Update on U.S. Pandemic Influenza Vaccine Development · innovation for new technologies in the areas of vaccines, therapeutics and diagnostics for influenza •There has never been

5/15/2014 1

United States Department of

Health & Human ServicesOffice of the Assistant Secretary for Preparedness and Response

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

Update on U.S. Pandemic

Influenza Vaccine Development

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

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

5/15/2014 2

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.

5/15/2014 3


Centers for Innovation in

Advanced Development & Manufacturing

Fill Finish Manufacturing

Network

Animal Studies Network

Clinical Studies Network

Analytic Decision Support

Regulatory & Technical Expertise

BARDA Approach to Making Medical

Countermeasures Available

2012

2013

2010

2014

2011

2006


Cell-based

Vaccines

Egg-based

Vaccines

Recombinant

Vaccines

Universal

Vaccines

Flublok®

Licensed 01/16/13

FLUCELVAX®

Licensed 11/20/12

H5N1 Vaccine

Licensed 04/17/07

Advanced

Development

Begins FY15

BARDA is Achieving National

Pandemic Influenza Vaccine Goals

More, Faster, & Better Vaccines!

5/15/2014 4


BARDA: Influenza Vaccine Manufacturing

Improvement Initiative

WTReassortment

17 daysSeed

6 promising donors

to improve vaccine yield

Faster potency reagents,

Alternative assays

7 days faster sterility assay

ASPR: Resilient People. Healthy Communities. A Nation Prepared.7

BARDA: Enhancing Domestic Vaccine

Manufacturing Capacity

• Expanding Existing Capacity by Retrofitting Vaccine Manufacturing Infrastructure

sanofi pasteur – Swiftwater, PA

• Changing Flu Vaccine Industry

Novartis – Holly Springs, NC

2013 ISPE Facility of the Year

5/15/2014 5


Centers for Innovation in Advanced

Development and Manufacturing


Fill Finish Manufacturing Network

Cook

Pharmica

DSM

Pharmaceuticals

JHP

Pharmaceuticals

Nanotherapeutics/Baxter

5/15/2014 6


Licensed/Active Influenza Vaccine Producers

BARDA/WHO Cooperative Agreement Grantees

Current Geographical Distribution

of Influenza Vaccine Production

Mexico

Birmex

Brazil

Instituto

Butantan South

Africa

Biovac

India

Serum

Institute

Vietnam

IVAC

VABIOTECH

PATH

Thailand

GPO Indonesia

Bio Farma

Egypt

VASERA

South Korea

Green CrossSerbia

Torlak

Institute

BARDA/WHO Licensed Vaccine for Human Use (as of 2/2014)

Kazakhstan

RIBSP

Romania

Cantacuzino

Institute

10

ASPR: Resilient People. Healthy Communities. A Nation Prepared. 11

Egg-based

inactivated

Cell-culture

inactivated

LAIV

Recombinant

(SUV & VLPs)

Universal

Vectors/

Adjuvant

WIV Egg inactivated

Split

Split w/ iscomatrix

QIV Split

H5N1 AS03

WIV

H5N1 WIV w/ Adjuvant

Split

Adimmune- Taiwan

Split w/ SPA03 H5N1, WIV

WIV

QIV, High dose,

intradermal

EB66; H5N1 Monkey Kidney CellMDCK subunit (EU) US

2009/2010

Vero, Influject/

Cevapan(EU)

dNS1 - Vero Egg H5N1/H9N2/H7N9 Egg, H5N2

H5 Egg, Thailand

Serum Institute

of India Ltd

EggQIV, Egg Egg (Russia)

dNS1- Vero

VLP / HA VLP, Insect cells VLP, 293 cells rHA, Plants rHA Insect cells VLP, Plants rHA, Insect cellsVLP, Insect Cells

Salmonella, Oral Yeast, IN - Oral

Salmonella, OralChimeric VLP +

microneedles

Molecular HAs

NYU / MSSMHA stalk; Chimeric

Novel peptides

NP & ISS Tech Peptide based

HA, Flagellin, e coli

MVA Based Adenovirus M & NP Adenovirus Adenovirus, Oral

Split

MVA

MVA Based

DNADNA / Vaxfectin

Influenza Vaccine Landscape

20MAR2014

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

InstitutulCantacuzino

Split

Egg, Thailand

Egg, Thailand

PER.C 6

H1 Egg, Thailand

Egg inactivatedSynBio LAIV

Proprietary Adjuvant

Seasonal

COBRA HA VLP

Vero, Influject/

Cevapan(EU)

Japan EB66

NIAID

Nanoparticle

Pandemic

Seasonal

Pandemic

Seasonal &

Pandemic

US License

EB66

rHA + GLA-SE

Mar 2014 Study Start

5/15/2014 7


Which Flu Vaccine is Right for You?


• 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

Influenza Vaccine Challenges: Limitations of Current Vaccines

5/15/2014 8


Goal: Develop more effective

influenza vaccines that

provide a long duration of

protection against a broad

range of influenza virusesEffective

Safe for all ages

Rapid Response

Simple Manufacture

Universal?

Broadly Reactive

Where Do We Go From Here?

Long lasting immunity


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

5/15/2014 9


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


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

5/15/2014 10

Rick Bright, PhDActing Director

Influenza Division

BARDA

U.S. Department of Health and Human Services

[email protected]

Documents

Update on U.S. Pandemic Influenza Vaccine Development · innovation for new technologies in the areas of vaccines, therapeutics and diagnostics for influenza •There has never been