Filippo Ansaldi DiSSal, UNIVERSITÀ DEGLI STUDI DI GENOVA IRCCS AOU SAN MARTINO-IST, GENOVA

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1 Vaccinazioni: Consolidare i Risultati Guardando a Nuove Frontiere Chiavari, Hotel Monterosa, 28 Novembre 2014 Via Monsignor Luigi Marinetti 6 Filippo Ansaldi DiSSal, UNIVERSITÀ DEGLI STUDI DI GENOVA IRCCS AOU SAN MARTINO-IST, GENOVA

2 Copertura vaccinale (%) Italia Liguria ob. min. perseguibile

3 Copertura vaccinale 2012/13 in Liguria anni: 3,1% AMG: approx Prevalenza condizione AMG Mal. Cron. Resp. Mal. Cron. Cardiovasc. Diabete Mellito e altre Insuf. Renale Cron. Neoplasie Immunodepr. Gravidanza

4 Intrinsic and extrinsic rewards Severity Vulnerability Response efficacy Threat appraisal Protection motivation Behaviour Self-efficacy Coping appraisal Response costs Severity: How severe do you perceive the disease? Vulnerability: How likely are you to contract it? Response efficacy: Do you think the recommended behaviour does protect against the disease? Self efficacy: Do you feel capable of performing the recommend behaviour? Rewards: Positive aspects of starting or continuing the unhealthy behaviour Reponse costs: Costs associated with the recommended behaviour

5 u Cosa non va?! " percezione del rischio e dell impatto! " conoscenza delle performance del vaccino! " conoscenza delle criticità del vaccino u Quali sono le soluzioni?! quadro epidemiologico precisamente definito! valutazione di efficacia del vaccino! superamento delle criticità del vaccino: - soluzioni disponibili oggi - potenziali soluzioni per domani

6 A review of 21 studies on attitudes and predictors [>21,000 respondents] Fear of adverse reactions Lack of concern Incovenient delivery Lack of perception of own risk Doubts about vaccine efficacy Avoidance of medications Dislike injections Self-perceived contra-indications Lack of availability 11-49% % 5-52% 15-33% 3-56% 4-27% Score Hollmeyer HG 1 et al., Vaccine World Health Organization (WHO), Geneva, Switzerland

7 Percezione Virus a potenzialità pandemica Virus epidemici Probabilità 1 0,8 0,6 0,4 0,2 0 Pandemia A(H1N1)pdm09 Pandemia??? Letalità ++++ Letalità +++ Letalità ++ Letalità + Danno

8 Impatto Decessi OspedalizzaI per sindrome respiratoria acuta per altre cause influenza correlate Accessi al PS per sindrome respiratoria acuta Casi domiciliari (conta9o con il PLS/ MMG) Italia (1.000 per polmonite, per altre cause) Liguria > >240 > >5.000 > > Casi senza contapo con SSN (giorni di lavoro persi: 0,6-2,5/caso)

9 Casi/ Casi Ospedalizzazioni Decessi < > Ospedalizzazioni e decessi/ HospitalizaQon per 10,000 populaqon Episodi di malata Giorni di scuola persi Giorni di lavoro persi dai genitori Familiari malaq entro 3 giorni EvenQ per 100 bambini 3-14 anni Neuzil et al. Arch Pediatr Adolesc Med Neuzil et al. J Infect Dis 2002.

10 Casi/ anno Casi Ospedalizzazioni Decessi < > Ospedalizzazioni e decessi/ Casi/ anno / /12 RR: 6,87-11,07 RR: 2,65-3,6 RR: 3,75-5,6 RR: 3,41-4,71 RR: 1,61-2, >84 Classe d età (anni)

11 Of the 12 periods with significant excess mortality post-1972, only one point (1988) did not correspond to a recorded influenza activity Lee JV, PLoS 2009

12 Lee JV, PLoS 2009

13 SS ILI activity SS ILI activity SSS, Children SSS, Adults Lab surv.: pos samples/week Lab surv.

14 ILI Casi/ mese ,3 Incidenza 18-64(/10000) Incidenza >64 anni 0,8 0,7 1,1 1,7 LRTI Casi/ mese Incidenza 18-64(/10000) Incidenza >64 anni 6,5 6,8 7,1 1,9 1,5 1,8

15 Efficacia Which epidemiological studies? " Administrative database and Obs studies à comparability V vs no-v populations à Evidence of bias in estimate " RCT à ethical issue? Which factor may interfere with vaccine effectiveness estimates? " Proxy indicator à antibody response? " Different clinical/virological end points (labconfirmed flu)? What do we know about influenza vaccine effectiveness estimates?

16 Potential Bias " Preferential vaccine adm in healthy " social contacts in healthy " risk of severe outcome in healthy " risk of severe outcome in HR pts during flu and no-flu season " Different access to Health Care System in healthy and HR pts Which epidemiological studies? " Administrative database and Obs studies «Difference in difference» à comparability V vs no-v populations Difference in odds between decedents and survivors during flu virus and no-virus à Evidence of bias in estimate circulation " RCT à ethical issue? Effectiveness in preventing hospitalization for flu and pneumonia. 8,5% (3,3-13,5) Which factor may interfere with vaccine effectiveness estimates? " Proxy indicator à antibody response? " Different clinical/virological end points (labconfirmed flu)? What do we know about influenza vaccine effectiveness estimates? (Fireman et al., AJE 2009 and Baxter et al., Vaccine 2010)

17 Efficacy Effectiveness Efficacy or Effectiveness (%) No trial Against Hospitalization

18 Gross et al., 1995 Vu et al., 2002 Jefferson et al., 2010 Lab-confirmed cases - - RCT: 58 (34-73) Obs: 41 (-15-70) Clinically-confirmed cases 56 (39-68) RCT and Obs: 35 (19-47) Hospitalization for influenza and pneumonia RCT: 41 (27-53) Obs:26 (13-38) Osterholm et al., 2012 Obs: 63 (28-81) 48 (28-65) Obs: 33 (27-38) Obs: 27 (21-31) - Mortality for any cause 68 (56-76) Obs: 50 (45-56) RCT: -2 ( ) Obs: 47 (39-54) - - Manzoli et al., 2012

19 Vaccine effecqveness (%) Vaccine effecqveness HospitalizaQon rate HospitalizaQon rate (per 100,000) Age (years) Nichol, Vaccine 2003 Goodwin et al., Vaccine 2006 Grubeck- Loebenstein et al., Nature Med 1998 Jefferson et al., Cochrane Database Syst Rev 2010

20 Criticità B 155, 156 D A 131 E 75, 83 C 50 AnIgenic sites A/Syd/97(H3N2)!A/Fuij/02 (H3N2)

21 Incidenza setmanale (/1,000) Old strain: Panama/99 Fuijian/02 New strain: Panama/99 Fuijian/02 California/04 SeTmana

22 SeroprotecQon rate (%) Vaccine Strain Drifted Strain Wuh/95 vs Syd/97, yrs1 Wuh/95 vs Syd/97, >75 yrs1 Pan/99 vs Wyo/03, >60 yrs2 Pan/99 vs Wyo/03, >60 yrs3 Pan/99 vs Wyo/03, >60 yrs4 Wyo/03 vs Cal/04, >60 yrs4 Cal/04 vs Wisc/05, >60 yrs5 1 De Jong et al., J Med Virol Del Giudice et al., Vaccine Kojimahara et al Ansaldi et al., Vaccine Ansaldi et al., Vaccine 2010

23 L'influenza è la terza causa di morte per malattia infettiva in Italia [dati ministero salute] Nella popolazione seguita da un MMG, si verifica >1 decesso ogni 5 anni >5 ospedalizzazioni ogni stagione >90 contatti/visite ogni stagione La classe d età I fattori di rischio Antigenic drift 75-50% età 23

24 A somministrazione IM " Split non adiuvati (frammentati) " Subunità non adiuvati (HA e NA) " Subunità adiuvati (con MF59 - virosomiali) " Vaccino a somministrazione intradermica convenzionali o plain " LAIV " Vaccini universali (M e HA) ü QUADRIVALENTE

25 6m-5 anni 5-17 anni Split Subunit MF59 adjuv Virosom ID LAIV anni 9 µg anni 15 µg >64 anni 15 µg Sicurezza OK OK OK OK OK, (**) Tollerabilità OK OK (*) (***) Accettabilità OK OK OK riferimento A causa del rischio di febbre alta, dovrebbero essere presi in considerazione vaccini influenzali stagionali alternativi per l immunizzazione dei bambini di età inferiore ai 5 anni. Nel caso in cui il vaccino sia utilizzato nei bambini, i genitori devono essere avvisati di controllare la febbre nei 2-3 giorni successivi alla vaccinazione. Immunogenità n.a. Crossprotection? n.a. Efficacia,??, bambini, adulti 25

26 " Perché un vaccino quadrivalente " Sicurezza ed immunogenicità del QIV " Benefici attesi dell introduzione del QIV

27 " In popolazioni ad elevato rischio: - Nei primi anni di vita - Negli anziani - Nei pazienti fragili " Mismatch antigenico - Antigenic shift - Antigenic drift - Co-circolazione dei lineage B Potenziare priming e boosting Contrastare l immunosenescenza Potenziare la cross-protection " Minor immunogenicità del virus vaccinale tipo B

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29 1999/2000 Picco nella classe <14 anni: 16/1000*sett. Picco nella classe anni: 15/1000*sett. 2001/02 Picco nella classe <14 anni: >40/1000*sett. Picco nella classe anni: 10/1000*sett. Ansaldi F et al., EJE 2004

30 Efficacia vaccinale (%) +42% +31% Season 2004/ / /07 Ceppo vaccinale A/New Cal/99(H1N1) A/Wyo/03(H3N2) B/Jangsu/03[Y] Ceppi circolanti A/Cal/04(H3N2) 95% B/Jangsu/03[Y] 5% A/New Cal/99(H1N1) A/Cal/04(H3N2) B/Jangsu/03[Y] A/Wisc/05(H3N2) 33% B/Malaysia/04[V] 62% A/New Cal/99(H1N1) A/Wisc/05(H3N2) B/Malaysia/04[V] A/New Cal/99(H1N1) 73% A/Wisc/05(H3N2)16% Isolati mismatching (%) 95% 95% 8% Belongia EA et al., JID 2009

31 Efficacia vaccinale (%) Stagione 2011/12 Ceppo vaccinale A/Cal/09(H1N1) Perth/09(H3N2) B/Brisbane/60/2008[V] Ceppi circolanti A/Cal/09(H1N1) 4% Vict/11+Brisb/11(H3N2) 23% B/Florida/4/2006 [Y] 72% Lo YC et al., Plos 2013

32 Stagione Ceppi vaccinali, emisfero Nord Virus circolanti in Europa e USA A/H1N1 A/H3N2 B A/H1N1 A/H3N2 B 1995/96 Texas/91 Johan/94 Beijing/93 Texas/91 Johan/94 Beijing/ /97 Bayern/95 Wuhan/95 Beijing/93 Bayern/95 Wuhan/95 Beijing/ /98 Bayern/95 Wuhan/95 Beijing/93 Bayern/95 Syd/97 Harbin/ /99 Beijing/95 Syd/97 Beijing/93 Bay/95+Beij/95 Syd/97 Beijing/ /00 Beijing/95 Syd/97 Beijing/93 NewCal/99 Syd/97 Beijing/ /01 NewCal/99 Pan/99 Yaman/98 Bay/95+NC/99 Syd/97 Sichuan/ /02 NewCal/99 Pan/99 Sich/99 (Y) NewCal/99 Syd/97 Sic/99+HK /03 NewCal/99 Pan/99 HK/01 (V) NewCal/99 Fuj/02(Pan/99) Sic/99+HK /04 NewCal/99 Pan/99 HK/01 (V) NewCal/99 Fuj/02 Jiangs/ /05 NewCal/99 Wyom/03 Jiangs/03 (Y) NewCal/99 Calif/04 J/03+Mal/ /06 NewCal/99 Calif/04 Jiangs/03 (Y) NewCal/99 Cal/04+Wis/05 J/03+Mal/ /07 NewCal/99 Wiscons/05 Malays/04 (V) NC/99+Sal/06 Wisc/05 J/03+Mal/ /08 Salom Is/06 Wiscons/05 Malays/04 (V) Sal/06+Bris/07 Wisc/05+Bri/07 Bri/07+Mal/ /09 Bris/07 Bris/07 Florida/06 (Y) Bris/07 Bris/07 Florida/06+Brisb/ /10 Bris/07 Bris/07 Bris/08 (V) - Bris/07 Bris/08 (V) 2009/10 Calif/09 Calif/ /11 Calif/09 Perth/09 Bris/08 (V) Calif/09 Perth/09 Bris/08 (V) 2011/12 Calif/09 Perth/09 Bris/08 (V) Calif/09 Vict/11+Brisb/11 Bris/08+Wisc/ /13 Calif/09 Vict/11 Wiscons/10 (Y) Calif/09 Vict/11+Texas/12 Bris/08 (V)+Mass/12 (Y) 2013/14 Calif/09 Vict/11 Mass/12 (Y) Calif/09 Texas/12 Bris/08 (V)+Mass/12 (Y) 2014/15 Calif/09 Texas/12 Mass/12 (Y)

33 Proporzione dei ceppi circolanti (%) Ambrose CS et al., HV 2012

34 Disegno: RCT in doppio cieco (3-17 anni) ed un braccio in aperto (6 mesi-3 anni) Popolazione dello studio: n mesi-17 anni 3 bracci (1:1:1): QIV, TIV B/Yamagata, TIV B/Victoria Langley JM et al., JID 2013

35 Rapporto dei titoli post vaccinali in pz immunizzati con QIV/TIV Versus lineage non-vaccinali Versus lineage vaccinali Langley JM et al., JID 2013

36 Tasso di seroconversione (%) in pz immunizzati con QIV/TIV Versus lineage vaccinali Versus lineage non-vaccinali Langley JM et al., JID 2013

37 Disegno: RCT in doppio cieco Popolazione dello studio: n anni, n anni 3 bracci (3:1:1): Q/LAIV, T/LAIV B/Yamagata, T/LAIV B/Victoria Block SL et al., PJID 2012

38 Block SL et al., PJID 2012

39 Feb 2009-FDA discute la possibilità dell inclusione del II ceppo B Feb 2012-WHO raccomanda i produttori di considerare lo sviluppo di QIV Mar 2012-EMA raccomanda i 4 ceppi Feb WHO emana linee guida per inserimento del II ceppo B Name Indications Pharmaceutical form Fluenz Tetra (AstraZeneca) Influsplit Tetra/Fluarix Tetra (GSK) Vaxigrip 481 (Sanofi)* MF59-adjuv Tetra (Novartis) ** Children and adolescents from 24 months to 18 years of age Adults and children from 36 months of age [à 6m:2016/17] Children and adults from 9 years of age [à 6m**] Children from 6m and 72m**. Nasal spray, suspension Intramuscolar injection, suspension Intramuscolar injection, suspension Intramuscolar injection, suspension *accepted for review ** phase III

40 Modello: Polymod matrix, age- dependent ü Protezione materna ü BoosQng ü Declino del Qtolo Ab ü Cross- immunizing events ü Efficacia di cross- protecqon Eichner M et al, BMC Infect Dis 2014

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42 L introduzione del QIV permetterebbe di prevenire 395,000 infezioni/anno [11,2% delle infezioni da virus B] Stima prudenziale [60% cross-protection]! Se considerassimo 30% cross-protection, l introduzione del QIV permetterebbe di prevenire 853,000 infezioni/anno.

43 Differenza (%) 0,2 1,7 2,4 2,1 2,1 Clements KM et al, HV 2014

44 Burden del virus influenzale B Limitata cross-protection Difficoltà nel prevedere il lineage prevalente QIV riflette l epidemiologia dei virus influenzali circolanti QIV mostra un profilo di sicurezza e tollerabilità simile al TIV Immunogenicità non-inferiore al TIV per i 3 ceppi contenuti in quest ultimo Protezione ottimale per entrambi i lineage B L introduzione del QIV potrebbe determinare l aumento del 0,2-7% dei casi prevenuti in relazione alla fascia d età e al modello, MA Difficoltà a stimare l effetto dell introduzione del QIV Rischio di Ag shortage (?) Costi incrementali: necessità di forti evidenze farmaco-economiche Strategie alternative

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47 " Oil-in-water emulsion: small and stable droplet of squalene, a normal component of cell membranes and metabolite of cholesterol synthesis " Droplet size: ~150 nm, sterile filtered " Viscosity: close to water, easy to inject " MF59 is biocompatible and biodegradable " Administration of MF59-adjuvanted vaccine does not stimulate antibodies against squalene SQUALENE MF59 adjuvant emulsion Antigens SPAN 85 TWEEN nm Novartis Vaccines, Data on File Podda A et al., 2003 Del Giudice G et al., 2006 O'Hagan.,2007

48 Antisqualene IgG and IgM antibodies in serum samples from individuals vaccinated with subunit influenza vaccine with the MF59 adjuvant (n=48) or with a plain, split influenza vaccine without the MF59 adjuvant (n=52) No statistically significant differences, either between vaccines or between time points for one vaccine. There were no trends over time detected as significant for either vaccine or either antibody (P =.6212) GMT Month Del Giudice G et al., 2006

49 Meta-analysis of 64 RCT data in Europa, USA, Australia and South America Study population: 28,000 subjects (20,500 vaccinees), 65% 65 years of age Subjects with solicited AEs on days 0 3 after first vaccination Solicited AEs (per 1,000) Overall population [ years] Elderly subjects Comparator MF59 adjuv Reactions with FLUAD were more frequent compared with non-adjuvanted vaccine, but were generally mild/moderate and short in duration Repeated immunizations did not increase AE incidence Podda, Vaccine 2001 Pellegrini, Vaccine 2009

50 Local reactions: pain, warmth, induration and erythema at the injection site Systemic reactions: myalgia, headache, fatigue and malaise Other reactions: fever ( 38 C), use of analgesic/antipyretic, stayed at home Weighted RR 1.74 [ ] Weighted RR 1.29 [ ] Comparator vs MF59, 39.1% vs 44.4% Weighted RR 1.32 [ ] Solicited AEs (per 1,000) Overall population Elderly subjects Weighted RR 1.08 [ ] Comparator MF59 adjuv Podda, Vaccine 2001 Pellegrini, Vaccine 2009

51 Meta-analysis of 13 RCTs; study population: n=3,549 [1 st immunisation], n=820 [2 nd ] and n=237 [3 rd ] 65 years of age Ratio between MF59 and comparator vaccine post-vaccination GMTs 2,5 2 1,5 1 0, A/H3N2 A/H1N1 B Podda, Vaccine 2001

52 Khurana et al., Sci Transl Med 2010

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54 Weller TH, 1948 Boger WP, 1957 McCarroll JR, 1958 Klein M, 1961 McElroy JT, 1969 Phillips CA, 1970 Foy HM, 1970 Marks MI, 1971 Brown H, 1977 Brooks JH, 1977 Halperin W, 1979 Herbert FA, 1979 Kenney RT, 2004 Auewarakul P 2007 Manuel O, 2007 Chiu SS, 2007; Sugimura T, 2008 Kunzi V, 2009 Nuovi dispositivi " Jet Injectors " Microago " Sistema micro-iniezione Volume e consistenza profondità Dolore Personale preparato e qualificato Chiu SS, 2009 Gelinck LB, 2009 Jo YM, 2009 Chuaychoo B, 2010 Accettabilità Risposta immunitaria [HR e gruppi di LR, riduzione Ag] Aspetti logistici

55 Jet Injectors Sistema di microiniezione Soluvia Microneedle Sticchi L et al., JPMH 2010

56 Elevata concentrazioni di APC residenti (1) Cellule di Langerhans e le cellule dermiche dendriqche ca9urano l anqgene. (2) Mentre l'anqgene è elaborato e presentato sulla superficie delle APC, la maturazione avviene con l'espressione delle molecole co- sqmolatorie. (3) Le APC migrano a9raverso i vasi linfaqci afferenq ai linfonodi. (4) Nel linfonodo, presentano l'anqgene processato alle cellule T naive (CD45RA +) provocando la maturazione delle cellule T, l'atvazione e la proliferazione.(5) Cellule T mature atvate (CD45RO +) esprimono l'anqgene CLA.(6) AnQgene CLA è in grado di legarsi alle selecqne E- e P- espresse dalle cellule endoteliali nel derma. (7)Questa interazione sqmola le cellule T ad esprimere LFA- 1 e VLA- 4 e le cellule endoteliali a produrre molecole di adesione intercellulare e vascolare (ICAM e VCAM).(8) L'interazione di queste molecole perme9e alle cellule T atvate di migrare a9raverso le venule postcapillari nel derma. (9 ) Le cellule T atvate possono migrare verso le aree di espressione dell'anqgene nel derma e dell'epidermide. (10) Le cellule T atvate possono secernere citochine come IFN- o- TNF e reclutare altre cellule effe9rici immuni, tra cui i neutrofili Walsh et al. CMAJ 2004

57 Migliorare immunogenicità ed efficacia Intanza 15 mcg anni anni Intanza 9 mcg Fluzone Intradermal Migliorare tollerabilità, accettabilità e copertura

58 Differenza ID-IM (%) Arnou R et al., Vaccine 2009

59 Differenza ID-IM (%) Arnou R et al., Vaccine 2009

60 Figure 1. How acceptable was/ were your local reaction(s)? Durando P 1, Alberti M 1, Pintaudi A 1, Accurso G 1, Rosselli R 2, Turello V 2, Marensi L 2, Ansaldi F 1, Sticchi L 1, Corsini D 3, Icardi G 1, and the Intradermal Influenza Vaccine Study Group* [de Florentiis D 1 ] *Intradermal Influenza Vaccine Study Group: Albanese E, Alicino C, Angeli C, Arenare L, Borzone F, Cacciani R, Cardamone G, de Florentiis D, Gallo D, Iudici R, Mantero P, Martini M, Opisso A, Petrucci A, Zacconi M. 1 Department of Health Sciences, San Martino Hospital, University of Genoa, Genoa, Italy 2 Local Public Health Unit of Genoa (ASL 3 Genovese), Genoa, Italy 3 Informa Srl, Rome, Italy Figure 2. How acceptable was your pain? Niente Un po ' moderatamente molto totalmente Figure 3. How satisfied were you with the injection system? Acceptable: 98.8% Acceptable: 98.4% Acceptable: 97.3% Satisfied: 99.6%

61 Differenza ID-IM (%) Dose antigene 9 mcg years, 9 mcg ID vs 15 mcg IM (Leroux 2008) years, 9 mcg ID vs 15 mcg IM (Beran 2009) H1N1 H3N2 B years, 9 mcg ID vs 15 mcg IM (Beran 2009) years, 9 mcg ID vs 15 mcg IM (Arnoui 2010) years, 9 mcg ID vs 15 mcg IM (Frenck 2011) years, HIV+, 9 mcg ID vs 15 mcg IM (Ansaldi, 2012) Dose antigene 15 mcg >60 years, 15 mcg ID vs 15 mcg IM (Arnou 2009) >60 years, 15 mcg ID-ID vs 15 mcg IM-IM (Arnou 2009) >60 years, 15 mcg ID-ID-ID vs 15 mcg IM-IM-IM (Arnou 2009) years, N.R.R.T., 15 mcg ID vs 15 mcg IM (Morel2010) Ansaldi F et al., Expert Opinion 2011

62 Differenza ID-IM (%) Dose antigene 9 mcg years, 9 mcg ID vs 15 mcg IM (Leroux 2008) years, 9 mcg ID vs 15 mcg IM (Beran 2009) years, 9 mcg ID vs 15 mcg IM (Beran 2009) years, 9 mcg ID vs 15 mcg IM (Arnoui 2010) years, 9 mcg ID vs 15 mcg IM (Frenck 2011) H1N1 H3N2 B Pool dati pubblicati [ad esempio contro A(H1N1)] Dose antigene: 9 mcg Popolazione: 3016 ID vs 2184 IM Prevented fraction: -1% (-0.4%, 3.4%) p= NS years, HIV+, 9 mcg ID vs 15 mcg IM (Ansaldi, 2012) Dose antigene 15 mcg >60 years, 15 mcg ID vs 15 mcg IM (Arnou 2009) >60 years, 15 mcg ID-ID vs 15 mcg IM-IM (Arnou 2009) >60 years, 15 mcg ID-ID-ID vs 15 mcg IM-IM-IM (Arnou 2009) Dose antigene: 15 mcg Popolazione: 2870 ID vs 1317 IM Prevented fraction: +4% (0.3%, 7.4%) p= years, N.R.R.T., 15 mcg ID vs 15 mcg IM (Morel2010) Ansaldi F et al., Expert Opinion 2011

63 Obiettivo. Valutare la capacità del vaccino antinfluenzale intradermico 15 µg a elicitare una efficace risposta anticorple contro i virus circolanti che presentano differente pattern antigenico rispetto allo strain vaccinale Stagione 2006/ /11 2 Vaccino ID versus Split Virosomale Popolazione 60 anni 60 anni Ceppo vaccinale Risposta immunitaria valutata versus A/Wisconsin/67/2005 (H3N2) A/California/7/2009 (H1N1) pdm 09 A/Wisconsin/67/2005 (H3N2) A/California/7/2009 (H1N1) pdm 09 A/Brisbane/10/07 (H3N2) Ceppi A(H3N2) circolanti nelle stagioni 2005/06 e 2006/07 Ceppi A(H1N1) pdm 09 circolanti nella stagioni 2010/11 1 Ansaldi F et al., Vaccine Ansaldi F et al., Human Vaccines 2013

64 Brisbane/07-like Nepal/06-like-like Wisconsin/05 California/04-like

65 Corrected post vaccination HI titer Vaccino IM split Vaccino ID 75 percentile Mediana 25 percentile Tasso di sieroprotezione (%) +4% +4% +32% 0 +12% +16% Wilcoxon test p<0.05 Ansaldi F et al., Vaccine 2012

66 Vaccino IM split Vaccino ID Post vaccination GMT (95% C.I.) Wilcoxon test p<0.05 Wilcoxon test p=0.05 Ansaldi F et al., Vaccine 2012

67 ü FLUENZ nasal spray, suspension, a single-use nasal applicator ü 0.2 ml intranasal spray (0.1 ml per nostril) ü Contains no preservatives (e.g., no thimerosal) or adjuvants ü FLUENZ is marketed by MedImmune under the trade name FluMist and was approved by the US Food and Drug Administration in 2003 ü The seasonal vaccine is currently approved in five countries including the US and Canada for 2-59 years, Hong Kong, South Korea, Israel, UAE, Macau for 2-49 years, Europe for 2-17 years ü Children from 24 months who have not been previously vaccinated against seasonal flu should be given a second dose after at least four weeks. Controindications: Children and adolescents with hypersensitivity to the active ingredients clinically immunodeficient due to conditions or immunosuppr. therapy salicylate (e.g. aspirin) therapy safety has been established in children of all ages with mild to moderate asthma. Not sufficient data on children with severe asthma. is not contraindicated for use in individuals with asymptomatic HIV infection 67 EMA Assessment report FLUENZ

68 ü LAIV vaccine is sprayed directly into the nasal cavity 1 ü Needle-free ü Active inhalation/sniffing not required ü Intranasal administration enables induction of immunity at the site of virus entry 2 ü Induces a broad innate, mucosal and systemic response 2 ü Designed to more closely mimic the immune response generated by wild-type influenza 2 Attenuated virus: disease-causing properties removed so as not to cause illness Cold-adapted: replicates efficiently only in the cooler areas of the nasopharynx Temperature-sensitive: does not replicate efficiently in warmer areas of the lower respiratory tract where influenza viruses typically replicate 1. FLUENZ SmPC 2. Tosh P et al. Mayo Clin Proc 2008; 83: Cox RJ, et al. Scand J Immunol. 2004;59: Assessment report Fluenz, Maassab HF, DeBorde DC. Vaccine. 1985b;3(5):

69 Clinical efficacy or immunogenicity data from 43 studies > subjects 31 studies included paediatric subjects Efficacy in paediatric subjects were assessed in 9 studies > children 6 placebo-controlled 3 TIV (trivalent inactivated influenza vaccine) controlled Safety data > 28,500 subjects 2 to 17 years of age from clinical studies > 52,500 children and adolescents from post authorization safety studies Flumist on the US market since 2003 > 39 million doses have been distributed 69

70 70 Solicited reactogenicity events days 0 10 post-vaccination in year 1 of TIV studies Incidence, % * * LAIV dose 1 TIV dose 1 LAIV dose 2 TIV dose * 0 Fever Data available from six TIV-controlled studies. *Statistically significant difference (p<0.05). Ambrose CS et al. Influenza Other Respi Viruses 2011; DOI: /j x. Adapted from Ambrose CS et al, 2011

71 Placebo studies D153-P501 and AV006 2 years to 6 years of age 1-2 LAIV (N=876-1,764) % Placebo (N=424-1,036) % Active-controlled study 2 years to 5 years of age 3 LAIV (N=2,170) % MI-CP111 TIV (N=2,165) % Event Runny nose/nasal congestion Decreased appetite Irritability Decreased activity (lethargy) Sore throat Headache Muscle aches Chills Fever 37,8 C 38,3 C Oral ,3 C 38,9 C Oral * Most common adverse reactions ( 10% in LAIV and at least 5% greater than in control) are runny nose or nasal congestion and fever >37,8 C in children 2-6 years of age Studies reflect the data collected between 2 pooled studies and 1 active-controlled study 1. Belshe, et al. N Engl J Med, 338:1405, Tam, et al. Pediatr Infect Dis J, 26:619, Belshe, et al. N Engl J Med, 356:685,2007.

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73 Proportion of subjects 2 8 years of age reporting solicited symptoms during days 0 10 after the first vaccination 73

74 Not indicated in children < 24 months of age due to increased risk of wheezing post vaccination Children with Hospitalisations and Wheezing from CP111 Adverse reaction Age group FLUENZ Active Control Hospitalisation (any cause) From randomisation through 180 days post last vaccination Wheezing Requiring bronchodilator therapy or with significant respiratory symptoms, from randomisation through 42 days post last vaccination 6 11 months 6.1 % 2.6 % 12+ months No significant difference 6 23 months 5.9 % 3.8 % 24+ months No significant difference (2.1 vs 2.5%) 74

75 The incidence of asthma exacerbations were comparable between groups No significant differences were observed between treatment groups in mean PEFR findings, asthma symptoms scores, or night-time awakening scores Asthma exacerbations occurring within 42 days of vaccination with LAIV or TIV TIV LAIV Incidence (%) Asthma exacerbations Hospitalisation Unscheduled clinic visits Increased medication PEFR: Peak expiratory flow rate. Fleming D et al. Pediatr Infect Dis J 2006; 25:

76 Manzoli L. et al. Pediatr Infect Dis J RCTs in US, former USSR and EU, evaluating the efficacy of TIVs and LAIVs, between 1968 and 2003 Population age range: 6 months 18 years Outcomes used: ILI, lab-confirmed flu, OMA Meta-analyses of the effect of vaccination with TIV and LAIV on LAB-CONFIRMED INFLUENZA in healthy children TIV VE= 62% [45-75] LAIV VE= 72% [38-87] Overall VE= 67% [51-78] Rhorer J. et al., Vaccine studies in Asia, Europe, Mid East, South America, USA including: - nearly 25,000 children aged 6-71 months - nearly 2,000 children aged 6-17 years. Meta-analyses of vaccine efficacy for LAIV versus placebo (year 1, two doses in naive-children) for antigenically similar subtypes, by any strain and by specific strain Overall VE for any strain= 77%, (age<36 months= 74%) Overall VE A/H1N1= 85% Overall VE A/H3N2= 76% Overall VE B= 73%

77 2012 RCTs (n=17), cohort studies (n=19) and case-control studies (n=11) Pop.: 300,000 observations Population age range: healthy children <16 years Sources: The Cochrane Central Register of Controlled Trials, Old Medline, Medline, Embase, Biological Abstracts and Science Citation Index

78 Results of two double-blind, multicentre phase III or IV trial [Carter NJ et al., 2011 Drugs 2011]

79 M2 protein HA (HA1+HA2 conserved epitopes) M2 is a ph-activated proton-selective ion channel!essential for viral replication HA is a glycoprotein! receptors binding and membrane fusion Lanying Du et al. Microbes and Infection. 2010

80 Extracellular domain of M2 protein, higly conserved in all influenza A strains In animal models: v Induction of cross-reactive antibody response v Conferring productive immunity against lethal influenza A (H5N1 strains) v The performance of M2e-based vaccines can be modulated by different adjuvant formulations! explore in the clinical setting and/or in monkeys v The intranasal route of M2e-vaccine administration improves protection Phase I clinical studies have been conducted demonstrating their safety and immunogenicity in humans! EFFICACY STUDIES??? Hikono H, et al. Vet Immunol Immunopathol Tomikins, et al. Emerg Infect Dis Schotsaert, et al. Expert Rev Vaccines. 2009

81 v Mice and ferrets primed with a plasmid DNA encoding H1N1 HA vaccine and boosted with seasonal vaccines or with replication-defective adenovirus 5 (rad5) encoding HA gene v High production neutralizing of influenza antibodies directed against the HA conserved stem region! cross-protection against H1N1 drifted strains in non-human primates v HA-stem directed antibodies can be elicited through prime-boost immunization model despite previous influenza exposure Wei CJ, et al. Science Wei CJ, et al. Sci Transl Med Lee PS, et al. Proc Natl Acad Sci USA. 2012

82 Conflitti di Interessi Negli ultimi 5 anni, Filippo Ansaldi e/o il gruppo di ricerca a cui appartiene sono stati investigator o principal investigator in studi e hanno partecipato ad Advisory Board sponsorizzati da Crucell, GSK, Novartis, Pfizer (precedentemente Wyeth), Sanofi Pasteur

83 Vaccino intero (non in commercio in Italia) M2 protein Lipid membrane Haemagglutinin Neuraminidase Split vaccine M1 protein Ribonucleoprotein, including: - Viral RNA - Polymerase - Nucleoprotein Subunit vaccine

84 Come viene prodotto un vaccino influenzale A/PR8/34 X Virus circolante Semina e Crescita Concentrazione mediante centrifugazione Inattivazione e Purificazione Test di potenza Approvazione degli Enti Regolatori Pooling Packaging e distribuzione 7 mesi