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Clinical Trial Results:
A Phase III Clinical Trial to Study the Immunogenicity, Tolerability, and Manufacturing Consistency of V503 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Preadolescents and Adolescents (9 to 15 year olds) with a Comparison to Young Women (16 to 26 year olds)

Summary
EudraCT number	2009-011617-25
Trial protocol	FI BE AT SE ES PL Outside EU/EEA
Global end of trial date	22 Apr 2021

Results information
Results version number	v2(current)
This version publication date	06 Apr 2023
First version publication date	08 Mar 2022
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

V503-002

ISRCTN number

US NCT number

NCT00943722

WHO universal trial number (UTN)

Sponsor organisation name

Merck Sharp & Dohme LLC

Sponsor organisation address

126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-000654-PIP01-09

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

22 Apr 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Apr 2021

Was the trial ended prematurely?

Main objective of the trial

The main objective was to demonstrate that the 9-valent HPV L1 VLP vaccine induces noninferior Geometric Mean Titers (GMTs) for serum anti-HPV 6, anti-HPV 11, anti-HPV 16, anti-HPV 18, anti-HPV 31, anti-HPV 33, anti-HPV 45, anti-HPV 52, and anti-HPV 58 in preadolescent and adolescent boys and girls 9 to 15 years of age compared to young women 16 to 26 years of age. A protocol-specified lot consistency (Lots 1, 2, 3 separate) outcome analysis in 9 to 15 year-old girls was done in the base study only. Extension studies (EXT 1 and 2) were conducted up to Month 36 and ~11 years respectively. No study vaccine was given and 16-26 year olds were excluded from extensions; per protocol, extensions provided data for 9- to15-year-old girls (Lots 1, 2, 3 pooled) and 9- to 15-year-old boys.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Aug 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Thailand: 200

Country: Number of subjects enrolled

Brazil: 50

Country: Number of subjects enrolled

Peru: 160

Country: Number of subjects enrolled

United States: 649

Country: Number of subjects enrolled

South Africa: 165

Country: Number of subjects enrolled

Belgium: 122

Country: Number of subjects enrolled

Costa Rica: 75

Country: Number of subjects enrolled

Colombia: 303

Country: Number of subjects enrolled

Austria: 46

Country: Number of subjects enrolled

Spain: 209

Country: Number of subjects enrolled

Taiwan: 159

Country: Number of subjects enrolled

Poland: 120

Country: Number of subjects enrolled

Chile: 40

Country: Number of subjects enrolled

Korea, Republic of: 149

Country: Number of subjects enrolled

Finland: 284

Country: Number of subjects enrolled

Sweden: 118

Country: Number of subjects enrolled

India: 225

Worldwide total number of subjects

3074

EEA total number of subjects

899

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

1283

Adolescents (12-17 years)

1360

Adults (18-64 years)

431

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The base study V503-002 was a 12-month study that is collecting safety and immunogenicity information for six months following the participants' third dose of study vaccine.

Screening details

Extension study 1 (EXT1) collected data to Month 36. Extension study 2 (EXT2) collected long-term data through ~11 years. No study vaccine was administered.

Period 1 title

Base Study

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Base Study: 9- to 15-Year-Old Females (Lot 1)

Arm description

Participants received the 9-valent human papillomavirus (9vHPV) L1 virus-like particle (VLP) vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Arm type

Experimental

Investigational medicinal product name

V503

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Multivalent human papillomavirus [HPV] L1 virus-like particle [VLP] vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Base Study: 9- to 15-Year-Old Females (Lot 2)

Arm description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 2.

Arm type

Experimental

Investigational medicinal product name

V503

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Multivalent HPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Base Study: 9- to 15-Year-Old Females (Lot 3)

Arm description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 3.

Arm type

Experimental

Investigational medicinal product name

V503

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Multivalent HPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Base Study: 9- to 15-Year-Old Males (Lot 1)

Arm description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Arm type

Experimental

Investigational medicinal product name

V503

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Multivalent HPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Base Study: 16- to 26-Year-Old Females (Lot 1)

Arm description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Arm type

Experimental

Investigational medicinal product name

V503

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intramuscular use

Dosage and administration details

Multivalent HPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Number of subjects in period 1	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lot 2)	Base Study: 9- to 15-Year-Old Females (Lot 3)	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)
Started	648	643	644	669	470
Vaccination 1	646	642	644	666	468
Vaccination 2	637	633	638	658	462
Vaccination 3	635	627	637	653	455
Completed	623	621	631	647	444
Not completed	25	22	13	22	26
Physician decision	1	-	-	-	1
Consent withdrawn by subject	12	13	2	13	8
Adverse event, non-fatal	-	-	-	1	-
Pregnancy	-	-	1	-	-
Lost to follow-up	12	8	10	8	11
unknown status	-	-	-	-	4
Protocol deviation	-	1	-	-	2

Period 2 title

Extension Study 1

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Extension Study: 9- to 15-Year-Old Females

Arm description

In the base study, participants received the 9vHPV L1 VLP vaccine (0.5 mL intramuscular injection) at Day 1, Month 2, and Month 6 and were evaluated at Month 7 and followed up to Month 12. In the extension studies after Month 12, the participants were followed up for safety and immunogenicity up to Month 36 (EXT1) and for immunogenicity, effectiveness, and safety up to Month 126 (~11 years postdose 3 [EXT2]).

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Extension Study: 9- to 15-Year-Old Males

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2 ^[1]	Extension Study: 9- to 15-Year-Old Females	Extension Study: 9- to 15-Year-Old Males
Started	1604	568
Completed	1489	527
Not completed	115	41
Consent withdrawn by subject	32	10
Adverse event, non-fatal	1	-
Unknown	44	21
Lost to follow-up	38	10

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Per protocol, the subject disposition for this extension study included only 2 treatment arms: 9- to 15-year-old males and 9- to15-year-old females.

Period 3 title

Extension Study 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Extension Study: 9- to 15-Year-Old Females

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Extension Study: 9- to 15-Year-Old Males

Arm description

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 3 ^[2]	Extension Study: 9- to 15-Year-Old Females	Extension Study: 9- to 15-Year-Old Males
Started	971	301
Completed	720	202
Not completed	251	99
Physician decision	1	3
Consent withdrawn by subject	137	50
Adverse event, non-fatal	1	-
Pregnancy	1	-
Lost to follow-up	111	46

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Per protocol, the subject disposition for this extension study included only 2 treatment arms: 9- to 15-year-old males and 9- to15-year-old females.

Baseline characteristics

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Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 1)

Reporting group description

Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 2)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 2.

Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 3)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 3.

Reporting group title

Base Study: 9- to 15-Year-Old Males (Lot 1)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Reporting group title

Base Study: 16- to 26-Year-Old Females (Lot 1)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Reporting group values	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lot 2)	Base Study: 9- to 15-Year-Old Females (Lot 3)	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)	Total
Number of subjects	648	643	644	669	470	3074
Age Categorical
Base Study
Units: Years
9 to 12 years	440	432	432	450	0	1754
13 to 15 years	208	211	212	219	0	850
16 to 26 years	0	0	0	0	470	470
Sex: Female, Male
Units: Participants
Female	648	643	644	0	470	2405
Male	0	0	0	669	0	669
Race
Units: Subjects
American Indian or Alaska Native	1	1	0	2	0	4
Asian	150	141	139	186	128	744
Black or African American	50	59	52	37	48	246
Multi-Racial	81	91	86	149	53	460
Native Hawaiian or Other Pacific Islander	0	0	0	3	1	4
White	366	351	367	292	240	1616
Ethnicity
Units: Subjects
Hispanic or Latino	176	191	193	195	128	883
Not Hispanic or Latino	472	452	451	474	342	2191

End points

Top of page

Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 1)

Reporting group description

Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 2)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 2.

Reporting group title

Base Study: 9- to 15-Year-Old Females (Lot 3)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 3.

Reporting group title

Base Study: 9- to 15-Year-Old Males (Lot 1)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Reporting group title

Base Study: 16- to 26-Year-Old Females (Lot 1)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Reporting group title

Extension Study: 9- to 15-Year-Old Females

Reporting group description

Reporting group title

Extension Study: 9- to 15-Year-Old Males

Reporting group description

Reporting group title

Extension Study: 9- to 15-Year-Old Females

Reporting group description

Reporting group title

Extension Study: 9- to 15-Year-Old Males

Reporting group description

Subject analysis set title

Base Study: 9- to 15-Year-Old Females (Lots 1, 2 or 3)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received the 9-valent human papillomavirus (9vHPV) L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3

Subject analysis set title

Base Study: 9- to 15-Year-Old Females (Lots 1, 2, or 3)

Subject analysis set type

Per protocol

Subject analysis set description

Participants received the multivalent HPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lots 1, 2, or 3.

Primary: Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

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End point title

Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1]) ^[1]

End point description

Serum antibody titers for HPV virus-like particles (VLPs), Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using a competitive luminex immunoassay (cLIA). Titers are reported in milli Merck Units/mL. The analysis population included 9-15-year-old females and 16-26-year-old females who received 3 vaccinations from Lot 1 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Primary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only the GMTs of girls 9 to 15 years of age compared to women 16 to 26 years of age.

End point values	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)
Number of subjects analysed	535	378
Units: milli Merck Units/mL
geometric mean (confidence interval 95%)
Anti-HPV 6 (n=517; 328)	1715.4 (1595.1 to 1844.7)	900.8 (822.3 to 986.9)
Anti-HPV 11 (n=517; 332)	1295.1 (1204.1 to 1393.0)	706.6 (645.2 to 773.8)
Anti-HPV 16 (n=529; 329)	6979.8 (6508.1 to 7485.8)	3522.6 (3223.5 to 3849.5)
Anti-HPV 18 (n=531; 345)	2153.7 (1980.4 to 2342.1)	882.7 (795.4 to 979.5)
Anti-HPV 31 (n=522; 340)	1891.6 (1745.7 to 2049.7)	753.9 (682.5 to 832.7)
Anti-HPV 33 (n=534; 354)	980.4 (911.7 to 1054.3)	466.8 (426.9 to 510.3)
Anti-HPV 45 (n=534; 368)	714.4 (651.9 to 782.8)	272.2 (243.8 to 303.9)
Anti-HPV 52 (n=533; 337)	932.9 (864.8 to 1006.4)	419.6 (381.4 to 461.5)
Anti-HPV 58 (n=531; 332)	1286.7 (1195.7 to 1384.6)	590.5 (538.2 to 647.9)

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[2]

P-value

< 0.001 ^[3]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

2.14

Notes
[2] - non-inferiority requires that the lower bound of two-sided 95% confidence interval (CI) of GMT ratio be greater than 0.67.
[3] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[4]

P-value

< 0.001 ^[5]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.98

Confidence interval

level

95%

sides

2-sided

lower limit

1.77

upper limit

2.22

Notes
[4] - Non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[5] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[6]

P-value

< 0.001 ^[7]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.44

Confidence interval

level

95%

sides

2-sided

lower limit

2.13

upper limit

2.8

Notes
[6] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[7] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[8]

P-value

< 0.001 ^[9]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

1.83

Confidence interval

level

95%

sides

2-sided

lower limit

1.63

upper limit

2.06

Notes
[8] - Non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[9] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[10]

P-value

< 0.001 ^[11]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.51

Confidence interval

level

95%

sides

2-sided

lower limit

2.21

upper limit

2.85

Notes
[10] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[11] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[12]

P-value

< 0.001 ^[13]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

1.87

upper limit

2.36

Notes
[12] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[13] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[14]

P-value

< 0.001 ^[15]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.62

Confidence interval

level

95%

sides

2-sided

lower limit

2.27

upper limit

3.03

Notes
[14] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[15] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

P-value

< 0.001 ^[17]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.22

Confidence interval

level

95%

sides

2-sided

lower limit

1.97

upper limit

2.51

Notes
[16] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[17] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Females

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[18]

P-value

< 0.001 ^[19]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.18

Confidence interval

level

95%

sides

2-sided

lower limit

1.93

upper limit

2.45

Notes
[18] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[19] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Top of page

End point title

Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] and 16- to 26-Year-Old Females [Lot 1]) ^[20]

End point description

Serum antibody titers for HPV VLPs, Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using a cLIA. Titers are reported in milli Merck Units/mL. The analysis population included 9-15-year-old males and 16-26-year-old females who received 3 vaccinations from Lot 1 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Primary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only the GMTs of males 9 to 15 years of age compared to females 16 to 26 years of age.

End point values	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)
Number of subjects analysed	570	378
Units: milli Merck Units/mL
geometric mean (confidence interval 95%)
Anti-HPV 6 (n=559; 328)	2084.7 (1944.0 to 2235.7)	900.8 (822.3 to 986.9)
Anti-HPV 11 (n=559; 332)	1487.1 (1386.5 to 1595.0)	706.6 (645.2 to 773.8)
Anti-HPV 16 (n=569; 329)	8628.9 (8065.9 to 9231.3)	3522.6 (3223.5 to 3849.5)
Anti-HPV 18 (n=567; 345)	2822.8 (2602.8 to 3061.5)	882.7 (795.4 to 979.5)
Anti-HPV 31 (n=564; 340)	2221.2 (2056.1 to 2399.5)	753.9 (682.5 to 832.7)
Anti-HPV 33 (n=567; 354)	1198.7 (1117.1 to 1286.2)	466.8 (426.9 to 510.3)
Anti-HPV 45 (n=570; 368)	907.0 (830.2 to 991.0)	272.2 (243.8 to 303.9)
Anti-HPV 52 (n=568; 337)	1037.8 (964.4 to 1116.9)	419.6 (381.4 to 461.5)
Anti-HPV 58 (n=566; 332)	1567.7 (1460.2 to 1683.1)	590.5 (538.2 to 647.9)

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

P-value

< 0.001 ^[22]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.31

Confidence interval

level

95%

sides

2-sided

lower limit

2.07

upper limit

2.59

Notes
[21] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[22] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[23]

P-value

< 0.001 ^[24]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

1.88

upper limit

2.36

Notes
[23] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[24] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[25]

P-value

< 0.001 ^[26]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.45

Confidence interval

level

95%

sides

2-sided

lower limit

2.19

upper limit

2.74

Notes
[25] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[26] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[27]

P-value

< 0.001 ^[28]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

3.2

Confidence interval

level

95%

sides

2-sided

lower limit

2.8

upper limit

3.65

Notes
[27] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[28] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[29]

P-value

< 0.001 ^[30]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.95

Confidence interval

level

95%

sides

2-sided

lower limit

2.6

upper limit

3.34

Notes
[29] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[30] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[31]

P-value

< 0.001 ^[32]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.57

Confidence interval

level

95%

sides

2-sided

lower limit

2.29

upper limit

2.88

Notes
[31] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[32] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[33]

P-value

< 0.001 ^[34]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

3.33

Confidence interval

level

95%

sides

2-sided

lower limit

2.89

upper limit

3.84

Notes
[33] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[34] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[35]

P-value

< 0.001 ^[36]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.47

Confidence interval

level

95%

sides

2-sided

lower limit

2.19

upper limit

2.79

Notes
[35] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[36] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

GMTs for HPV VLPs-Males

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[37]

P-value

< 0.001 ^[38]

Method

ANOVA

Parameter type

GMT ratio

Point estimate

2.66

Confidence interval

level

95%

sides

2-sided

lower limit

2.37

upper limit

2.98

Notes
[37] - non-inferiority requires that the lower bound of two-sided 95% CI of GMT ratio be greater than 0.67
[38] - one-sided tests of non-inferiority conducted at the alpha=0.025 level; model with a response of log individual titers and a fixed effect for comparison group

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

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End point title

Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (Lot Consistency Study) ^[39]

End point description

Serum antibody titers for HPV VLPs, Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using cLIA. Titers are reported in milli Merck Units/mL. The analysis population included 9-15-year-old females who received 3 vaccinations from Lots 1, 2, or 3 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Primary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only the GMTs across 3 lots.

End point values	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lot 2)	Base Study: 9- to 15-Year-Old Females (Lot 3)
Number of subjects analysed	535	549	565
Units: milli Merck Units/mL
geometric mean (confidence interval 95%)
Anti-HPV 6 (n=517; 536; 544)	1715.4 (1588.7 to 1852.2)	1763.3 (1635.4 to 1901.3)	1659.9 (1540.3 to 1788.7)
Anti-HPV 11 (n=517; 536; 544)	1295.1 (1197.8 to 1400.3)	1311.7 (1214.9 to 1416.3)	1232.0 (1141.7 to 1329.5)
Anti-HPV 16 (n=529; 542; 556)	6979.8 (6476.1 to 7522.8)	7292.9 (6772.7 to 7853.1)	6948.2 (6458.7 to 7474.9)
Anti-HPV 18 (n=531; 547; 563)	2153.7 (1970.9 to 2353.5)	2134.1 (1955.6 to 2329.0)	1966.6 (1804.3 to 2143.5)
Anti-HPV 31 (n=522; 542; 553)	1891.6 (1738.5 to 2058.2)	1867.8 (1719.3 to 2029.1)	1879.0 (1731.0 to 2039.6)
Anti-HPV 33 (n=534; 543; 560)	980.4 (909.2 to 1057.2)	922.7 (856.2 to 994.4)	931.1 (865.0 to 1002.3)
Anti-HPV 45 (n=534; 548; 565)	714.4 (650.1 to 785.0)	827.7 (754.1 to 908.5)	678.4 (619.0 to 743.6)
Anti-HPV 52 (n=533; 547; 562)	932.9 (860.8 to 1011.0)	1007.9 (931.0 to 1091.2)	971.2 (898.1 to 1050.3)
Anti-HPV 58 (n=531; 539; 560)	1286.7 (1190.0 to 1391.3)	1344.9 (1244.6 to 1453.3)	1208.1 (1119.6 to 1303.6)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[40]

Method

Parameter type

GMT ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.88

upper limit

1.08

Notes
[40] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[41]

Method

Parameter type

GMT ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.2

Notes
[41] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[42]

Method

Parameter type

GMT ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.11

Notes
[42] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[43]

Method

Parameter type

GMT ratio

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.19

Notes
[43] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[44]

Method

Parameter type

GMT ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

1.16

Notes
[44] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[45]

Method

Parameter type

GMT ratio

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.98

upper limit

1.26

Notes
[45] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[46]

Method

Parameter type

GMT ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.14

Notes
[46] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[47]

Method

Parameter type

GMT ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.17

Notes
[47] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[48]

Method

Parameter type

GMT ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.12

Notes
[48] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[49]

Method

Parameter type

GMT ratio

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.06

Notes
[49] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[50]

Method

Parameter type

GMT ratio

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.97

upper limit

1.26

Notes
[50] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[51]

Method

Parameter type

GMT ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.95

upper limit

1.2

Notes
[51] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0).

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[52]

Method

Parameter type

GMT ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.89

upper limit

1.13

Notes
[52] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[53]

Method

Parameter type

GMT ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.16

Notes
[53] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[54]

Method

Parameter type

GMT ratio

Point estimate

1.04

Confidence interval

level

95%

sides

2-sided

lower limit

0.91

upper limit

1.18

Notes
[54] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[55]

Method

Parameter type

GMT ratio

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

0.95

Notes
[55] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[56]

Method

Parameter type

GMT ratio

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.12

Notes
[56] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[57]

Method

Parameter type

GMT ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.17

Notes
[57] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[58]

Method

Parameter type

GMT ratio

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.94

upper limit

1.16

Notes
[58] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[59]

Method

Parameter type

GMT ratio

Point estimate

1.02

Confidence interval

level

95%

sides

2-sided

lower limit

0.9

upper limit

1.15

Notes
[59] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[60]

Method

Parameter type

GMT ratio

Point estimate

1.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.96

upper limit

1.2

Notes
[60] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[61]

Method

Parameter type

GMT ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

1.06

Notes
[61] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[62]

Method

Parameter type

GMT ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

1.16

Notes
[62] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[63]

Method

Parameter type

GMT ratio

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.85

upper limit

1.07

Notes
[63] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[64]

Method

Parameter type

GMT ratio

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.83

upper limit

1.03

Notes
[64] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[65]

Method

Parameter type

GMT ratio

Point estimate

1.24

Confidence interval

level

95%

sides

2-sided

lower limit

1.08

upper limit

1.42

Notes
[65] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

GMTs for HPV VLPs-Lot Consistency

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[66]

Method

Parameter type

GMT ratio

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

1.26

Notes
[66] - equivalence requires that the two-sided 95% CI for the ratio of the GMTs be entirely contained within the interval (0.5, 2.0)

Primary: Base Study: Percentage of Participants with Injection Site Adverse Experiences (AEs)

Top of page

End point title

Base Study: Percentage of Participants with Injection Site Adverse Experiences (AEs) ^[67] ^[68]

End point description

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine was also an AE. AEs such as redness, swelling, and pain/tenderness/soreness at the injection site were recorded. The analysis population included all participants who received at least one dose of 9vHPV vaccine and had available follow-up data. Per protocol, data from 9- to 15-year-old females were pooled regardless of lot administered.

End point type

Primary

End point timeframe

up to 5 days after any vaccination

Notes
[67] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned or conducted for this endpoint.
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only girls 9 to 15 years of age, women 16 to 26 years of age, and males 9 to 15 years of age.

End point values	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lots 1, 2 or 3)
Number of subjects analysed	662	466	1923
Units: Percentage of Participants
number (not applicable)	72.8	85.4	81.9

No statistical analyses for this end point

Primary: Base Study: Percentage of Participants with Systemic AEs

Top of page

End point title

Base Study: Percentage of Participants with Systemic AEs ^[69] ^[70]

End point description

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study vaccine, whether or not considered related to the use of the vaccine. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine was also an AE. Systemic AEs were those not categorized as injection-site AEs. The analysis population included all participants who received at least one dose of 9vHPV vaccine and had available follow-up data. Per protocol, data from 9- to 15-year-old females were pooled regardless of lot administered.

End point type

Primary

End point timeframe

up to 15 days after any vaccination

Notes
[69] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned or conducted for this endpoint.
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only girls 9 to 15 years of age, women 16 to 26 years of age, and males 9 to 15 years of age.

End point values	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lots 1, 2 or 3)
Number of subjects analysed	662	466	1923
Units: Percentage of Participants
number (not applicable)	41.8	57.1	45.0

No statistical analyses for this end point

Primary: Base Study: Percentage of Participants with Body Temperature ≥100.0°F (≥37.8ºC)

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End point title

Base Study: Percentage of Participants with Body Temperature ≥100.0°F (≥37.8ºC) ^[71] ^[72]

End point description

Participants collected their oral body temperature in the evening of their vaccination day and at the same time each day thereafter for 4 days. The maximum body temperature obtained within 5 days of any of the 3 vaccinations was recorded. The percentage of participants who had at least 1 oral body temperature reading that was ≥100.0°F (≥37.8ºC) was summarized. The analysis population included all participants who received at least one dose of 9vHPV vaccine and had available follow-up data. Per protocol, data from 9- to 15-year-old females were pooled regardless of lot administered.

End point type

Primary

End point timeframe

up to 5 days after any vaccination

Notes
[71] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned or conducted for this endpoint.
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only girls 9 to 15 years of age, women 16 to 26 years of age, and males 9 to 15 years of age.

End point values	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lots 1, 2, or 3)
Number of subjects analysed	660	463	1908
Units: Percentage of Participants
number (not applicable)	10.0	8.4	8.4

No statistical analyses for this end point

Primary: Extension Study: GMTs For Each of the HPV Types Contained in the Vaccine

Top of page

End point title

Extension Study: GMTs For Each of the HPV Types Contained in the Vaccine ^[73]

End point description

Serum antibody titers (milli Merck Units/mL) measured by cLIA to each of the 9vHPV types were assessed. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered. The analysis population included all participants who (1) Received all 3 vaccinations with the correct dose of the correct clinical material within acceptable day ranges, (2) Were seronegative by cLIA to the appropriate HPV type at Day 1, (3) Had a Month 7 serology result within an acceptable day range and (4) Had no other protocol violations that could interfere with the evaluation of participant’s immune response to the study vaccine. To be included in the analysis population for HPV 6 and 11, participants must have been seronegative by cLIA to both HPV 6 and 11 at Day 1. To be included in the analysis population for any other vaccine HPV type, participants needed to be seronegative by cLIA at Day 1 only for the HPV type being analyzed.

End point type

Primary

End point timeframe

126 months after post-vaccination 3 (Up to ~11 years)

Notes
[73] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned or conducted for this endpoint.

End point values	Extension Study: 9- to 15-Year-Old Females	Extension Study: 9- to 15-Year-Old Males
Number of subjects analysed	971	301
Units: milli Merck Units/mL
geometric mean (confidence interval 95%)
Anti-HPV 6 (n=341,176)	122.3 (111.1 to 134.7)	129.5 (112.5 to 149.1)
Anti-HPV 11 (n=332,169)	80.2 (72.5 to 88.8)	91.0 (78.4 to 105.6)
Anti-HPV 16 (n=338,173)	403.0 (357.3 to 454.5)	414.3 (353.8 to 485.3)
Anti-HPV 18 (n=347,178)	128.1 (116.7 to 140.7)	148.4 (130.2 to 169.2)
Anti-HPV 31 (n=343,177)	108.9 (97.6 to 121.6)	128.6 (111.2 to 148.8)
Anti-HPV 33 (n=344,178)	59.2 (53.7 to 65.2)	69.6 (60.7 to 79.7)
Anti-HPV 45 (n=325,169)	42.1 (37.7 to 47.1)	49.8 (43.0 to 57.8)
Anti-HPV 52 (n=348,176)	55.3 (50.5 to 60.6)	59.6 (52.0 to 68.4)
Anti-HPV 58 (n=342,175)	76.5 (69.2 to 84.6)	90.5 (78.4 to 104.6)

No statistical analyses for this end point

Primary: Extension Study: Percentage of Participants who are Seropositive to Each of the HPV Types Contained in the Vaccine

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End point title

Extension Study: Percentage of Participants who are Seropositive to Each of the HPV Types Contained in the Vaccine ^[74]

End point description

Serum antibody titers for HPV VLPs, Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined and reported in milli Merck Units/mL. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered. The analysis population included all participants who (1) Received all 3 vaccinations with the correct dose of the correct clinical material within acceptable day ranges, (2) Were seronegative by cLIA to the appropriate HPV type at Day 1, (3) Had a Month 7 serology result within an acceptable day range and (4) Had no other protocol violations that could interfere with the evaluation of participant’s immune response to the study vaccine. To be included in the analysis population for HPV 6 and 11, participants must have been seronegative by cLIA to both HPV 6 and 11 at Day 1. To be included in the analysis population for any other vaccine HPV type, participants needed to be seronegative by cLIA at Day 1 only for the HPV type being analyzed.

End point type

Primary

End point timeframe

126 months after post-vaccination 3 (Up to ~11 years)

Notes
[74] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned or conducted for this endpoint.

End point values	Extension Study: 9- to 15-Year-Old Females	Extension Study: 9- to 15-Year-Old Males
Number of subjects analysed	971	301
Units: Percentage of Participants
number (confidence interval 95%)
Anti-HPV 6 (n=341,176)	82.7 (78.3 to 86.6)	84.1 (77.8 to 89.2)
Anti-HPV 11 (n=332,169)	85.2 (81.0 to 88.9)	87.0 (81.0 to 91.7)
Anti-HPV 16 (n=338,173)	97.3 (95.0 to 98.8)	98.3 (95.0 to 99.6)
Anti-HPV 18 (n=347,178)	80.1 (75.5 to 84.2)	83.7 (77.4 to 88.8)
Anti-HPV 31 (n=343,177)	90.1 (86.4 to 93.0)	92.7 (87.8 to 96.0)
Anti-HPV 33 (n=344,178)	85.2 (81.0 to 88.8)	89.3 (83.8 to 93.4)
Anti-HPV 45 (n=325,169)	81.8 (77.2 to 85.9)	92.3 (87.2 to 95.8)
Anti-HPV 52 (n=348,176)	88.2 (84.4 to 91.4)	89.2 (83.7 to 93.4)
Anti-HPV 58 (n=342,175)	96.5 (94.0 to 98.2)	97.1 (93.5 to 99.1)

No statistical analyses for this end point

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Top of page

End point title

Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1]) ^[75]

End point description

Serum antibody titers for HPV virus-like particles (VLPs), Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using cLIA. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30, HPV Type 11: ≥16; HPV Type 16: ≥20, HPV Type 18: ≥24, HPV Type 31: ≥10, HPV Type 33: ≥8, HPV Type 45: ≥8, HPV Type 52: ≥8, and HPV Type 58: ≥8. The analysis population included 9-15-year-old females and 16-26-year-old females who received 3 vaccinations from Lot 1 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Secondary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only girls 9 to 15 years of age compared to women 16 to 26 years of age.

End point values	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)
Number of subjects analysed	535	378
Units: Percentage of Participants
number (confidence interval 95%)
Anti-HPV 6 cLIA ≥30 mMU/mL (n=517; 328)	99.8 (98.9 to 100)	99.7 (98.3 to 100)
Anti-HPV 11 cLIA ≥16 mMU/mL (n=517; 332)	100 (99.3 to 100.0)	100 (98.9 to 100.0)
Anti-HPV 16 cLIA ≥20 mMU/mL (n=529; 329)	100 (99.3 to 100.0)	100 (98.9 to 100.0)
Anti-HPV 18 cLIA ≥24 mMU/mL (n=531; 345)	99.8 (99.0 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 31 cLIA ≥10 mMU/mL (n=522; 340)	100.0 (99.3 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 33 cLIA ≥8 mMU/mL (n=534; 354)	100.0 (99.3 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 45 cLIA ≥8 mMU/mL (n=534; 368)	99.8 (99.0 to 100.0)	99.5 (98.1 to 99.9)
Anti-HPV 52 cLIA ≥8 mMU/mL (n=533; 337)	100.0 (99.3 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 58 cLIA ≥8 mMU/mL (n=531; 332)	100.0 (99.3 to 100.0)	100.0 (98.9 to 100.0)

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[76]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

1.5

Notes
[76] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[77]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

1.8

Notes
[77] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[78]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[78] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[79]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[79] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[80]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.6

Notes
[80] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[81]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[81] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[82]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

1.5

Notes
[82] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[83]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[83] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Female Seroconversion

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

913

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[84]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[84] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] versus 16- to 26-Year-Old Females [Lot 1])

Top of page

End point title

Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] versus 16- to 26-Year-Old Females [Lot 1]) ^[85]

End point description

Serum antibody titers for HPV VLPs, Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post-vaccination 3 using cLIA. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30, HPV Type 11: ≥16; HPV Type 16: ≥20, HPV Type 18: ≥24, HPV Type 31: ≥10, HPV Type 33: ≥8, HPV Type 45: ≥8, HPV Type 52: ≥8, and HPV Type 58: ≥8. The analysis population included 9-15-year-old males and 16-26-year-old females who received 3 vaccinations from Lot 1 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Secondary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[85] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only males 9 to 15 years of age compared to females 16 to 26 years of age.

End point values	Base Study: 9- to 15-Year-Old Males (Lot 1)	Base Study: 16- to 26-Year-Old Females (Lot 1)
Number of subjects analysed	570	378
Units: Percentage of Participants
number (confidence interval 95%)
Anti-HPV 6 cLIA ≥30 mMU/mL (n=559; 328)	99.8 (99.0 to 100.0)	99.7 (98.3 to 100.0)
Anti-HPV 11 cLIA ≥16 mMU/mL (n=559; 332)	100.0 (99.3 to 100.0)	100.0 (98.9 to 100.0)
Anti-HPV 16 cLIA ≥20 mMU/mL (n=569; 329)	100.0 (99.4 to 100.0)	100.0 (98.9 to 100.0)
Anti-HPV 18 cLIA ≥24 mMU/mL (n=567; 345)	100.0 (99.4 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 31 cLIA ≥10 mMU/mL (n=564; 340)	100.0 (99.3 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 33 cLIA ≥8 mMU/mL (n=567; 354)	100.0 (99.4 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 45 cLIA ≥8 mMU/mL (n=570; 368)	100.0 (99.4 to 100.0)	99.5 (98.1 to 99.9)
Anti-HPV 52 cLIA ≥8 mMU/mL (n=568; 337)	100.0 (99.4 to 100.0)	99.7 (98.4 to 100.0)
Anti-HPV 58 cLIA ≥8 mMU/mL (n=566; 332)	100.0 (99.4 to 100.0)	100.0 (98.9 to 100.0)

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[86]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.5

Notes
[86] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[87]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[87] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[88]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[88] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[89]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.6

Notes
[89] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[90]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[90] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[91]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.6

Notes
[91] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[92]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.1

upper limit

Notes
[92] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[93]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[93] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Male Seroconversion

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Males (Lot 1) v Base Study: 16- to 26-Year-Old Females (Lot 1)

Number of subjects included in analysis

948

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[94]

P-value

< 0.001

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.2

Notes
[94] - Noninferiority is demonstrated if the lower limit of the 95% CI for the percentage point difference is greater than -5. Percentage point difference was based on the Miettinen & Nurminen method.

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

Top of page

End point title

Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (Lot Consistency Study) ^[95]

End point description

Serum antibody titers for HPV VLPs, Types 6, 11, 16, 18, 31, 33, 45, 52 and 58 were determined 4 weeks post- vaccination 3 using cLIA. The serostatus cutoffs (milli Merck U/mL) for HPV types were as follows: HPV Type 6: ≥30, HPV Type 11: ≥16; HPV Type 16: ≥20, HPV Type 18: ≥24, HPV Type 31: ≥10, HPV Type 33: ≥8, HPV Type 45: ≥8, HPV Type 52: ≥8, and HPV Type 58: ≥8. The analysis population included 9-15-year-old females who received 3 vaccinations from Lot 1, 2 or 3 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

End point type

Secondary

End point timeframe

4 weeks post-vaccination 3 (Month 7)

Notes
[95] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint included only females across 3 lots.

End point values	Base Study: 9- to 15-Year-Old Females (Lot 1)	Base Study: 9- to 15-Year-Old Females (Lot 2)	Base Study: 9- to 15-Year-Old Females (Lot 3)
Number of subjects analysed	535	549	565
Units: Percentage of Participants
number (confidence interval 95%)
HPV 6 cLIA ≥30 mMU/mL(n=517; 536; 544)	99.8 (98.9 to 100.0)	99.8 (99.0 to 100.0)	99.3 (98.1 to 99.8)
HPV 11 cLIA ≥16 mMU/mL (n=517; 536; 544)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 16 cLIA ≥20 mMU/mL (n= 529; 542; 556)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 18 cLIA ≥24 mMU/mL (n= 531; 547; 563)	99.8 (99.0 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 31 cLIA ≥10 mMU/mL (n=522; 542; 553)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.8 (99.0 to 100.0)
HPV 33 cLIA ≥8 mMU/mL (534; 543; 560)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 45 cLIA ≥8 mMU/mL (n= 534; 548; 565)	99.8 (99.0 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 52 cLIA ≥8 mMU/mL (n=533; 547; 562)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)
HPV 58 cLIA ≥8 mMU/mL (n=531; 539; 560)	100.0 (99.3 to 100.0)	100.0 (99.3 to 100.0)	99.6 (98.7 to 100.0)

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[96]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[96] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[97]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[97] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 11

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[98]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[98] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[99]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[99] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[100]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.7

Notes
[100] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 6

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[101]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

0.9

Notes
[101] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[102]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[102] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[103]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.1

Notes
[103] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 18

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[104]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.5

Notes
[104] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[105]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[105] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[106]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[106] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[107]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[107] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 16

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[108]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[108] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5).

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[109]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

Notes
[109] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[110]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.5

Notes
[110] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[111]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[111] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[112]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[112] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 33

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[113]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[113] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 31

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[114]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

Notes
[114] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[115]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

1.1

Notes
[115] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 45

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[116]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[116] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[117]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[117] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[118]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[118] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[119]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[119] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1100

Analysis specification

Pre-specified

Analysis type

equivalence ^[120]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[120] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 52

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 1) v Base Study: 9- to 15-Year-Old Females (Lot 2)

Number of subjects included in analysis

1084

Analysis specification

Pre-specified

Analysis type

equivalence ^[121]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.7

Notes
[121] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

GMTs for HPV VLPs-Lot Seroconversion

Statistical analysis description

Anti-HPV 58

Comparison groups

Base Study: 9- to 15-Year-Old Females (Lot 2) v Base Study: 9- to 15-Year-Old Females (Lot 3)

Number of subjects included in analysis

1114

Analysis specification

Pre-specified

Analysis type

equivalence ^[122]

Method

Miettinen and Nurminen

Parameter type

Percentage Point Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

1.3

Notes
[122] - equivalence requires that the two-sided 95% CI for the difference in percentages between lots be entirely contained within the interval (-5, 5). Percentage point difference was based on the Miettinen & Nurminen method.

Secondary: Extension Study: Combined Incidence of Condyloma, Penile Intraepithelial Neoplasia, and Penile/Perineal/Perianal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Males

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End point title

Extension Study: Combined Incidence of Condyloma, Penile Intraepithelial Neoplasia, and Penile/Perineal/Perianal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Males

End point description

The combined incidence of penile/perineal/perianal cancer related to HPV in males was assessed. For each study participant, person-years follow-up was calculated starting from the beginning of the long-term follow-up study (i.e., Month 42 visit) or the date when the study participant reached 16 years of age, whichever came later. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered. Incidence was estimated as cases per 10,000 person-years. The primary effectiveness analysis population was the per-protocol effectiveness population, which included participants who were seronegative (by cLIA) to the relevant HPV type(s) at Day 1 (seronegative to both HPV 6 and 11 for analysis of HPV 6 and 11 HPV11-related endpoints), received all 3 doses of 9vHPV vaccine with the correct dose of the clinical material within 1 year, and had no other protocol violation that could interfere with evaluation of vaccine effectiveness.

End point type

Secondary

End point timeframe

Up to ~11 years

End point values	Extension Study: 9- to 15-Year-Old Males
Number of subjects analysed	261
Units: Cases per 10,000 person-years
number (confidence interval 95%)	0.0 (0.0 to 28.9)

No statistical analyses for this end point

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Females

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End point title

Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Females

End point description

Persistent infection is when a participant is positive to at least 1 common gene for the same HPV type in the HPV PCR assay in ≥2 cervicovaginal/external genital swab, biopsy, or definitive therapy samples at ≥2 visits, 6 months apart. Person-years follow-up was from beginning of long-term follow-up or when study participant reached 16 years of age, whichever came later. Per protocol, the extension study included 9- to 15-year-old females regardless of lot administered. Incidence was estimated as cases per 10,000 person-years. The analysis population was the per-protocol effectiveness population, which included participants who were seronegative (by cLIA) to the relevant HPV type(s) at Day 1 (seronegative to both HPV 6 and 11 for analysis of HPV 6 and 11 HPV11-related endpoints), received all 3 doses of 9vHPV vaccine with the correct dose of the clinical material within 1 year, and had no other protocol violation that could interfere with evaluation of vaccine effectiveness.

End point type

Secondary

End point timeframe

Up to ~11 years

End point values	Extension Study: 9- to 15-Year-Old Females
Number of subjects analysed	872
Units: Cases per 10,000 person-years
number (confidence interval 95%)	52.4 (33.6 to 78.0)

No statistical analyses for this end point

Secondary: Extension Study: Combined Incidence of Cervical Intraepithelial Neoplasia, Adenocarcinoma In Situ, Vulvar Intraepithelial Neoplasia, Vaginal Intraepithelial Neoplasia, and Cervical/Vulvar/Vaginal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Females

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End point title

Extension Study: Combined Incidence of Cervical Intraepithelial Neoplasia, Adenocarcinoma In Situ, Vulvar Intraepithelial Neoplasia, Vaginal Intraepithelial Neoplasia, and Cervical/Vulvar/Vaginal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Females

End point description

The combined incidence of all cervical/vulvar/vaginal cancers was assessed. Person-years follow-up was calculated starting from the beginning of the long-term follow-up study or the date when the study participant reached 16 years of age, whichever came later. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered. Incidence was estimated as cases per 10,000 person-years. The primary effectiveness analysis population was the per-protocol effectiveness population, which included participants who were seronegative (by cLIA) to the relevant HPV type(s) at Day 1 (seronegative to both HPV 6 and 11 for analysis of HPV 6 and 11 HPV11-related endpoints), received all 3 doses of 9vHPV vaccine with the correct dose of the clinical material within 1 year, and had no other protocol violation that could interfere with evaluation of vaccine effectiveness.

End point type

Secondary

End point timeframe

Up to ~11 years

End point values	Extension Study: 9- to 15-Year-Old Females
Number of subjects analysed	866
Units: Cases per 10,000 person-years
number (confidence interval 95%)	2.2 (0.1 to 12.2)

No statistical analyses for this end point

Secondary: Extension Study: Percentage of Participants with Vaccine-Related or Procedure-Related Serious Adverse Event who Received 9vHPV Vaccine at 9 to 15 Years of Age

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End point title

Extension Study: Percentage of Participants with Vaccine-Related or Procedure-Related Serious Adverse Event who Received 9vHPV Vaccine at 9 to 15 Years of Age

End point description

A serious adverse event (SAE) included a death which resulted in the participant discontinuing the study, a serious adverse experience that is considered by an investigator who is a qualified physician to be possibly, probably, or definitely vaccine related or study procedure related. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered. The analysis population included all participants who received at least 1 study vaccination in the base study and had follow-up data.

End point type

Secondary

End point timeframe

Up to ~11 years

End point values	Extension Study: 9- to 15-Year-Old Females	Extension Study: 9- to 15-Year-Old Males
Number of subjects analysed	971	301
Units: Percentage of Participants
number (not applicable)	0.0	0.0

No statistical analyses for this end point

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Males

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End point title

Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Males

End point description

Persistent infection is when a participant is positive to at least 1 common gene for the same HPV type in the HPV PCR assay in ≥2 cervicovaginal/external genital swab, biopsy, or definitive therapy samples at ≥2 visits, 6 months apart. Person-years follow-up was from beginning of long-term follow-up or when study participant reached 16 years of age, whichever came later. Incidence was estimated as cases per 10,000 person-years. The analysis population was the per-protocol effectiveness population, which included participants who were seronegative (by cLIA) to the relevant HPV type(s) at Day 1 (seronegative to both HPV 6 and 11 for analysis of HPV 6 and 11 HPV11-related endpoints), received all 3 doses of 9vHPV vaccine with the correct dose of the clinical material within 1 year, and had no other protocol violation that could interfere with evaluation of vaccine effectiveness.

End point type

Secondary

End point timeframe

Up to ~11 years

End point values	Extension Study: 9- to 15-Year-Old Males
Number of subjects analysed	265
Units: Cases per 10,000 person-years
number (confidence interval 95%)	54.6 (21.9 to 112.4)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Base Study: Up to 5 days after any vaccination for nonserious injection site AEs, Up to 15 days after any vaccination for nonserious systemic AEs, and up to 7 months for SAEs. Extension Study, and all cause mortality: Up to ~11 years post vaccination 3.

Adverse event reporting additional description

Base Study and Extension Study: All participants who received at least one dose of 9vHPV and had available follow-up data. All randomized participants were included in the all cause mortality.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Base Study: 9-to 15- Year Old Females (Lot 2)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 2.

Reporting group title

Base Study: 9-to 15- Year Old Females (Lot 1)

Reporting group description

Reporting group title

Base Study: 16-to 26- Year- Old Females Base

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Reporting group title

Extension Study: Females

Reporting group description

Reporting group title

Extension Study: Males

Reporting group description

Reporting group title

Base Study: 9-to 15- Year Old Females (Lot 3)

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 3.

Reporting group title

Base Study: 9-to 15- Year Old Males

Reporting group description

Participants received the 9vHPV L1 VLP vaccine, 0.5 mL intramuscular injection at Day 1, Month 2, and Month 6. Vaccine dose administered is obtained from manufacturing Lot 1.

Serious adverse events	Base Study: 9-to 15- Year Old Females (Lot 2)	Base Study: 9-to 15- Year Old Females (Lot 1)	Base Study: 16-to 26- Year- Old Females Base	Extension Study: Females	Extension Study: Males	Base Study: 9-to 15- Year Old Females (Lot 3)	Base Study: 9-to 15- Year Old Males
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 639 (0.31%)	6 / 643 (0.93%)	15 / 466 (3.22%)	5 / 1664 (0.30%)	0 / 580 (0.00%)	8 / 641 (1.25%)	11 / 662 (1.66%)
number of deaths (all causes)	0	0	0	2	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gun shot wound
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue injury
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	1 / 639 (0.16%)	0 / 643 (0.00%)	5 / 466 (1.07%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 5	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain injury
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical incompetence
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abortion threatened
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	1 / 1664 (0.06%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ectopic pregnancy
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foetal distress syndrome
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Premature baby
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	2 / 1664 (0.12%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 639 (0.00%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 639 (0.00%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthmatic crisis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 639 (0.00%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Acute psychosis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 639 (0.16%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	3 / 662 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated tuberculosis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	1 / 1664 (0.06%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Infectious mononucleosis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngotonsillitis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	1 / 662 (0.15%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 639 (0.00%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	1 / 641 (0.16%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	0 / 466 (0.00%)	1 / 1664 (0.06%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 639 (0.00%)	1 / 643 (0.16%)	0 / 466 (0.00%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 639 (0.00%)	0 / 643 (0.00%)	1 / 466 (0.21%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	0 / 641 (0.00%)	0 / 662 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Base Study: 9-to 15- Year Old Females (Lot 2)	Base Study: 9-to 15- Year Old Females (Lot 1)	Base Study: 16-to 26- Year- Old Females Base	Extension Study: Females	Extension Study: Males	Base Study: 9-to 15- Year Old Females (Lot 3)	Base Study: 9-to 15- Year Old Males
Total subjects affected by non serious adverse events
subjects affected / exposed	537 / 639 (84.04%)	538 / 643 (83.67%)	404 / 466 (86.70%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	554 / 641 (86.43%)	505 / 662 (76.28%)
Nervous system disorders
Headache
subjects affected / exposed	123 / 639 (19.25%)	122 / 643 (18.97%)	106 / 466 (22.75%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	113 / 641 (17.63%)	99 / 662 (14.95%)
occurrences all number	171	184	166	0	0	156	144
General disorders and administration site conditions
Injection site pain
subjects affected / exposed	513 / 639 (80.28%)	508 / 643 (79.00%)	393 / 466 (84.33%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	530 / 641 (82.68%)	465 / 662 (70.24%)
occurrences all number	1192	1177	984	0	0	1224	929
Injection site erythema
subjects affected / exposed	194 / 639 (30.36%)	184 / 643 (28.62%)	132 / 466 (28.33%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	195 / 641 (30.42%)	159 / 662 (24.02%)
occurrences all number	291	265	223	0	0	282	220
Pyrexia
subjects affected / exposed	58 / 639 (9.08%)	76 / 643 (11.82%)	43 / 466 (9.23%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	65 / 641 (10.14%)	84 / 662 (12.69%)
occurrences all number	68	91	53	0	0	75	94
Injection site swelling
subjects affected / exposed	240 / 639 (37.56%)	208 / 643 (32.35%)	154 / 466 (33.05%)	0 / 1664 (0.00%)	0 / 580 (0.00%)	227 / 641 (35.41%)	175 / 662 (26.44%)
occurrences all number	376	320	273	0	0	384	252

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Were there any global substantial amendments to the protocol? Yes

19 Jan 2010

V503-002-10-This amendment extended the duration of the immunogenicity follow-up from 7 months to 3 years duration for the 9-15 year old pre-adolescent and adolescent boys and girls.

08 Nov 2012

V503-002-20- This amendment increased the long-term immunogenicity, safety, and effectiveness follow-up of 9-15 year old girls and boys administered 9vHPV vaccine to 10 years post-dose three.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Primary: Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

Primary: Base Study: GMTs for Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

Primary: Base Study: Percentage of Participants with Injection Site Adverse Experiences (AEs)

Primary: Base Study: Percentage of Participants with Injection Site Adverse Experiences (AEs)

Primary: Base Study: Percentage of Participants with Systemic AEs

Primary: Base Study: Percentage of Participants with Systemic AEs

Primary: Base Study: Percentage of Participants with Body Temperature ≥100.0°F (≥37.8ºC)

Primary: Base Study: Percentage of Participants with Body Temperature ≥100.0°F (≥37.8ºC)

Primary: Extension Study: GMTs For Each of the HPV Types Contained in the Vaccine

Primary: Extension Study: GMTs For Each of the HPV Types Contained in the Vaccine

Primary: Extension Study: Percentage of Participants who are Seropositive to Each of the HPV Types Contained in the Vaccine

Primary: Extension Study: Percentage of Participants who are Seropositive to Each of the HPV Types Contained in the Vaccine

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1])

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] versus 16- to 26-Year-Old Females [Lot 1])

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Males [Lot 1] versus 16- to 26-Year-Old Females [Lot 1])

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

Secondary: Base Study: Percentage of Participants who Seroconvert to Each of the HPV Types Contained in the Vaccine (Lot Consistency Study)

Secondary: Extension Study: Combined Incidence of Condyloma, Penile Intraepithelial Neoplasia, and Penile/Perineal/Perianal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Males

Secondary: Extension Study: Combined Incidence of Condyloma, Penile Intraepithelial Neoplasia, and Penile/Perineal/Perianal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Males

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Females

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Females

Secondary: Extension Study: Combined Incidence of Cervical Intraepithelial Neoplasia, Adenocarcinoma In Situ, Vulvar Intraepithelial Neoplasia, Vaginal Intraepithelial Neoplasia, and Cervical/Vulvar/Vaginal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Females

Secondary: Extension Study: Combined Incidence of Cervical Intraepithelial Neoplasia, Adenocarcinoma In Situ, Vulvar Intraepithelial Neoplasia, Vaginal Intraepithelial Neoplasia, and Cervical/Vulvar/Vaginal Cancer Related to HPV 6/11/16/18/31/33/45/52/58 in Females

Secondary: Extension Study: Percentage of Participants with Vaccine-Related or Procedure-Related Serious Adverse Event who Received 9vHPV Vaccine at 9 to 15 Years of Age

Secondary: Extension Study: Percentage of Participants with Vaccine-Related or Procedure-Related Serious Adverse Event who Received 9vHPV Vaccine at 9 to 15 Years of Age

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Males

Secondary: Extension Study: Combined Incidence of HPV 6/11/16/18/31/33/45/52/58-Related Persistent Infection for a Duration of 6 Months in Males

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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