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

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

3. Indipendent studies on the immunogenicity of prophylactic HPV vaccines
Study design
Gardasil®
(Padova)
Cervarix®
(Bologna, Milan)
1-6 M after 3rd dose of vaccine
11-13 yrs N = 126
15-26 yrs N = 50
11-13 yrs N = 107
4 Y after 3rd dose of vaccine
11-13 yrs N = 74
15-26 yrs N = 60
15-26 yrs (in progress)
Study subjects were vaccinated within organized vaccination programs in Veneto, Emilia Romagna, and Lombardy Regions.
Standard 3-doses vaccination schedule.

4. Neutralizing antibody (ED50)
Comparison of immunogenicity of prophylactic HPV vaccines: HPV16 and HPV18 NAb titers induced by HPV vaccines
Girls aged yrs **
Neutralizing antibody (ED50)
Gardasil
Cervarix
HPV16
HPV18
Significantly higher HPV16 and HPV18 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®
Barzon et al. Vaccine 2014
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
<0.0001
HPV18
124/126 (98,4%; %)
1,804 (1,574; 2,110)
11,962 (9,536; 14,363)

5. Neutralizing antibody (ED50)
Comparison of immunogenicity of prophylactic HPV vaccines: HPV31 and HPV45 cross-NAb titers induced by HPV vaccines
Girls aged yrs *
Neutralizing antibody (ED50)
Gardasil
Cervarix
HPV31
HPV45
Significantly higher seropositivity rate and HPV31 and HPV45 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®
Barzon et al. Vaccine 2014
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
<0.0001
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

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

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

8. Immunogenicity of HPV vaccines in different age groups
Comparison of HPV16 and HPV18 NAbs titers in Cervarix® and Gardasil® vaccinees
Females aged yrs and yrs 1 10
100
1000
10000
100000
11-13 yrs
15-26 yrs
NAbs (GMT)
HPV16
HPV18
Cervarix®
Gardasil® *
* P<.0001 Cervarix vs. Gardasil
Significantly higher HPV16 and HPV18 NAb titers in both adolescents and young women after vaccination with Cervarix® than vaccination with Gardasil®
Barzon et al.

9. B-cell response at 1-6 months after 3rd dose of GARDASIL®
Immunogenicity of HPV vaccines in different age groups
Females aged yrs and yrs
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
11-13 yrs (N = 60)
20-26 yrs (N = 45)
% of Ag-specific memory B-cells
HPV11
HPV16
HPV18
HPV6
*** **
IgG Titre (1/dilution)
Mann-Whitney analysis
(*) p <0,05
(**) 0,01<p<0,001
(***) p<0,0001.
Caputo et al.

10. Long-term immunogenicity of prophylactic HPV vaccines: Comparison of HPV16 and HPV18 NAb titers at 4 years post vaccination
Girls vaccinated at yrs
Evaluation at 4 yrs after vaccination ** 1 10
100
1000
10000
100000
HPV16
HPV18
NAbs (GMT)
Gardasil®
Cervarix®
Significantly higher seropositivity rate and HPV16 and HPV18 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®: Data at 4 years after vaccination.
Barzon et al.
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
<0.0001
HPV18
61/74 (82.4%; %)
102 (<40; 267)
2,265 (770; 3,760)

11. Long-term immunogenicity of prophylactic HPV vaccines: Comparison of HPV16 and HPV18 NAb titers at 1-6 mo. and 4 yrs post vaccination
Girls vaccinated at yrs
Evaluation at 1-6 mo. and 4 yrs after vaccination ** 1 10
100
1000
10000
100000
Gardasil®
Cervarix®
NAbs (GMT)
HPV16
HPV18
1-6 mo
4 yr ** ** ** ** ** ** **
** P < .0001
Barzon et al.

12. Long-term immunogenicity of HPV vaccines
Long-term immunogenicity of Gardasil®
Gardasil® vaccine
Strong reduction of both the frequency of memory B-cells and IgG titres 4 years after vaccination
11-13-y old
HPV6
20-26-y old
% of Ag-specific memory B-cells
HPV11
HPV16
HPV18
IgG Titre (1/dilution)
***
4 Y after vaccine
1-6 M after vaccine
Mann-Whitney analysis
(***) p<
Caputo et al.

13. Study subjects: n=42 females vaccinated with Cervarix®,
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 An indipendent study
Endpoints of immunogenicity against HPV16 and HPV18 in the JIA patients and healthy controls
 Parameter
HPV16 NAbs
HPV18 NAbs
JIA patients
(n=21)
Healthy controls
NAb positivity rate (%)
Before 3rd dose (month 6)
20/21 (95.2)
21/21 (100.0)
One month after 3rd dose
(month 7)
NAb ED50 GMT (fold increase)
Baseline
<40
Before 3rd dose (month 6)
(6.9)^
(12.2)^
(7.6)^
463 (11.6)^
6, (170.9)^*°
12, (304.4)^*
5,120
(128)^*
6,347.86
(158.7)^*
^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.
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
Costa Rica Vaccine trial: women aged yrs, randomized to receive a bivalent HPV vaccine or hepatitis A vaccine.
Conclusions: two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.
Kreimer et al. J Natl Cancer Inst 2011

16. Antibody response after < 3 doses of a bivalent HPV vaccine
Post-hoc analysis of the Costa Rica Vaccine Trial
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.
Safaeian et al. Cancer Prev Res 2013

17. Immune response to the bivalent vaccine administered as a 2-dose or 3-dose schedule up to 4 y after vaccination
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.
Romanowski et al. Hum Vaccine Immunother 2014

18. Immune response to the bivalent vaccine administered as a 2-dose or 3-dose schedule up to 4 y after vaccination
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.
Romanowski et al. Hum Vaccine Immunother 2014

19. Non-inferiority of Ab response to the bivalent HPV16/18 vaccine in adolescents vaccinated with 2D vs 3D schedule at 21 months
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)
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.
Lazcano-Ponce L et al. Vaccine 2014

20. 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
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