Transcript Prevalence of high/moderate-risk human papillomaviruses in

HPV Vaccines
Dr W H LI
Queen Elizabeth Hospital
5 August 2007
Content
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Introduction
Basic Information for Human Papillomavirus
HPV Vaccine Target Antigens
Vaccine Types
Phase II/III clinical trials
Gardasil / Cervarix
FAQ
Conclusion
Introduction (1)

Cervical cancer is one of the leading
causes of cancer mortality worldwide
 Estimated to have 470 000 new cases
and 230 000 deaths every year
worldwide with 80% of the cases
occurred in developing countries
Cervical Cancer in Hong Kong
439
(2004)
126
(2005
)
Introduction (2)

Even though screening reduces the risk of
cervical cancer, it does not prevent precancerous lesions, which need careful /
expensive follow-ups and intervention
 Although there are effective treatment for CIN
lesions, recurrence still occur and
management of recurrent disease maybe
difficult
 Establishing screening programs is not the
only solution to the problem
Introduction (3)

Especially in developing / under-developed
countries, limited national screening program,
late presentation of disease and limited
treatment facilities are the main obstacles in
fighting against cervical cancer
 High morbidity / mortality for advanced
disease
 New modality for prevention and treatment of
cervical cancer is required
Introduction (4)
Cancer
Association with
HPV
Cervical
≥95%
Vaginal
50%
Vulval
>50%
Penile
50%
Anal
>70%
Human papillomavirus is the perfect candidate to investigate for
Prevention and Treatment of Anogenital Tract Cancers
Introduction (5)

HPV infection is primarily transmitted by
genital contact:
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Penetrative sexual intercourse
Oral-genital, manual-genital, genital-genital
Sharing sex toys / auto-innoculation (from your
own hand to your genital tract)
Non sexual route include transmission from
mother to newborn baby (Caesarean section
not indicated)
Introduction (6)

Up to 70% of sexually active women will
become infected with HPV during their sexual
life, but the majority of these infections are
transient with 70-90% spontaneously cleared
within 12-30 months
 High-risk HPV highly associated with precancerous cervical lesions and cervical
cancer (up to 99.7% with highly sensitive
PCR tests)
 Most important factor is persistent typespecific high-risk HPV infection
Introduction (7)

Most prevalent HPV types associated
with cervical cancer are:
 HPV
16 (54.3%)
 HPV 45 (4.2%)
 HPV 33 (4.3%)
 HPV 52 (2.5%)
HPV 18 (12.6%)
HPV 31 (4.2%)
HPV 58 (3%)
*Prevalence of HPV 58 in Chinese may be up to 23.8%
Introduction (8)

HPV vaccines that protect against HPV
infections theoretically prevent women
from developing pre-cancerous lesions
and cervical cancer (Prophylactic
vaccine)
 HPV vaccine that control the HPV
infected cells theoretically treat women
with active disease or act as adjuvant
agent (Therapeutic vaccine)
Introduction (9)

HPV type 16 and 18 present in
 ~70%
of Ca cervix cases
 ~50 % HGSIL cases
 ~14-25% LGSIL cases

Provides an estimate of the potential
impact of a vaccine against HPV-16 and
HPV-18
Basic Information for
Human Papillomavirus
Human Papillomavirus
Human Papillomavirus


Non enveloped virions
consists of 72capsomere capsid
(outer coat) containing
the double stranded
circular DNA genome
Capsid made up of the
major structural protein
L1 (80%) and minor
structural protein L2
(20%)
HPV genome

3 regions:
– Long control region
(LCR) without coding
potential

Origin of replication and
regulation of HPV gene
expression
– Regulatory (early)
proteins E1-E8
– Structural (late) proteins
L1 and L2 (capsid)
Gene Function/HPV Proteins
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L1: Major capsid protein: can form virus-like particles.
L2: Minor capsid protein: possible DNA packaging protein
E1: DNA-dependent ATPase, ATP dependent helicase: allow unwinding of the
viral genome and act as an elongation factor for DNA replication.
E2: Responsible for recognition and binding of origin of replication. Exists in two
forms: full length (transcriptional transactivator) and truncated (transcriptional
repressor). The ratio of these found in the heterotrimeric complex formed before
complexing with E1 regulates transcription of viral genome.
E3: ???
E4: Late Expression: C terminal binds intermediate filament, allowing release of
virus-like particles. Also involved in transformation of host cell by deregulation of
host cell mitogenic signalling pathway.
E5: Obstruction of growth suppression mechanisms: e.g EGF receptor;
activation of mitogenic signalling pathways via transcription factors: c-Jun and cFos (important in ubiquitin pathway degradation of p53 complex by E6).
Inactivation of p21 (p53 induced expression halts cell cycle until DNA is proofread for mutations).
E6: E6 Transformation of host cell by binding p53 tumour suppressor protein.
E7: Transforming protein, binds to pRB
E8-E2 fusion protein: Long distance transcription and replication repressor
protein
HPV Proteins

Structural proteins L1 and L2:
 Building

Replication proteins E1 and E2
 Viral

the capsid (outer coat)
replication inside the infected cells
Oncoproteins E6 and E7
 Inhibiting
and pRB)
tumour suppressor genes (p53
Life Cycle


After HPV infection,
early (replication)
proteins (E1, E2, E6
and E7) are expressed
within the basal
epithelial layers and
viral replication occurs
As infected cells reach
the surface, late
proteins (structural) L1
and L2 proteins are
produced and allow
shedding of mature
virions with exfoliated
cells
Tumourigenesis
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Majority of tumour
showed integration of
HR HPV DNA into host
genome
Integration disrupts the
HPV virus in the E2
open reading frame.
Loss of E2 increase
expression of E6 and
E7 leading to
uncontrolled
proliferation and tumour
formation
HPV Vaccine Target Antigens

Capsid proteins L1 and L2 (Viral entry)
 Replication proteins E1 and E2
 Oncoproteins E6 and E7
HPV Vaccine Target Antigens (1)

Capsid proteins L1 and L2 (outer coat of the
HPV particles)
– Interact with the surface molecules of human
epithelial cells during early stages of infection to
gain entry for the viral DNA
– Ideal targets for prophylactic but not therapeutic
vaccines since L1/L2 are not present when HPVs
are integrated into tumour cells
– Most candidate vaccines target L1 since L1>L2 for
30x
HPV Vaccine Target Antigens (2)

Replication proteins E1 and E2
– Necessary for HPV to replicate within cells
before the virus is integrated into host DNA
– Expressed in early stage of HPV infection
– Targets for therapeutic vaccines to treat
early stages of disease such as low-grade
dysplasia
HPV Vaccine Target Antigens (3)

Oncoproteins E6 and E7
– Bind tumour supressor genes (p53/pRB)
which are involved in malignant
transformation / continue tumour growth
– Expressed in the later stage of disease
– Targets for therapeutic vaccines to treat
later stages of disease
HPV Vaccines
Prophylactic Vaccines
– Before HPV exposure
– Antibody-mediated
immunity at genital
mucosal surface
– Inactivate HPV before
the virus infects the host
cells
– Takes many years to
make impact on the
prevalence of cervical
cancer
Therapeutic Vaccines
– Already exposed to HPV
– Cell-mediate immunity at
the genital mucosal
surface
– Adjunct to standard
therapies
 Prevent progression
of low-grade lesions
 Induce regression of
existing lesions
 Control metastasis
 Prevent recurrence
Ideal HPV Vaccine


Safe and effective
Both prophylactic and therapeutic
– Stimulating cell-mediated immunity to eliminate
lesions when neutralizing antibodies fail to block
all of the virus
– Distributed to young women whether or not that
are infected with HPV


Single inoculation with long-term protection
Cheap and easy to handle and administer
Vaccine Types

Virus-like particles (VLPs)
 Recombinant live vector vaccine
 Protein and peptide vaccines
 “Naked” DNA vaccines
 Edible vaccines
Virus-Like Particles (VLPs) - 1
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

Capsid proteins L1 and L2 will self-assemble
into virus-like particles (VLPs) when
expressed in cells – Empty viral capsids
VLPs resembles native HPV particles and
include the conformational epitopes that
induce virus-neutralizing antibodies
The immune system perceives VLPs as
infectious (indeed they are not since they do
not include viral DNA) and induce the
immune response
Virus-Like Particles (VLPs) - 2

Immune response targets the capsid
proteins (at the time of viral entry),
therefore ideal for prophylactic vaccine
Vaccination
No
Vaccination
Selection of HPV Types in
Vaccine Development
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HPV type 16 and 18 present in
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~70% of Ca cervix cases
~50 % HGSIL cases
~14-25% LGSIL cases
Provides an estimate of the potential impact of a
vaccine against HPV-16 and HPV-18
 Quadrivalent
vaccine also include HPV 6/11
to prevent genital warts
– HPV 6/11 account for 90% of genital warts
– Clinically apparent in 1% of sexually active US
adult population
– Estimated lifetime risk of genital warts ~10%
Selection of Trial Endpoints
 Although
prevention of cancer is the
final endpoint for the success of a
prophylactic vaccine
 Studies to allow patients to develop
cancers as endpoint are unethical
 Surrogate endpoints are precancerous
lesions (CIN, AIS, VAIN, VIN)
Multicenter Randomised Double Blind
Controlled (Phase II) Trials
Monovalent
A Controlled Trial of a Human Papillomavirus Type 16 Vaccine (Nov 2002,
NEJM)
Median FU
17.4 mths
Bivalent
Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection
with HPV Type 16 and 18 in Young Women: A Randomised Controlled Trial (Nov
2004, Lancet)
Up to
mths
Quadrivalent
Prophylactic Quadrivalent HPV (Types 6,11,16 and 18) L1 Virus-Like Particle
Vaccine in Young Women: A Randomised Double-Blind Placebo-Controlled
Multicenter Phase II Efficacy Trial (May 2005, Lancet Oncology)
36 mths
Monovalent
Efficacy of Human Papillomavirus-16 Vaccine to prevent Cervical Intraepithelial
Neoplasia (Jan 2006, Obstetrics & Gynecology)
48 mths
Bivalent
Sustained efficacy up to 4.5 years of a Bivalent L1 virus-like particle vaccine
against human papillomavirus Types 16 and 18: follow-up from a randomised
control trial (15 April 2006, Lancet)
4.5 years
Quadrivalent
High Sustained efficacy of a prophylactic quadrivalent human papillomavirus
types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up (Nov
2006, British Journal of Cancer)
5 years
27
Multicenter Randomised Double Blind
Controlled (Phase III) Trials
Quadrivalent
(Gardasil)
Quadrivalent
(Gardasil)
Bivalent
(Cervarix)
Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital
Diseases (May 2007, NEJM)
(FUTURE I Trial)
N=5455
Average 3 yrs
Efficacy of a quadrivalent prophylactic human papillomavirus (types 6,11,16
and 18) L1 virus-like particle vaccine against high-grade vulval and vaginal
lesions: a combined analysis of 3 randomised clinical trials (May 2007,
The Lancet)
N=18174
Mean FU 3 yrs
Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade
Cervical Lesions (May 2007, NEJM)
(FUTURE II Trial)
N=12167
Average 3 yrs
Efficacy of prophylactic human papillomavirus L1 virus-like particle vaccine on
risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma
in situ: a combined analysis of four randomised clinical trials (June 2007,
The Lancet)
N=20583
Mean FU 3 yrs
Efficacy of a prophylactic adjuvanted bivalent L1 virus-like particle types 16
and 18 in young women: an interim analysis of a phase III double-blind,
randomised controled trial (June 2007)
N=18644
Mean FU 14.8
mths
FUTURE I/II Trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease
Study Design
Vaccine
Dose
Sexual Partners
Quadrivalent (HPV 6/11/16/18)
Gardasil
Bivalent (HPV 16/18)
Cervarix
L1 VLP
L1 VLP
0 / 1 mth / 6 mth
0 / 2 mth / 6 mth
<=4
<=6
No prior abnormal pap smears
HPV seronegative and HPV DNA negative in cervico-vaginal
sample for the respective HPV types in the vaccine
(For per-protocol and Modified Intention-To-Treat analysis)
FU Schedule
FU Protocol
Further Investigations
Mth 1, 2, 3, 6, 7, 12, 24, 36,
54,60
Every 6 months
Pap smear, HPV DNA testing and HPV antibody
Colposcopy and biopsy according to standard
Phase II / III Clinical Trials
Lesions associated with Vaccine Type HPV
Per-protocol
Endpoints
Future I
16 countries
6463 (16-24y)
3yrs
Future II
13 countries
12167 (15-26y)
3 yrs
Combined
High-grade
VAIN/VIN 2/3
18174 (16-26y)
3 yrs
Combined
High-grade
CIN2/3/AIS
20583 (16-26y)
3 yrs
Bivalent Phase II
776 (15-25y)
Up to 4.5 yrs
Bivalent Phase III
18644 (15-25y)
Average 14.8m
Total
Vuval/Vaginal Condyloma
VAIN/VIN 1 / 2 or 3
CIN 1 / 2 or 3 or AIS
CIN 2/3/AIS
VAIN/VIN 2/3
CIN 2/3/AIS
Lesions
Rregardless
of Any HPV
Type
(Baseline vaccinerelated HPV –ve
All 3 doses)
Modified ITT
ITT
(Baseline vaccinerelated HPV –ve)
(Irrespective of
baseline HPV)
100%
100%
100%
100%
95%
96%
82%/91%
98%
73%
76%
63%/62%
55%
34%
51%
18%/26%
20%
98%
(CIN 3 x 1)
95%
44%
17%
100%
97%
71%
49%
99%
(CIN 3 x 1 )
98%
44%
18%
CIN 2+
100%
CIN 2+
90.4%
(HPV 16 x 1 &
HPV 18 x 1)
Side Effects
Gardasil
Cervarix
Vaccine
Placebo
Vaccine
Placebo
Fever
10.3%
8.6%
12.4%
10.9%
Pain
83.9%
75.4%
16.3%
4.4%
Redness (All)
>5cm
24.6%
18.4%
43.8%
1.2%
27.6%
0.1%
25.4%
15.8%
42.0%
2.4%
19.8%
0.5%
0.1%
0.1%
Swelling (All)
>5cm
Serious
Adverse
Experience
Death
0.06% Vaccine-related
(Brochospasm/Asthma/Pain with
impaired joint movement)
No death related to vaccination
No death related to vaccination
Two HPV Vaccines Available
 Gardasil
(HPV 6/11/16/18) approved in
many countries including HK (Oct 2006)
 Cervarix
(HPV16/18) approved in
Australia (July 2007), Indonesia, Kenya
and pending approval in Europe and
USA etc
Which is better ?







Gardasil (0/2/6m IMI)
Storage 0-8 deg C
HPV 6/11/16/18
Adjuvant
contained
aluminum
Age 9-26 yrs
Up to 5 years
Efficacy 99%
– 1 case CIN 3: HPV 58 at
baseline and 5 histology
samples, HPV 16 in only 1
sample




Cervarix (0/1/6m IMI)
Storage 0-8 deg C
HPV 16/18
Adjuvant AS04
– Claimed to enhance immune
response and longer duration



Age10-45yrs (Australia)
Up to 4.5 years
Efficacy 90.4%
– 2 cases CIN 2+: Multiple
infection
with
preceding
cytology
HPV
16/18
-ve
(Efficacy 100%)

Cross-protection ?
– 45 and 31
Pending results from a head-to-head trial to compare
immunogenicity of Cervarix and Gardasil initiated in 2007
Phylogenetic Tree of HPV Family
Genotypying of
HPV is based on
DNA sequences of
the L1 genes
18
45
11
6
33
16
35
31
Human
Genital
Papillomavirus
Human
Cutaneous
Papillomavirus
Cross-Protection for Bivalent
Vaccine (Cervarix)
HPV Type Incident Infection
6-mth Persistent 12-mth Persistent
Infection
Infection
45
94.2%
59.9%
62.3%
31
54.5%
36.1%
10.8%
33
8.6%
36.5%
45.1%
52
18.6%
31.6%
46.5%
58
14.0%
-31.4%
-1.1%
No cross protection for other HPV types other than 16/18 has been approved
FAQ (For Gardasil)



















When and whom to vaccinate ?
Vaccination for females <9yr and >26 yrs ?
Vaccination in sexually active females
Prior HPV testing before vaccination
Past history of abnormal pap smear / histology ?
History of genital warts
Antibody testing before vaccination
Will a booster be required ?
Vaccination in pregnancy / during lactation
Duration of protection
Interrupted schedules / Incorrectly vaccinated individuals
Simultaneous administration of other vaccines
Immunocompromised patients
Precautions / Contraindications
Any therapeutic effect ?
Role of cervical screening ?
Other ways to prevent HPV infection
Vaccination in males ?
Social acceptance
When and Whom to Vaccinate
 Licensed
for use in 9-26 yr females
– Age 16-26:

Based on phase II/III studies conducted among females
aged 16-26 yrs
– Age 9-15:
Based on immunological studies
 Not inferior to 16-26yrs

– Recommendation at age 11-12:

Before sexual exposure
– US: 3.7% females sexually active before age 13
– HK: 4.9% before age 15
High probability of HPV acquisition within several yrs of
sexual exposure
 Immune system “ages” after puberty

– Antibody level after vaccination 9-10y > 13-15y > 16-23y

Incorporate into adolescent vaccination program
Vaccination for females
<9yrs and > 26 yrs
 Not
licensed for use in these age range
 Protocol 019 (FUTURE III)
– In 3870 24-45yr women followed for 3 years
– Primary endpoint:
Persistent HPV 16/18 infection and related disease
 Efficacy against HPV 16/18-related CIN 2/3 and AIS

 Off-label
use: Counseling on limitations and
based on clinical judgment
 No studies are under way among children
aged <9 years
Vaccination in Sexually Active
Females

May also benefit from the vaccine
– May have less benefit since they may have already been
infected
– Unlikely that they acquired all 4 types
– Even if the patient has been infected, vaccination would
provide protection against infection with HPV vaccine types
not already acquired
Prior HPV Testing before
Vaccination

No indication for prior HPV testing:
1. Specific HPV testing not performed routinely in clinical
setting


Although Hybrid Capture 2 is available to test for high-risk
HPV (16/18/31/33/35/39/45/51/52/56/58/59/68)
Does not identify specific HPV types
2. Unlikely that the women having all 4 HPV types (0.1%)
Positive to >= 1 types
Positive to >= 2 types
Positive to >= 3 types
Positive to >= 4 types

23.7%
6%
1.1%
0.1%
Even if the patient has been infected, vaccination would
provide protection against infection with HPV vaccine types
not already acquired
3. HPV infection mostly transient in young women and a
positive HC 2 test may cause confusion and unnecessary
anxiety
Prior HPV Testing before
Vaccination
In the combined analysis of previous studies
– Analysis of Intent-To-Treat subset:
Received at least 1 dose of vaccine (Protocol violation)
 Any follow-up 1 month after the first dose
 Even if pap smear abnormal on day 1
 Regardless of initial PCR or serology for HPV (Overall 27% of
the study population at baseline had evidence of infection with
a vaccine HPV type)
i.e. Presumed HPV status unknown / no prior HPV testing before
vaccination / Regardless of pap smears results (General
Population)

–
Prevention of vaccine-related (6/11/16/18) lesions:



CIN2/3/AIS – 39% - 46.4%
VAIN 2/3 and VIN 2/3 – 69.1%
Genital warts – 68.5%
Past history of Abnormal Pap
Smears / Histology

No contraindication for vaccination:
1. Females with equivocal / abnormal pap smears
could be infected with any HPV types (high/lowrisk)



Might not be infected with any of the 4 vaccine-types
(6/11/16/18)
Unlikely to have infected all 4 types (0.1%)
Vaccination would protect them against infection with
HPV vaccine types not already acquired
2. With increasing severity of pap smear (such as
HGSIL)


Likelihood of infection with HPV 16/18 increases
Benefit of vaccine wound decrease
History of Genital Warts
 No
contraindication
– Most often HPV 6 or HPV 11
– But might not have infection with both
types or infection with HPV 16 or HPV 18
– Vaccination would protect them against
infection with HPV vaccine types not
already acquired
Antibody Testing before
Vaccination

No indication for prior antibody testing:
1. Not all naturally
antibodies

infected
individuals
have
Only 54%-69% with incident HPV 6/16/18 seroconvert
2. Serological assays are only available in research
settings and only being done by the
manufacturer

Key laboratory reagents are not standardized
3. No gold standard for setting a threshold for a
positive result
Decision to Vaccinate
should NOT be based on
Pap testing, HPV DNA or
HPV serologic testing
Booster

Not recommended at this moment
1. High efficacy for preventing anogenital lesions through 5
years follow-up
2. High seropositivity remained at 36 months:
–
–
–
–
HPV 6
HPV 11
HPV 16
HPV 18
94%
96%
100%
76%
3. No evidence of waning efficacy among seronegative
individuals
4. Demonstration of
HPV 6
HPV
11
immune memory
when a challenge
dose was given
at 5 yrs
HPV 16
HPV 18
Vaccination in Pregnancy
 Not
recommended for
pregnancy (Category B)
–
use
during
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are
no adequate and well-controlled studies in pregnant women / Animal studies have
shown an adverse effect, but adequate and well-controlled studies in pregnant women
have failed to demonstrate a risk to the fetus in any trimester
 Not
been causally associated with
adverse outcome
Vaccination in Pregnancy
 Vaccine
group 1396/10418 (13.4%)
Placebo group 1436/9120 (15.7%)
vs
– No difference in live birth, difficulty with delivery,
spontaneous abortion, late fetal deaths
– No difference in congenital abnormality (vaccine
25 VS placebo 22)
Vaccination within 30 days of
conception
Spontaneous
Abortion
Congenital
Abnormality
Vaccination more than 30 days
of conception
Vaccine
Placebo
Vaccine
Placebo
19/112
26/115
266/1198
283/1218
5
0
20
22
Vaccination in Pregnancy
 If
a women is found to be pregnant after
initiating the vaccination series:
– The reminder of the dose(s) should be
delayed until after delivery
– No intervention is needed (TOP not
indicated)
Vaccination During Lactation
 No
contraindication
– Serious adverse event:
Vaccine
Placebo
17/500 (3.4%)
9/495 (1.8%)
12 Respiratory infection
5 Gastroenteritis
– None were considered vaccine related
Duration of Protection
 Data
available for up to 5 years and exact
duration depends on on-going trials
– Phase III trials up to 3 years
– A subset 241 participants still demonstrated 100%
efficacy up to 5 years
– Women in the Nordic countries will be followed for
at least 14 years and serological testing will be
obtained at 5 and 10 years
Interrupted Schedules
(0/2m/6m)
 Does
not need to be restarted
– Interrupted after 1st dose:
 Second
dose to be given as soon as possible
and the 2nd and 3rd dose be separated by at
least 12 weeks
– Interrupted after 2nd dose:
 Third
dose to be given as soon as possible
Incorrectly Vaccinated Individuals
(0/2m/6m)
 Studies:
– Interval between 1st and 2nd dose

Ranged from 6-12 weeks
– Interval between 2nd and 3rd dose

Ranged from 12-23 weeks
– Variation in interval did not diminish the antibody
titre after vaccination
 Minimum
intervals:
– Between 1st and 2nd dose: 4 weeks
– Between 2nd and 3rd dose: 12 weeks
 Inadequate
doses/shorter than recommended
dosing interval should be readministered
Simultaneous Administration of
Other Vaccines
 No
contraindication:
– Can be given with other age appropriate
vaccine
– Not live vaccine with no components that
adversely impact safety or efficacy of other
vaccination
Immunocompromised Patients
 No
contraindication
– Non-infectious vaccine
– Immune response or vaccine efficacy
might be lower
Precautions / Contraindications




Can be given with minor illness such as diarrhoea or
mild URTI
Withhold in persons with moderate or severe acute
illness
Manufacturing process for GARDASIL is free of egg
or egg derivatives. Therefore, GARDASIL can be
used in subjects with egg allergy
Contraindicated with history of allergy to yeast or to
any known vaccine component
Any Therapeutic Effect ?



No therapeutic effect on existing infection / precancerous
lesions / genital warts demonstrated
However, among subcohort of women:
– HPV 16 DNA +ve / seronegative at enrollement less likely to
develop HPV 16 related CIN 2/3 than those received
placebo
– No such benefit if they were HPV 16 DNA +ve and
seropositive at enrollment
– Vaccination may have some benefit in recent infection or in
the early stage of disease (Hypothesis only)
Sub-analysis in 1,565 women who were infected with HPV at
the time of study enrollment
– 28 percent reduction in the rate of progression to CIN 2 or worse
– Not statistically significant
Role of Cervical Screening Program


Even if an ideal vaccine is developed,
reduction of cervical cancer would not
become apparent for at least a decade
Decline in abnormal pap smears, especially
in high risk groups, may become evident
within months
Role of Cervical Screening Program

Pap smear screening programs remain vital
– Millions have already been exposed to HPV

Multivalent vaccine may protect them from other HPV
types (immunological interference)
– Unless a multivalent vaccine can prevent every
type of high-risk HPV, a proportion of women will
continue to develop cervical cancer
– Certain cervical cancers may not be associated
with HPV
– Some women may not respond immunologically to
the vaccine

Efficacy in immunocompromised patients (HIV, organ
transplant) unclear
– Vaccine coverage will not be 100% especially in
under-developed and developing countries
Role of Cervical Screening Program
 Need
to continue Pap smear screening even
after vaccination
 Screening program may evolved from
cytopathology basis to DNA basis
 Need modification of screening
recommendations when more long term data
is available
– Safety and cost-effectiveness to lengthen the
screening interval
Providers should educate women about the
importance of cervical cancer screening
Other Ways to Prevent HPV Infection
 Avoid
potential cofactors involved in
HPV carcinogenesis:
– Stop smoking
– Prevent Co-infection with other STDs
(Chlamydia and Herpes)
 Use
of Condom
 Decrease the number of sexual partners
Vaccination in Males



Immunological studies showed immune response
equally well among adolescent boys and girls
Theoretically prevents Genital warts / Anal cancer in
males
Important transmission vector
– Protect females from HPV 16 and 18 infection by herd
immunity


Not licensed for use yet
Protocol 020 to evaluate young men
–
–
–
–
3870 men in 16-26 year old men
Endpoints: HPV 6/11/16/18 related external genital lesions
HPV 6/11/16/18 infection
HPV 16/18 AIN (anal cancer)
Social Acceptance
 Stigmata
of STD
– Unwilling to discuss about sexuality / STD to
children
– Concern about riskier sexual behaviors after
vaccination
– Over 80% of respondents indicated that they
would get or let their daughters get vaccinated
against cervical cancer
– Over 95% of respondents would like to know more
about the new cervical cancer vaccine
Conclusion

HPV Vaccines have high efficacy in
preventing vaccine-related anogenital
diseases
 On-going studies to establish its duration of
protection and impact on general health /
cervical cancer
 Pap smear screening is still the most
important and useful test to prevent cervical
cancer
Thank You