Prophylactic and

Therapeutic
HPV Vaccines
From Innovation to
Application

Anna Lissa B. Hamada, MD, PhD

Outline
HPV and CC
Prophylactic Vaccines
Safety, Efficacy and Immunogenicity
Therapeutic Vaccines
From Concept to Clinical trials
HPV and Cervical Cancer
More than 99% of cervical cancers are
associated with oncogenic HPV
Up to 80% of sexually active women will acquire
an HPV infection during their lifetime
Only oncogenic HPV can cause cervical cancer
- HPV 16, 18 > 70% cases
- HPV 16, 18, 45, 31 > 80% cases
 HPV infection is entirely epithelial

1. Stanley M. Vaccine 2006; 24: S16-22

2. Antonsson A et al. J Clin Microbiol 2003; 41: 2509-14

3. Tindle R. Nat Rev. 2002; 2: 1-7
4. Park C and Choi Y. Immunol 2005; 114: 2-10
5. Mandell G et al. Principles and Practice of Infectious Diseases. 2005: 57
6. Hildesheim A et al. JAMA 2007; 298: 743-53
7. Burd E. Clin Microbiol Rev 2003; 16: 1-17
1. Stanley M. Vaccine 2006; 24: S16-22

2. Antonsson A et al. J Clin Microbiol 2003; 41: 2509-14

3. Tindle R. Nat Rev. 2002; 2: 1-7
4. Park C and Choi Y. Immunol 2005; 114: 2-10
5. Mandell G et al. Principles and Practice of Infectious Diseases. 2005: 57
6. Hildesheim A et al. JAMA 2007; 298: 743-53
7. Burd E. Clin Microbiol Rev 2003; 16: 1-17
HPV evades the immune system

HPV is a master of evading the immune

system
Very low levels of protein, no viraemia
No cell death, no inflammation
HPV E6 and E7 genes down-regulate
interferon response
HPV 16 down regulates TLR9 responses
Infectious cycle of oncogenic HPVs
 In the absence of inflammation
Keratinocytes do not release
pro-inflammatory cytokines
No activation of Langerhan
LC Cells (LCs) and/or stromal
dendritic cells (DCs)
DCs No stimulus for DC
activation, migration, antigen
processing and presentation
HPVs evade the innate immune response and delay
activation of adaptive immunity
 Limitations of Natural Infection Immunity

• Detectable antibody levels only occur in ~50%

of women following natural infection1

• In women who have detectable antibody

levels following natural infection, their levels of
antibodies are low2
• Low antibody levels may not be
protective against re-infection1

Natural infection antibody levels are not reliably protective1

1. Viscidi R et al. Cancer Epidemiol Biomarkers Prev 2004; 13: 324-27
2. Stanley M. Vaccine 2006; 24: S16-22
High Levels of Serum Neutralizing
Antibodies are Critical for Protection1

Antibodies neutralize virus and

prevent entry into cells1
 Data suggest that antibodies in
the serum transudate to the site
Epithelium of infection2,3

Higher antibody levels in serum

correlate with higher levels at
the site of infection3,4
Basal layer

Antibodies in the Serum 1. Stanley M. HPV Today 2007; 11: 1-16

2. Stanley M. Vaccine 2006; 24: S106-13
3. Nardelli-Haefliger D et al. J Natl Cancer Inst 2003; 95: 1128
4. Presentation Poncelet S. ESPID 2007
 Impact of AS04 Adjuvant :
Higher frequency of memory B cells
HPV 16 HPV 18
Frequency of HPV specific memory B cells
000 3000
3.6 x*
Q3

1 000 Q3

2000

8000 = AS04
= [Al(OH)3]
1000 an

4000
Median

Q1 Q1
0 0
pre day 60 day 210 pre day 60 day 210

vaccination vaccination

* statistically significant (p <0.05, Wilcoxon’s test) Giannini SL, et al. Vaccine 2006; 24: 5937–49
Development of Prophylactic
Vaccines
Virus-like particles (VLPs) that target the
L1 portion of the specific HPV type
Gardasil (Merck)
Quadrivalent (6,11,16 and 18)
Cervarix (GlaxoSmithKline)
Bivalent (16 and 18)
Structure of Human Papillomavirus (HPV)
and Virus Like Particle (VLP)
 Noninfectious HPV VLP Infectious HPV

Capsid proteins:
L1

Lacks
L2 protein L2
Lacks viral DNA Viral DNA
 L1 VLPs Mimic the HPV Virion1–4

HPV VLP

1. Stanley M. Vaccine. 2006;24(Suppl 1):S16–S22.

2. Berzofsky JA, et al. J Clin Invest. 2004;114:450–462.
3. Baker TS, et al. Biophys J. 1991;60:1445–1456.
4. Chen XS, et al. Mol Cell. 2000;5:557–567.
 Immune Response to HPV Vaccine:
Proposed Mechanism1–4

1. Stanley M. Vaccine. 2006;24(Suppl 1):S16–S22.

2. Batista FD, et al. EMBO J. 2000;19:513–520.
3. Tyring SK. Curr Ther Res Clin Exp. 2000;61:584–596.
4. Chen XS, et al. Mol Cell. 2000;5:557–567.
APC
MHC
 B7

TCR
IgG
CD28

TH B
CD4
CD40L-CD40
T-helper cell
B Cell
 The Role of Antigen Presenting Cells

APC
MHC
 B7
HLADR

TCR
IgG
CD28
antibody secreting
plasma cell

CD4
TH B
CD40L-CD40
T-helper cell Memory
B cell
B Cell
 The Role of TLR4 in Immune Activation

LPS
TLR4

APC

Immed iate Long-term

defense defense
mechanisms mechan isms
Modlin RL, et al. N Engl J Med 1999, 340: 1834-5
 MPL Mode of Action

LPS MPL
TLR4

APC

Immed iate defense Long-term defense

mechan isms mechan isms

Modlin RL, et al. N Engl J Med 1999, 340: 1834-5

 HPV L1 VLP Vaccine
(Gardasil)1
Quadrivalent HPV (Types 6, 11, 16, 18)
L1 VLP vaccine
VLPs manufactured in Saccharomyces
cerevisiae
AAHS Aluminum adjuvant 225 µg per dose
0.5 mL injection volume
3 doses within 6 months : 0,2,6 months

GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
*VLP = Virus-like particle.
1. Villa LL, Costa RL, Petta CA, et al. Lancet Oncol. 2005;6:271–278.
Cervarix
Manufactured in Baculovirus
expression system
 L1-HPV 16 20µg
Highly purified L1-HPV 18 20µg
antigens

+
Adjuvant System
Alumimium hydroxide 500µg
MPL 50µg

Given at months 0,1, 6 as an intramuscular injection

 Prophylactic HPV Vaccines

EFFICACY & SAFETY

Prophylactic HPV Vaccines are clinically
effective against HPV-associated infection
and disease
Both Vaccines have a good safety profile
 Clinical trials in over 25,000 participants
demonstrated 100% efficacy of Gardasil against
pre-cancerous lesions
Gardasil prevented 95-100% of HPV 16/18/6/11-related CIN, AIS or EGL in
women not yet infected with either HPV 16, 18, 6, or 11 at baseline

Cervical Cancer Vulvar/Vaginal Cancer

100% Effective
 Against Human Papillomavirus 16- and 18- Against Human Papillomavirus 16- and 18-related
related CIN 2/3 or AIS VIN 2/3 or VaIN 2/3

Cervical Dysplasia Genital Warts

95% Effective 99% Effective

Against Human Papillomavirus 6-, 11-, 16- and Against Human Papillomavirus 6-, 11-, 16- and 18-
18-related CIN (CIN 1, CIN 2/3) or AIS related genital lesions (genital warts, VIN, VaIN)

Participants (women 16 to 26) in 33 countries around the world

1Perprotocol populations
CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ; EGL = external genital lesions; VIN/ VaIN =
Vulva/ Vaginal intraepithelial neoplasia
Data on File, MSD
 Cervarix 6.4 year Results:
Substantial Protection against
HPV-16/18 Infections and CIN Outcomes
 Cervarix AL(OH)3 Vaccine Efficacy
Endpoints*
n n % 95% CI
6 Month
0 34 100 90.0 - 100
Persistence

12 Month 0 20 100 81.8 - 100

CIN1+ 0 15 100
73.4 - 100
CIN2+ 0 7 100 51.3 - 100

*Combined analysis initial efficacy study and extended follow-up

ATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints
CIN2+ defined as CIN2, CIN3, ICC, AIS; CIN1+ defined as CIN1, CIN2, CIN3, ICC & AIS

Presentation Harper, D. SGO, Tampa Fla, USA, March 10, 2008

 Prophylactic HPV Vaccines

IMMUNOGENICITY
Gardasil: Persistence of anti-HPV Response
Anti-HPV-16

Seropositivity
Month 60 98.8%
Month 60 + 1 week 100%
Month 61 98.8%

Anti-HPV-18

Seropositivity
Month 60 64.7%
Month 60 + 1 week 97.6%
Month 61 97.7%

S.-E. Olsson et al. / Vaccine 25 (2007) 4931–

4939
Cervarix: Neutralizing Antibody Response
Anti-HPV-16
Seropositivity ≥98%
 HPV 16 & 18
~10 fold
Months
biologically active
higher titers as
Anti-HPV-18
compared to
Seropositivity ≥98% natural infection

Natural Infection

Months
Submitted and accepted - Journal of Obstetrics and Gynecology. S. Gall et Titers determined on HPV16/18 ELISA positive/ DNA negative subjects
al.
log ED50
 Impact of AS04 Adjuvant :
Higher frequency of memory B cells
HPV 16 HPV 18
Frequency of HPV specific memory B cells
16000 3000
3.6 x*
Q3
2.2 x
12000 Q3

2000

8000 = AS04
= [Al(OH)3]
1000 Median

4000
Median

Q1 Q1
0 0
pre day 60 day 210 pre day 60 day 210

vaccination vaccination

* statistically significant (p <0.05, Wilcoxon’s test) Giannini SL, et al. Vaccine 2006; 24: 5937–49
Cross protection

Brown et al., Slides presented at HPV Vaccines: Beyond Expectations CME/CE, Medscape CME
Therapeutic Vaccines
 Strategies of therapeutic
vaccines
treat established HPV infections and
could therefore have an immediate effect
on the prevalence of HPV-associated
disease and malignancies
aim to eliminate pre-existing lesions and
even malignant tumors by generating
cell-mediated immunity against HPV-
infected cells
Target antigens for Tx vaccine
Early region proteins are expressed
throughout the life cycle and regulate
progression of the disease
E6 & E7 are constitutively expressed by
HPV-associated tumors while absent in
uninfected cells
E2 functions as the master regulator and
transciptional suppressor of E6 & E7
 Therapeutic Vaccine Approaches

Live-vector-based vaccines
 ADVANT te DISADVANT potential
AGES: intercellular AGES risk of
Highly spread of toxicity
immunogen antigen associated
produ
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of available of use of live
vectors neutr vectors
Can allows for alizing may also
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 Therapeutic Vaccine Approaches

Live-vector-based vaccines
Bacterial - capable of eliciting strong E7-specific T-
cell-mediated immune responses
Listeria monocytogenes
ability to generate both CD8 + and CD4 + immune
responses
Evades phagocytosis by macrophages by secreting
listeriolysin O
deliver antigens into both MHC-I and MHC-II pathways,
inducing strong cellular immune responses
Can induce regression in solid tumors
Phase I/II clinical trials
 Therapeutic Vaccine Approaches

Live-vector-based vaccines
Viral
Vaccinia virus
High efficiency of infection
constructs encoding E7 (linked to proteins that enhance
antigen presentation in DCs) generate E7-specific
immune responses that can cause regression of E7-
expressing tumors in mice 1-3
recombinant vaccinia vector encoding an HPV-16/18
E6/E7 fusion protein, TA-HPV, evaluated in Phase I/II
clinical trials
induced T-cell-mediated immune responses in patients
with cervical intraepithelial neoplasia (CIN) 4-6
TA-HPV tested with some success in patients with VIN 7-8
and VAIN 9
1. Hsieh CJ, et al. Vaccine 2004 ; 22 : 3993 -4001; 2. Lamikanra A, J Virol 2001 ; 75 : 9654 -64;3. Lin KY, et al. Cancer Res 1996 ; 56 : 21 -6; 4. Borysiewicz LK, et al. Lancet
1996 ; 347 : 1523 -7;5. Adams M, et al. Adv Exp Med Biol 2001 ; 495 : 419 -27;6. Kaufmann AM, et al. Clin Cancer Res 2002 ; 8 : 3676 -85;7. Davidson EJ, et al.Cancer Res
2003 ; 63 : 6032 -41;8. Kang TH, et al. Cancer Res 2007 ; 67 : 802 -11
9. Baldwin PJ, et al. Clin Cancer Res 2003 ; 9 : 5205 -13
 Therapeutic Vaccine Approaches

Live-vector-based vaccines
Viral
Vaccinia virus (cont)
recombinant vaccinia vector encoding the E2 viral protein,
MVA-E2
tested in patients with CIN 10,11 and flat condyloma lesions 11
patients developed antibodies against the MVA-E2 and
generated a specific cytotoxic T lymphocyte (CTL) response
against papilloma-transformed cells11

10. Corona Gutierrez CM, et al. Hum Gene Ther 2004 ; 15 : 421 -31;11. Garcia-Hernandez E, et al. Cancer Gene Ther 2006 ; 13 : 592 -7
 Therapeutic Vaccine Approaches

Live-vector-based vaccines
Viral
Adenovirus
E2 reduced papilloma-forming sites has been observed in
rabbits1
CRT/E7 fusion delivered by a replication-deficient adenovirus
vector (Ad-CRT/E7) protected mice against E7-expressing
tumor challenge and induced a therapeutic effect against
established tumors2
engineeed to express E7 linked to:
Mycobacterium tuberculosis heat-shock protein 70 (hsp70)3
cytokine interleukin (IL)-12 4 - have been shown to induce E7-
specific immune responses in vivo

1. Brandsma JL, et al. J Virol 2004 ; 78 : 116 -23;2. Gomez-Gutierrez et al. Cancer Immunol Immunother 2007 ; 56 : 997 -1007; 3. Liu DW, et al. J Virol 2000 ; 74 :
2888 -94; 4. Jin HS, et al.Gynecol Oncol 2005 ; 97 : 559 -67; 4.
 Therapeutic Vaccine Approaches

Live-vector-based vaccines
Viral
Semliki Forest virus (SFV)
capable of inducing immune responses strong
1,2
enough to break host tolerance to HPV antigens

1. Riezebos-Brilman A, et al. Gene Ther 2005 ; 12 : 1410 -4; 2. Daemen T, et al. Antivir Ther 2004 ; 9 : 733 -42
 Therapeutic Vaccine Approaches

Peptide-/protein-based
vaccines
HPV antigenic proteins - taken up by dendritic cells
(DCs) and presented in association with the MHC class I
and/or class II pathways on human leukocyte antigen
(HLA) molecules, to mount an immune response against
the pathogen
 Therapeutic Vaccine Approaches

Peptide-based vaccines
A D e unogeni
D I s c
VA S s epitopes
N A a of HPV
TA D r antigens
G V y before
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 Therapeutic Vaccine Approaches

Peptide-based vaccines
In preclinical studies - augmenting peptide
vaccine potency by employing the intranasal
route of administration 1
linking peptides to immunostimulatory molecules
to generate protective immunity and specific
CTL responses 2
DC-activating agents such as 4′ -monophosphoryl lipid
A (MPL)
GM-CSF to increase and sustain levels of CTL
responses 3

1. Manuri PR, et al. Vaccine 2007 ; 25 : 3302 -10; 2. Qin Y, et al. Gynecol Oncol 2005 ; 96 : 475 -83; 3. Zwaveling S, et al. J Immunol 2002 ; 169 : 350 -8
 Therapeutic Vaccine Approaches

Peptide-based vaccines
Combining peptides with CpG
oligodeoxynucleotide (CpG ODN)
provides a ‘danger signal’ for Toll-like receptor 9 by
mimicking bacterial DNA, enhances the
immunogenicity 1,2
linkage of peptides to lipids
enhancement of epitopes to prevent peptide
degradation
E6 and E7 long peptides result in the control of
both established virus-induced lesions and
latently infected sites in a preclinical cottontail
rabbit papillomavirus model2

1. Chen YF, et al. J Virol 2004 ; 78 : 1333 -43;2. Daftarian P, et al. Vaccine 2006 ; 24 : 5235 -44
 Therapeutic Vaccine Approaches

Protein-based vaccines
 ADVANT es as well DISADVANT better
AGES: as need AGES antibody
Safe to responses
establish P
Easy to o than CTL
produce patient’s
HLA type o responses
Stable r APCs may
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y of MHC u MHC class I
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e- c Liposome
based may polycation
vaccin elicit DNA(LPD)
ISCOMA
TRIX

Salmonel
la
Exotoxin
A (EXA)
Heat
shock
proteins
(hsp)
 Therapeutic Vaccine Approaches

Protein-based vaccines
Fusion protein comprised of HPV-16 E7 and
Mycobacterium bovis bCG hsp65 induced CTL
responses in mice leading to tumor regression
[54]
TA-GW -a fusion of HPV-6 L2 and E7 absorbed
onto Alhydrogel
well tolerated by patients in two clinical trials and was
effective in clearing HPV genital warts in a subset of
patients [55,56]
HPV-16 E6/E7 fusion protein with the
ISCOMATRIX adjuvant has also recently been
tested in a Phase I study
significantly enhanced CD8 + T cell responses to both
E6 and E7

1. Chen YF, et al. J Virol 2004 ; 78 : 1333 -43;2. Daftarian P, et al. Vaccine 2006 ; 24 : 5235 -44
 Therapeutic Vaccine Approaches

Protein-based vaccines
TA-CIN
fusion of HPV-16 L2, E6 and E7, induced antibodies in all
the women tested and induced T cell immunity in a
subset of them, proving to be safe 1
PD-E7
mutated HPV-16 E7 fused with a fragment of
Haemophilus influenzae protein D and formulated in the
GlaxoSmithKline Biologicals adjuvant AS02B, has been
evaluated in Phase I/II clinical trials and was shown to
induce significant E7-specific CTL responses in patients
with CIN-1 and CIN-3 lesions 2
fusion of HPV-16 E7 and M. bovis hsp65 has been
shown to be well tolerated in patients with high-
grade anal intraepithelial neoplasia (AIN) 3,4
1. de Jong A, et al. Vaccine 2002 ; 20 : 3456 -64 2. Hallez S, et al. Cancer Immunol Immunother 2004 ; 53 : 642 -50; 3. Chu NR. Expert Opin Biol Ther
2003 ; 3 : 477 -86; 4. Palefsky JM, et al. AIDS (London, England) 2006 ; 20 : 1151 -5
 Therapeutic Vaccine Approaches

DNA Vaccines
Naked DNA is safe, stable, relatively easy to manufacture
and can be used to sustain the expression of antigen in
cells for longer periods of time than RNA or protein
vaccines
Furthermore, unlike live-vector vaccines, DNA vaccines
do not elicit neutralizing antibody production in the
patient, and thus can be repeatedly administered to
the same patient effectively
 Therapeutic Vaccine Approaches

DNA vaccines
 ADVAN not DISADVANT to
TAGES: elicit AGES enhance
Safe neutrali DNA the
Easy to zing may potency
produce antibod by:
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 Therapeutic Vaccine Approaches
Increase antigen-expressing
dendritic cell populations
Gene gun
linking antigen with proteins capable of
intercellular transport
HPV-16 E7 fused to herpes simplex virus type 1 VP22
(HSV-1 VP22), a viral protein with intercellular
trafficking properties
dramatically enhanced E7-specific CD8 + T-cell
responsesand generated greater antitumor effects than
DNA vaccines encoding E7 alone [66]
E7 linked to Marek’s disease virus type 1 VP22 (MDV-1
VP22), a protein with some homology to HSV-1 VP22,
and observed powerful antitumor immunity as well
[67]
 Enhance antigen expression,
processing and presentation in
dendritic cells
Codon optimization
replacing rarely used codons with more commonly
recognized codons can enhance translation of a DNA
vaccine in DCs
Linkage of antigen to proteins that target the
antigen to the endoplasmic reticulum can lead to
enhanced MHC class I antigen presentation and
greater CTL responses
E7 linked to calreticulin (CRT), a protein shown to
significantly enhance MHC class I antigen presentation,
elicited the greatest E7-specific CD8 + T-cell responses
among all the DNA vaccines tested [75]
 Enhance antigen expression,
processing and presentation in
dendritic cells
MHC-I Single chain trimer (SCT) technology
pIRES-E6- β 2m-K b - could generate increased E6 peptide-
specific CD8 + T-cell responses compared with mice
vaccinated with DNA encoding wild type E6
fusion of antigen to MHC class II-targeting molecules
redirect an antigen to the class II pathway and generate
greater CD4 + T cell responses that augment CTL responses
Sig/E7/LAMP-1, was tested in the context of a DNA vaccine
and produced greater numbers of E7-specific CD4 + T cells
and also higher E7-specific CTL activity in mice than vaccines
composed of Sig/E7 or wild-type E7 DNA alone
 Enhance dendritic cell
and T-cell interaction
DNA encoding antiapoptotic proteins
can be used to prolong DCs survival and enhance the long-
term ability of DCs to prime T cells
co-delivery of DNA encoding E7 with DNA encoding
inhibitors of apoptosis such as
B-cell leukemia/lymphoma x(BCL-xL),
B-cell lymphoma protein 2 (BCL-2),
X-linked inhibitor of apoptosis protein (XIAP) and
ominant negative caspases
enhance E7-specific CD8 + T cell responses in mice [81] .
 Enhance dendritic cell
and T-cell interaction
coadministration of DNA vaccines encoding E7
with short interfering RNA (siRNA) targeting
the key proapoptotic proteins BCL-2
homologous antagonist/killer (Bak) and
BCL2-associated X protein (Bax)
improved DC resistance to apoptotic cell death
and enhance antitumor CD8 + T cell responses
in mice [86]
 ZYC-101
A microencapsulated DNA vaccine encoding
multiple HLA-A2-restricted E7-derived epitopes,
tested in patients with CIN-2/3 lesions and in
patients with high-grade anal intra-epithelial
lesions
RESULTS
10/12 individuals with anal displasia had
increased immune responses to the peptide
epitopes encoded in the DNA vaccine
5/15 women with CIN-2/3 had complete
histological
responses and 11 induced HPV-specific T-cell
responses
 pNGVL4a-Sig/E7(detox)/hsp70)
HPV-16 E7 DNA vaccine (which abolished the Rb
binding site) linked to M. tuberculosis hsp70 was
performed in patients with CIN-2/3 lesions

RESULTS
some of the patients who received the
maximum dose of DNA vaccine
(4 mg/vaccination) showed detectable E7-
specific CD8 + T-cell immune responses
Other Vaccines

RNA replicon vaccines

Whole Cell Vaccines
DC-based vaccines
Tumor cell-based vaccines
Conclusion (1)
Available HPV Vaccines at present are
prophylactic vaccines
Both are highly effective, safe and
immunogenic
Potentially prevent 80% of CC and
precancerous lesions (including partial
protection from other types not inlcuded
in the vaccines)
However, it would take decades to see
full impact on CC incidence reduction
Conclusion (2)
The current HPV vaccines are highly
unlikely to clear established infection
thus there remains a medical need to
develop therapeutic vaccines which
potentially can accelerate reduction in CC
incidence further by broader coverage of
the population
There are a number of therapeutic
vaccines in development and early clinical
trials that show promise
Take Home Messages
All sexually active women are at risk of HPV
infection, disease and ultimately cervical cancer
To effectively control HPV-associated disease, a
concerted effort is needed from all stakeholders
Disease awareness, educational programs as
well as screening programs have to continue
despite the availability of prophylactic HPV
vaccines
The addition of therapeutic vaccines to the CC
regimen will further decrease the incidence of
cervical cancer
The future looks promising to help eradicate this
dreadful disease
Thank you