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Training in Reproductive Health Research
Geneva, March 17 2006
Dr. Sonia R. Pagliusi
Immunization, Vaccines & Biologicals
=
;
World Health Organization
Milestones for HPV vaccines
introduction
SITES DISEASES=
Vulvar carcinom=
a
Papillomaviruses and Human Diseases
(from Pagliusi et al. 2=
005)
Cervical cancer represents 90% of HPV associated global
disease burden
(Adapted from
Globocan, 2002)
Women Cancer Mortality
Global Cancer Mortality
(Adapted from
World Health Report, 2004)
Cervical cancer is the foremost cause of women
cancer mortality in developing countries=
cancer mortality in developing countries=
Asia accounts=
for
about half of all cases
14.=
700
71.=
900
32=
.600
78.=
900
61=
.600
59.=
900
29=
.900
265=
.900
14=
2.700
2.0=
00
(global incidence ~493.=
000
and mortality ~273.000 cases, adapted from Globocan 2002)
Global distributi=
on of
annual number of
new cervical cancer cases and
mortality=
new cervical cancer cases and
mortality=
(Adapted from Munoz et =
al.,
2004)
Four HPV types are significantly associa=
ted with cervical can=
cer
worldwide
Fom Pagliusi and Aguado
2004
Regional distribu=
tion
of HPV type prevalence in cervical cancer (=
% of
all cases analysed)
»
Prophylactic vaccine candidates are being developed: Recombinant L1
proteins self-assemble into VLPs
•
•
•
•
•=
Safe, immunogenic and well tolerated =
(Harro
et al. 2001)
• Complete protection against persistent =
HPV
infections in vaccinated women has been demonstrate=
d in
independent studies (Koutsky, 2002; Harper et al. 20=
04; Villa et al.
2005)
•
Monomer
Capsomer
5x&=
#13;
Capsid*
=
72x
*courtesy from Nieland&=
#13;
HPV vaccine candidates are becoming
available
•ATT cohort analysis
•Safety Collection
•Safety Data
% w= /any AE
% w/injection site AE
% w= /any AE
% w/injection site AE
•Seroconversion
•Efficacy criteria
• <=
/span>Persistent
Infection
(Per-Pro= tocol)
(Per-Pro= tocol)
• Persistent Infection
(In= tention-To-Treat)
(In= tention-To-Treat)
• Transient or Persistent
Infection (Per-Protocol)
Infection (Per-Protocol)
•CIN
•1533 subjects
•14 days post vax
•
93% (V) vs. 92% (P)
86% (V) vs. 82% (P)
93% (V) vs. 92% (P)
86% (V) vs. 82% (P)
•99.7%
•
•100% (HPV 16)
•93% (HPV 16)
91% (HPV 16)
91% (HPV 16)
•
•100% (9 women)
•721 subjects
•7 days post vax
•
96% (V) vs. 93% (P)
95% (V) vs. 86% (P)
96% (V) vs. 93% (P)
95% (V) vs. 86% (P)
•100%
•
•100% (HPV 16/18)
•84% (HPV 16/18)
•87% (HPV 16)
•
•100% (6 women)
Merck (16)
GSK (16+18)
Koutsky et al. 2002 Harper et al. 2004<=
span
lang=3DEN-GB style=3D'font-family:"Arial Unicode MS";mso-ascii-font-family=
:"Arial Unicode MS";
mso-fareast-font-family:"Arial Unicode MS";mso-bidi-font-family:"Arial Uni=
code MS";
mso-hansi-font-family:"Arial Unicode MS";font-size:83%;color:white;mso-col=
or-index:
0;mso-special-format:lastCR;display:none'>
Summary of two independent phase IIb stu=
dies
•12,167 women aged 16-26 yrs in North and South America, Europe and Asia
• No cases of HPV 16/18-related CIN 2/3 or adenocarcinoma in situ in the completely vaccinated group
• Efficacy 100% in those vaccinated according to protocol and 97% including partially vaccinated women
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0;
visibility:hidden'>•
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0'>• 3 doses at day 1, month 2 and month 6
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0;
visibility:hidden'>•
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0;
visibility:hidden'>•
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0'>• 21 cases in the placebo group
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0;
visibility:hidden'>•
<=
span
style=3D'font-family:Arial;font-size:75%;color:white;mso-color-index:0;
visibility:hidden'>•
Results of Merck pha=
se
III study&=
#13;
•=
=
Objective
is to measure the level of protection =
conferred
by vaccine against cervical cancer
•=
=
Primary
endpoint for efficacy should be a specific =
measurable
outcome
•=
=
Outcome
should represent a beneficial effect on =
illness,
symptoms or quality of life
•=
=
Primary
endpoint determines the study design and sample si=
ze
•=
=
Secondary
endpoints can be assessed in sub-studies, e.g.=
by
staging of disease
Choice of endpoints for vaccine effi=
cacy
trials
What
public health authorities would like to know to be
convinced of the efficacy of HPV vaccines against
cervical cancer?
1.Desira=
ble
to have a globally-agreed measurable effica=
cy
endpoint
2.Time a=
nd
ethical considerations make it necess=
ary
to use surrogate endpoint, rather than invasi=
ve
cervical cancer
•=
Malignancies
develop slow and cancer as outcome or endpoint requires very
large and lengthy studies
<=
/div>
•=
State-of-art
clinical management requires that premalignant =
stages
are treated immediately
Endpoints for HPV vaccine efficacy
9-15 years
=
HPV
i=
nfection
=
Transient
i=
nfection
=
Low
grade
=
dysplasia
=
High
grade
=
dysplasia
=
Invasive
=
cancer
Persistent
infection
4-5
years=
Lab parameters: Virology:
<=
/span>
–Incident HPV infections
–Persistent HPV <=
/span>infections
Clinical and lab parameter=
s: =
Cytology/Histology
:
–LSIL and/or HSIL
=
;
CIN 1 and/or CIN2-3
> 2
=
years=
2-5
years=
~1
year<=
span
style=3D'mso-special-format:lastCR;display:none'>
The etiology of cervical
cancer and opportunities for preventi=
on
•CIN of moderate and high grade combined with virological data be used as primary endpoint for <=
span
style=3D'position:absolute;top:38.0%;left:11.42%;width:92.5%;height:5.25%'=
>proof of efficacy of HPV vaccines, and cancer as <=
span
style=3D'position:absolute;top:43.25%;left:11.42%;width:84.45%;height:5.25=
%'>secondary endpoint
•Maintain long-term follow up to document breakthrough cases, and reveal correlates of protection
•In future HPV vaccine trials in developing countries issues of including a control group need to be appropriately addressed
•Once the endpoint is demonstrated, vaccination should be offered to control group
–
Surrogate endpoints for
HPV vaccine efficacy
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•Support for the
• science base by developing
•a HPH lab network
&=
#13;
•=
Global written standards
Global measurement standards
Immunization, Vaccin=
es
& Biologicals
Vaccine quality standards
WHO products
Vaccine quality standards
WHO products
Conclusion
=
• <=
/span>Safety and immunogenicity profile of HPV vaccine <=
span
style=3D'position:absolute;top:23.0%;left:13.1%;width:91.76%;height:4.5%'>=
candidates appear satisfactory, and there is evidence that types 16 and 18 will target the majority of cases worldwide
=
=
• =
Recommended endpoint for efficacy of a cervical cancer =
vaccine is CIN of moderate or high grade, and if proven, =
vaccination may have an impact in public health problem
=
• =
In a post vaccination era it is desirable to monitor vaccine =
performance and survey the epidemiology of HPV and <=
span
lang=3DEN-GB style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bi=
di-font-family:
Arial;mso-hansi-font-family:Arial;font-size:83%;color:white;mso-color-inde=
x:
0'>cancer
=
• =
Ideally, preventive programmes should include both <=
span
lang=3DEN-GB style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bi=
di-font-family:
Arial;mso-hansi-font-family:Arial;font-size:83%;color:white;mso-color-inde=
x:
0'>primary and secondary prevention activities, including =
environmental, educational, technology and vaccination <=
span
lang=3DEN-GB style=3D'font-family:Arial;mso-ascii-font-family:Arial;mso-bi=
di-font-family:
Arial;mso-hansi-font-family:Arial;font-size:83%;color:white;mso-color-inde=
x:
0'>components
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