be used for several influenza seasons before reformulation
•Reduce annual “guesswork” for strain selection
•Reduce production costs (thus vaccine costs/year round production)
•Reduce vaccine “mismatches”
•Reduce the potential for vaccine shortages
• Increase the global supply of vaccine
• Could be stockpiled for epidemics/pandemics
• Surge capacity
─ Rapid scale-up, reduce production bottlenecks
Universal Influenza Vaccine
14
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 27
Universal Vaccine Strategies Leveraging Old and New Discoveries
Adjuvants
Administration
Vaccine Design
• Identify broadly reactive
epitopes (HA Stalk, M2
extracellular, NP)
•Multi-epitope vaccines
•Vector delivered vaccine
•Target occluded sites
•Broaden B cell epitope
recognition
•Th1 vs Th2 responses
•Humoral vs Cell-mediated
• Location:
Intranasal, intradermal or
intramuscular
• Timing: Prime/boost
• Regimen
R. Rappuoli, F1000 Medicine Reports 3 (2011): 16.
HA1
(variable region)
HA2
(conserved region)
Source: NIAID http://tinyurl.com/69n9lap
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 28
• No universal definition or target product profile
• Regulatory science will need to evolve with the technical science development
─ Protective immune responses may be to something other than the HA protein (non-HAI)
─ New surrogates of immunity may need to be identified
─ Alternate potency/release assays will be needed
• Large scale efficacy trials or other “creative” clinical development approaches may be required
• Funding is limited
─ Most candidates are in preclinical development stage
Developmental Challenges for Universal Vaccines
15
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 29
National Pandemic Influenza Vaccine Development Strategy:
Multi-Step & Integrated Approach
“More and better vaccines sooner”
Cell-based
Vaccines
Egg-based
Vaccines
Recombinant-based
Vaccines
Universal
Vaccines
Flublok
Licensed 01/16/13
Flucelvax
Licensed 11/20/12
ASPR: Resilient People. Healthy Communities. A Nation Prepared. 30
Final Thoughts
• The landscape of new influenza vaccine development is active and rapidly evolving
• Significant technical challenges for innovative technologies
• Continued scientific discoveries provide greater opportunities for innovation
• Post-pandemic fatigue and economic challenges affect all partners
• Leveraging government, nonprofit and industry collaborations will be essential to continued public health success
Recommended