A phase III, double-blind, randomized, controlled study to evaluate the safety, immunogenicity and efficacy of GlaxoSmithKline Biologicals* HPV 16/18 L1/AS04 vaccine administered intramuscularly according to a three-dose schedule (0, 1, 6 month) in healthy adult female subjects aged 26 years and above.

Human papillomavirus (HPV) infection has been clearly established as the
central cause of cervical cancer. GlaxoSmithKline Biologicals has developed a
virus-like particle (VLP) vaccine against the high-risk types HPV-16 and HPV-18
formulated with the adjuvant AS04. AS04 is comprised of aluminium salts and
3-deacylated monophosphoryl lipid A (MPL®). In phase II studies, this vaccine
has been shown to be safe, immunogenic and efficacious in the prevention of
incident and persistent HPV-16/18 infections and associated cytological
abnormalities. Although prophylactic vaccination primarily targets adolescents
and young adults, vaccination should also be made available to older women who
may be (re-) exposed to the virus and may not have generated protective
immunity.

* To demonstrate efficacy of the candidate vaccine in the prevention of (1)
persistent infection (6-month definition) with HPV-16 or HPV-18 (by polymerase
chain reaction [PCR]) and/or (2) histopathologically-confirmed CIN1+ associated
with HPV-16 or HPV-18 cervical infection detected within the lesional component
of the cervical tissue specimen (by PCR), overall and stratified according to
initial (Month 0) HPV-16 or HPV-18 serostatus (by enzyme-linked immunosorbent
assay [ELISA]).

If efficacy is demonstrated, the following objective will be assessed
sequentially:
- To demonstrate efficacy of the candidate vaccine compared with control in the
prevention of (1) persistent infection (6-month definition) with HPV-16 or
HPV-18 (by PCR) and/or (2) histopathologically-confirmed CIN1+ associated with
HPV-16 or HPV-18 cervical infection detected using the HPV TAA, overall and
stratified according to initial (Month 0) HPV-16 or HPV-18 serostatus (by
ELISA).

A phase III, double blind, controlled, multicentre study in Asia Pacific,
Europe, Latin America and North America, with two parallel groups of 2700
subjects each:
- HPV vaccine group (receiving HPV-16/18 L1/AS04)
- control group (receiving Al(OH)3)
Treatment will be allocated by randomization (1:1). Enrollment will be
stratified per region by age and previous HPV history. Three doses of
vaccine/control will be administered intramuscularly according to a 0, 1,
6-month schedule. The duration of the study will be 84 months for each subject.
There will be seventeen scheduled visits per subject: at Month 0, 1, 6, 7, 12,
18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78 and 84.

One group will receive three HPV (HPV-16/18 L1/AS04) vaccinations (0.5ml,
intramuscular) at month 0, 1 en 6
One group will receive three control (Al(OH)3 vaccin) vaccinations (0.5ml,
intramuscular) at month 0, 1 en 6

Risks and burden are linked to the protocol procedures, such as vaccination,
blood sampling, gynaecological examination, cervical cytology and colposcopy.
Although these are routine procedures, carried out by medically qualified
personnel, they may cause side effects or discomfort to the volunteers.
However, it is expected that these procedures will generally be well-tolerated.
Previous studies with the investigational vaccine in approximately 700 healthy
adult women showed that most side effects observed (pain, redness and swelling
at the vaccination site, tiredness, gastro-intestinal complaints, fever,
itching, flu-like symptoms, sore throat) were usually mild, lasting 3-4 days,
did not require medical intervention and did not hamper the normal daily
activities. No serious, vaccine related adverse events have been reported so
far.