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Giorgio Palù, MD Dipartimento di Medicina Molecolare Università di Padova I dati a sostegno dei due vaccini anti-HPV La vaccinazione anti-HPV: nuove conoscenze.

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Presentation on theme: "Giorgio Palù, MD Dipartimento di Medicina Molecolare Università di Padova I dati a sostegno dei due vaccini anti-HPV La vaccinazione anti-HPV: nuove conoscenze."— Presentation transcript:

1 Giorgio Palù, MD Dipartimento di Medicina Molecolare Università di Padova I dati a sostegno dei due vaccini anti-HPV La vaccinazione anti-HPV: nuove conoscenze

2 Immunogenicity of prophylactic HPV vaccines Investigator-driven studies at University of Padova: 1. Comparison of immunogenicity of bivalent and quandrivalent HPV vaccines in the target population of organized vaccination programs. 2. Immunogenicity of HPV vaccines in different age groups. 3. Long-term immunogenicity of HPV vaccines. 4. Immunogenicity, safety, and tolerability of a bivalent HPV vaccine in adolescents with juvenile idiopathic arthritis.

3 Study design Gardasil® (Padova) Cervarix® (Bologna, Milan) 1-6 M after 3 rd dose of vaccine yrs N = yrs N = M after 3 rd dose of vaccine yrs N = yrs N = 50 4 Y after 3 rd dose of vaccine yrs N = yrs N = 60 4 Y after 3 rd dose of vaccine yrs N = yrs (in progress) Indipendent studies on the immunogenicity of prophylactic HPV vaccines Study subjects were vaccinated within organized vaccination programs in Veneto, Emilia Romagna, and Lombardy Regions. Standard 3-doses vaccination schedule.

4 Comparison of immunogenicity of prophylactic HPV vaccines: Comparison of immunogenicity of prophylactic HPV vaccines: HPV16 and HPV18 NAb titers induced by HPV vaccines HPV type Gardasil® group (n=126) Cervarix® group (n=107) P value HPV16 Positivity rate GMT (95% CI) 126/126 (100%) 5,092 (4,230; 6,151) 107/107 (100%) 22,136 (18,811; 26,073) NS < HPV18 Positivity rate GMT (95% CI) 124/126 (98,4%; %) 1,804 (1,574; 2,110) 107/107 (100%) 11,962 (9,536; 14,363) NS < Barzon et al. Vaccine 2014 ** Neutralizing antibody (ED 50 ) Gardasil Cervarix HPV16HPV18 Girls aged yrs Significantly higher HPV16 and HPV18 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®

5 Comparison of immunogenicity of prophylactic HPV vaccines: Comparison of immunogenicity of prophylactic HPV vaccines: HPV31 and HPV45 cross-NAb titers induced by HPV vaccines HPV type Gardasil® group (n=50) Cervarix® group (n=50) P value HPV31 28/50 (56%; 42.2, 69.7%) GMT: 13.0 (6.5; 25.8) 46/50 (92.7%; 84.5, 99.5%) GMT: (92; 269) <0.05 < HPV45 3/50 (6%; -0.6, 12.6%) GMT: 1.3 (0.3; 3.1) 18/50 (36%; 22.7, 49.3%) GMT: 4.7 (2.1; 10.2) < <0.01 * * Neutralizing antibody (ED 50 ) Gardasil Cervarix HPV31HPV45 Barzon et al. Vaccine 2014 Girls aged yrs Significantly higher seropositivity rate and HPV31 and HPV45 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®

6 Comparison of immunogenicity of prophylactic HPV vaccines: Comparison of immunogenicity of prophylactic HPV vaccines: Kinetics of HPV NAb titers NAbs in vaccinated subjects at 1-6 months after the third dose of vaccine Barzon et al. Vaccine 2014 Girls aged yrs Decrease of NAb titres after vaccination with Gardasil®; stable NAb titres after Cervarix®

7 Comparison of immunogenicity of prophylactic HPV vaccines: Comparison of immunogenicity of prophylactic HPV vaccines: memory B-cell responses (ELISPOT) Gardasil® Cervarix® HPV16 HPV18 % of Ag-specific memory B-cells p< Caputo et al. Girls aged yrs Significantly higher frequency of HPV16- and HPV18-specific memory B-cells after vaccination with Cervarix® than vaccination with Gardasil®

8 yrs15-26 yrs11-13 yrs15-26 yrs NAbs (GMT) HPV16 HPV18 Cervarix ® Gardasil ® * * * * * P<.0001 Cervarix vs. Gardasil Immunogenicity of HPV vaccines in different age groups Comparison of HPV16 and HPV18 NAbs titers in Cervarix® and Gardasil® vaccinees Barzon et al. Females aged yrs and yrs Significantly higher HPV16 and HPV18 NAb titers in both adolescents and young women after vaccination with Cervarix® than vaccination with Gardasil®

9 B-cell response at 1-6 months after 3rd dose of GARDASIL® Gardasil® induces similar HPV-specific frequency of memory B-cells in age-matched cohorts but lower IgG titres in the year-aged group than in the year-aged group yrs (N = 60) yrs (N = 45) % of Ag-specific memory B-cells HPV11 HPV16HPV18 HPV6 HPV11 HPV16HPV18 HPV6 *** ** *** IgG Titre (1/dilution) ** *** HPV11 HPV16HPV18 HPV6 HPV11 HPV16HPV18 HPV6 ** Mann-Whitney analysis (*) p <0,05 (**) 0,01

10 Long-term immunogenicity of prophylactic HPV vaccines: Long-term immunogenicity of prophylactic HPV vaccines: Comparison of HPV16 and HPV18 NAb titers at 4 years post vaccination HPV type Gardasil® group (n=74) Cervarix® group (n=74) P value HPV16 Positivity rate GMT (95% CI) 73/74 (98.6%; 96.0, 100) 806 (473; 1,140) 74/74 (100%) 4,814 (2,612; 7,017) NS < HPV18 Positivity rate GMT (95% CI) 61/74 (82.4%; %) 102 (<40; 267) 74/74 (100%) 2,265 (770; 3,760) < ** HPV16HPV18 NAbs (GMT) Gardasil® Cervarix® Girls vaccinated at yrs Girls vaccinated at yrs Evaluation at 4 yrs after vaccination Evaluation at 4 yrs after vaccination Barzon et al. Significantly higher seropositivity rate and HPV16 and HPV18 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®: Data at 4 years after vaccination.

11 Long-term immunogenicity of prophylactic HPV vaccines: Long-term immunogenicity of prophylactic HPV vaccines: Comparison of HPV16 and HPV18 NAb titers at 1-6 mo. and 4 yrs post vaccination Gardasil®Cervarix® NAbs (GMT) HPV16 HPV mo 4 yr Girls vaccinated at yrs Girls vaccinated at yrs Evaluation at 1-6 mo. and 4 yrs after vaccination Evaluation at 1-6 mo. and 4 yrs after vaccination ** ** P <.0001 Barzon et al.

12 4 Y after vaccine 1-6 M after vaccine Strong reduction of both the frequency of memory B-cells and IgG titres 4 years after vaccination Mann-Whitney analysis (***) p< Gardasil® vaccine Long-term immunogenicity of HPV vaccines Long-term immunogenicity of Gardasil® Caputo et al y old HPV y old % of Ag-specific memory B-cells y old HPV y old y old HPV y old y old HPV y old IgG Titre (1/dilution) *** y old HPV y old y old HPV y old y old HPV y old y old HPV y old

13 Immunogenicity of the bivalent HPV vaccine in JIA patients Immunogenicity of the bivalent HPV vaccine in JIA patients An independent study Immunogenicity, safety, and tolerability of a bivalent HPV vaccine in adolescents with juvenile idiopathic arthritis  Study subjects: n=42 females vaccinated with Cervarix®, 3-doses vaccination schedule.  Juvenile idiopatic arthritis patients (n = 21)  Healthy controls (n = 21)  Age range: 12-25yr  Clinical and immunological evaluation at month 0, 6, and 7 after the first vaccine dose. Esposito et al. Expert Rev Vaccines 2014

14 Immunogenicity of a bivalent HPV16/18 vaccine in JIA patients Immunogenicity of a bivalent HPV16/18 vaccine in JIA patients An indipendent study ^p< vs baseline; *p< vs before the third dose (month 6); °p<0.05 vs healthy controls one month after the third dose (month 7). No other significant between-group difference. Parameter Parameter HPV16 NAbs HPV18 NAbs JIA patients (n=21) Healthy controls (n=21) JIA patients (n=21) Healthy controls (n=21) NAb positivity rate (%) NAb positivity rate (%) Before 3 rd dose (month 6) Before 3 rd dose (month 6) 20/21 (95.2) 21/21 (100.0) One month after 3 rd dose One month after 3 rd dose (month 7) (month 7) 21/21 (100.0) NAb ED 50 GMT (fold increase) NAb ED 50 GMT (fold increase) Baseline Baseline<40 Before 3 rd dose (month 6) Before 3 rd dose (month 6) (6.9)^ (12.2)^ (7.6)^463 (11.6)^ One month after 3 rd dose One month after 3 rd dose (month 7) (month 7) 6, (170.9)^*° 12, (304.4)^* 5,120 (128)^* 6, (158.7)^* Endpoints of immunogenicity against HPV16 and HPV18 in the JIA patients and healthy controls Esposito et al. Expert Rev Vaccines 2014

15 Efficacy of < 3 doses of a bivalent HPV16/18 vaccine: Proof-of-principle from the Costa Rica Vaccine Trial Kreimer et al. J Natl Cancer Inst 2011 Conclusions: two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses. Costa Rica Vaccine trial: women aged yrs, randomized to receive a bivalent HPV vaccine or hepatitis A vaccine.

16 Antibody response after < 3 doses of a bivalent HPV vaccine Post-hoc analysis of the Costa Rica Vaccine Trial Safaeian et al. Cancer Prev Res 2013 HPV16 HPV18 At 4 years, 100% of women in all groups remained HPV16/18 seropositive. HPV16 and HPV18 Ab titers among the extended two-dose group (0 and 6 months) were non- inferior to the three-dose group.

17 Immune response to the bivalent vaccine administered as a 2-dose or 3- dose schedule up to 4 y after vaccination Romanowski et al. Hum Vaccine Immunother 2014 Phase I/II randomized, partially-blind study in girls and young women aged 9 to 25 y. Vaccination with HPV16/18 AS04-adjuvanted vaccine at: 3 doses (20 μg/20 μg) at months 0, 1, and 6 (Group 3D 20/20 M0,1,6; y), 2 doses (20 μg/20 μg) at months 0 and 6 (Group 2D 20/20 M0,6; 9-14 y), Comparable HPV16/18 antibody responses to a 2D M0,6 schedule in girls aged 9–14 y to the standard 3D in women aged 15–25 y up to 4 years after first vaccination.

18 Immune response to the bivalent vaccine administered as a 2-dose or 3- dose schedule up to 4 y after vaccination Romanowski et al. Hum Vaccine Immunother 2014 Antibody responses to non-vaccine types HPV31 and HPV45 were similar in girls aged 9–14 y in the 2D 20/20 group and in women aged 15–25 y in the standard 3D group in terms of seroconversion rates and GMTs up to month 48, as measured by ELISA.

19 Non-inferiority of Ab response to the bivalent HPV16/18 vaccine in adolescents vaccinated with 2D vs 3D schedule at 21 months Lazcano-Ponce L et al. Vaccine 2014 Statistical non-inferiority of 2D vs 3D groups. At 21 months, comparing the adolescent 2D vs 3D groups, the GMT ratio and 95% CI were 1.66 ( ) and 1.67 ( ) for HPV16 and 18, respectively. The 2D regimen was non-inferior when compared to the 3D response in same-age girls and with women aged years after 21 months of follow-up. Open-label nonrandomized independent clinical trial in females aged 9-10 and y. Vaccination with HPV16/18 AS04-adjuvanted vaccine at: 3 doses (20 μg/20 μg) at months 0, 1, and 6 (9-10 y and y), 2 doses (20 μg/20 μg) at months 0 and 6 (9-10 y) (part of an extended 3D schedule 0, 6, 60)

20 Immunogenicity of 2 doses of quadrivalent HPV vaccine in younger adolescents vs 3 doses in young women: Immunogenicity of 2 doses of quadrivalent HPV vaccine in younger adolescents vs 3 doses in young women: A randomized independent study The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36. Dobson et al. JAMA 2013

21 Summary and conclusions Using immunological endpoints to infer vaccine efficacy organized vaccination programs First investigator-driven studies in the target population of organized vaccination programs. High-level HPV16 and HPV18 NAbs are induced by both bivalent and qundrivalent HPV vaccines HPV16 and HPV18 NAbs titres, total IgG,and memory B-cells are significantly higher in Cervarix® vaccinees than in Gardasil® vaccinees. HPV31 and HPV45 cross-NAbs are induced more frequently and at higher level by Cervarix® than by Gardasil® NAb titers are related to age of vaccination. Cervarix® assures an acceptable degree of protection in adolescents and young adults with juvenile idiopathic arthritis. High and sustained immune response allows a reduction of vaccine doses. Evaluation of the immune response to define the duration and the immunological correlates of protection

22 Acknowledgements Department of Molecular Medicine, University of Padova Luisa Barzon Antonella Caputo Laura Squarzon Serena Masiero Barbara Mantelli Monia Pacenti Silvia Berto Giorgia Marcati Department of Public Health, ULSS16 Padova Lorena Gottardello Department of Specialist, Diagnostic, and Experimental Medicine, University of Bologna Tiziana Lazzarotto Liliana Gabrielli Department of Public Health, Emilia- Romagna Region Maria Grazia Pascucci Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan Susanna Esposito Nicola Principi

23 Vaccino Quadrivalente RCP – 27 marzo 2014 La schedula di vaccinazione dipende dall’età del soggetto. Individui dai 9 ai 13 anni di età inclusi Gardasil può essere somministrato in accordo ad una schedula a 2 dosi (0,5 ml a 0, 6 mesi) (vedere paragrafo 5.1). Se la seconda dose di vaccino viene somministrata prima di 6 mesi dopo la prima dose, una terza dose deve essere sempre somministrata. Alternativamente Gardasil può essere somministrato in accordo ad una schedula a 3 dosi (0,5 ml a 0, 2, 6 mesi). La seconda dose deve essere somministrata almeno un mese dopo la prima dose e la terza dose almeno 3 mesi dopo la seconda dose. Tutte e tre le dosi devono essere somministrate entro un periodo di 1 anno. Individui di età pari o superiore a 14 anni Gardasil deve essere somministrato in accordo ad una schedula a 3 dosi (0,5 ml a 0, 2, 6 mesi). La seconda dose deve essere somministrata almeno un mese dopo la prima dose e la terza dose deve essere somministrata almeno 3 mesi dopo la seconda dose. Tutte e tre le dosi devono essere somministrate entro il periodo di 1 anno.

24 Quanto espresso dalle autorità regolatorie  L’EMA ha approvato la schedula vaccinale del vaccino bivalente a 2-dosi (M0,6) per le adolescenti di età 9-14 anni ritenendo che sia attesa la stessa efficacia ottenuta con la schedula 3-dosi (M0,1,6) nelle ragazze/giovani donne di età anni. La schedula 2-dosi rappresenta l’unica posologia in questa fascia d’età  L’EMA ha approvato la modifica della schedula vaccinale del vaccino quadrivalente per la fascia di età compresa tra 9-13 anni aggiungendo la schedula vaccinale 2-dosi (M0,6) come alternativa alla schedula standard 3-dosi (M0,2,6), raccomandando un follow-up delle adolescenti vaccinate con la schedula ridotta e uno studio di effectiveness o di impatto  Con una schedula vaccinale più semplice ci si attende una maggiore aderenza al ciclo vaccinale completo e un aumento delle coperture vaccinali, unitamente a vantaggi organizzativi ed economici


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