Immunogenicity of GlaxoSmithKline Biological's Human Papillomavirus (HPV) Vaccine (580299) Versus Merck's Gardasil® in Healthy Females 18-45 Years of Age

Infections, Papillomavirus Clinical Trial

Official title:

Phase IIIb, Observer-blind Study to Compare Immunogenicity of GSK Biologicals' HPV-16/18 L1/AS04 Vaccine Versus Gardasil® [Quadrivalent Human Papillomavirus (HPV-6,11,16,18 L1 VLP) Recombinant Vaccine Merck & Co., Inc.]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00423046
• Other study ID #: 108933
• Status: Completed
• Phase: Phase 3
• Start date: January 24, 2007
• Est. completion date: May 14, 2012

Study information

• Verified date: December 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

HPV infection has been established as a necessary cause of cervical cancer. GSK Biologicals has developed an HPV-16/18 L1 VLP AS04 vaccine (Cervarix TM) which targets the 2 most common oncogenic HPV types (HPV-16 and HPV-18), found in > 70%, approximately, of all cervical cancers. Recently, Merck's HPV vaccine Gardasil® [quadrivalent human papillomavirus (HPV-6,11,16,18 L1 VLP) recombinant vaccine] has been approved by the FDA for prevention of genital tract cancers and pre-cancers and genital warts in females. Although the GSK HPV vaccine and Gardasil® have different compositions and are expected to have different efficacy profiles, each vaccine targets prevention of HPV-16 and 18 genital tract cancers and pre-cancers. Therefore, a comparison of the immunogenicity of the two vaccines is warranted. This Phase 3b study is designed to compare the immunogenicity of the GSK vaccine (HPV-16/18) to Gardasil® in healthy adult females 18-45 years of age.

The Protocol Posting has been updated as the study will be extended by 3 additional years.

Description:

This Protocol Posting has been updated following Protocol Amendment 25, November 2010

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1106
• Est. completion date: May 14, 2012
• Est. primary completion date: March 7, 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• A woman whom the investigator believes that she or her legally acceptable representative (in the event that the subject is illiterate) can and will comply with the requirements of the protocol (e.g., completion of the diary cards, return for follow-up visits).

• A woman between and including 18 and 45 years of age at the time of the first vaccination.

• Written informed consent must be obtained from the subject prior to enrollment.

• Subject must be free of obvious health problems as established by medical history and history-directed clinical examination before entering into the study.

• Subject must have a negative urine pregnancy test.

• Subject must be of non-childbearing potential, or if she is of child bearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for 2 months after completion of the vaccination series.

• Subject must have an intact cervix.

Exclusion Criteria:

• Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period up to Month 60.

• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose or planned administration during the study period up to Month 60.

• Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after (i.e. days 0-29) each dose of vaccine. Administration of routine vaccines up to 8 days before each dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.

• Pregnant or breastfeeding. Women must be at least 3 months post-pregnancy and not breastfeeding to enter the study.

• A woman planning to become pregnant or planning to discontinue contraceptive precautions during approximately the first eight months of the study (Months 0-8).

• Previous administration of components of the investigational vaccine

• Previous or planned vaccination against HPV outside of this protocol.

• Any medically diagnosed or suspected immunodeficient condition based on medical history and physical examination.

• History of allergic disease, suspected allergy or reactions likely to be exacerbated by any component of the study vaccines.

• Hypersensitivity to latex.

• Known acute or chronic, clinically significant pulmonary, cardiovascular, neurologic, hepatic or renal functional abnormality, as determined by previous physical examination or laboratory tests.

• History of significant medical conditions and currently under treatment.

• Received immunoglobulins and/or blood product within 90 days preceding enrolment or planned administration during the study period up to Month 60. Enrollment will be deferred until the subject is outside of specified window.

• Acute disease at the time of enrolment. Enrollment will be deferred until condition is resolved. All vaccines can be administered to persons with a minor illness

• Heavy bleeding (menstruation or other) or heavy vaginal discharge in which a pelvic exam cannot be performed. Enrollment will be deferred until condition is resolved according to investigator's medical judgement.

Related Conditions & MeSH terms

• Infection
• Infections, Papillomavirus
• Papillomavirus Vaccines

Intervention

Biological:
• GSK Biologicals HPV 16/18 vaccine 580299 (CervarixTM)
Three doses administered intramuscularly at months 0, 1 and 6
• Gardasil ® (Merck & Co. Inc)
Three doses administered intramuscularly at months 0, 2 and 6
• Placebo
One dose administered intramuscularly at month 1 to maintain blinding
• Placebo
One dose administered intramuscularly at month 2 to maintain blinding

Locations

Country	Name	City	State
United States	GSK Investigational Site	Arkansas City	Kansas
United States	GSK Investigational Site	Atlanta	Georgia
United States	GSK Investigational Site	Aurora	Colorado
United States	GSK Investigational Site	Austin	Texas
United States	GSK Investigational Site	Bardstown	Kentucky
United States	GSK Investigational Site	Boise	Idaho
United States	GSK Investigational Site	Boynton Beach	Florida
United States	GSK Investigational Site	Bronx	New York
United States	GSK Investigational Site	Carnegie	Pennsylvania
United States	GSK Investigational Site	Chandler	Arizona
United States	GSK Investigational Site	Chapel Hill	North Carolina
United States	GSK Investigational Site	Chaska	Minnesota
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Coral Gables	Florida
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Fort Worth	Texas
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Lancaster	Pennsylvania
United States	GSK Investigational Site	Louisville	Colorado
United States	GSK Investigational Site	Miami	Florida
United States	GSK Investigational Site	Milford	Massachusetts
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Omaha	Nebraska
United States	GSK Investigational Site	Philadelphia	Pennsylvania
United States	GSK Investigational Site	Saint Paul	Minnesota
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	San Diego	California
United States	GSK Investigational Site	San Francisco	California
United States	GSK Investigational Site	Stevensville	Michigan
United States	GSK Investigational Site	Tacoma	Washington
United States	GSK Investigational Site	Upper Saint Clair	Pennsylvania
United States	GSK Investigational Site	Vista	California
United States	GSK Investigational Site	Walla Walla	Washington
United States	GSK Investigational Site	Warwick	Rhode Island
United States	GSK Investigational Site	Wenatchee	Washington
United States	GSK Investigational Site	West Covina	California
United States	GSK Investigational Site	Wichita	Kansas
United States	GSK Investigational Site	Willoughby Hills	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (9)

Coursaget P et al. (2011) Priming as a basis for long-term protection and implications for HPV vaccination. Gynecologic Oncology . 121:S1-S9.

Coursaget P et al. (2011) Priming as a basis for long-term protection and implications for HPV vaccination. Gynecologic Oncology. 121:S1-S9.

Einstein MH, Baron M, Levin MJ, Chatterjee A, Edwards RP, Zepp F, Carletti I, Dessy FJ, Trofa AF, Schuind A, Dubin G; HPV-010 Study Group. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin. 2009 Oct;5(10):705-19. Epub 2009 Oct 14. — View Citation

Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S, Rosen J, Chakhtoura N, Lebacq M, van der Most R, Moris P, Giannini SL, Schuind A, Datta SK, Descamps D; HPV-010 Study Group. Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years. Hum Vaccin. 2011 Dec;7(12):1359-73. doi: 10.4161/hv.7.12.18282. Epub 2011 Dec 1. — View Citation

Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S, Rosen J, Chakhtoura N, Meric D, Dessy FJ, Datta SK, Descamps D, Dubin G; HPV-010 Study Group. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years. Hum Vaccin. 2011 Dec;7(12):1343-58. doi: 10.4161/hv.7.12.18281. Epub 2011 Dec 1. — View Citation

Einstein MH, Levin MJ, Chatterjee A, Chakhtoura N, Takacs P, Catteau G, Dessy FJ, Moris P, Lin L, Struyf F, Dubin G; HPV-010 Study Group. Comparative humoral and cellular immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: follow-up through Month 48 in a Phase III randomized study. Hum Vaccin Immunother. 2014;10(12):3455-65. doi: 10.4161/hv.36117. — View Citation

Einstein MH, Takacs P, Chatterjee A, Sperling RS, Chakhtoura N, Blatter MM, Lalezari J, David MP, Lin L, Struyf F, Dubin G; HPV-010 Study Group. Comparison of long-term immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: end-of-study analysis of a Phase III randomized trial. Hum Vaccin Immunother. 2014;10(12):3435-45. doi: 10.4161/hv.36121. — View Citation

Schwarz TF, Kocken M, Petäjä T, Einstein MH, Spaczynski M, Louwers JA, Pedersen C, Levin M, Zahaf T, Poncelet S, Hardt K, Descamps D, Dubin G. Correlation between levels of human papillomavirus (HPV)-16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Hum Vaccin. 2010 Dec;6(12):1054-61. Epub 2010 Dec 1. — View Citation

Verstraeten T, Descamps D, David MP, Zahaf T, Hardt K, Izurieta P, Dubin G, Breuer T. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Vaccine. 2008 Dec 2;26(51):6630-8. doi: 10.1016/j.vaccine.2008.09.049. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibodies	Titers are displayed as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum.	At Month 7
Secondary	Titers of Anti-human Papilloma Virus 16 (Anti-HPV-16) and Anti-human Papilloma Virus 18 (Anti-HPV-18) Neutralizing Antibodies	Titers are given as Geometric Mean Titers (GMTs). Titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum.; Data for Month 7 on subjects aged 18 to 26 years are given in the outcome above as a primary outcome measure.	At Month 6, 7, 12, 18, 24, 36, 48 and 60
Secondary	Number of Subjects With Antibody Titers (Neutralizing Assay) Against Other Oncongenic HPV Types Greater Than or Equal to the Cut-off Value	Other oncogenic HPV types include HPV-31 and HPV-45. The titer value (=serum dilution giving a 50 percent reduction of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both other oncogenic types HPV-31 and HPV-45.	At Month 7
Secondary	Titers of Antibodies to Other Oncogenic HPV Types Measured by Neutralization Assay	Other Oncogenic Types include HPV-31 and HPV-45. Titers were measured by neutralization assay and are given as Geometric Mean Titers (GMTs). The titer is the serum dilution giving a 50 percent reduction of the signal compared to a control without serum	At Month 7
Secondary	Number of Subjects With Antibody Titers (Neutralizing Assay) Against Human Papilloma Virus 16 (Anti-HPV-16) and Human Papilloma Virus 18 (Anti-HPV-18) Greater Than or Equal to the Cut-off Value	The titer value (=serum dilution giving a 50 percent reduction of the signal compared to a control without serum) used as the cut-off for seroconversion was 40 for both HPV-16 and HPV-18.	At Month 6, 7, 12, 18, 24, 36, 48 and 60
Secondary	Number of Subjects With Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibody Titers Above Cut-off Values, Measured by Enzyme-linked Immunosorbent Assay (ELISA)	Cut-off values assessed were greater than or equal to 8 ELISA units per milliliter (EL.U/mL) for HPV-16 and greater than or equal to 7 EL.U/mL for HPV-18.	At Month 6, 7, 12, 18, 24, 36, 48 and 60
Secondary	Titers of Anti-HPV-16 and Anti-HPV-18 Immunoglobulin G (IgG) Antibodies Measured by Enzyme-linked Immunosorbent Assay (ELISA)	Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).	At Month 6, 7, 12, 18, 24, 36, 48 and 60
Secondary	Number of Subjects With Antibody Titers to Other Oncogenic HPV Types Greater Than or Equal to a Cut-off Value, Measured by Enzyme-linked Immunosorbent Assay (ELISA)	Other oncogenic types include HPV-31 and HPV-45. Cut-off values assessed were greater than or equal 59 EL.U/mL in the sera of subjects seronegative before vaccination.	At Month 6, 7, 12, 18, 24, 36 and 48
Secondary	Titers of Antibodies to Other Oncogenic HPV Types Measured by Enzyme-linked Immunosorbent Assay (ELISA)	Other oncogenic types include HPV-31 and HPV-45. Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).	At Month 6, 7, 12, 18, 24, 36 and 48
Secondary	Number of HPV-16 and HVP-18 Specific CD4 Cells Producing at Least 2 Different Cytokines Per Million of CD4 T Cells	Number of cells were expressed as geometric mean, minimum and maximum values of specific CD4 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD4 T-cells.	At Month 7, 12, 18, 24, 36 and 48
Secondary	Number of HPV-16 and HVP-18 Specific CD8 Cells Producing at Least 2 Different Cytokines Per Million of CD8 T Cells	Data were expressed as geometric mean, minimum and maximum values of specific CD8 cells producing at least 2 cytokines (CD40 Ligand, Interleukin-2, Tumor Necrosis Factor Alpha or Interferon-gamma) per million of CD8 T-cells.; Analyses for further time points were not performed, as there was no response at these time points.	At Month 7, 12 and 18
Secondary	Number of HPV-16 and HVP-18 Specific B-cells Per Million B Cells	HPV-16 and HPV-18 Specific Memory B Cells were measured by Enzyme-linked immunosorbent spot (ELISPOT) assay and expressed as geometric mean, minimum and maximum values of specific B-cells per million of cells.	At Month 7, 12, 18, 24, 36 and 48
Secondary	Titers of HPV-16 IgG and HPV-18 IgG (by ELISA) in Cervico-vaginal Secretions (CVS)	Titers are given as Geometric Mean Titers (GMTs) expressed as Enzyme-linked Immunosorbent Assay Units Per Milliliter (EL.U/mL).	At Month 7, 12, 18, 24, 36 and 48
Secondary	Number of Subjects Completing the 3-dose Vaccination Schedule		Up to Month 7
Secondary	Number of Subjects Reporting Any, Grade 3 and Related Solicited Local Symptoms	Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling spreading beyond 50 millimeters (mm) of injection site. All solicited local symptoms were assessed as related to study vaccination.	During the 7-day period (Day 0-6) following vaccination
Secondary	Number of Subjects Reporting Any, Grade 3 and Related Solicited General Symptoms	Assessed solicited general symptoms were arthralgia, fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], gastrointestinal, headache, myalgia, rash and urticaria. Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever > 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.	During the 7-day period (Day 0-6) following vaccination
Secondary	Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs)	Unsolicited AE covers any AE reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.Grade 3 AE = AE that prevented normal activity. Related AE = AE assessed by the investigator as causally related to the study vaccination.	During the 30-day period (Day 0-29) following vaccination
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up to Month 7
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up To Month 12
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up To Month 18
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up To Month 24
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSC include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up To Month 36
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.	Up to Month 48
Secondary	Number of Subjects Reporting New Onset of Chronic Diseases (NOCDs) and Medically Significant Conditions (MSCs)	NOCDs include autoimmune disorders, asthma, type I diabetes, allergies. MSCs include AEs prompting emergency room or physician visits that are not related to common diseases or routine visits for physical examination or vaccination, or serious adverse events (SAEs) that are not related to common diseases. Common diseases include upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervico-vaginal yeast infections, menstrual cycle abnormalities and injury.; Note: NOCD and MSC cases were unblinded at the Month 60 analysis.	Up to Month 60
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 7
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 12
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 18
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 24
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 36
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAEs was not assessed.	Up to Month 48
Secondary	Number of Subjects With Any, Grade 3 and Related Serious Adverse Events (SAEs)	SAEs assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, result in disability/incapacity or are a congenital anomaly/birth defect in the offspring of a study subject. Related SAE = SAE assessed by the investigator as causally related to the study vaccination. Intensity of SAE(s) was not assessed.; Note: SAEs were unblinded at the Month 60 analysis.	Up to Month 60

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