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