giorgio palù, md dipartimento di medicina molecolare università di padova i dati a sostegno dei...
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Giorgio Palù, MDDipartimento di Medicina Molecolare
Università di Padova
I dati a sostegno dei due vaccini anti-HPVI dati a sostegno dei due vaccini anti-HPV
La vaccinazione anti-HPV: nuove conoscenze
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.
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
1-6 M after 3rd dose of vaccine
11-13 yrs N = 107
15-26 yrs N = 50
4 Y after 3rd dose of vaccine
11-13 yrs N = 74
15-26 yrs N = 60
4 Y after 3rd dose of vaccine
11-13 yrs N = 74
15-26 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.
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 rateGMT (95% CI)
126/126 (100%)5,092 (4,230; 6,151)
107/107 (100%) 22,136 (18,811; 26,073)
NS<0.0001
HPV18 Positivity rateGMT (95% CI)
124/126 (98,4%; 96.2-100%)1,804 (1,574; 2,110)
107/107 (100%)11,962 (9,536; 14,363)
NS<0.0001
Barzon et al. Vaccine 2014
** **
****
Ne
utr
ali
zin
g a
nti
bo
dy
(E
D50
)
Gardasil GardasilCervarix Cervarix
HPV16 HPV18
Gardasil Cervarix Gardasil Cervarix100
101
102
103
104
105
GM
T w
ith 9
5%CI
(log
)
HPV16 HPV18
Girls aged 11-13 yrs
Significantly higher HPV16 and HPV18 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®
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: 157.2 (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)
<0.0001<0.01
* *
Neu
tral
izin
g a
nti
bo
dy
(ED
50)
Gardasil GardasilCervarix Cervarix
HPV31 HPV45
Gardasil Cervarix Gardasil Cervarix100
101
102
103
104
105
GM
T w
ith
95%
CI (l
og)
HPV31 HPV45Barzon et al. Vaccine 2014
Girls aged 11-13 yrs
Significantly higher seropositivity rate and HPV31 and HPV45 NAb titers after vaccination with Cervarix® than vaccination with Gardasil®
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 11-13 yrsDecrease of NAb titres after vaccination with Gardasil®; stable NAb titres after Cervarix®
Comparison of immunogenicity of prophylactic HPV vaccines: memory B-cell responses (ELISPOT)
Gardasil®
Cervarix®
HPV16 HPV18
% o
f Ag-
spec
ific
mem
ory
B-ce
lls
p< 0.0001 p< 0.0001
Caputo et al.
Girls aged 11-13 yrs
Significantly higher frequency of HPV16- and HPV18-specific memory B-cells after vaccination with Cervarix® than
vaccination with Gardasil®
1
10
100
1000
10000
100000
11-13 yrs 15-26 yrs 11-13 yrs 15-26 yrs
NA
bs (
GM
T)
HPV16
HPV18
Cervarix® Gardasil®
**
**
* P<.0001 Cervarix vs. Gardasil
Immunogenicity of HPV vaccines in different age groupsComparison of HPV16 and HPV18 NAbs titers in Cervarix® and Gardasil® vaccinees
Barzon et al.
Females aged 11-13 yrs and 15-26 yrs
Significantly higher HPV16 and HPV18 NAb titers in both adolescents and young women after vaccination with Cervarix® than vaccination with Gardasil®
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 cohortsbut lower IgG titres in the 20-26 year-aged group than in the 11-13 year-aged group
11-13 yrs (N = 60) 20-26 yrs (N = 45)
% o
f Ag-
spec
ific
mem
ory
B-ce
lls
HPV
11
HPV
16
HPV
18
HPV
6
HPV
11
HPV
16
HPV
18
HPV
6***
***
***
**
***
***
IgG
Titr
e (1
/dilu
tion)
**
***
***
***
***
HPV
11
HPV
16
HPV
18
HPV
6
HPV
11
HPV
16
HPV
18
HPV
6
**
**
**
Mann-Whitney analysis(*) p <0,05(**) 0,01<p<0,001(***) p<0,0001.
Immunogenicity of HPV vaccines in different age groups
Caputo et al.
Females aged 11-13 yrs and 20-26 yrs
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 rateGMT (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 Positivity rateGMT (95% CI)
61/74 (82.4%; 73.8-91.0%)102 (<40; 267)
74/74 (100%)2,265 (770; 3,760)
<0.0001<0.0001
** **
1
10
100
1000
10000
100000
HPV16 HPV18
NA
bs
(GM
T)
Gardasil®
Cervarix®
• Girls vaccinated at 11-13 yrs
• 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.
Long-term immunogenicity of prophylactic HPV vaccines: Comparison of HPV16 and HPV18 NAb titers at 1-6 mo. and 4 yrs post vaccination
1
10
100
1000
10000
100000
Gardasil® Cervarix®
NA
bs (
GM
T)
HPV16
HPV18
1-6 mo 1-6 mo 4 yr4 yr
• Girls vaccinated at 11-13 yrs
• Evaluation at 1-6 mo. and 4 yrs after vaccination
****
****
****
****
** P < .0001
Barzon et al.
4 Y after vaccine1-6 M after vaccine
Strong reduction of both the frequency of memory B-cells and IgG titres 4 years after vaccination
Mann-Whitney analysis(***) p<0.0001.
Gardasil® vaccine
Long-term immunogenicity of HPV vaccinesLong-term immunogenicity of Gardasil®
Caputo et al.
11-1
3-y
old
HPV6
20-2
6-y
old%
of A
g-sp
ecifi
c m
emor
y B-
cells
11-1
3-y
old
HPV11
20-2
6-y
old
11-1
3-y
old
HPV16
20-2
6-y
old
11-1
3-y
old
HPV18
20-2
6-y
old
IgG
Titr
e (1
/dilu
tion)
*** *** *** *** *** *** ***
*** *** *** *** *** *** ******
11-1
3-y
old
HPV6
20-2
6-y
old
11-1
3-y
old
HPV11
20-2
6-y
old
11-1
3-y
old
HPV16
20-2
6-y
old
11-1
3-y
old
HPV18
20-2
6-y
old
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
Immunogenicity of a bivalent HPV16/18 vaccine in JIA patients An indipendent study
^p<0.0001 vs baseline; *p<0.0001 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 HPV16 NAbs HPV18 NAbs
JIA patients (n=21)
Healthy controls(n=21)
JIA patients (n=21)
Healthy controls(n=21)
NAb positivity rate (%) Before 3rd dose (month 6) 20/21 (95.2)
21/21 (100.0) 21/21 (100.0) 21/21 (100.0)
One month after 3rd dose (month 7)
21/21 (100.0) 21/21 (100.0) 21/21 (100.0) 21/21 (100.0)
NAb ED50 GMT (fold increase)
Baseline <40 <40 <40 <40
Before 3rd dose (month 6) 274.40 (6.9)^ 487.43 (12.2)^ 302.03 (7.6)^ 463 (11.6)^
One month after 3rd dose (month 7)
6,834.38 (170.9)^*°
12,177.48 (304.4)^*
5,120 (128)^*
6,347.86 (158.7)^*
Endpoints of immunogenicity against HPV16 and HPV18 in the JIA patients and healthy controls
Esposito et al. Expert Rev Vaccines 2014
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 18-25 yrs, randomized to receive a bivalent HPV vaccine or hepatitis A vaccine.
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.
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; 15-25 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.
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.
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 (1.55-1.81) and 1.67 (1.51-1.86) 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 18-24 years after 21 months of follow-up.
Open-label nonrandomized independent clinical trial in females aged 9-10 and 18-24 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 18-24 y), • 2 doses (20 μg/20 μg) at months 0 and 6 (9-10 y) (part of an extended 3D schedule 0, 6, 60)
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
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
Acknowledgements
• Department of Molecular Medicine, University of PadovaLuisa Barzon Antonella Caputo Laura SquarzonSerena MasieroBarbara MantelliMonia PacentiSilvia BertoGiorgia Marcati
• Department of Public Health, ULSS16 PadovaLorena Gottardello
• Department of Specialist, Diagnostic, and Experimental Medicine, University of BolognaTiziana LazzarottoLiliana Gabrielli
• Department of Public Health, Emilia-Romagna RegionMaria Grazia Pascucci
• Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, MilanSusanna EspositoNicola Principi
Vaccino QuadrivalenteRCP – 27 marzo 2014
La schedula di vaccinazione dipende dall’età del soggetto.
Individui dai 9 ai 13 anni di età inclusiGardasil 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 anniGardasil 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.
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 15-25 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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