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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% Library Lecture author Onlineby © ESCMID Confirmed H5N1 avian influenza virus endemic areas (poultry and wild birds) since 2003 Avian influenza A H5N1 virus - HA: Receptor specificity - Library 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 Library Lecture author Onlineby © ESCMID Introduction - Attachment to the upper respiratory tract - Seasonal H3N2 Pandemic H1N1 HPAIV H5N1 Last four pandemics Library Lecture 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) Library Lecture author Onlineby © ESCMID Air traffic from Mexico ~ 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 Library Lecture author Onlineby © ESCMID The Mexican flu virus... ...where did it come from? The Flu Orphans Children in the Alaskan village of Nushagak survived the Spanish flu of 1918 140 124 120 41% `Library2009 100 e pandemic 80 71 24% Mortalitit 60 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 Despite the relative mildness of this pandemic, severe illness and death did occur. After the first influenza waveLecture countries reported frequent ICU admissions, often in younger individuals. Most of the admitted individualsauthor had serious underlying Onlineby medical conditions, about© 30% did not. ARDS was often associated with shock and DIC. ESCMID In USA 300,000 – 2,000,000 years lost (vaccination!!!) INFLUENZA: are we prepared? - medical interventions – Library Surveillance Humans and animals: “early warningLecture” en “rapid response” Antiviral therapy preventive and therapeutic…resistanceauthor development ??? Onlineby Vaccination © Cornerstone of prevention !!! ESCMID Library Lecture author Onlineby © ESCMID SCIENCE 2009 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 Library Lecture 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 Several novel generations of influenza vaccines are being developed (adjuvanted, DNA, LAIV, vectored, VLP, and protein / peptide-based …vaccines) Lecture Novel adjuvants have led to flu vaccine candidates against avian influenza (H5,H9…)and pandemic flu that are Ag-sparingauthor and broadly active Online Vectored vaccines are promising nextby generation flu vaccine candidates © 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 In vitro expanded T lymphocytes (influenza virus A/Ned/18/94 (H3N2)) BLCL infected with influenza H3N2 or H5N1 virus 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 Approved: MF59 (squalene emulsion) seasonal AS03 (squalene/tocopherol emulsion) pandemic Virosomes (liposomes) Lectureseasonal Polyoxidonium (poly-electrolyte)seasonal Clinical studies (phase 1, 2) Iscoms (with virosomes) author AF3 (squaleneOnline o/w byemulsions) SE (squalene o/w emulsions) GLA (TLR 4 agonist)© Covaccine (TLR 4 agonist) Flagellin (TLR 5 agonist) ESCMID IC31 (dI:dC – TLR9 agonist) Inulin (complement activator) 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 Library Lecture author Onlineby © ESCMID Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naïve ferrets B. Baras et al., Vaccine. 2011 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
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  • Options for the Use of Human H5N1 Influenza Vaccines and the WHO H5N1 Vaccine Stockpile

    Options for the Use of Human H5N1 Influenza Vaccines and the WHO H5N1 Vaccine Stockpile

    Options for the use of human H5N1 influenza vaccines and the WHO H5N1 vaccine stockpile THIRD DRAFT – 02/11/07 WHO SCIENTIFIC CONSULTATION: TECHNICAL CONSIDERATIONS FOR DEVELOPING OPTIONS FOR USE OF HUMAN H5N1 INFLUENZA VACCINES AND A WHO H5N1 VACCINE STOCKPILE GENEVA, 01-03 OCTOBER 2007 GENEVA, 2007 CONTENTS Executive summary ................................................................................................... 3 1. Characteristics of human H5N1 influenza vaccines 1.1: Safety......................................................................................................................... 8 1.2: Immunogenicity....................................................................................................... 10 1.3: Cross-reactivity........................................................................................................ 12 1.4: Degree and duration of protection ........................................................................... 13 1.5: Conclusions and priority areas ................................................................................ 14 2. Options for using human H5N1 influenza vaccines................................ 16 2.1: To protect people at high risk of contracting zoonotic avian H5N1 influenza........ 17 2.2: To “prime” selected groups or whole populations in anticipation of a possible H5N1 influenza pandemic ....................................................................................... 18 2.3: To immunize selected groups or whole populations in anticipation of