Prophylactic HPV VaccinesProphylactic HPV VaccinesAchievements & ChallengesAchievements & Challenges

Henry C. KitchenerHenry C. Kitchener

LisbonLisbonDecember 2007December 2007

Cumulative incidence of HPV infection Cumulative incidence of HPV infection from time of first sexual intercoursefrom time of first sexual intercourse

E6

E7

E2E1

E4

E5

L1

L2

Adapted from Doorbar 2005

Model of HPV CarcinogenesisModel of HPV Carcinogenesis

15 – 20

HPV Infection

20 – 25

CIN1/2

AGE 25 – 35

CIN3

30+

Cancer

Persists Integrates

&

CofactorsClears

FREQUENCY 50% 1%

Genomic Damage

Human PapillomavirusHuman Papillomavirus• Small DNA Virus

• 7 early and 2 late genes

• Oncogenic and non-oncogenic types

• Non-oncotypes include 6 and 11 – genital and respiratory papillomavirus

• Fifteen oncotypes found in 99% of cervical cancers

• Five oncotypes are associated with 80% of cancers • Two oncotypes 16/18 are associated with

70% of cancers

Cervical CancerCervical Cancer

Prophylactic VaccinationProphylactic Vaccination

L1 Capsid proteins can self assemble into virus like particles (VPLs)

VPLs are highly immunogenic – up to 100 fold level of neutralising antibody associated with natural infection

Cervarix (HPV 16-18) VaccineCervarix (HPV 16-18) VaccineMean Titres & Seropositivity Rates Mean Titres & Seropositivity Rates According to HPV Type & GroupAccording to HPV Type & Group

Harper et al, Lancet, 2006

Rationale for Vaccination Rationale for Vaccination ProgrammeProgramme

• To prevent type specific infection, thus ultimately preventing type specific associated CIN3

• Prevention of infection by 2 types could prevent most cancers

• Primary prevention of cervical cancer by vaccination could be more cost effective than secondary prevention

• Vaccination offers a primary prevention strategy for countries without effective screening programmes

Definitions used in randomised Definitions used in randomised trials of HPV vaccinestrials of HPV vaccines

“Per Protocol”Cervix HPV –ve/Sero –ve/16/18 lesions

“Unrestricted Susceptible”

Cervix HPV –ve/Sero –ve/± all 3 doses/16/18 lesions

“Intention to Treat”

All randomised subjects (real world)

All lesions

Quadrivalent vaccine against human papillomavirus to prevent high grade cervical lesions.

The FUTURE II study Group

NEJM (2007) 356: 1915-27

Quadrivalent HPV Vaccine to Quadrivalent HPV Vaccine to prevent Cervical Lesions(15-26yrs)prevent Cervical Lesions(15-26yrs)

Future II NEJM (2007)

Per Protocol

Unrestricted

ITT Population

4408

4970

4559

5055

(HPV16)

(HPV18)

5043

5602

5054

5602

(HPV16)

(HPV18)

60806087

PlaceboVaccine

Quadrivalent HPV Vaccine to Quadrivalent HPV Vaccine to prevent Cervical Lesions(16/18)prevent Cervical Lesions(16/18)

Future II NEJM (2007)

161127192149ITT (any HPV)

104579641ITT

432401Unrestricted

291280Per protocol

PlacVaccPlacVacc

CIN3CIN2

Quadrivalent Vaccine Efficacy to Quadrivalent Vaccine Efficacy to Prevent Cervical Lesions (16/18)Prevent Cervical Lesions (16/18)

Vaccine Efficacy(%)Per Protocol 98

Unrestricted susceptible 95

ITT Population 44

ITT (Any Type) 17

Future II NEJM (2007)

Prevalence rates for four of the commonest Prevalence rates for four of the commonest

five types and HPV 45 by cytological gradefive types and HPV 45 by cytological grade

1.5%

7.0%

17.4%

40.1%

53.4%

0.7%

3.6%5.8%

8.2%

11.6%

0.7%3.1%

6.7%

14.6% 15.3%

0.5%1.7%

3.6% 3.7%

7.4%

0.8%

4.2%

8.0%

10.9%

7.9%

18.0%

24.2%

55.8%

82.8%

92.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Neg/inf Bord Mild Moderate Sev+

Cytology result

HP

V t

ype

pre

vale

nce

HPV 16 HPV 18 HPV 31 HPV 45 HPV 52 All HR-HPV

Impact of Quadrivalent Vaccine Impact of Quadrivalent Vaccine on Vulval Condylomataon Vulval Condylomata

78%Intention to treat

97%Unrestricted

Susceptible

100%Per protocol

Vaccine Efficacy

Impact of quadrivalent vaccine Impact of quadrivalent vaccine (6, 11, 16 & 18) on VAIN and VIN(6, 11, 16 & 18) on VAIN and VIN

49%

51%

43%

53

33

21

27

16

12

Intention to treat

- all high grade lesions

- all VIN

- All VAIN

71%319Intention to treat population

HPV 16/18 related VIN 2/3 or VAIN 2/3

97%291Unrestricted susceptible population HPV 16/18 related VIN 2/3 or VAIN 2/3

100%150Pre protocol susceptible population

HPV 16/18 related VIN 2/3 or VAIN 2/3

EfficacyPlaceboVaccine

Joura et al, Lancet (2007)

Efficacy of a prophylactic adjuvanted bivalent L1 virus like particle vaccine against infection with HPV16 and 18 in young women:

An interim analysis of a phase III double blind randomised trial.

Paavonen et al, Lancet (2007) 369:2161-70

CIN2+ lesions with CIN2+ lesions with HPV16 or HPV18 DNAHPV16 or HPV18 DNA

100% (74.2 – 100.0)20200CIN2+ with HPV16 or 18 DNA in lesion and in preceding cytology sample

90.4% (53.4 – 99.3)23

17

6

21

16

5

2

1

1

CIN2+ with HPV16 or 18

CIN2 with HPV16 or 18

CIN3 with HPV16 or 18

Vaccine EfficacyTotalControl Group

Vaccine Group

Paavonen et al, Lancet (2007)

Efficacy of Cervarix in Women initially Efficacy of Cervarix in Women initially seropositive or seronegative for HPV 16/18 in a seropositive or seronegative for HPV 16/18 in a

Phase II TrialPhase II Trial

10023831908293Additional**

91.624831928293Pre-specified*Seropositive or seronegative

10020783807788Additional**

90.421783827788Pre-specified*Seronegative1

nNnN

Vaccine Efficacy

%

HAV Control

HPV VaccineAnalysis of HPV-

16/18 CIN2+

HPV-16/18 baseline

(DNA negative)

*Assignment of cases according to HPV DNA in lesion** Causality assignment considering preceding infection in case of multiple HPV types in lesion

1 Paavonen et al; Lancet 2007; 369:2161-70

Cervarix (HPV 16/18) VaccineCervarix (HPV 16/18) VaccineVaccine Efficacy Against Incident Infection with HPV 45, HPV 31, HPV 52, Vaccine Efficacy Against Incident Infection with HPV 45, HPV 31, HPV 52, HPV 33 and HPV 58 in Cervical Samples from Intention-to-Treat AnalysesHPV 33 and HPV 58 in Cervical Samples from Intention-to-Treat Analyses

1651714529HPV58

4851540524HPV52

1351912529HPV33

3051614528HPV31

175181528HPV45

Women Reporting ≥ event of HPV 45, 31, 33, 52 or 58 who did not report the same event in initial study

Total WomenWomen Reporting ≥ event of HPV 45, 31, 33, 52 or 58 who did not report the same event in initial study

Total Women

PlaceboVaccine

Harper et al, Lancet (2006)

Key Issues (1)Key Issues (1)Who to VaccinateWho to Vaccinate

• Females aged 11-13– Sexually naive; good immunogenicity

• Catch up of older adolescents– Will be less cost effective

• Women up to 25 years– Would be less protective

• Should boys be vaccinated? – Will the vaccine be protective?

– Herd immunity but male HPV-related cancer is rare

Key Issues (2)Key Issues (2)Vaccine SpecificVaccine Specific

• Duration of protection

– Follow-up of current/previous studies

• Cross protection

– Other oncotypes

• Cost effectiveness

Key Issues (3)Key Issues (3)ImplementationImplementation

• Education– Key messages for children and parents

• Co-existence with cervical screening– Scope for de-intensifying screening

• How to reach women in underdeveloped countries– Expense/cold chain/acceptability

Chronology of Vaccination & Chronology of Vaccination & Changes to ScreeningChanges to Screening

Impact of the VaccinesImpact of the Vaccines

• 50-60% of CIN2/3 will be prevented and perhaps only 20% of low grade cytological abnormalities

• The majority of VAIN and VIN may be prevented

• Prevention of genital warts (Gardasil)

• Less lower genital tract disease will result in less treatment associated morbidity

• There should be an impact on other HPV associated cancer e.g. head and neck

Impact of the VaccinesImpact of the Vaccines

• Prevention of 70% cervical cancers

• 450,000 cases per year, worldwide

– Infertility

– Suffering

• 250,000 deaths per year worldwide

• Uptake of vaccine in developing world will save many thousands of lives

“The incidence of this disease might, in great measure, be prevented by inoculation.”

“From ignorance and prejudices the parents …. instead of inoculating their children, crowd into houses …. when the disease is at its most contagious.”

“Every argument is in support of inoculation, however conclusive, makes no impression upon their minds.”

Small pox, 1791Thomas Pollock