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Table 1 Characteristics of randomized controlled trials included in the review.

From: Efficacy and Safety of Prophylactic Vaccines against Cervical HPV Infection and Diseases among Women: A Systematic Review & Meta-Analysis

 

Koutsky &

Mao et al[28, 29]

Harper

et al [8, 9]

Villa

et al [23, 30]

FUTURE I

[17, 31, 32]

FUTURE II

[25, 31, 32]

PATRICIA

[16, 33]

Muñoz

et al [18]

Phase

III

III

II

III

III

III

III

No. of study sites

16

32

5

62

90

135

38

Countries included

1

3

5

16

13

14

7

Year of study enrollment

10/1998-11/1999

11/2003-07/2004

Not reported

01/2002-03/2003

06/2002-05/2003

05/2004-06/2005

06/2004-04/2005

Funding source

Merck

GlaxoSmithKline

Merck

Merck

Merck

GlaxoSmithKline

Merck

Inclusion Criteria

Age

16-25

15-25

16-23

16-24

15-26

15-25

24-45

Lifetime no. of sexual partners

≤ 5

≤ 6

≤ 4

≤ 4

≤ 4

≤ 6

No restriction

Exclusion Criteria

Pregnancy, history of abnormal Pap smear

History of abnormal Pap smear, or ablative or excisional treatment of cervix; ongoing treatment for external condylomata; seropositive for HPV 16 or 18; DNA positive for any of 14 HR HPV in past 90 days

Pregnancy, history of abnormal Pap smear

Pregnancy, history of abnormal Pap smear or genital warts

Pregnancy, history of abnormal Pap smear

History of colposcopy, pregnancy, breastfeeding, autoimmune diseases or immunodeficiency

Pregnancy, history of genital warts, present or past cervical disease, immunocompromised

Intervention & Comparator

Vaccine component

HPV 16 VLPs

HPV 16, 18 VLPs

HPV 6, 11, 16, 18 VLPs

HPV 6, 11, 16, 18 VLPs

HPV 6, 11, 16, 18 VLPs

HPV 16, 18 VLPs

HPV 6, 11, 16, 18 VLPs

VLP amount (μg)

40

20/20

20/40/40/20

20/40/40/20

20/40/40/20

20/20

20/40/40/20

Vaccine adjuvant

225 μg AAHS

AS04 (500 μg/50 μg)

225 μg AAHS

225 μg AAHS

225 μg AAHS

AS04 (500 μg/50 μg)

225 μg AAHS

Comparator

Placebo

Placebo

Placebo

* Placebo/Placebo+Hepatitis B vaccine

Placebo

Hepatitis A vaccine

Placebo

Comparator adjuvant

225 μg AAHS

500 μg aluminium hydroxide

225 or 450 μg AAHS

225 μg AAHS

225 μg AAHS

500 μg aluminium hydroxide

225 μg AAHS

Administration schedule

month 0, 2, 6

month 0, 1, 6

months 0, 2, 6

month 0, 2, 6

month 0, 2, 6

month 0, 1, 6

month 0, 2, 6

Clinical Protocol

Frequency of HPV DNA test

6 month interval

6 month interval

6 month interval

6 month interval

6 month interval

6 month interval

6 month interval

Frequency of cytology test

6 month interval

6 month interval

6 month interval

6 month interval

12 month interval

12 month interval

6 month interval

Length of trial (months)

41.0

Initial trial: 27 Follow-up study: 53

Initial trial: 36 Follow-up study: 60

36.0 (mean)

36.0 (mean)

39.4 (mean)

26.4 (mean)

Endpoints

Primary

Persistent HPV 16 infection

Incidence infection with HPV 16, and/or 18.

Combined incidence of HPV 6, 11, 16 and/or 18-associated 6-month persistent infection, CIN1-3, AIS, VIN1-3, VaIN1-3, external genital warts and cervical, vulvar or vaginal cancer.

Incidence of HPV 6, 11, 16, and/or 18-associated genital warts, CIN1-3, VIN1-3, VaIN1-3, AIS, and cervical, vulvar or vaginal cancer

HPV 16 and/or 18-associated CIN 2-3, AIS and cervical cancer

HPV 16/18-associated CIN2+

Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, and genital warts associated with HPV 6, 11, 16 or 18, or with HPV 16 or 18 alone.

Secondary

Transient or persistent HPV 16 infection

Persistent infection with HPV 16, 18 or 16/18; HPV 16/18-associated LSIL, HSIL, CIN1-3 and cancer

  

Combined incidence of HPV 6, 11, 16 and/or 18-associated CIN1-3, AIS and cancer; Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58.

Persistent infection, CIN1-3 and AIS associated with HPV 31, 33, 45, 52, 58

Persistent infection with HPV 16, 18 or other oncogenic types; HPV 16/18-associated CIN1+; immunogenicity and safety

Combined incidence of 6-month persistent infection, CIN1-3, VIN1-3, VaIN1-3, AIS, cervical, vulvar or vaginal cancer, or genital warts associated with HPV 6 or 11

Populations for Efficacy Analysis

Per-protocol population (PPP)

All subjects that received 3 doses of vaccine/placebo; DNA negative for HPV 16 in cervical swab and biopsy from day 1 to month 7; seronegative for HPV 16 on day 1; had no protocol violation; had a month 7 visit within 14-72 days after the third vaccination

All subjects that received 3 doses of vaccine/placebo; DNA negative for 14 HR HPV on day 1; cytologically negative and seronegative for HPV 16 and 18 on day 1; had no protocol violation

All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation

All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 6, 11, 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.†

All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative for HPV 16 or 18 on day 1; remained DNA negative for the same HPV type(s) through month 7; had no protocol violation.†

All subjects that received 3 doses of vaccine/placebo; seronegative to HPV 16 or 18 on day 1; DNA negative to HPV 16 or 18 on day1 and month 6; had normal or low-grade cytology at baseline, had no protocol violation

All subjects that received 3 doses of vaccine/placebo within a year; seronegative and DNA negative in cervicovaginal swab and/or biopsy samples for HPV 6, 11, 16 or 18 on day 1; remained DNA negative to the same HPV type(s) through month 7; had no protocol violation; had one or more follow-up visits after month 7

Intention-to-treat (ITT)/Modified Intention-to-treat (MITT) population

MITT2: All subjects that received ≥1 dose of vaccine/placebo.

ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative for 14 HR HPV on day 1; had data available for outcome measurement.

MITT: All subjects that received ≥1 dose of vaccine/placebo; seronegative and DNA negative to HPV 6, 11, 16 or 18 on day 1.

ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of HPV-associated anogenital disease.

ITT: All subjects that had undergone randomization, regardless of their baseline HPV status or evidence of cervical neoplasia

ITT: All subjects that received ≥1 dose of vaccine/placebo; DNA negative to HPV 16 or 18 on day 1; had data available for outcome measurement.

ITT: All subjects that received ≥1 dose of vaccine/placebo; had one or more follow-up visits after day1.

Methodological Quality

Allocation concealment

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Blinding

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Adequate

 

Dropout/loss-to-follow-up reported

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 

Expected efficacy (1-RR)

0.75

 

0.70

 

0.80

 

0.80

 

0.80-0.90

 

0.85

 

0.80

 

Sample size calculation performed

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 

Yes

 
 

α = 0.05 (one-sided)

β = 0.10

α = 0.05 (two-sided)

β = 0.20

α = 0.05 (two-sided)

β = 0.10

α = 0.0125 (one-sided)

β = 0.09

α = 0.02055 (one-sided)

β = 0.10

α = 0.05 (two-sided)

β = 0.06

--

β = 0.13

  1. HR HPV: High-risk HPV includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68; CIN: Cervical intraepithelial neoplasia; AIS: Adenocarcinoma in situ; CIN1+: Cervical intraepithelial neoplasia grade 1 or worse, including CIN1-3, AIS and cervical cancer. CIN2+: Cervical intraepithelial neoplasia grade 2 or worse, including CIN2-3, AIS and cervical cancer; LSIL: Low-grade intraepithelial lesion; HSIL: High-grade intraepithelial lesion; VIN: Vulvar intraepithelial neoplasia; VaIN: Vaginal intraepithelial neoplasia. VLPs: Virus-like particles; AAHS: Amorphous aluminium hydroxyphosphate sulphate. AS04: 500 μg aluminum hydroxide and 50 μg 3-O-desacyl-4'-monophosphoryl lipid A; RR: Risk ratio, the ratio of event rates of vaccine and control group.
  2. * A subset of 466 subjects in the treatment arm received quadrivalent vaccine and Hepatitis B vaccine, and 467 subjects in control arm received placebo and Hepatitis B vaccine.
  3. † Per-protocol population for evaluation of cross-protection included subjects who received ≥1 vaccination and, at enrollment were seronegative and DNA negative for each of vaccine HPV types (6, 11, 16, and 18); were DNA negative for each of 10 non-vaccine types (31, 33, 35, 39, 45, 51, 52, 56, 58, and 59); and had a normal Pap test result.