Broad Spectrum HPV (Human Papillomavirus) Vaccine Study in 16-to 26-Year-Old Women (V503-001)

Conditions

Cervical Cancer, Genital Warts, Human Papillomavirus Infection, Vaginal Cancer, Vulvar Cancer

Brief summary

The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of V503 in comparison to GARDASIL. The primary hypotheses tested in the study were 1) V503 administered to 16- to 26-year-old adolescents and young women is generally well-tolerated, 2) V503 reduces combined incidence of Human Papillomavirus (HPV) Type 31/33/45/52/58-related disease compared with GARDASIL, and 3) V503 induces non-inferior geometric mean titers for HPV Type 6/11/16/18 antibodies compared with GARDASIL.

Detailed description

The study included a dose-finding evaluation of a 3-dose regimen of V503 and GARDASIL, a safety/efficacy evaluation of a 3-dose regimen of the selected V503 dose formulation and GARDASIL, and an extension consisting of 2 substudies: an evaluation of immune memory in participants receiving a fourth vaccination with V503 (Cohort 1), and an opportunity for participants who received GARDASIL in the Base Study to receive a 3-dose regimen of V503 (Cohort 2).

Joura E, Kjaer SK, Bautista O, Luxembourg A, Saah A, Giuliano A.

2025-10-301 citations

10.1097/aog.0000000000006113

Immunogenicity of the 9-valent human papillomavirus vaccine: Post hoc analysis from five phase 3 studies

Anna R. Giuliano, Joel M. Palefsky, Stephen E. Goldstone, Jacob Bornstein, Ilse De Coster et al. (16 authors)

Human Vaccines & Immunotherapeutics2025-01-223 citations

10.1080/21645515.2024.2425146

Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up

Susanne K. Kjær, Mari Nygård, Karin Sundström, Christian Munk, Sophie Berger et al. (12 authors)

Human Vaccines & Immunotherapeutics2020-12-1648 citations

10.1080/21645515.2020.1839292

Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population

Anna R. Giuliano, Elmar A. Joura, Suzanne M. Garland, Warner K. Huh, Ole-Erik Iversen et al. (15 authors)

Gynecologic Oncology2019-04-1190 citations

10.1016/j.ygyno.2019.03.253

Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries

Suzanne M. Garland, Punnee Pitisuttithum, Hys Ngan, C.-H. Cho, C -Y Lee et al. (34 authors)

The Journal of Infectious Diseases2018-03-0748 citations

10.1093/infdis/jiy133

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA, Bartholomew D, Cestero RM, Fedrizzi EN, Hirschberg AL, Mayrand MH, Ruiz-Sternberg AM, Stapleton JT, Wiley DJ, Ferenczy A, Kurman R, Ronnett BM, Stoler MH, Cuzick J, Garland SM, Kjaer SK, Bautista OM, Haupt R, Moeller E, Ritter M, Roberts CC, Shields C, Luxembourg A.

2017-09-05311 citations

10.1016/s0140-6736(17)31821-4

Antibody persistence and evidence of immune memory at 5years following administration of the 9-valent HPV vaccine.

Guevara A, Cabello R, Woelber L, Moreira ED, Joura E, Reich O, Shields C, Ellison MC, Joshi A, Luxembourg A.

2017-08-0531 citations

10.1016/j.vaccine.2017.07.017

Phase II studies to select the formulation of a multivalent HPV L1 virus-like particle (VLP) vaccine

Alain Luxembourg, Darron R. Brown, Céline Bouchard, Anna R. Giuliano, Ole-Erik Iversen et al. (13 authors)

Human Vaccines & Immunotherapeutics2015-04-2737 citations

10.1080/21645515.2015.1012010

A 9-Valent HPV Vaccine against Infection and Intraepithelial Neoplasia in Women

Elmar A. Joura, Anna R. Giuliano, Ole‐Erik Iversen, Céline Bouchard, Constance Mao et al. (27 authors)

New England Journal of Medicine2015-02-181,382 citations

10.1056/nejmoa1405044

Interventions

BIOLOGICALComparator: GARDASIL

GARDASIL (quadrivalent HPV \[Types 6, 11, 16, and 18\] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen

BIOLOGICALExperimental: V503

V503 (9-valent HPV \[Types 6, 11, 16, 18, 31, 33, 45, 52, and 58\] L1 virus-like particle vaccine), 0.5 mL injection in 3 dose regimen (and a fourth injection for Cohort 1 only).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

PREVENTION

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

FEMALE

Age

16 Years to 26 Years

Healthy volunteers

Yes

Inclusion criteria

* Female between 16- to 26-years-old * Has never had Pap testing or has only had normal Pap (Papanicolaou) test results * For the immune memory substudy in the extension (Cohort 1): was randomized to V503 in the base study and was in the per-protocol immunogenicity population for ≥1 HPV type * For the 3-dose V503 vaccination substudy in the extension (Cohort 2): was randomized to GARDASIL in the base study and received ≥1 dose of GARDASIL

Exclusion criteria

* History of an abnormal cervical biopsy result * History of a positive test for HPV * History of external genital/vaginal warts * Currently a user of any illegal drugs or an alcohol abuser * History of severe allergic reaction that required medical attention * Are pregnant * Received marketed HPV vaccine or participated in an HPV trial * Currently enrolled in a clinical trial * Currently has or has a history of certain medical conditions or is currently taking or has taken certain medications (details will be discussed at the time of consent.)

Design outcomes

Primary

Measure	Time frame	Description
Base Study: Percentage of Participants With Study Medication Withdrawn Due to an Adverse Event	Up to Month 6	An adverse event is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an adverse event.
Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	4 weeks postdose 3 in the base study	Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. Statistical analysis was performed only for HPV types contained in both vaccines.
Base Study: Percentage of Participants With One or More Adverse Event	Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)	An AE is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE.
Base Study: Percentage of Participants With One or More Injection-site Adverse Event	Up to Day 5 after any vaccination	An AE is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. AEs such as redness, swelling, and pain/tenderness/soreness at the injection site were recorded.
Base Study: Percentage of Participants With One or More Non-injection-site (Systemic) Adverse Event	Up to Day 15 after any vaccination	An AE is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. Systemic AEs were those not categorized as injection-site AEs.
Base Study: Percentage of Participants With One or More Vaccine-related Adverse Event	Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)	An AE is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE. An AE that is judged by the investigator to be definitely related, probably related, or possibly related to the study drug is defined as a vaccine-related AE.
Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis)	From Day 1 until >=30 cases accumulate, up to Month 54 in the base study	HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports data based on the protocol-specified plan of conducting hypothesis testing when at least 30 cases had accumulated. The cutoff date for this analysis was 10 April 2013. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm.
Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update)	Up to Month 54 in the base study	HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports cumulative study data through 10 March 2014. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm.

Secondary

Measure	Time frame	Description
Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Persistent Infection	Up to Month 54 in the base study	Combined Incidence of HPV Type 31/33/45/52/58-related persistent infection as determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. Persistent infection was defined as infection detected in samples from \>=2 consecutive visits 6 months (+/-1 month visit window) or longer apart. Incidence was defined as the number of cases of persistent infection per 10,000 person-years of follow-up in a treatment arm.
Base Study: Percentage of Participants Who Are Seropositive for HPV Types 6/11/16/18/31/33/45/52/58	4 weeks postdose 3	Serum antibodies to HPV types were measured with a Competitive Luminex Immunoassay. 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 Types 33, 45, 52, and 58: ≥8.

Other

Measure	Time frame	Description
Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 7 Postdose 4	Month 60 + 1 week: Day 7 postdose 4 in the Extension Study (Cohort 1)	Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. This outcome measure applied to Cohort 1 participants only.
Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Day 28 Postdose 4	Month 61: 28 days postdose 4 in the Extension Study (Cohort 1)	Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. This outcome measure applied to Cohort 1 participants only.
Extension Study: Geometric Mean Titers to HPV Types 6/11/16/18/31/33/45/52/58 at Predose 4	Month 60: predose 4 in the Extension Study (Cohort 1)	Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. This outcome measure applied to Cohort 1 participants only.

Participant flow

Pre-assignment details

A total of 15,334 participants were screened and 14,840 were randomized into the study.

Participants by arm

Arm	Count
Low-dose V503 V503 (9-Valent Human Papillomavirus \[HPV\] Vaccine) low-dose 0.5 mL injection in a 3-dose regimen in the base study.	315
Mid-dose V503 V503 (9-Valent HPV Vaccine) mid-dose 0.5 mL injection in a 3-dose regimen in the base study. A subset of participants (Cohort 1) received a fourth V503 mid-dose vaccination in the extension study.	7,106
High-dose V503 V503 (9-Valent HPV Vaccine) high-dose 0.5 mL injection in a 3-dose regimen in the base study.	310
Gardasil Gardasil (4-Valent HPV Vaccine) 0.5 mL injection in a 3-dose regimen in the base study. Participants (Cohort 2) were offered the V503 mid-dose 3-dose regimen in the extension study.	7,109
Total	14,840

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Base Study	Adverse Event	1	11	0	5
Base Study	Lost to Follow-up	12	749	9	701
Base Study	Physician Decision	0	4	0	7
Base Study	Protocol Violation	0	6	0	6
Base Study	Withdrawal by Subject	7	482	5	503
Extension Study	Adverse Event	0	0	0	5
Extension Study	Lost to Follow-up	0	0	0	77
Extension Study	Physician Decision	0	0	0	7
Extension Study	Pregnancy	0	0	0	6
Extension Study	Protocol Violation	0	0	0	11
Extension Study	Withdrawal by Subject	0	0	0	120

Baseline characteristics

Characteristic	Low-dose V503	Mid-dose V503	High-dose V503	Gardasil	Total
Age, Continuous	21.7 Years STANDARD_DEVIATION 2.4	21.9 Years STANDARD_DEVIATION 2.5	21.9 Years STANDARD_DEVIATION 2.4	21.8 Years STANDARD_DEVIATION 2.5	21.9 Years STANDARD_DEVIATION 2.5
Sex: Female, Male Female	315 Participants	7106 Participants	310 Participants	7109 Participants	14840 Participants
Sex: Female, Male Male	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	278 / 310	6,551 / 7,071	280 / 305	6,268 / 7,078	130 / 150	89 / 3,049
serious Total, serious adverse events	4 / 310	233 / 7,071	5 / 305	184 / 7,078	1 / 150	25 / 3,049

Outcome results

Primary

Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update)

HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports cumulative study data through 10 March 2014. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm.

Time frame: Up to Month 54 in the base study

Population: The Per-protocol Efficacy population included all participants who received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable day ranges, were seronegative at Day 1 and PCR negative at Day 1 through Day 7 to the relevant HPV types, and had at least 1 follow-up visit following Month 7.

Arm	Measure	Value (NUMBER)
Mid-dose V503	Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update)	0.5 Cases per 10,000 person-years follow-up
Gardasil	Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (End-of-study Update)	19.0 Cases per 10,000 person-years follow-up

95% CI: [85, 99.9]Exact test, 1-sided

Primary

Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis)

HPV Type 31/33/45/52/58-related high-grade Cervical Intraepithelial Neoplasia (CIN 2/3), Adenocarcinoma in Situ (AIS), Invasive Cervical Carcinoma, high-grade Vulvar Intraepithelial Neoplasia (VIN 2/3), high-grade Vaginal Intraepithelial Neoplasia (VaIN 2/3), vulvar cancer, or vaginal cancer were determined by clinical/pathologic criteria and positive Polymerase Chain Reaction (PCR) assay for virus subtype. This outcome measure reports data based on the protocol-specified plan of conducting hypothesis testing when at least 30 cases had accumulated. The cutoff date for this analysis was 10 April 2013. Disease incidence was defined as the number of primary efficacy cases per 10,000 person-years of follow-up in a treatment arm.

Time frame: From Day 1 until >=30 cases accumulate, up to Month 54 in the base study

Population: The Per-protocol Efficacy population included all participants who received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable day ranges, were seronegative at Day 1 and PCR negative at Day 1 through Day 7 to the relevant HPV types, and had at least 1 follow-up visit following Month 7.

Arm	Measure	Value (NUMBER)
Mid-dose V503	Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis)	0.5 Cases per 10,000 person-years follow-up
Gardasil	Base Study: Combined Incidence of HPV Type 31/33/45/52/58-related Disease (Test of Hypothesis)	15.8 Cases per 10,000 person-years follow-up

p-value: <0.000195% CI: [80.9, 99.8]Exact test, 1-sided

Primary

Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58

Serum antibodies to HPV types 6/11/16/18/31/33/45/52/58 were measured with a Competitive Luminex Immunoassay. Titers are reported in milli Merck Units/mL. Statistical analysis was performed only for HPV types contained in both vaccines.

Time frame: 4 weeks postdose 3 in the base study

Population: The Per-protocol Immunogenicity population included all participants who were not protocol violators, received all 3 vaccinations of mid-dose V503 or Gardasil within acceptable ranges, were seronegative at Day 1 and PCR negative from Day 1- Month 7 for the relevant HPV types, and had a Month 7 serum sample collected within an acceptable range

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 11 (n=3995, 3982)	666.3 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 33 (n=4702, 4691)	415.9 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 18 (n=4539, 4541)	804.6 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 45 (n=4792, 4750)	252.8 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 16 (n=4032, 4062)	3131.1 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 52 (n=4455, 4335)	379.7 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 31 (n=4466, 4377)	658.4 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 58 (n=4486, 4446)	482.5 milli Merck U/mL
Mid-dose V503	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 6 (n=3993, 3975)	893.1 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 58 (n=4486, 4446)	NA milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 6 (n=3993, 3975)	875.2 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 11 (n=3995, 3982)	830.0 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 16 (n=4032, 4062)	3156.6 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 18 (n=4539, 4541)	678.7 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 31 (n=4466, 4377)	9.7 milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 33 (n=4702, 4691)	NA milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 45 (n=4792, 4750)	NA milli Merck U/mL
Gardasil	Base Study: Geometric Mean Titers (GMTs) to HPV Types 6/11/16/18/31/33/45/52/58	Anti-HPV Type 52 (n=4455, 4335)	NA milli Merck U/mL

Comparison: Anti-HPV Type 6p-value: <0.00195% CI: [0.99, 1.06]ANOVA

Comparison: Anti-HPV Type 11p-value: <0.00195% CI: [0.77, 0.83]ANOVA

Comparison: Anti-HPV Type 16p-value: <0.00195% CI: [0.96, 1.03]ANOVA

Comparison: Anti-HPV Type 18p-value: <0.00195% CI: [1.14, 1.23]ANOVA

Primary

Base Study: Percentage of Participants With One or More Adverse Event

An AE is 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 product. Any worsening of a preexisting condition which is temporally associated with the use of the study vaccine is also an AE.

Time frame: Up to Month 7 (low- and high-dose V503) or up to Month 54 (mid-dose V503 and Gardasil)