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 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 Scientific advice and guidance Response support Preparedness and capacity strengthening Training and technical assistance Communication Photo: ECDC

This was a mild pandemic…

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

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 season Source: EuroMoMo and Mølbak et al 2015 EuroSurveillance H3N2H1N1/ H3N2 H3N2H1N1 H1N1/ H3N2

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

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

Age ‐ specific cumulative incidence for the 2009 influenza pandemic: a meta ‐ analysis of A(H1N1)pdm09 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 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 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 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 inform clinical care of severe H1N1 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 outbreak- ready research capacity in both high- and low resource settings. Ortiz et al. Crit Care Med 2013

Pandemic vaccine 17

Elements of pandemic vaccination preparedness vaccines availability vaccines uptake vaccines uptake vaccine development vaccine authorisation vaccine procurement vaccination policy public acceptance social marketing vaccine monitoring

Abelin et al. Vaccine 2010 Timeliness of vaccine production

Absolute numbers of doses of seasonal influenza vaccine distributed by WHO region between 2004 and Palache et al. Vaccine, Volume 32, Issue 48, 2014, Europe ca. 80M doses

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

Seasonal influenza vaccination coverage in older age groups in EU/EEA MSs (n=24) EU target for influenza season † Sweden- reports were received for only around 60% of the population for influenza season *Norway and 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, , EU

Narcolepsy signal after Pandemrix currently investigated August, narcolepsy reported in vaccinated children in Sweden and Finland – ECDC contacts VAESCO September, 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, Sweden reports 4-fold increase of narcolepsy … …does not dare to laugh… 24

Experience with Pandemrix in Europe – the 2009 pandemic vaccine mostly used As of 8 August 2010 it was estimated that million doses had been distributed in the EEA, at least 30.8 million individuals had been vaccinated and 11,276 reports of suspected adverse events had been received to the Eudravigilance database* The vaccine contained two active components + excipients –Influenza A (H1N1)pdm09 antigen –AS03-adjuvant (squalene + α-tocoferol) *22 nd EMA pandemic pharmacovigilance update published 19 August, 2010

Pandemrix and narcolepsy – estimates of risk from 6 European countries CountryAge in years Study design Definition of onset Follow-up period Risk RR/OR 95% CI Finland4-19Cohort1 st contact to HC 1 Jan 2009 – 15 Aug – 30.8 France <19 ≥19 Case- control Date for referral to MSLT 1 April 2009 – 30 April, – – 11.0 Ireland5-19Cohort1 st contact to HC 1 Apr Dec – 34.7 Norway4-19Cohort Date of EDS recorded by patient/family 1 Oct 2009 – 30 June *Not reported Sweden ≤ Cohort Date of diagnosis G Oct 2009 – 31 Dec Oct 2009 – 31 Dec – United Kingdom 4-19 Case- Cohort SCCS Date of EDS recorded by GP 6 months post- vaccination – – *Reported as at least 10-fold increase in final scientific publication

The biological mechanism for vaccine- associated narcolepsy? “…Antibodies from vaccine-associated narcolepsy sera cross- reacted 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

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

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

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:

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