Global Pandemic Preparedness Research Efforts Klaus Stöhr 3 Today Medium-term applied research linked to medical and public health interventions addressing the current pandemic situation in Asia Natural history Medical impact Effectiveness of interventions Vaccines; antivirals; nonpharmaceutical Economic impact Virological research Interpandemic period Pandemic Interpandemic period Research to address long-term inter-pandemic and pandemic challenges 1
Priority Public Health Interventions International 4 Generic Surveillance exist Research during pandemics and pre-pandemic phase Risk assessment and communication Several Medical interventions Vaccines sub-optimally effective Antivirals are not accessible in time Treatment of viral and secondary bacterial pneumonia (antimicrobials) Effectiveness is incompletely understood Non-pharmaceutical interventions Slowing down local spread of pandemic virus package of activities to reduce local transmission/infection rate Aversion of pandemic package of activities aiming at eliminating a new subtype with increasing fitness Many possible interventions during an influenza pandemic Combination might vary Reducing morbidity or mortality or economical implications or societal interruption Priority Public Health Interventions International 5 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 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 2
1. Risk assessment 6 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 transmissibility Studies on the infection rate in the general population in affected countries 2. Control of source and pathways of transmission 7 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); 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? 3
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 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 8 4.1 Aversion of a pandemic 9 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? 4
4.2 Slowing down local spread 10 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? incompletely understood and their relative importance unknown. Hospital infectious control; case management; non-pharmaceutical interventions 5. Clinical research on the immunogenicity of pandemic vaccines 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 11 5
12 Vaccine availability scenarios 4000 Trivalent Monovalent 3500 Whole virus Adjuv. (4x) 2 doses 3000 2500 2000 1500 1000 million doses 500 0 1 2 3 4 5 6 7 8 Projected daily vaccine production 0.72 million 2.17 million 3.25 million 13 million month R. Hehme GSK; Presentation Vaccine Meeting Lisbon, May 2004 5. Clinical research on the immunogenicity of pandemic vaccines 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 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 sparing) H5N1 registration=pandemic vaccine registration 13 6
Pandemic influenza virus emergence and possible begin of pandemic vaccine production 14 Expected scenario today Preparation of production sites Clinical testing Pilot production for clinical testing Vaccine production 0 1 2 3 4 5 6 7 8 9 10 11 month Pandemic strain emerges Reaches Europe/Australia Global distribution Pandemic influenza virus emergence and possible begin of pandemic vaccine production 15 Expected scenario today Preparation of production sites Clinical testing Pilot production for clinical testing Vaccine production 0 1 2 3 4 5 6 7 8 9 10 11 month Pandemic strain emerges Reaches Europe/Australia Global distribution 7
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 package of an complete pandemic preparedness concept. 16 7. Epidemiology and natural history: mid-long term 17 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 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 8
8. Vaccines: long-term 18 Current problems Pandemic vaccines Stockpiling not possible for all subtypes as current vaccines confer protection only against small number of variant viruses Surge capacity Seasonal vaccines Annual revaccination; costs 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 4 3.5 3 2.5 2 1.5 1 0.5 0 Billion USD 5 % increase vaccine price 6 7 8 9 10 11 12 13 14 15 If only 5% was taken/added for research: 1.41 billion. 9
8. Vaccines: long-term Current problems Pandemic vaccines Stockpiling not possible for all subtypes as current vaccines confer protection only against small number of variant viruses Surge capacity Seasonal vaccines Annual revaccination; costs Cross-subtype specific influenza vaccines which confer longlasting immunity Would address both pandemic and epidemic dilemmas Estimated global investment into antiviral stockpiling 1.4 billion USD 20 Research prioritization and coordination 22 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 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?!. 10
Summary 23 Major needs for research exist Urgent short-term research Risk assessment reassortment Assessment of the effectiveness of non-pharmaceutical interventions Preparation of research during pandemic Long-term research Hetero-subtype specific influenza vaccine with long-lasting immunity Best bang for the bug. Need for international coordination!? Creating the environment for translating scientific evidence in immediate public health action 24 Research will initially cost money And will save lives and money! will also apply to fundamental research If you think research is expensive - try disease. Mary Lasker 1901-1994 11