Update on U.S. Pandemic Influenza Vaccine Development

United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Update on U.S. Pandemic Influenz...
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United States Department of

Health & Human Services Office of the Assistant Secretary for Preparedness and Response

Update on U.S. Pandemic Influenza Vaccine Development Rick Bright, PhD Acting Director, Influenza Division Biomedical Advanced Research and Development Authority (BARDA) Office of the Assistant Secretary for Preparedness & Response 2014 National Adult and Influenza Immunization Summit May 15, 2014 Atlanta, GA

A Nation Unprepared: US Influenza Vaccines in 2004

• All licensed seasonal vaccines were egg-based (1940s-1950s technology) • Vaccine was produced in a six month production window (January-June each year); no capability outside of that window, no egg supply • Annual immunization was required due to virus drift and limitations of vaccines ─ Vaccine effectiveness estimated at 30-70% • Shortage of seasonal influenza vaccine in fall 2004 due to production failure at one facility highlighted US vulnerability • Limited domestic manufacturing capacity to respond to a pandemic, very limited global capacity as well 1

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Establishing Pandemic Influenza Vaccine Capabilities: USG Requirements





The requirements addressed by the BARDA Influenza Portfolio are derived from a number of documents that guide the US Government efforts to prepare for pandemic, include: • Establish and maintaining a dynamic pre-pandemic vaccine stockpile • Establish manufacturing capacity to produce sufficient pandemic vaccine for the entire U.S. population within 6 months of pandemic declaration • Improve, optimize and/or innovate vaccine production technologies Goal: More and better influenza vaccine, faster

BARDA’s Mission Enhance national preparedness for CBRN threats, pandemic influenza, and emerging infectious diseases by supporting innovation, developing and acquiring medical countermeasures, and building manufacturing infrastructure.

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BARDA Approach to Making Medical Countermeasures Available Centers for Innovation in Advanced Development & Manufacturing

2012 Regulatory & Technical Expertise

Fill Finish Manufacturing Network

2006 2013

Analytic Decision Support

Animal Studies Network

2011

2010 Clinical Studies Network

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BARDA is Achieving National Pandemic Influenza Vaccine Goals

Universal Vaccines Recombinant Vaccines Cell-based Vaccines Egg-based Vaccines

Advanced Development Begins FY15

Flublok® Licensed 01/16/13

FLUCELVAX® Licensed 11/20/12

H5N1 Vaccine Licensed 04/17/07

More, Faster, & Better Vaccines! ASPR: Resilient People. Healthy Communities. A Nation Prepared.

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BARDA: Influenza Vaccine Manufacturing Improvement Initiative

WT

Reassortment 17 days

Seed

6 promising donors to improve vaccine yield

Faster potency reagents, Alternative assays

7 days faster sterility assay

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BARDA: Enhancing Domestic Vaccine Manufacturing Capacity •

Expanding Existing Capacity by Retrofitting Vaccine Manufacturing Infrastructure

• Changing Flu Vaccine Industry

2013 ISPE Facility of the Year sanofi pasteur – Swiftwater, PA

Novartis – Holly Springs, NC 7

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Centers for Innovation in Advanced Development and Manufacturing

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Fill Finish Manufacturing Network

Cook Pharmica

JHP Pharmaceuticals

DSM Pharmaceuticals

Nanotherapeutics/Baxter

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Current Geographical Distribution of Influenza Vaccine Production Romania Cantacuzino Institute Kazakhstan RIBSP Serbia Torlak Institute

Egypt VASERA

Mexico Birmex

South Korea Green Cross Vietnam IVAC VABIOTECH PATH

India Serum Institute Thailand GPO

Brazil Instituto Butantan

Indonesia Bio Farma

South Africa Biovac

Licensed/Active Influenza Vaccine Producers BARDA/WHO Cooperative Agreement Grantees BARDA/WHO Licensed Vaccine for Human Use (as of 2/2014) ASPR: Resilient People. Healthy Communities. A Nation Prepared.

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Influenza Vaccine Landscape Pre Clinical Egg-based inactivated

Split w/ SPA03

Proprietary Adjuvant

Phase 1 WIV

Split w/ iscomatrix

Egg inactivated

Phase 2 H5N1, WIV

H5N1 WIV w/ Adjuvant

Phase 3

Market Approval QIV, High dose, intradermal

H5N1 AS03

WIV

QIV

Split

Split

Egg, Thailand

Pandemic

Institutul Cantacuzino

Split

Adimmune- Taiwan

Seasonal

HuaLan

Seasonal

Seasonal

MDCK subunit (EU) US 2009/2010

Vero, Influject/ Cevapan(EU)

Seasonal WIV

Split

Cell-culture inactivated

EB66

EB66; H5N1

PER.C 6

Monkey Kidney Cell

Japan EB66

Vero, Influject/ Cevapan(EU)

Mar 2014 Study Start

Serum Institute of India Ltd

LAIV dNS1 - Vero

Egg, Thailand

Recombinant (SUV & VLPs)

H1N1 Cell; HN-VAC (India)

VLP / HA

VLP, Insect cells

VLP, 293 cells

Salmonella, Oral

rHA, Plants

Yeast, IN - Oral

Salmonella, Oral

Chimeric VLP + microneedles

Egg, H5N2

Egg H5N1/H9N2/H7N9

rHA, Plants

QIV, Egg

dNS1- Vero

H5 Egg, Thailand

H1 Egg, Thailand

rHA Insect cells

VLP, Plants

VLP, Insect Cells

rHA, Insect cells

Split

HA, Flagellin, e coli

rHA + GLA-SE

Egg

Egg (Russia)

Seasonal

rHA Insect Cells

Pandemic Molecular HAs

Universal

NYU / MSSM

Vectors/ Adjuvant

COBRA HA VLP

M2e Liposome

Novel peptides

NIAID Nanoparticle

MVA Based

Adenovirus M & NP

MVA Based

DNA

rHA, Plants

SynBio LAIV

HA stalk; Chimeric

Mass Gen Hospital Listeria

Adenovirus

NP & ISS Tech

Egg inactivated

Seasonal & Pandemic US License

Adenovirus, Oral

Pandemic

MVA

Seasonal

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Peptide based

DNA / SnyCon w/ Electroporation

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Which Flu Vaccine is Right for You?

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Influenza Vaccine Challenges: Limitations of Current Vaccines • Vulnerable to antigenic drifts and shifts • Antibodies target highly variable regions of HA and NA • Single site mutations can reduce efficacy • Provide minimal cross-protection within subtypes or against other subtypes of influenza • Short duration of immunity, particularly in at-risk populations (e.g., pediatric, geriatric) • Vaccine efficacy is modest • Requires viral isolate for production • Avian influenza strains will likely require adjuvant

There is a need for new, improved influenza vaccines ASPR: Resilient People. Healthy Communities. A Nation Prepared.

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Where Do We Go From Here?

Safe for all ages Effective

Goal: Develop more effective influenza vaccines that provide a long duration of protection against a broad range of influenza viruses

Long lasting immunity Broadly Reactive Rapid Response Simple Manufacture

Universal? ASPR: Resilient People. Healthy Communities. A Nation Prepared.

Universal Influenza Vaccines

• What is a “universal vaccine”? ─ Idealized vaccine: single vaccine for any influenza A subtype ─ A vaccine that provides safe, effective and long-lasting immunity against a broad spectrum of influenza viruses

• Could be used for several seasons ─ ─ ─ ─ ─

Simplify the vaccine strain selection process Simplify the influenza vaccination process Reduce vaccine mismatches Reduce potential for vaccine shortages Increase global supply of vaccine

• Potentially reduce vulnerability to novel influenza viruses ─ Population would be “primed” for newly emerging viruses ASPR: Resilient People. Healthy Communities. A Nation Prepared.

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Universal Vaccine Strategies Leveraging Old and New Discoveries • Broaden B cell epitope recognition

• Identify broadly reactive epitopes (HA Stalk, M2 extracellular, NP)

• Th1 vs Th2 responses

• Multi-epitope vaccines • Vector delivered vaccine

Vaccine Design

Adjuvants

• Humoral vs Cell-mediated

• Target occluded sites

Administration HA1 (variable region)

HA2 (conserved region)

• Location: Intranasal, intradermal or intramuscular • Timing: Prime/boost • Regimen

R. Rappuoli, F1000 Medicine Reports 3 (2011): 16.

Source: NIAID http://tinyurl.com/69n9lap

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Closing Thoughts •

In 2005, the US was in a very vulnerable position to be able to respond to seasonal or pandemic outbreaks of influenza



The USG, through BARDA, NIH, FDA and CDC, has taken bold and significant steps to address these vulnerabilities, particularly in areas of innovation for new technologies in the areas of vaccines, therapeutics and diagnostics for influenza



There has never been a greater global capacity to respond to a pandemic outbreak of influenza, nor a greater global capacity to produce influenza vaccines



There has never been a greater variety of influenza vaccines available to address population variation than there are today



The landscape of new influenza vaccine development is active and rapidly evolving – 94+ products/candidates; continued scientific discoveries will provide greater opportunities for innovation



While the field of influenza vaccine types appear to be moving towards a variety of niche vaccines in the near term, it is apparent from the landscape that the ultimate aim is to develop a single, more effective influenza vaccine that could be used by all populations ASPR: Resilient People. Healthy Communities. A Nation Prepared.

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Rick Bright, PhD Acting Director Influenza Division BARDA U.S. Department of Health and Human Services [email protected]

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