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

NCT04508309CompletedPHASE3INTERVENTIONAL

Summary

This randomized controlled trial will evaluate a bivalent HPV vaccine, Cecolin®, in alternate 2-dose regimens, compared to an established HPV vaccine. Gardasil® will be used as the comparator vaccine, as this vaccine is most widely used in low- and low-middle income countries.

Key Facts

Lead Sponsor

PATH

Enrollment

1025

Start Date

2021-03-15

Completion Date

2023-12-14

Study Type

INTERVENTIONAL

Official Title

Phase 3 Randomized, Active-Comparator Controlled, Open-Label Trial to Evaluate the Immunogenicity & Safety of Alternate 2-Dose Regimens of Cecolin® Compared to Gardasil® in 9-14 Year-Old Girls in Low and Low-Middle Income Countries

Interventions

Cecolin®Gardasil®

Conditions

Cervical Cancer

Eligibility

Age Range

9 Years – 14 Years

Sex

FEMALE

Inclusion Criteria:

1. Healthy (determined by investigator's assessment following medical history and physical examination, laboratory evaluation could be performed at the investigator's discretion) female between the ages of 9 - 14 years (all inclusive) at time of enrollment
2. Ability and willingness to provide parental consent and, if applicable based on local in-country regulations, participant assent
3. Parent/Legally Acceptable Representative provides informed consent
4. Anticipated ability and willingness to complete all study visits and evaluations
5. Living within the catchment area of the study without plans to move during the conduct of the study

Exclusion Criteria:

1. Presence of fever or acute disease on the day of vaccination (oral or axillary temperature ≥ 38˚ C)
2. If participants have childbearing potential, must not be breastfeeding or confirmed pregnant
3. Receipt of an investigational product within 30 days prior to randomization
4. Receipt of blood and/or blood products (including immunoglobulin) 3 months prior to any dose of vaccination or blood sampling
5. Receipt of a live virus vaccine (varicella virus containing vaccine, any measles, mumps, or rubella virus containing vaccine such as Measles, Mumps, and Rubella (MMR), or yellow fever vaccine but not including live attenuated influenza virus vaccine) 4 weeks prior and after each dose of HPV vaccine
6. History of any physical, mental, or developmental disorder that may hinder a participant's ability to comply with the study requirements
7. Any malignancy or confirmed or suspected immunodeficient condition such as HIV infection, based on medical history and physical examination
8. Receipt of or history of receipt of any medications or treatments that affect the immune system
9. Allergies to any components of the vaccine
10. Current or former participation in HPV vaccine related research.
11. Prior receipt of an investigational or licensed HPV vaccine
12. Any other condition(s) that in the opinion of the investigator would jeopardize the safety or rights of a participant participating in the trial or would render the participant unable to comply with the protocol

Outcome Measures

Primary Outcomes

Geometric Mean Concentration (GMC) of Anti-HPV-16 Immunoglobulin G (IgG) Antibodies One Month After the Second Dose

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).

Geometric Mean Concentration of Anti-HPV-18 Immunoglobulin G Antibodies One Month After the 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).

Secondary Outcomes

Geometric Mean Titer (GMT) of Anti-HPV-16 Neutralizing Antibodies

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

Geometric Mean Titer (GMT) of Anti-HPV-18 Neutralizing Antibodies

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

Seroconversion Rate For HPV-16 One Month After the Second Dose

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).

Seroconversion Rate For HPV-18 One Month After the Second Dose

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).

GMC of Anti-HPV-16 IgG Antibodies One Month After the Second Dose: Comparison of Gardasil/Cecolin Mixed Dose With Gardasil 2-dose Regimen

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).

GMC of Anti-HPV-18 IgG Antibodies One Month After the Second Dose: Comparison of Gardasil/Cecolin Mixed Dose With Gardasil 2-dose Regimen

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).

GMC of Anti-HPV-16 IgG Antibodies 18-Months After Second Dose

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)

GMC of Anti-HPV-18 IgG Antibodies 18-Months 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)

Number of Participants With Solicited Adverse Events

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

Number of Participants With Unsolicited Adverse Events

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)

Number of Participants With Serious Adverse Events (SAEs)

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)

Locations

International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh

Malaria Research Centre, Agogo Presbyterian Hospital, Agogo, Ghana

Linked Papers

2025-11-24

Human papillomavirus (HPV) vaccination for the prevention of cervical cancer and other HPV-related diseases: a network meta-analysis

Cervical cancer is the fourth most common cause of cancer-related death amongst females worldwide. Persistent infection with high-risk human papillomavirus (HPV) is the key factor in cervical cancer development. HPV vaccines aim to prevent cancer by generating antibodies against HPV infection. To evaluate the safety and efficacy of HPV vaccines, in females and males, to prevent cervical cancer and other HPV-related diseases, in standard (pairwise) and network meta-analysis (NMA) of randomised controlled trials. On 10 January 2022, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase. We searched Epistemonikos, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, the Health Technology Assessment database and vaccine manufacturer websites, and we checked reference lists from other relevant systematic reviews. We applied for Clinical Study Reports (CSRs) from the European Medicines Agency. An update search of electronic databases was done on 18 September 2024. We included randomised controlled trials (RCTs) regardless of language or publication status, assessing HPV vaccines pre-qualified by the World Health Organization (WHO) (Cervarix, Gardasil, Gardasil-9 and Cecolin). We used methods recommended by Cochrane. We primarily used CSRs to collect data, and we included outcome data irrespective of participants' baseline HPV infection or serostatus. We assessed risk of bias using the Cochrane tool (RoB 2). All outcomes were dichotomous, and we estimated risk ratios (RR) with 95% confidence intervals (CI). We used pairwise analysis for all outcomes. Where data were available, we carried out NMA for critical outcomes for networks in females and males in three age groups, ranking the vaccines using surface under the cumulative ranking curve (SUCRA) and mean ranks. We assessed the certainty of evidence using the GRADE approach. We included 60 individual studies with 157,414 participants ranging in follow-up from seven months to 11 years. Few participants were under 15. There were no studies for males under 15 years and males over 25 years. We obtained CSRs for 33 of the included studies. We assessed the risk of bias as low to 'some concerns' for the critical outcomes. Cancer and pre-cancer outcomes The studies were not of sufficient duration for cancers to develop. Four studies reported on cancer. No cancers were detected. Critical pre-cancer outcomes were reported in 15- to 25-year-old populations by 11 studies and in > 25-year-old females by three studies with up to seven years follow-up. None were reported in the under 15 years age group. In 15- to 25-year-old females, there was a reduction in CIN2+ irrespective of HPV type after six years (RR 0.70, 95% CI 0.56 to 0.88) (moderate-certainty) and a larger reduction in CIN2+ from vaccine-matched HPV types after six years (RR 0.40, 95% CI 0.30 to 0.54) (moderate-certainty). In females over 25 years old, there was little to no difference between Cervarix and Gardasil compared with control (moderate-certainty). There was no evidence on CIN2+ irrespective of HPV type from studies assessing Cecolin, or from studies assessing different dose schedules. In 15- to 25-year-old females, there was a slight reduction in vaccine-matched HPV-type high-grade vulval (VIN) or vaginal (VaIN) intraepithelial neoplasia following vaccination with Gardasil or Gardasil-9 (moderate-certainty). The NMA found a slight reduction of 1 case per 1000 following Gardasil (RR 0.21, 95% CI 0.1 to 0.45) and 0 cases per 1000 following Gardasil-9 (RR 0.16, 95% CI 0.05 to 0.51). Little to no difference was found in the NMA for Cervarix compared with control (RR 0.28, 95% CI 0.06 to 1.37), or for Cervarix, Gardasil and Gardasil-9 compared to each other. There was a reduction in high-grade anal intraepithelial neoplasia (AIN) irrespective of HPV type in the Gardasil group in one study in men who have sex with men (RR 0.75, 95% CI 0.53 to 1.07) (low-certainty). For both high-grade penile intraepithelial neoplasia (PeIN) irrespective of HPV type and vaccine-matched HPV-type high-grade PeIN, little to no difference per 1000 participants was reported in the Gardasil group in one study with 3880 participants at 36 months follow-up (RR 1.00, 95% CI 0.20 to 4.93) (low-certainty). Serious adverse events In a pairwise analysis of serious adverse events in 39 studies across all vaccine types with 97,272 participants, there was little to no difference in the HPV vaccine groups compared with the control group at up to 72 months follow-up (RR 0.99, 95% CI 0.94 to 1.04) (high-certainty). Treatment rates for HPV-related pre-invasive disease In pairwise analysis of five studies with 38,606 participants, there were 12 fewer people that needed to seek treatment per 1000 participants (95% CI 5 to 17 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 84 months follow-up (RR 0.76, 95% CI 0.65 to 0.89) (moderate-certainty). Anogenital warts In pairwise analysis of three studies with 21,271 participants, there were 25 fewer cases of anogenital warts irrespective of HPV type per 1000 participants (95% CI 22 to 28 fewer per 1000) in the HPV vaccine groups compared with the control group rate at up to 48 months follow-up (RR 0.38, 95% CI 0.32 to 0.46) (high-certainty). In the NMA for females 15 to 25 years old, Gardasil-9 was most likely to reduce the risk of developing anogenital warts. The evidence in this network meta-analysis of HPV vaccines is based on extensive searches and analyses. There is evidence from randomised controlled trials that HPV vaccination reduces the risk of pre-cancerous outcomes such as CIN2+ and anogenital warts. No data were available for cervical cancer or other cancer outcomes, and no data on pre-cancer outcomes were available for vaccination under age 15 years. There were no safety concerns noted in the studies.

2025-03-19

Immunogenicity and safety of an Escherichia coli-produced bivalent human papillomavirus vaccine (Cecolin) in girls aged 9–14 years in Ghana and Bangladesh: a randomised, controlled, open-label, non-inferiority, phase 3 trial

Human papillomavirus (HPV) vaccines have been available for nearly 20 years. However, the overall coverage of girls aged 15 years and younger is low, especially in low-resource settings, where the burden of cervical cancer is highest. Increasing access and facilitating implementation of HPV vaccination will contribute to cervical cancer elimination efforts. To generate data in different dosing regimens and in low-resource settings, we aimed to evaluate the safety and immunogenicity of various schedules of an Escherichia coli-expressed bivalent HPV vaccine (2vHPV) compared with a widely used quadrivalent vaccine. This randomised, controlled, open-label, non-inferiority, phase 3 trial enrolled healthy girls aged 9-14 years from single sites in Ghana and Bangladesh. Participants were randomly assigned via interactive web response system technology equally into five study groups, stratified by site: two doses of 2vHPV, the first at baseline and the second 6, 12, or 24 months later; a quadrivalent HPV vaccine (4vHPV) at baseline followed 24 months later by 2vHPV; or two doses of 4vHPV given 6 months apart (referent). We tested for antigen-specific (HPV-16 and HPV-18) binding antibodies by ELISA at baseline and before and 1 month after the second dose. The primary objective was to show immunological non-inferiority of the 2vHPV vaccine schedules to the referent 1 month after the second dose in the per-protocol population, with a non-inferiority margin of 0·5 for the lower bound of the 98·3% CI for the geometric mean concentration (GMC) ratio. Adverse events and serious adverse events were evaluated as secondary endpoints in the total vaccinated population. The study is registered at ClinicalTrials.gov (NCT04508309) and is completed. Between March 15 and Nov 18, 2021, 1025 girls were enrolled and received 2vHPV at baseline and 6 months (n=205), 12 months (n=206), or 24 months (n=204); 4vHPV at baseline and 6 months (n=205); or 4vHPV at baseline and 2vHPV at 24 months (n=205). 96-99% of participants across groups were included in the per-protocol analysis. 1 month after the second dose, 2vHPV non-inferiority was shown, with GMC ratios between 1·1 and 2·4 (lower bound of the 98·3% CI of the GMC ratio between 0·9 and 1·9) for HPV-16, and between 1·3 and 1·7 (1·0 and 1·4) for HPV-18. As an exploratory objective, we assessed 2vHPV immunogenicity after one dose, finding that it was similar to that of 4vHPV up to 24 months, with GMC ratios at 24 months of 1·1 (95% CI 0·9-1·4) for HPV-16 and 1·4 (1·1-1·7) for HPV-18. The frequency of adverse events was similar across study groups, with no related unsolicited events reported. Serious adverse events were rare and none were determined to be related to vaccination. Non-inferior immune responses for extended two-dose regimens of 2vHPV support dosing flexibility. For up to 24 months, one dose of 2vHPV elicited immunogenicity that was similar to one dose of 4vHPV, for which single-dose efficacy has been shown, supporting a single-dose use of 2vHPV. The Bill & Melinda Gates Foundation and the German Federal Ministry of Education and Research and immunological testing was funded in part by the National Cancer Institute, National Institutes of Health. For the Bengali translation of the abstract see Supplementary Materials section.

Linked Investigators

Hanna Bergman

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