overview of cervical cancer vaccines meeting of the cervical cancer committee of the maryland...
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Overview of Cervical Cancer Vaccines
Meeting of the
Cervical Cancer Committee of the Maryland Comprehensive Cancer Control Panel
May 9, 2005
Allan Hildesheim
Division of Cancer Epidemiology and Genetics
National Cancer Institute
BACKGROUND
Infectious Agents Involved in Cancer Pathogenesis
1. Helicobacter Pylori (5.5%)• Stomach Cancer
2. Human Papillomaviruses (5.2%)• Cervix• Other Ano-Genital Sites• Oropharynx/Mouth
3. Hepatitis B/C Viruses (4.9%)• Liver Cancer
4. Epstein-Barr Virus (1.0%)• Burkitt’s Lymphoma• Other Lymphomas (HD/NHL)• Nasopharngeal Carcinoma (NPC)
5. HIV & HHV-8 (1.0%)• Kaposi’s Sarcoma• B-cell NHL• Leiomyosarcoma• SCC of the Conjunctiva
• Schistosomiasis (0.3%)• Bladder Cancer
• HTLV-I/II (0.1%)• ATLL
• Liver Flukes (<0.1%)• Cholangiocarcinoma
% of Cancers Attributable to Infectious Agents(Based on 2002 incidence data)
• 17.7% (1,900,000 cases) of worldwide incidence of cancer attributed to infection.
• This figure is higher (27%) in developing nations and lower (8%) in developed nations.
From Parkin, M., 2005
The Most Common Cancers in Women
Breast
Cervix
Ovary
Endometrium
Annual number of cases (thousands)
More developed countries Less developed
countries
Colon/rectum
Lung
Stomach
Adapted from Parkin et al, Eur J Cancer 37:S4, 2001
600 0200400 200 400 600
Pyramid of DiagnosesUnited States
Pyramid of DiagnosesUnited States
HSIL300,000
CA15,000
LSIL1,000,000
ASCUS2,000,000
HPV Persistence
HPV Genotypes
• Tissue tropism– Cutaneous vs. mucosal
• Cancer association– Oncogenic – Non-oncogenic – Unknown
• 13 HPV types recognized to be linked to cancer
• HPV-16 accounts for 50% of tumors
Experimental/Animal Evidence in Support of a Causal Link Between HPV and Cervical Cancer
• HPV E6/E7 proteins are capable of binding and inactivating p53 & pRb. Cancer-associated HPV types better able to do so than low-risk types.
• Integration of viral genome into host in invasive tumors invariably conserves the E6/E7 coding regions (and disrupts E2).
• BPV is linked to the development of alimentary tract cancers in cows.
• CRPV is linked to the development of skin tumors in rabbits.
HPV Infection at Baseline Predicts Subsequent Precancer and Cancer
Sherman et al. (JNCI, 2003)
02468
1 2 3 4 5 6 7 8 9 10
HPV +HPV -
Cum
ulat
ive
Inci
denc
e (%
)
Year of follow-up
Portland Results (Khan et al. [WS1-03])
Follow-up time (years)
1 2 3 4 5 6 7 8 9 10 11
Cu
mu
lati
ve in
cid
enc
e ra
te (
%)
0
5
10
15
20
HPV16+HPV18+HC2+HR HPV-
VACCINES
Two Broad Classes of HPV Vaccines
• Prophylactic • Therapeutic
Two Broad Classes of HPV Vaccines
• Prophylactico Antibody-mediated
o Rely on IR to structural proteins (L1/L2)
o Most promising candidate is the VLP-based vaccine
• Therapeutic
Two Broad Classes of HPV Vaccines
• Prophylactico Antibody-mediated
o Rely on IR to structural proteins (L1/L2)
o Most promising candidate is the VLP-based vaccine
• Therapeutico CMI-mediated
o Rely on IR to proteins required for maintenance of infection & transformation (E2/E6/E7)
HPV Vaccine Development Stages
• Pre-clinical/Animal Studies
• Phase I/IIA Safety & Immunogenicity Trials
• Phase IIB Virological Efficacy Trials (Proof-of-Principle)
• Phase III Efficacy Studies (Pivotal for Licensure)
HPV Vaccine Development Stages
Pre-clinical/Animal Studies
Evidence that Immunization with VLPs Protects Against Infection: Canine Model
0
100
0
100
0102030405060708090
100
War
tE
xtra
ct
PB
S
L1
VL
Ps
Den
. L1
VL
Ps
% Warts
ImmunogenSuzich et al, PNAS, 1995
HPV Vaccine Development Stages
Pre-clinical/Animal Studies
Phase I/IIA Safety & Immunogenicity Trials
NCI/JHU Phase I HPV Vaccine TrialMean Symptom Incidence for All
Vaccine Types and Placebo
0
20
40
60
80
100
Per
cent
Symptoms
N=177 vaccine administrations, N=35 placebo administrations
V
P
V
V
V VP
P
P P
V=Vaccine
P=Placebo *Excludes concurrent illness+ < 5 mm excluded Harro et al, JNCI 2001
1.0E+00
1.0E+01
1.0E+02
1.0E+03
1.0E+04
1.0E+05
1.0E+06
1.0E+00 1.0E+01 1.0E+02 1.0E+03 1.0E+04 1.0E+05 1.0E+06
Cervical Anti-VLP Levels (unitless)
Ser
um
An
ti-V
LP
Lev
el (
un
itle
ss)
Preimmune
2 Months
7 Months
NCI/JHU Phase IIA VLP Trial Results also Indicate that Cervical Anti-HPV16 VLP Antibody Levels Increase
Following Vaccination
Castle et al, Unpublished
HPV Vaccine Development Stages
Pre-clinical/Animal Studies
Phase I/IIA Safety & Immunogenicity Trials
Phase IIB Virological Efficacy Trials (Proof-of-Principle)
HPV16 L1 VLP Proof of Principle Efficacy Trial (1)
• Placebo controlled trial of 2392 16-23 year old women given 3 intramuscular doses of HPV16 L1 VLP vaccine with alum adjuvant.
• Analyzed 1533 women who had been fully vaccinated and who were HPV negative throughout vaccination period.
• Mean duration of follow-up: 17.4 months.
From Koutsky et al., New Eng J Med 347:1645, 2002
HPV16 L1 VLP Proof of Principle Efficacy Trial (2)
• Transient HPV16 infection: 27 cases in placebos, 6 in vaccinees.
• Persistent HPV16 infection: 41 cases in placebos, none in vacinees.
• Total incident infection (transient + persistent): 68 in placebos, 6 in vaccinees.
• HPV16 associated cytologic abnormalities: 9 in placebo (mild or moderate), none in vacinees.
From Koutsky et al., New Eng J Med 347:1645, 2002
GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Design
• Placebo controlled trial of 1113 15-25 year old women given 3 intramuscular doses of HPV16/18 L1 VLP vaccine with AS04 adjuvant.
• Analyzed 1113 (100%) women in an Intent-to-Treat (ITT) analysis, and 721 (65%) who had been fully vaccinated and who were HPV negative throughout vaccination period (ATP cohort).
• Mean duration of follow-up: 18 months.
Harper et al., The L:ancet 2004
GSK HPV16/18 L1 VLP Proof of Principle Efficacy Trial Results
ITT Analysis
010
2030
4050
6070
8090
100
HPV16 HPV18 HPV16/18
Incident InfectionsPersistent Infections
% Efficacy
Harper et al., The Lancet, 2004
*
* 100% efficacy in ATP analysis
HPV Vaccine Development Stages
Pre-clinical/Animal Studies
Phase I/IIA Safety/Immunogenicity Trials
Phase IIB Virological Efficacy Trials (Proof-of-Principle)
Phase III Efficacy Studies (Pivotal for Licensure)
Three Ongoing Efforts
Merck Pharmaceuticals – Gardasil (HPV-16/18/6/11) – Filling in US end 2005
GlaxoSmithKline Biologicals – Cervarix (HPV-16/18) – Filling in Europe 2006
National Cancer Institute in Costa Rica – (HPV-16/18 Cervarix)
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Fife et al., Vaccine 22:2943, 2004
Levels of anti-HPV16 VLP antibodies in serum up to 36 months following initial vaccination
1
10
100
1000
10000
anti
-HP
V16
VL
P I
gG
-20 -10 0 10 20
Days before and after ovulation
v49b
v34b
v49
v71
v56
v21
v34
v35
v31
Titers of anti-HPV16 VLP IgG in cervical secretions during ovulatory cycles
Nardelli et al, JNCI, 2003
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?
0 2 70
2000
4000
6000
8000
10000
012345678
An
tib
od
y T
iter
(G
MT
)
Ab
SI
Cyt
oki
ne
(pg
/ml)
Pro
lifer
atio
n (
S.I.
)
0 2 70
2000
4000
6000
8000
10000
0
100
200
300
400
An
tib
od
y T
iter
(G
MT
)
Time (month)
Ab
IL-5
IFN-g
IL-10
Induction of CMI and Humoral Responses by L1 VLP
(Pinto et. al. JID, 2003)
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?
Will vaccination protect men or reduce transmission by men to their partners?
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Could an L1-based vaccine partially protect against other HPV types or have any viral therapeutic (20 prevention) benefit?
Will vaccination protect men or reduce transmission by men to their partners?
Who should be vaccinated?
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific?
Will vaccination protect men or reduce transmission by men to their partners?
Who should be vaccinated?
Should vaccine valency be increased? If so, which types should be included?
Distribution of HPV Types in Cervical Cancer by Geographical Region
0102030405060708090
100
Africa C/SAmerica
SE Asia Europe N America
HPV 45HPV 31HPV 18HPV 16
Bosch et al, JNCI, 1995
HPV Vaccine DevelopmentMany Unanswered Questions
How long will protection last?
Could an L1-based vaccine have any therapeutic (20 prevention) benefit, and if so would that benefit be non-type-specific?
Will vaccination protect men or reduce transmission by men to their partners?
Who should be vaccinated?
Should vaccine valency be increased? If so, which types should be included?
How will an effective vaccine affect the need for cervical cancer screening?
Acknowledgements
• National Cancer Institute:
– Jay Berzofsky (immunology)
– Clayton Harro (vaccinology)
– Martha Hutchinson (cytology)
– Douglas Lowy (virology)
– Ligia Pinto (immunology)
– Mark Schiffman (epidemiology)
– John Schiller (virology)
– Mark Sherman (pathology)
– Diane Solomon (pathology)
– Sholom Wacholder (statistics)
• PEG Costa Rica:
– Mario Alfaro (cytology)– Jose Bonilla (immunology)– Concepcion Brattit (Assist PI)– Enrique Freer (virology)– Diego Guillen (pathology)– Rolando Herrero (co-PI)– Jorge Morales (colposcopy)– Ana Cecilia Rodriguez (Assist PI)– PEG Colleagues and Staff