Table 1 Characteristics of randomised control trials included in the review

Phase

IIa

II

III

III

III

III

Age range

16-25 years

16-23 years

16-24 years

15-26 years

24-45 years

15-25 years

15-25 years

Countries included

USA

5 countries

16 countries

13 countries

38 international study sites

14 countries

North America and Brazil

Period of enrollment

October 1998 to November 1999

2002-2007

January 2002 – March 2003

June 2002 - May 2003

June 2004 - April 2005

May 2004 -June 2005

November 2003 – July 2004

Inclusion criteria

Not pregnant, no prior Pap tests and with a lifetime history of 0-5 male sex partners

Non pregnant, healthy women, no prior abnormal Pap smears, and with a lifetime history of 0-4 male sex partners. Among virgins, enrolment was limited to those 18 years and over of age and seeking contraception.

Not pregnant, reporting no prior Pap tests and lifetime history of 0-4 sex partners. No history of genital warts

Not pregnant, reporting no prior Pap tests and lifetime history of 0-4 sex partners.

Healthy non pregnant women, agreed to contraception, intact cervix, with no history of coloscopy.

Healthy non pregnant women, 0-6 sexual partners, agreed to contraception, intact cervix, with no history of coloscopy. Not breastfeeding and without chronic or autoimmune disease

Healthy women with 0-6 sexual partners. No history of abnormal Pap test or ablative or extensional treatment for external condylomata; who were cytologically negative, seronegative for HPV-16 and HPV-18 antibodies by ELISA, and HPV-DNA negative by PCR for 14 high risk HPV types, no more than 90 days before study entry.

Intervention comparator

Vaccine

HPV 16 vaccine (N = 768)

HPV-6/11/16/18 (N = 276)

HPV-6/11/16/18 (N = 2723)

HPV-6/11/16/18 (N = 6087)

HPV 6, 11, 16, 18 (N = 1911)

HPV16/18 (N = 8093)

HPV 16/18 (N = 560)

Comparator

Placebo (N = 765)

Placebo (N = 275)

Placebo (N = 2732)

Placebo (N = 6080)

Placebo (N = 1908)

Hepatitt A vaccine (N = 8069)

Placebo (N = 553)

Administration schedule

day 1, month 2 and month 6.

day 1, month 2 and month 6.

day 1, month 2 and month 6.

day 1, month 2 and month 6.

day 1, month 2 and month 6.

0,1 and 6 month

0,1 and 6 month

Length of follow up

Up to 48 months

36 months and extension study of 2 years

Up to 48 months

Up to 48 months

Median 4 years

Up to 48 months

incl 27 mths and 4,5 yrs; ≤ 8.4 yrs (Brazilian centers)

Study populations

Intention to treat (ITT)

Subjects who received at least one vaccination, included all protocol violators and subjects who tested positive for HPV-16 infection at enrollment.

Subjects who were naıve to the relevant HPV type(s) at enrolment and had received at least one vaccination

Subjects who received at least 1 dose of vaccine or placebo and returned for follow-up.

Subjects who received at least 1 dose of vaccine or placebo and returned for follow-up.

Subjects who received X1 dose of vaccine or placebo and returned for follow-up.

Total vacine cohort (TVC) included all who received at least one vaccine dose and were evaluable for efficacy, irrespctive of baseline HPV status, cytological status, and serostatus.

Subjects who had received at least one dose of study vaccine or placebo in the initial efficacy study, and who had any data available for outcome measurement in the extended follow-up phase.

Per protocol population (PPP)

Subjects who tested seronegative for HPV16 at the first study visit, tested negative for HPV16 DNA at all visits between day 1 and month 7 inclusive, and completed the entire three dose vaccine series.

Subjects who were PCR and seronegative to HPV 6, 11, 16, or 18 at enrolment, remained PCR-negative to the same vaccine-HPVtype (s) (to which they were naı¨ve at enrolment) through 1 month postdose three, received three doses of vaccine or placebo within 1 year, and did not violate the protocol.

Subjects who received all 3 doses of vaccine or placebo within 12 months. Were seronegative and HPV DNA negative on PCR analysis for HPV-6, HPV-11, HPV-16, or HPV-18.

Subjects who received all 3 doses of vaccine or placebo within 12 months. Were seronegative and HPV DNA negative on PCR analysis for HPV-6, HPV-11, HPV-16, or HPV-18.

Subjects who were seronegative at day 1 and PCR-negative (from day 1 through month 7 to the relevant vaccine HPV type(s) and did not violate the protocol.

According to protocol for efficacy (ATP-E) included all participants that received three doses of vaccine or placebo with a negative HPV DNA test, seronegative for HPV16 and/or 18 and with normal or low-grade cytology on day 1.

Subjects in the extended follow up phase who received three doses of HPV 16/18 vaccine or placebo, and who were negative for high-risk HPV DNA and seronegative for HPV 16 and 18 DNA

Safety population

Included all randomized participants

Included all randomized participants with follow-up information

Included all subjects who completed the vaccination report card from day 1 through day 15 after

Included all randomized participants with follow-up information

Included all randomized participants

Included all assessible women who did not use any investigational or non-registered product or any HPV vaccine other than study vaccine during the study period.

Outcomes used in article

HPV related CIN2+

HPV related CIN2+ VIN2+ /VaIN2+ HPV related Condyloma SAE

CIN2+ HPV related CIN2+ VIN2+ /VaIN2+ related and not Condyloma SAE

CIN2+ HPV related CIN2+ VIN2+ /VaIN2+ related and not Condyloma SAE

CIN2 Condyloma VIN2+ VaIN2+ SAE

CIN2+ HPV related CIN2+ SAE

mortality CIN2+ SAE

Risk of bias

None

None

None

None

None

None

None

Funding source

Merck Research Laboratories

Merck Research Laboratories

Merck Research Laboratories

Merck Research Laboratories

Merck Research Laboratories

GlaxoSmith Kline Biologicals

GlaxoSmith Kline Biologicals