Albert Osterhaus Head Dept Virology Chairman ESWI CSO Viroclinics-Biosciences BV Library Pandemic flu and the anti-H1N1 vaccine: Lecture a retrospective view. author Onlineby ©

ESCMID ESCMID conference on the impact of vaccines on Public Health Prague, 2nd April 2011 Human influenza: three appearances Library Seasonal influenza (A: H3N2, H1N1; B) Lecture Avian influenza author (A: H7N7, H5N1…)Online by © PandemicESCMID influenza (A: H1N1, H2N2, H3N2, H1N1…?) INFLUENZA A VIRUS Recent zoonotic transmissions Library

Subtype Country Year # Cases # Deaths

H7N7 UK Lecture1996 1 0 H5N1 Hongkong 1997 18 6 H9N2 SE-Asia 1999author >2 0 H5N1 HongkongOnlineby 2003 2? 1 H7N7 Netherlands© 2003 89 1 H7N2 USA 2003 1 0 H7N3 Canada 2004 2 0 H5N1ESCMIDSE-Asia/M-East/ 2003-11 .>500 >300* Europe/W-Africa *CFR ~ 60% Confirmed H5N1 avian influenza virus endemic areas (poultry and wild birds) since 2003 Library

Lecture author Onlineby © ESCMID Avian influenza A H5N1 virus - HA: Receptor specificity -

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Shinya et al., Nature 440, 2006 Lecture Van Riel et al., Science 2006 author Van Riel et al., Online Am J Pathol 2007 by Van Riel et al., © Am J Pathol 2009

Van Riel et al., ESCMID Am J Pathol 2010 Introduction - Attachment to the upper respiratory tract -

Library Seasonal H3N2 Pandemic H1N1 Lecture author Online by HPAIV H5N1 © ESCMID Last four pandemics Library

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Credit: US National Museum of Health and Medicine author 1918 1957Online 1968 2009 “Spanish Flu” “Asian Flu” by “Hong Kong Flu” © ”Swine Flu” >40 million deaths 1-4 million deaths 1-4million deaths ??? A(H1N1)ESCMIDA(H2N2) A(H3N2) A(H1N1) Air traffic from Mexico Library

Lecture author Onlineby © ESCMID ~ 1998 PB2,PA: Triple reassortant

~ 1968 ~ 1998 PB1: LibraryN-America

~ 1918 Classical swine HA, NP, NS: Lecture ~ 1979 NA, MA: authorEurasian swine Eurasia Onlineby A/California/4/2009 © PB2 PB1 The H1N1v flu virus PA Courtesy: Ron Fouchier HA NP ESCMID NA MA NS The Mexican flu virus...... where did it come from? Library

Lecture author Onlineby © ESCMID The Flu Orphans Children in the Alaskan village of Nushagak survived the Spanish flu of 1918

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e pandemic 71 60 24% Mortalitit 48 40 16% 26 26 20 2% 9% 9% Lecture7 0 0-4 Yrs 5-24 Yrs 25-49 Yrs 50-64 Yrs ≥65 Yrs Unknown Age Groups author Onlineby © ESCMID

11 Alaska State Library Avian influenza A virus - Adaptation -

E. De Wit & R.A.M. Fouchier, J Clin Virol (2008) E. De Wit, Y. Kawaoka, M.D. De Jong & R.A.M. Fouchier, Vaccine (2008) Library E. De Wit E, Munster VJ, van Riel D, et al., J.Virol 2010 HA

NS1 Lecture author Onlineby © ESCMID PB1, PB2, PA, NP NA 2009 influenza A (H1N1) virus: relevant mutations Library Virulence associated substitution in HA: D222G Lecture(Herfst et al., J.Virol. 2010)

Oseltamivir resistance substitutionauthor in NA: H275Y Onlineby © (de Vries et al., J.Clin Microbiol. 2010) ZanamivirESCMID resistance substitution in NA: I223R (de Vries et al NEJM 2010) 2009 influenza A (H1N1) virus: relevant mutations Library Virulence associated substitution in HA: D222G Lecture(Herfst et al., J.Virol. 2010)

Oseltamivir resistance substitutionauthor in NA: H275Y Onlineby © (de Vries et al., J.Clin Microbiol. 2010) ZanamivirESCMID resistance substitution in NA: I223R (de Vries et al NEJM 2010) 2009 pandemic Influenza associated ARDS

Davies A et al JAMA, Dominguez-Cheritet et al JAMA, Jain S et al N Engl J Med 2009 Library ƒ Despite the relative mildness of this pandemic, severe illness and death did occur. ƒ After the first influenza waveLecture countries reported frequent ICU admissions, often in younger individuals. ƒ Most of the admitted individualsauthor had serious underlying Onlineby medical conditions, about© 30% did not. ƒ ARDS was often associated with shock and DIC. ESCMID ƒ In USA 300,000 – 2,000,000 years lost (vaccination!!!) INFLUENZA: are we prepared? - medical interventions – Library ƒ Surveillance Humans and animals: “early warningLecture” en “rapid response” ƒ Antiviral therapy preventive and therapeutic…resistanceauthor development ??? Onlineby ƒ Vaccination © Cornerstone of prevention !!! ESCMID SCIENCE 2009

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Rappuoli et al. 2009, Science DIAGNOSTIC READ-OUTS

Clinical & Virological Parameters Seasonal H1N1 pH1N1 2009 HPAI H5N1 Library Lung Weight Lecture author Online by Munster et al., Science 2009 © Del Giudice et al., Science TM 2009 Temperature Virus Load Chutinimitkul et al., J.Virol 2010 Herfst et al., Vet.Pathol. 2010 Bosch et al., J.Virol. 2010 ESCMID Kreijtz et al., J.Gen.Virol. 2010 v.d.Brand et al., JID 2010 v.d.Brand et al., J.Virol 2010 Examples of licensed monovalent pandemic influenza H1N1v vaccines

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author` Whole virus OnlineSplit virus Subunit Live attenuated by (surface antigen) Baxter (Austria) 8 manufacturers© in China Novartis (US) MedImmune (US) Omnivest (Hungary) CSL (Australia) Microgen (Russia) Sanofi Pasteur (France) Green Cross (Korea) ESCMIDGSK Biologicals

WHO. Marie-Paule Kieny. Update of the development of A(H1N1) pandemic influenza vaccines. November 9, 2009 Future generations: avian and pandemic influenza vaccines Library ƒ Several novel generations of influenza vaccines are being developed (adjuvanted, DNA, LAIV, vectored, VLP, and protein / peptide-based …vaccines) Lecture ƒ Novel adjuvants have led to flu vaccine candidates against avian influenza (H5,H9…)and pandemic flu that are Ag-sparingauthor and broadly active Online ƒ Vectored vaccines are promising nextby generation flu vaccine candidates © ƒ LAIV is used for seasonal vaccination and is a promising pandemic vaccine candidate ESCMID Cross reactivity of human virus specific CTL -Virus infected cells- Library ƒ In vitro expanded T lymphocytes (influenza virus A/Ned/18/94 (H3N2)) ƒ BLCL infected with influenza H3N2 or H5N1 virus ƒ IFNγ ELISPOT assay Lecture HLA-A1, A2, B8, B35 HLA-A1, A3, B8, B35 author Onlineby HLA-A1, A2, B8, B27 © ESCMID

Kreijtz et al. J Virol 2008, 82(11):5161-5166 Vaccination against H3N2 prevents induction of heterosubtypic immunity by H3N2 infection against fatal H5N1 infection Library

LectureKreijtz et al., Hum Vaccin. 2009 Bodewes et al ., Plos One 2009 Bodewes et al ., Lancet 2010 authorBodewes et al ., J.Virol 2011 Onlineby © ESCMID Vaccination against H3N2 prevents induction of heterosubtypic immunity by H3N2 infection against fatal H5N1 infection Library

LectureKreijtz et al., Hum Vaccin. 2009 Bodewes et al ., Plos One 2009 Bodewes et al ., Lancet 2010 authorBodewes et al ., J.Virol 2011 Onlineby © Q: universal flu vaccination of children? ESCMID Adjuvanted influenza vaccines / candidates Library ƒ Approved: ƒ MF59 (squalene emulsion) seasonal ƒ AS03 (squalene/tocopherol emulsion) pandemic ƒ Virosomes (liposomes) Lectureseasonal ƒ Polyoxidonium (poly-electrolyte)seasonal ƒ Clinical studies (phase 1, 2) ƒ Iscoms (with virosomes) author ƒ AF3 (squaleneOnline o/w byemulsions) ƒ SE (squalene o/w emulsions) ƒ GLA (TLR 4 agonist)© ƒ Covaccine (TLR 4 agonist) ƒ Flagellin (TLR 5 agonist) ESCMIDƒ IC31 (dI:dC – TLR9 agonist) ƒ Inulin (complement activator) ƒ JVRS-100 (cationic liposome) Assessment of pre-pandemic H5N1 clinical trials Library Type of vaccine Compliance with EU licensing criteria

Split vaccine no adjuvant LectureNeed two doses of 90 µg Split/subunit vaccine with alum Need two doses of 30-45 µg Whole virus (egg) with alum Needauthor two doses of 10-15 µg Subunit with MF59 adjuvant Onlineby Need two doses of 7.5 µg Whole virus Vero cell culture, no adjuvant© Need two doses of 7.5 µg Split vaccine with AS adjuvant Need two doses of 3.8 µg

Data presentedESCMID at WHO meeting, February 2007 (Sanofi Pasteur, 4 Companies in Jp, CSL, Microgen, Sinovac, GSK, Novartis,Baxter) The three CHMP criteria are exceeded by all the adjuvanted doses: seroconversion rates

100 3.8µg H5 7.5µg H5 15µg H5 30µg H5 Library

75 3.8µg H5 AS 7.5µg H5 AS 15µg H5 AS 30µg H5 AS Lecture

50 CHMP author criteria Online 40 by © 25 Seroconversion rate (%) rate Seroconversion ESCMID 0 Post first dose Post second dose IX International Symposium on Respiratory Viral Infections ; March 3 – 6, 2007, Hong Kong Ferrets vaccinated with AS-adjuvanted H5N1 split candidate vaccine • 2 immunisations of ferrets at D0 and D21 (H5N1 A/Vietnam/1194/04 split / AS) • Heterologous challenge (wild-type virus A/Indonesia/5/05, 105 TCID50) at D49 • Post challenge results at D5 Library

Dead Alive % Survival Pooled controls 12 0 0 (15 µg Antigen Lecture only or AS only) 1.7 µg H5N1 – AS 1author5 Online 83 3.8 µg H5N1 – AS 0by 6 100 7.5 µg H5N1 – AS 0© 5 100 15 µg H5N1 – AS 06 ESCMID 100

Baras et al., PLoS One 2008 NB: similar data with clade 2.2 and 2.3 viruses Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets B. Baras et al., Vaccine. 2011 Library

Lecture author Onlineby © ESCMID Seasonal vaccine provides priming against A/H1N1 pandemic influenza Library

Vaccines Lecture- = PBS A = seasonal H1N1 authorF = seasonal H1N1 + Online MF59 by C = pdm H1N1 © C+ = pdm H1N1 + MF59

ESCMID Del Guidice et al. Science TM 2009 v.d.Brand et al J.Virol. 2010 Preliminary immunogenicity results post-dose one exceed the regulatory threshold

GMT SPR SCR Library 1000 100 100 90 90 80 80 70 70 100 60 60 50 Lecture 50 40

% subjects % 40 10 subjects % 30 30 20 author 20 Online10 10 1 0 by 0 D0 D21 D0 D21 © D0 D21 D0 D21 D21 D21 H1N1 (5.25µg) H1N1 (21µg) H1N1 (5.25µg) H1N1 (21µg) H1N1 (5.25µg) H1N1 (21µg) + + +

AS03A AS03A AS03A

ESCMIDPrior to receipt of official regents vaccines were formulated using an alternative assay for HA content. HA potencies were then retested by SRD once calibrated reagents were available.

Devaster JM. et al. Immunogenicity and safety of an A/H1N1v AS03A-adjuvanted pandemic influenza vaccine candidate: Preliminary results from a randomized, controlled trial in adults. Vaccine Congress 2009, Singapore. ADJUVANTS AND FLU VACCINES POINTS TO CONSIDERLibrary

ƒ Seasonal flu-vaccine ~ Annual boosting of primed individualsLecture (limited effect) ~ Yearly administration of alum may carry risks ~ FLUAD (MF59, Novartis) for elderly:author > longevity antibody ƒ Pandemic flu-vaccineOnline does byit require adjuvant? ~ Priming of non-exposed ©individuals ~ Without adjuvant larger doses of antigen required (90 ug: H5N1) ~ AdjuvantESCMID can enhance capacity (5 to 15-fold dose reduction) ~ Little effect in primed individuals (H1N1 vs H5N1) Efficacy of live attenuated vaccines against 2009 pandemic H1N1 influenza in ferrets: WHO initiative Stittelaar et al. submitted Library

Lecture author Onlineby © ESCMID New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets Friesen R.H. et al, PLoS One. 2010 Library

Lecture author Onlineby © ESCMID Two vaccination effectivenes studies "Mexican flu" Library The Scottish VIPER study and a German study ƒ vaccination was effective Lecture 97% in 15-65 age group 83% in > 65 age group author ƒ vaccination reducedOnline risk of byInfluenza ƒ vaccination reduced risk© of pneumonia and hospitalisation ƒ vaccinationESCMID reduced mortality Additional data report that the vaccines were safe!!! Germany: Effectiveness of GSK’s AS03-adjuvanted pandemic H1N1 2009 vaccine

289 H1N1 cases with complete data: Library - 228 cases were vaccinated < 14 days before onset of symptoms - 61 cases were vaccinated > 14 days before onset of symptoms Lecture

O. Wichmann, P. Stöcker, G. Poggensee, et al. Pandemic influenza A(H1N1) 2009 breakthrough infections and estimates effectiveness in Germany 2009-2010. Euro Surveillanceauthor 2010. Onlineby © ESCMID Direct effectiveness of GSK’s AS03- adjuvanted pandemic H1N1 2009 vaccine Library ƒ German data:

ƒ Persons 14 to 59 years: 96,8%Lecture ƒ Persons ≥ 60 years: 83,3%

ƒ Scottish data: author Onlineby ƒ At risk persons (all© ages): 95,0% ƒESCMIDCanadian data: ƒ Children 36 months to < 10 years: 100% Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age- stratified, head-to-head trial Library

AS03A-adjuvanted vaccine was more immunogenic against pandemic influenza ALecture H1N1 virus than whole- virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy shouldauthor be considered for older people. Onlineby ©

ESCMID Karl G Nicholson et al., The Lancet Infectious Diseases, 2011 In the lay press pandemic vaccines 2009 were said to be unsafe

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Lecture author Onlineby © ESCMID

Available at: http://www.patriotsaints.com. Last accessed 02 November 2010. Safety surveillance of influenza A(H1N1)v monovalent vaccines during the 2009-2010 mass vaccination campaign in France Library

Lecture author Onlineby © ESCMID Caillet et al. Eur J Clin Pharmacol, 2010 Conclusion by the EMA:

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“The CHMP re-assessed the benefit-risk profile of Celvapan [Baxter], Focetria [Novartis] and Pandemrix [GSK]. Taking into account the comprehensive informationLecture available on the clinical safety and efficacy of these vaccines, the CHMP concluded that

the benefit-risk profile continuesauthor to be positive. Onlineby Consequently, the CHMP© recommended the further use of the vaccines within the EU in the authorised indication even after the pandemic was declared over.” ESCMID European Medicines Agency updates on the review of Pandemrix and reports of narcolepsy (23 September 2010)

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ƒ “As per 17 September 2010, there are 81 reports from healthcare professionals suggestive of narcolepsy, all collected through spontaneous reporting systems.” Lecture ƒ “The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) agreed that at present the benefit-risk balance for Pandemrix continues to be authorpositive, and that while the review is still ongoing there was noOnline need forby Europe-wide restrictions on use.” ƒ “Available evidence does not© confirm a link; more research needed.” ƒ Recently new data from Finland and other Scandinavian countries emerged (geneticESCMID predisposition, latitude association, geographical restriction, 9x increased incidence: report Finland …). EMA and European studies ongoing!

European Medicines Agency. Press release 23 September 2010. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC500096998.pdf. Pandemic H1N1 virus… …what may happen next?

ƒ Co-circulation with other influenza viruses Library (e.g. H3N2 and avian H5N1) ƒ Change virulence (re-assortmentLecture or mutation) ƒ Acquire antiviral resistance (re-assortmentauthor or mutation) ƒ Circulate as seasonalOnline flu virusby © ESCMID THERE WILL BE ANOTHER FLU PANDEMIC: H5N1…? Influenza research at Erasmus MC - The team leaders -

Prof. Dr. R.A.M. Fouchier VirologyLibrary Prof. Dr. T. Kuiken Pathology Prof. Dr. M. Koopmans Lecture Epidemiology Prof. Dr. C.A.B. Boucherauthor Antiviral research Onlineby Dr.A.van der Eijk / Dr.P.Fraaij© Clinical research Prof.Dr. G.F. Rimmelzwaan Immunology Dr. M.ESCMID Schutten Diagnostics Dr. A. Andeweg Genomics Influenza research at Erasmus MC - collaborations -

Erasmus MC VirologyViroclinics- Biosciences BV Vincent Munster Koert Stittelaar Library Emmie de Wit Rob van Lavieren Debby van Riel Leon de Waal Theo Bestebroer Carel van Baalen Ger van der Water FemkeBerkhoff Lecture Geert van Amerongen Edwin Veldhuis-Kroeze Robert Dias d’Ullois Leo Sprong Marion Koopmans Paul Zoeteweij author Martin Schutten JamesOnline Simon… many others Jan de Jong . by Charles Boucher Sanofi Pasteur© Annemiek van der Eijk GSK Pieter Fraaij Roche Guus Rimmelzwaan Novartis Bart HaagmansESCMIDSolvay Thijs Kuiken Nobilon Ron Fouchier Crucell Ab Osterhaus et al.