Preparing for Pandemic Influenza Anna Lönnroth European 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 virus (Paul Digard, Dept Pathology, University of Cambridge)

Viral Replication

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 & 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. 1918

8 Deaths 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

1918 “Spanish flu” Killed million H1N1 Past Influenza Pandemics 1957 “Asian flu” killed H2N “Hong Kong flu” killed H3N “Hong Kong” First Human H5N1 (killing 6/18)

Human virusRe-assortant virus Avian virus Man as a mixing vessel (Albert Osterhaus, Erasmus University, Rotterdam, Netherlands)

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 Kong H7N7 – Netherlands

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

14 Influenza vaccine needs to be reformulated with each epidemic 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? 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

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

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

Industrial 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 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?

EC Research Funding

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 €

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 €

viRgil The first-ever European Vigilance Network  Influenza  Hepatitis B  Hepatitis C Addressing current and emerging antiviral drug resistance EU contribution 9,000,000 € NoE

FP6 Open Call Post-genomic approaches to a human pandemic influenza vaccine Dead-line for proposals 16 November 2004 IP