1. Global Pandemic Preparedness Research Efforts text Klaus Stöhr WHO Global Influenza Programme 3 Today  Medium-term applied research linked to medical and public health interventions addressing the current pandemic situation in Asia text Interpandemic period  Natural history  Medical impact  Effectiveness of interventions - Vaccines; antivirals; non- pharmaceutical  Economic impact  Virological research Pandemic Interpandemic period Research to address long-term inter-pandemic and pandemic challenges WHO Global Influenza Programme 1

2. 4 Priority Public Health Interventions International  Generic  Many possible interventions during an influenza pandemic exist esearch during pandemics and pre-pandemic phase - Risk assessment and communication - Several  Medical interventions - sub-o ptimally effective - are not accessible in time - Effectiveness is incompletely understood eumonia (antimicrobials)  Non-pharmaceutical interventions  Opportunities for research - Slowing down local spread of pandemic virus  package of activities to reduce text local transmission/infection rate - Aversion of pandemic  package of activities aiming at eliminating a new subtype with increasing fitness  Combination might vary - Reducing morbidity or mortality or economical implications or societal interruption WHO Global Influenza Programme 5 Priority Public Health Interventions International  Generic - Surveillance - Research during pandemics and pre-pandemic phase - Risk assessment and communication  Medical interventions - Vaccines - Antivirals - Treatment of viral and secondary bacterial pneumonia (antimicrobials)  Non-pharmaceutical interventions - Slowing down local spread of pandemic virus  package of activities to reduce text local transmission/infection rate - Aversion of pandemic  package of activities aiming at eliminating a new subtype with increasing fitness  Combination might vary - Reducing morbidity or mortality or economical implications or societal interruption WHO Global Influenza Programme 2

3. 6 Opportunities for research 1. Risk assessment  New developments - 1997: direct transmission of avian influenza virus to humans – 2004: No reassortment despite long + widespread presence of new influenza type of known human pathogenicity multiple transmission to humans with co-circulation of human influenza virus  What is the likelihood and outcome of reassortment between H5N1 and currently circulating human or pig influenza A viruses? - Lab trials (appropriate biosafety): viable reassortants; pathogenicity and text transmissibility  Studies on the infection rate in the general population in affected countries WHO Global Influenza Programme 7 Opportunities for research 2. Control of source and pathways of transmission  New developments - Domestic ducks are (a potent?) reservoir for HPAI - H5N1 with increased pathogenicity in poultry and mice and found in Pigs Wild birds Mammals (felines)  What is the role of various animal/bird species in the epidemiology of influenza viruses of pandemic potential? - Vector and reservoir studies (domestic and wild animals/birds); text Serological/virological studies in various animal/bird species in H5N1 affected/non-affected countries  What are the best disease control options in animals in the currently affected countries? WHO Global Influenza Programme 3

4. 8 Opportunities for research 3. Case management and hospital infection control - 74 cases; 49 death (VTN: 55/35) Two publications on the clinical course of the disease…. - Very little understanding of key clinical, epidemiological and virological parameters of H5N1 infection in humans Risk groups, IKP, Ab kinetics, excretion patterns; duration of infectivity Efficacy of antiviral drugs; adapted diagnostic tests/protocolls  Coordinated clinical research and case management - Network of linked laboratories in affected countries; standardized treatment and study protocols; mechanism of sample and information exchange; complementary analyses text - International clinical research network on emerging infectious diseases in Asia (WHO and NIH initiative) Strengthen national capacity and resources and facilitate international collaboration and exchange Concept paper developed; international partners/funding institution identified; next step: engagement of national partners and enrollment of hospitals WHO Global Influenza Programme 9 Opportunities for research 4.1 Aversion of a pandemic  New developments - Possibility of early detection of new subtype with increasing transmissibility - Antiviral and H5N1 vaccine stockpile feasible  Could massive prophylactic use of antivirals (vaccines) in/around an epi centre extinguish an emerging new subtype or at least buy time? - Modelling very foundation for any decision making - Particular large number of assumptions.  Research on H5N1 vaccine stockpile  Could an international stockpile of respective size(?) be established and maintained? WHO Global Influenza Programme 4

5. 10 Opportunities for research 4.2 Slowing down local spread  New developments - Recommendations available on non-pharmaceutical measures at the international and national level during different phases of an influenza pandemic - Built on best available science  What effectiveness will non-pharmaceutical interventions have? - Research package necessary during pandemics  What are the pathways of transmission of influenza viruses? text - incompletely understood and their relative importance unknown. - Hospital infectious control; case management; non-pharmaceutical interventions WHO Global Influenza Programme 11 Opportunities for research 5. Clinical research on the immunogenicity of pandemic vaccines  New developments - Pandemic vaccine prototype strain available since April 2004 - Vaccine stockpile feasible  Establish immunogenicity of H5N1 vaccines from currently circulating strain and implement antigen sparing strategies text WHO Global Influenza Programme 5

6. 12 Vaccine availability scenarios million doses 4000 3500 3000 2500 2000 1500 1000 500 text 0 1 Trivalent Monovalent Whole virus Adjuv. (4x) 2 doses 2 3 4 5 month  Projected daily vaccine production - 0.72 million - 2.17 million - 3.25 million - 13 million 6 7 8 R. Hehme GSK; Presentation Vaccine Meeting Lisbon, May 2004 WHO Global Influenza Programme 13 Opportunities for research 5. Clinical research on the immunogenicity of pandemic vaccines  New developments - Pandemic vaccine prototype strain available since April 2004 - Vaccine stockpile feasible  Establish immunogenicity of H5N1 vaccines from currently circulating strain and implement antigen sparing strategies - Requires research coordination between countries and companies to avoid duplication Public funds to compensate for lack of commercial interest - Current status text Promising progress since Nov 2004 2 clinical trials started (USA) 10 more companies in Australia, Canada, France, Germany, Japan, USA before the end of the year (all antigen sp aring)  H5N1 registration=pandemic vaccine regi stration WHO Global Influenza Programme 6

7. Pandemic influenza virus emergence and possible begin of pandemic vaccine production  Expected scenario today text 0 1 2 3 4 5 6 7 8 9 10 11 month Pandemic strain emerges Reaches Europe/Australia Global distribution 14 WHO Global Influenza Programme Pandemic influenza virus emergence and possible begin of pandemic vaccine production  Expected scenario today text 0 1 2 3 4 5 6 7 8 9 10 11 month Pandemic strain emerges Reaches Europe/Australia Global distribution 15 WHO Global Influenza Programme 7

8. 16 Opportunities for research 6. Vaccine production: surge capacity  Current problems - Little to no surge capacity for seasonal and pandemic influenza vaccines  What alternative production systems exist and how could existing ones be improved? - Cell-culture; recombinant vaccines - Improved Ag harvest from eggs  Should be assessed as part of a text package of an complete pandemic preparedness concept. WHO Global Influenza Programme 17 Opportunities for research 7. Epidemiology and natural history: mid-long term  Current problems - Public health risk of emerging avian and mammalian viruses very difficult to assess and to predict. - Determinants for human pathogenicity of influenza viruses ill understood - Role of migratory birds as vector/reservoir of HPAI unclear  Studies on the ecology and molecular biology of animal influenza viruses - Genetic foundation for host specificity and pathogenicity text Molecular studies on the genetic determination of pathogenicity and host specificity Laboratory trials on the susceptibility of domestic animals to H5 - Virological/serological studies on the prevalence and molecular evolution of influenza viruses in animals/birds WHO Global Influenza Programme 8

9. 18 Opportunities for research 8. Vaccines: long-term  Current problems - Pandemic vaccines Stockpiling not possible for all subtypes as curr ent vaccines confer protection only against small number of variant viruses Surge capacity - Seasonal vaccines Annual revaccination; costs text WHO Global Influenza Programme 19 Annual vaccine costs to health  Annual seasonal vaccine production - 300 million doses – Assumptions WS price 7.5 USD 5% increase  Costs by 2015: 28.3 billion text 4 5 % increase vaccine price 3.5 3 2.5 2 1.5 1 0.5 0 6 7 8 9 10 11 12 13 14 15  If only 5% was taken/added for research: 1.41 billion. WHO Global Influenza Programme 9

10. 20 Opportunities for research 8. Vaccines: long-term  Current problems - Pandemic vaccines Stockpiling not possible for all subtypes as curr ent vaccines confer protection only against small number of variant viruses Surge capacity - Seasonal vaccines Annual revaccination; costs  Cross-subtype specific influenza vaccines which confer long- lasting immunity - Would address both pandemic and epidemic dilemmas text  Estimated global investment into antiviral stockpiling - 1.4 billion USD WHO Global Influenza Programme 22 Research prioritization and coordination  Identification of research priorities does not equal international coordination of research efforts  Several research projects already initiated - Many individual projects Governments; academia; national research and philanthropic institutions. - WHO Global Influenza Network including WHO Animal Influenza Network: operational research and direct support to control efforts - Several loose ends text  Need for an meeting on coordination of international support to avian influenza surveillance and control in Asia (donor meeting with gap analyses) - Coordination meeting on research?!. WHO Global Influenza Programme 10