Preparing for

Pandemic Influenza

Anna LönnrothEuropean Commission

DG Research: Health Research

Priority Medicines for Europe and the World

Chapter 6.2 Pandemic Influenza Background paper

prepared by

David Fedson, M.D., in collaboration with the

WHO Global Influenza Programme

Influenza virusInfluenza virus

(Paul Digard, Dept Pathology, University of Cambridge)

Viral ReplicationViral Replication

Annual influenza epidemics

Annual influenza epidemics

3-5 million cases of severe illness

Significant mortality among the

elderly and in developing countries

Enormous health care costs, economic

loss and work absenteeism

Current vaccines about 70 % protective

drift

shift

Antigenic drift & shiftAntigenic drift & shift

(Albert Osterhaus, Erasmus University, Rotterdam, Netherlands)

7

A U.S. Army influenza ward in Luxembourg, during the 1918 epidemic. Photo courtesy National Museum of Health and Medicine, Armed Forces Institute of Pathology, Washington, D.C.

19181918

8Deaths from infectious diseases fell in the United States during the 20th century. The spike shows the 1918 influenza pandemic, which killed more than 40 million people, include about 500,000 Americans. Graph: CDC.

Deaths from infectious diseases in USA

Deaths from infectious diseases in USA

1918“Spanish flu”

Killed 40-50 million

H1N1

Past Influenza Pandemics

Past Influenza Pandemics

1957“Asian flu”

killed 98.000

H2N2

1968“Hong Kong flu”

killed 46.000

H3N2

1997“Hong Kong”

First Human H5N1

(killing 6/18)

Human virusRe-assortant virus

Avian virus Avian virus

Man as a mixing vessel

Man as a mixing vessel

(Albert Osterhaus, Erasmus University, Rotterdam, Netherlands)

Future Influenza Pandemics

Future Influenza Pandemics

Next?

Between 1997 and 2004, the H5N1 strain has gained in pathogenicity

H5N1 re-emerged in Vietnam in late 2003, killing about 70% of the infected

Possible human-human transmission of H5N1 in Thailand September 2004?

H9N2 – Hong KongH7N7 – Netherlands

Worst case scenario

Worst case scenario Pandemic of human-adapted avian influenza

such as the 1997 H5N1 strain

Could easily reach mortality rate

of 30-40%

Within a few months, 25% could

have been infected

Over 1/2 billion deaths

…or worse

Lessons learned form SARS outbreak

Identify strategies to “buy time”

Crisis management

Planning in the interpandemic period

Pandemic planning

Pandemic planning

14

Influenza vaccine needs to be reformulated with each epidemic

Limitations of current influenza vaccine

Limitations of current influenza vaccine

Low vaccine uptake although cost-effective (< 20% of expected)

Prediction & public health intervention in advance difficult

Vaccine production up-scaling capacity insufficient & access inequity

Available production technology inadequate for pandemic vaccine?

Delayed vaccine production

What about treatment?

What about treatment?

1. Vaccination is by far the most efficient way to

control influenza

2. Currently available drugs are not very efficient,

but may become important in reducing mortality

and prevent transmission (M2 inhibitors +

Neuraminidase inhibitors)

3. Production capacity insufficient to meet

sudden demands + access inequity

Evaluate immunogenicity and safety of different monovalent, low-dose, adjuvanted ‘pandemic like’ vaccines and vaccination scheduled (avian HA)

Develop ‘antigen sparing’ strategies

Evaluate safety and effectiveness of Reverse Genetics + resolve IPR & regulatory issues

Prepare reagent libraries to speed up vaccine testing

Develop vaccine production technologies

SHORT term R&D SHORT term R&D

Explore expansion of interpandemic use and manufacturing capacity

Develop more efficient anti-viral drugs

Investigate mechanisms of drug resistance

Develop & evaluate non-medical control measures

Assess impact of common medications on clinical course of influenza-related illness

Study the public health impact of vaccination

SHORT term R&D SHORT term R&D

Develop broad spectrum vaccines that provide long lasting protection (conserved antigens)

Explore further DNA-based vaccines

Continue to develop anti-viral drugs

…underpinned by basic immunology on vaccine response, pathophysiology & host defence

Ensure availability of effective antibiotics

Evaluate long-term adverse events

LONG term R&D LONG term R&D

Industrial hurdlesIndustrial hurdles

Only 300 million vaccine doses are currently

produced each year (trivalent)

Upscaling challenges:

- Market insufficiency

- Market uncertainty

- Stockpiling impossible

- Regulatory & liability

issues

Research & Development

IPR on Reverse Genetics Technology

Address liability issues

“GMO” concerns

Incentives neededIncentives needed

Current capacity and resources do not

match needs for pandemic planning

2/3 of the world’s influenza

vaccine producers are

located in Europe

Why Europe?Why Europe?

EC Research Funding

EC Research Funding

FLUPAN FLUPAN

Reverse genetics technology to develop reference strains of (avian) vaccine viruses

Production of pilot lots in cell culture systems

Immunogenicity/Safety evaluation in Phase I/II clinical trials

Libraries of reagents for avian/swine flu vaccines

New methods to rapidly detect the emergence of pandemic influenza strains in animals

EU contribution 1,765,000 €EU contribution 1,765,000 €

NOVAFLU NOVAFLU

More effective epidemic and pandemic vaccine strategies

Optimization of vaccine strain selection

Reverse genetics for high growth in cell lines

Evaluation of animal models

Identification of better immune correlates of protection

EU contribution 1,765,000 €EU contribution 1,765,000 €

viRgil viRgil

The first-ever European Vigilance Network

InfluenzaHepatitis BHepatitis C

Addressing current and emerging antiviral drug resistance

EU contribution 9,000,000 €EU contribution 9,000,000 €

NoE NoE

FP6 Open Call FP6 Open Call

Post-genomic approaches Post-genomic approaches

to a human pandemic to a human pandemic

influenza vaccineinfluenza vaccine

Dead-line for proposals 16 November 2004Dead-line for proposals 16 November 2004

IP IP