Phase 3 Trial of a Bivalent Human Papilloma Virus (HPV) Vaccine (Cecolin®) in Young Girls

Anti-HPV-16 IgG antibodies were measured using HPV-16 virus-like particle (VLP) enzyme-linked immunosorbent assay (ELISA) one month after the second dose at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-16 assay was 1.41 international units (IU)/mL.

Time frame: One month after the second dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-16 antibody negative at baseline, and had a valid serology result one month after second dose.

Anti-HPV-18 IgG antibodies were measured using HPV-18 VLP ELISA one month after the second dose at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-18 assay was 1.05 IU/mL.

Time frame: One month after the second dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-18 antibody negative at baseline, and had a valid serology result one month after second dose.

Anti-HPV 16 serum neutralizing antibodies were measured in a subset of participants by pseudovirion-based neutralization assay (PBNA) at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-16 PBNA was a titer of \< 21. Samples were collected prior to the second dose and 1 month after the second dose for all treatment groups, and 18 months after the second dose for participants in Groups 1 and 4.

Time frame: Prior to 2nd dose (Month 6 for Groups 1 & 4, Month 12 for Group 2, and Month 24 for Groups 3 & 5), one month post 2nd dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5) and 18 months after 2nd dose for Groups 1 and 4 only

Population: Per Protocol Population, PBNA Subset

Anti-HPV 18 serum neutralizing antibodies were measured in a subset of participants by pseudovirion-based neutralization assay (PBNA) at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-18 PBNA was a titer of \< 16. Samples were collected prior to the second dose and 1 month after the second dose for all treatment groups, and 18 months after the second dose for participants in Groups 1 and 4.

Time frame: Prior to 2nd dose (Month 6 for Groups 1 & 4, Month 12 for Group 2, and Month 24 for Groups 3 & 5), one month post 2nd dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5) and 18 months after 2nd dose for Groups 1 and 4 only

Population: Per Protocol Population, PBNA Subset

Anti-HPV-16 IgG antibodies were measured using HPV-16 VLP ELISA 18 months after the second dose for participants who received a 6-month dosing regimen (Groups 1 and 4) only.

Time frame: 18 months after the second dose (Month 24)

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-16 antibody negative at baseline, and had a valid serology result 18-months after the second dose. Only participants who received the 6 month dose regimens were assessed for this endpoint.

Anti-HPV-16 IgG antibodies were measured using HPV-16 VLP ELISA one month after the second dose at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-16 assay was 1.41 IU/mL. Anti-HPV-16 IgG GMCs measured 1 month after the second dose were compared between the Gardasil at Month 0 and Cecolin at 24 months two-dose regimen (Group 5) and the Gardasil at Month 0 and 6 two-dose regimen (Group 4).

Time frame: One month after the second dose (Month 7 for Group 4 and Month 25 for Group 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-16 antibody negative at baseline, and had a valid serology result one month after second dose.

Anti-HPV-18 IgG antibodies were measured using HPV-18 VLP ELISA 18 months after the second dose for participants who received a 6-month dosing regimen (Groups 1 and 4) only.

Time frame: 18 months after the second dose (Month 24)

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-18 antibody negative at baseline, and had a valid serology result 18 months after the second dose. Only participants who received the 6-month dosing regimens were assessed for this endpoint.

Anti-HPV-18 IgG antibodies were measured using HPV-18 VLP ELISA one month after the second dose at the Frederick National Laboratory for Cancer Research in Frederick, Maryland, United States. The lower limit of quantitation of the HPV-18 assay was 1.405 IU/mL. Anti-HPV-18 IgG GMCs measured 1 month after the second dose were compared between the Gardasil at Month 0 and Cecolin at 24 Months two-dose regimen (Group 5) and the Gardasil at Month 0 and 6 two-dose regimen (Group 4).

Time frame: One month after the second dose (Month 7 for Group 4 and Month 25 for Group 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-16 antibody negative at baseline, and had a valid serology result one month after second dose.

An SAE was any AE that resulted in any of the following outcomes: 1. Death 2. Was life-threatening 3. Required inpatient hospitalization or prolongation of existing hospitalization. 4. Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 5. Congenital abnormality or birth defect. 6. Important medical event that may not have resulted in one of the above outcomes but may have jeopardized the health of the study participant or (and) required medical or surgical intervention to prevent one of the outcomes listed in the above definition of SAEs. SAEs were collected from the time of first vaccination through the end of the study for each participant.

Time frame: From first dose through the end of study (up to 730 days for Groups 1 and 4, 395 days for Group 2, and 760 days for Groups 3 and 5)

Population: Total Vaccinated Population includes all randomized participants who received at least one dose of study vaccination.

Solicited adverse events (AEs) were assessed by study staff 30 minutes after each vaccination and then daily for seven days after each vaccination by the participants using a memory aid. The following specific solicited AEs were monitored for this trial: * Local Reactions: * Pain, erythema/redness, swelling, induration, pruritus, abscess. * General/Systemic Reactions: * Fever (oral or axillary temperature ≥ 38.0°C), headache, vomiting, nausea, fatigue, chills, muscle pain, cough, diarrhea, dizziness, allergic dermatitis, rash, syncope, and anorexia.

Time frame: For 30 minutes after each vaccination and for up to 7 days after each vaccination

Population: Total Vaccinated Population includes all randomized participants who received at least one dose of study vaccination.

Unsolicited AEs were any AEs reported spontaneously by the participant, identified during interview at study visits, observed by the study personnel during study visits or those identified during review of medical records or source documents. Unsolicited AEs were events occurring from the time of each study injection through approximately 30 days after each vaccination. Solicited AEs with onset after the solicitation period and through Day 30 post-vaccination were captured as unsolicited AEs.

Time frame: For 30 days after each dose (Month 0 (all groups), Month 6 (Groups 1 and 4), Month 12 (Group 2), and Month 24 (Groups 3 and 5)

Population: Total Vaccinated Population includes all randomized participants who received at least one dose of study vaccination.

Seroconversion rate is defined as the percentage of participants with a 4-fold rise in anti-HPV 16 IgG antibodies as measured by ELISA from baseline one month following the second dose.

Time frame: Baseline and one month after second dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5).

Population: Per Protocol Population

Seroconversion rate is defined as the percentage of participants with a 4-fold rise from baseline in anti HPV-18 IgG antibodies as measured by ELISA one month following the second dose.

Time frame: Baseline and one month after second dose (Month 7 for Groups 1 & 4, Month 13 for Group 2, and Month 25 for Groups 3 & 5).

Population: Per Protocol Population

To evaluate the persistence of antibody responses to HPV after a single dose of vaccine, anti-HPV-16 IgG antibodies were measured using HPV-16 VLP ELISA immediately prior to the second dose.

Time frame: Prior to the second dose (Month 6 for Groups 1 & 4, Month 12 for Group 2, and Month 24 for Groups 3 & 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-16 antibody negative at baseline, and had a valid serology result prior to receiving the second dose.

To evaluate the persistence of antibody responses to HPV after a single dose of vaccine, anti-HPV-18 IgG antibodies were measured using HPV-16 VLP ELISA immediately prior to the second dose.

Time frame: Prior to the second dose (Month 6 for Groups 1 & 4, Month 12 for Group 2, and Month 24 for Groups 3 & 5).

Population: The Per Protocol Population includes participants who had no major protocol deviations that were determined to potentially interfere with the immunogenicity assessment of the study vaccine, were HPV-18 antibody negative at baseline, and had a valid serology result prior to receiving the second dose.