New Vaccines Approved and on the Way · Deputy Director, Influenza Division Biomedical Advanced Research and Development Authority (BARDA) Influenza Vaccine Innovation New Vaccines

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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

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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)


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

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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


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


•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

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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

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•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

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•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


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First U.S. Cell-Based Facility Landmark Public-Private Partnership

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Licensed Influenza Vaccine Producers

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Global Influenza Vaccine Production circa 2006


Licensed/Active Influenza Vaccine Producers

BARDA/WHO Cooperative Agreement Grantees

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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

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•More


•Faster


•Better



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

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Traditional Egg-based Vaccine Manufacturing Processes

Virus

Isolate &

Re-assort

Amplify

Egg Production Filling

Packaging Distribution

Testing

Egg Based


Influenza Vaccine Manufacturing Improvement Initiative

WT Reassortment

17 days Seed

•Faster sterility assays

•Reagent calibration and potency assays

•Novel set of optimized donor viruses

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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


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

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•More


•Faster


•Better




Recombinant Vaccine Production

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Recombinant technologies provide

vaccine sooner with less dependence

on influenza virus strain properties

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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


Other Novel Approaches

• DNA vaccines

• Live-viral vectors (adenovirus, modified vaccinia)

• Other expression systems (E. coli, Neurospora)

• Synthetic vaccinology – from sequence to vaccine

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The Influenza Crystal Ball

Adapted from: Paul Lewis, MD Oregon State Public Health


• 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

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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


• 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

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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


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

Documents

New Vaccines Approved and on the Way · Deputy Director, Influenza Division Biomedical Advanced Research and Development Authority (BARDA) Influenza Vaccine Innovation New Vaccines