Translational medicine lessons from the 2009 pandemic Pasi

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Translational medicine lessons from the 2009 pandemic Pasi Penttinen, European Centre for Disease Prevention

Translational medicine lessons from the 2009 pandemic Pasi Penttinen, European Centre for Disease Prevention and Control, Solna, Sweden I have no, real or perceived, conflicts of interest that relate to this presentation.

Translational medicine “Translational medicine is a discipline within biomedical and public health research that

Translational medicine “Translational medicine is a discipline within biomedical and public health research that aims to improve the health of individuals and the community by "translating" findings into diagnostic tools, medicines, procedures, policies and education. ” Wikipedia

Core functions of ECDC • Disease surveillance • Epidemic intelligence • Risk assessment •

Core functions of ECDC • Disease surveillance • Epidemic intelligence • Risk assessment • Scientific advice and guidance • Response support • Preparedness and capacity strengthening • Training and technical assistance • Communication Photo: ECDC

This was a mild pandemic…

This was a mild pandemic…

Distribution of number of influenza samples and proportion positive in 28 EU+ 2 countries,

Distribution of number of influenza samples and proportion positive in 28 EU+ 2 countries, seasons 2008/09 -2009/10 Amato-Gauci et al. Eurosurveillance 2013

Announced and reported deaths due to pandemic influenza in 28 EU+ 2 countries, by

Announced and reported deaths due to pandemic influenza in 28 EU+ 2 countries, by week of report, season 2009/10 Amato-Gauci et al. Eurosurveillance 2013

Excess deaths among the elderly and all during the pandemic and 2014 -2015 season

Excess deaths among the elderly and all during the pandemic and 2014 -2015 season H 1 N 1 H 3 N 2 H 1 N 1/ H 3 N 2 Source: Euro. Mo and Mølbak et al 2015 Euro. Surveillance H 1 N 1/ H 3 N 2

The proportions pyramid Pandemic 0. 15 -0. 25% of cases Seasonal 0. 15 -0.

The proportions pyramid Pandemic 0. 15 -0. 25% of cases Seasonal 0. 15 -0. 25% of cases 2 -5% of cases 17% of cases 5% of pop. 3% of pop. Zambon in Textbook of Influenza, Girard MP et al. Vaccine 2010 and Hayward AC et al. Lancet Resp Dis 2014

Probability of infection by age during 2009 pandemic Riley S, et al. PLo. S

Probability of infection by age during 2009 pandemic Riley S, et al. PLo. S Med 2011

Age‐specific cumulative incidence for the 2009 influenza pandemic: a meta‐analysis of A(H 1 N

Age‐specific cumulative incidence for the 2009 influenza pandemic: a meta‐analysis of A(H 1 N 1)pdm 09 serological studies from 19 countries Kerkhove et al. Influenza and Other Respiratory Viruses 2013

The first pandemic… … with instant communications … in the context of the International

The first pandemic… … with instant communications … in the context of the International Health Regulations … with early diagnostic tests (PCR) available … when antiviral drugs readily available and stockpiled … when effective intensive care was available … with uncontrolled coverage in blogs Amato-Gauci et al. Eurosurveillance 2013

Fineberg IHR review committee on pandemic 2009 “The world is ill-prepared to respond to

Fineberg IHR review committee on pandemic 2009 “The world is ill-prepared to respond to a severe influenza pandemic or to any similarly global, sustained and threatening public health emergency. Beyond implementation of core public health capacities called for in the IHR, global preparedness can be advanced through research, strengthened health-care delivery systems, economic development in low- and middle-income countries and improved health status. ” “…WHO should develop and apply measures that can be used to assess the severity of every influenza epidemic…” WHO 2011

Severity assessment: Role of clinical studies in a pandemic Preparedness for rapid studies in

Severity assessment: Role of clinical studies in a pandemic Preparedness for rapid studies in first affected countries: Serological studies Transmission studies Risk factor studies Effective and efficient treatment protocols Effectiveness of non-pharmaceutical interventions in healthcare • Vaccine effectiveness studies • • •

Management of severe influenza There is a paucity of high quality clinical research to

Management of severe influenza There is a paucity of high quality clinical research to inform clinical care of severe H 1 N 1 influenza • no beneficial interventions appropriate for low-resource settings. • due to the logistical difficulties of conducting clinical research in response to a public health emergency? • underscores the need for the development of outbreakready research capacity in both high- and low resource settings. Ortiz et al. Crit Care Med 2013

Pandemic vaccine

Pandemic vaccine

Timeliness of vaccine production Abelin et al. Vaccine 2010

Timeliness of vaccine production Abelin et al. Vaccine 2010

Seasonal influenza vaccination recommendations Older age groups European Council Recommendation 2009 * WHO recommendations

Seasonal influenza vaccination recommendations Older age groups European Council Recommendation 2009 * WHO recommendations 2012 *Target 75% coverage by 2015 Chronic medical conditions * Health- Children care workers Pregnant women

90 80 70 60 50 40 30 20 10 0 EU target for 2014

90 80 70 60 50 40 30 20 10 0 EU target for 2014 -15 influenza season 2012 -13 median 45% T UK he Vaccination -N Ne or the th er rlan n UK Ire ds -S lan UK cot d -E lan n d UK glan -W d ale s Ita Sp ly a Ire in la Fr nd Ge anc rm e an M y D a Lu enm lta xe m ark b Sw our ed g Po en† rtu Fi gal n No land rw Hu ay* ng Ice ary Ro lan m d Sl ania ov a Cr kia o Sl atia ov Lit eni hu a an Po ia lan La d t Es via to nia coverage (%) Seasonal influenza vaccination coverage in older age groups in EU/EEA MSs (n=24) 2008 -09 2009 -10 2010 -11 2011 -12 2012 -13 † Sweden- reports were received for only around 60% of the population for 2009 -10 influenza season *Norway- 2008 -09 and 2009 -10 coverage results calculated for those >65 and clinical risk groups together

Influenza VE by age and risk groups, type/subtype multicentre case control study, I-MOVE, 2008

Influenza VE by age and risk groups, type/subtype multicentre case control study, I-MOVE, 2008 -14, EU Adjusted vaccine effectiveness (%) 100 80 78 73 66 65 60 60 56 47 63 60 59 56 51 49 52 51 47 42 40 30 29 20 15 0 196 65 -74 96 75+ Age group 2688 1463 1422 2656 <65 15 -64 0 -14 15 -64 Age Group 291 2506 2119 1004 431 65+ A(H 1 N 1) B 15 -64 Age group Type/Subtype TG 503 65+ Age group 4210 B 3098 2911 2614 2810 A A 0 -14 15 -59 (H 1 N 1)(H 3 N 2) Type/Subtype 479 60+ Age group accine 2008/9 (study population: > 64 years) Pandemic vaccine 2009/10 (imputed data) Seasonal vaccine 2010/11 (imputed data) Seasonal vaccine 2011/12 (target group only; VE against AH 3) Seasonal vaccine 2012/13 2371 2112 A A (H 3 N 2)(H 1 N 1) 2 -stage Subtype Seaonal vaccine 2013 (preliminary)

Narcolepsy signal after Pandemrix currently investigated August, 2010 - narcolepsy reported in vaccinated children

Narcolepsy signal after Pandemrix currently investigated August, 2010 - narcolepsy reported in vaccinated children in Sweden and Finland – ECDC contacts VAESCO …does not dare to laugh… September, 2010 - EMA reviews data and concludes "available evidence insufficient …further studies necessary" – VAESCO submits protocol February, 2011 – Finland reports 9 fold increase of narcolepsy in vaccinated Finnish adolescents March, 2011 - Sweden reports 4 -fold increase of narcolepsy … 24

Pandemrix and narcolepsy – estimates of risk from 6 European countries Country Finland France

Pandemrix and narcolepsy – estimates of risk from 6 European countries Country Finland France Ireland Norway Sweden United Kingdom Age in years Study design Definition of onset Follow-up Risk period RR/OR 4 -19 Cohort 1 st contact to HC 1 Jan 2009 – 15 Aug 2010 Casecontrol Date for referral to MSLT 1 April 2009 – 30 April, 2011 Cohort 1 st contact to HC 4 -19 Cohort Date of EDS recorded by patient/family ≤ 19 Cohort 21 -30 31+ Cohort 4 -19 Case. Cohort SCCS <19 ≥ 19 5 -19 12. 7 6. 1 – 30. 8 5. 1 2. 11 – 2. 3 3. 9 1. 4 – 11. 0 1 Apr 2009 31 Dec 2010 13. 0 4. 6 – 34. 7 1 Oct 2009 – 30 June 2010 14. 5* Not reported 4. 06 2. 87 – 5. 58 2. 18 1. 58 1. 00 -4. 75 0. 68 -3. 44 16. 2 9. 9 3. 1 – 84. 5 2. 1 – 47. 9 1 Oct 2009 – Date of diagnosis 31 Dec 2010 G 47. 4 1 Oct 2009 – 31 Dec 2011 Date of EDS recorded by GP 95% CI 6 months postvaccination *Reported as at least 10 -fold increase in final scientific publication 26

The biological mechanism for vaccineassociated narcolepsy? “…Antibodies from vaccine-associated narcolepsy sera crossreacted with both

The biological mechanism for vaccineassociated narcolepsy? “…Antibodies from vaccine-associated narcolepsy sera crossreacted with both influenza nucleoprotein and hypocretin receptor 2…” “… Thus, differences in vaccine nucleoprotein content and respective immune response may explain the narcolepsy association with Pandemrix. ” Ahmed et al Science Transl Medicine 2015

Antivirals

Antivirals

Survival of hospitalized influenza patients by time to treatment with oseltamivir Muthuri et al.

Survival of hospitalized influenza patients by time to treatment with oseltamivir Muthuri et al. Lancet Resp Med 2014

Consumption of neuraminidase inhibitors in the community and hospital sector in Europe, 2013 Austria,

Consumption of neuraminidase inhibitors in the community and hospital sector in Europe, 2013 Austria, the Czech Republic, Germany, Hungary and Luxembourg reported data to ECDC only for consumption in the community sector.

ECDC Expert opinion on public health use of neuraminidase inhibitors • Panel of independent

ECDC Expert opinion on public health use of neuraminidase inhibitors • Panel of independent experts convened in March 2015 • Three recent meta-analyses reviewed: – Cochrane 2014 (Jefferson et al. ) – MUGAS (Dobson et al. ) – PRIDE (Muthuri et al. ) • The panel concluded – no significant new evidence in the meta-analyses – supports continuing recommending use of neuraminidase inhibitors in EU/EEA Member States • Public consultation on ECDCs website: www. ecdc. europa. eu

Conclusions • Despite a “mild pandemic”, impact on public health and medical services important

Conclusions • Despite a “mild pandemic”, impact on public health and medical services important • Assessment of severity during a pandemic needs active and well-prepared clinical researchers • The two available medical countermeasures- vaccines and antivirals were and are inadequately utilised in Europe

Thank you for your attention! ECDC Disease programme for Influenza and other respiratory viruses

Thank you for your attention! ECDC Disease programme for Influenza and other respiratory viruses www. flunewseurope. org