Partially Blind Study to Evaluate Immunogenicity & Safety of GSK Bio's HPV Vaccine 580299 in Healthy Women Aged 9-25 Yrs

NCT00541970CompletedPHASE1INTERVENTIONAL

Summary

Human Papillomavirus (HPV) infection has been established as a necessary cause of cervical cancer. GlaxoSmithKline (GSK) Biologicals has developed an HPV vaccine (580299) which targets the 2 most common oncogenic HPV types (HPV-16 and HPV-18), found in approximately 70% of all cervical cancers. In previous trials this vaccine has been found to be efficacious in the prevention of incident and persistent HPV-16/18 infections and associated cytological abnormalities and cervical dysplasia. In this partially-blind study, GSK Biologicals will evaluate the safety and immunogenicity of the HPV vaccine using an alternative schedule and an alternative dosing when administered in healthy young females aged 9 to 25 years, as compared to the standard HPV vaccine. The Protocol Posting has been updated in order to comply with the FDA Amendment Act, Sep 2007. The protocol posting has been updated following a protocol amendment.

Key Facts

Lead Sponsor

GlaxoSmithKline

Enrollment

961

Start Date

2007-10-17

Completion Date

2013-03-18

Study Type

INTERVENTIONAL

Official Title

Evaluation of the Safety and Immunogenicity of GSK Biologicals' HPV Vaccine 580299 When Administered in Healthy Females Aged 9 - 25 Years Using an Alternative Schedule and an Alternative Dosing as Compared to the Standard Schedule and Dosing

Interventions

CervarixPlacebo

Conditions

InfectionsPapillomavirus

Eligibility

Age Range

9 Years – 25 Years

Sex

FEMALE

Inclusion Criteria:

* Subjects who the investigator believes that they and/or their parents can and will comply with the requirements of the protocol should be enrolled in the study.
* A female subject between, and including, 9 and 25 years of age at the time of the first vaccination.
* Written informed consent/assent obtained from the subject prior to enrolment. For subjects above the legal age of consent, written informed consent must be obtained from the subject. For subjects below the legal age of consent, written informed consent from the subject's parents/legally acceptable representative, and written informed assent must be obtained from the subject.
* Healthy subjects as established by medical history and history-oriented clinical examination before entering into the study.
* Subject must be of non-childbearing potential, or if she is of childbearing potential, she must practice adequate contraception for 30 days prior to vaccination, have a negative pregnancy test and continue such precautions for two months after completion of the vaccination series.

Exclusion Criteria:

* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period (up to Month 24).
* Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose.
* Concurrently participating in another clinical study, at any time during the study period (up to Month 24), in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device).
* Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before and 30 days after the first dose of vaccine. Planned administration/administration of routine vaccines, up to 8 days before the first dose of study vaccine is allowed. Enrolment will be deferred until the subject is outside of specified window.
* Pregnant or breastfeeding female.
* A woman planning to become pregnant or planning to discontinue contraceptive precautions during the study period, up to two months after the last vaccine dose.
* Previous vaccination against HPV or planned administration of any HPV vaccine other than that foreseen by the study protocol during the study period (up to Month 24).
* Previous administration of components of the investigational vaccine.
* Cancer or autoimmune disease under treatment.
* Any medically diagnosed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
* History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
* Hypersensitivity to latex.
* Acute disease at the time of enrolment.
* Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory tests.
* Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period (up to Month 24).

Outcome Measures

Primary Outcomes

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL).

Time frame: One month after vaccination with the last dose of the Cervarix vaccine (Cervarix 1/Placebo Group: Month 3; Other groups: Month 7).

Number of Subjects With Report of Any, and Grade 3 Solicited Local Symptoms

Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the solicited local symptom irrespective of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 redness/swelling = redness/swelling larger than (\>) 50 millimeters (mm).

Time frame: Within 7 days (Day 0-6) after vaccination.

Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms

Assessed solicited general symptoms were arthralgia, fatigue, fever (defined as axillary temperature equal or above (≥) 37.5 degrees Celsius (°C), gastrointestinal symptoms, which included nausea, vomiting, diarrhoea and/or abdominal pain, headache, myalgia, rash and urticaria. Grade 3 symptoms = symptoms that prevented normal activity. Grade 3 fever = axillary temperature ≥ 39 °C. Grade 3 urticaria = urticaria distributed on at least 4 body areas. Related symptom = symptom assessed by the investigator to be causally related to vaccination.

Time frame: Within 7 days (Day 0-6) after vaccination.

Secondary Outcomes

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies .

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The analysis was performed on the subjects who were administered a 2-dose vaccination schedule.

Time frame: At Month 3, 1 month after the second dose of vaccine or placebo

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). Groups were stratified into 3 age strata: 9-14, 15-19 and 20-25 years of age at the time of first vaccination. The 15-19 years age stratum in the group receiving the Cervarix vaccine on a 3-dose vaccination schedule was considered an active comparator.

Time frame: At Month 7, 1 month after the last dose of vaccine or placebo.

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL).

Time frame: At Month 12, at Month 18, at Month 24, at Month 36, and at Month 48 during the safety follow-up phase.

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL).

Time frame: At Month 7, 1 month after the last dose of vaccine or placebo.

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents BAS results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range.This outcome presents CREA results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents EOS results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents Hct results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents ALT results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents LYM results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents MON results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents NEU results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents RBC results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents WBC results.

Time frame: At Month 7 (M7)

Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed.

Assessed parameters were alanine aminotransferase (ALT), basophils (BAS), creatinine (CREA), eosinophils (EOS), haematocritis (Hct), lymphocytes (LYM), monocytes (MON), neutrophils (NEU), platelets (PLA), red blood cells (RBC) and white blood cells (WBC). Subjects were categorized according to their results at pre-vaccination at Month 0 (PRE) which were normal, above normal or below the normal range. Per parameter and range, it was assessed whether laboratory values of the subjects were normal, above normal or below the normal range. This outcome presents PLA results.

Time frame: At Month 7 (M7)

Number of Seroconverted Subjects Against Human Papillomavirus 16 (HPV-16) and Human Papillomavirus 18 (HPV-18)

Seroconversion was defined as the appearance of antibodies (i.e.titers greater than or equal to (≥) cut-off value) in the serum of subjects seronegative before vaccination. Assay cut-off was defined as ≥ 8 ELISA units per milliliter (EL.U/mL) for HPV-16, and 7 EL.U/mL for HPV-18. Seronegative subjects are subjects who had an antibody concentration below cut-off value. Cut-off values were 8 EL.U/mL for antibody concentrations against HPV-16, and 7 EL.U/mL for antibody concentrations against HPV-18.

Time frame: At Month 12, at Month 18, at Month 24, at Month 36, and at Month 48 during the safety follow-up phase.

Titers of Anti-Papillomavirus 16 (Anti-HPV-16) and Anti-human Papillomavirus 18 (Anti-HPV-18) Antibodies

Titers are given as Geometric Mean Titers (GMTs) expressed in Enzyme-linked immunosorbent assay (ELISA) units per milliliter (EL.U/mL). The assay cut-off for Month 60 was defined as ≥ 19 ELISA units per milliliter (EL.U/mL).

Time frame: At Month 60 of the safety follow-up phase

Number of Seroconverted Subjects Against Human Papillomavirus 16 (HPV-16) and Human Papillomavirus 18 (HPV-18)

Seroconversion was defined as the appearance of antibodies (i.e. titers greater than or equal to (≥) cut-off value) in the serum of subjects seronegative before vaccination. Assay cut-off was defined as ≥ 19 ELISA units per milliliter (EL.U/mL). Seronegative subjects are subjects who had an antibody concentration below cut-off value.

Time frame: At Month 60 of the safety follow-up phase

Number of Subjects With Pregnancy Outcomes.

Pregnancy outcomes were ectopic pregnancy, elective termination with no apparent congenital anomaly (ACA), elective termination with congenital anomaly (CA), lost to follow up, pregnancy ongoing, spontaneous abortion with no ACA and live infant with no ACA.

Time frame: From Month 0 to Month 48.

Number of Subjects With Pregnancy Outcomes.

Pregnancy outcomes were ectopic pregnancy, elective termination with no apparent congenital anomaly (ACA), elective termination with congenital anomaly (CA), lost to follow up, pregnancy ongoing, spontaneous abortion with no ACA and live infant with no ACA.

Time frame: Throughout the study period, from Month 0 to Month 60.

Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs).

An unsolicited adverse event (AE) is any adverse event (i.e. any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product) 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 = an event that prevented normal activity. Related = an event assessed by the investigator as causally related to the study vaccination.

Time frame: Within 30 days (Day 0-29) after vaccination.

Number of Subjects With Medically Significant Conditions (MSCs).

MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination.

Time frame: From Month 0 to Month 7.

Number of Subjects With Medically Significant Conditions (MSCs).

MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination.

Time frame: From Month 0 to Month 48.

Number of Subjects With Medically Significant Conditions (MSCs).

MSCs were defined as: AEs prompting emergency room or physician visits that were not (1) related to common diseases or (2) routine visits for physical examination or vaccination, or SAEs that were not related to common diseases. The following did not require reporting as long as they were not considered SAEs and occurred more than 30 days after each vaccination: upper respiratory infections, sinusitis, pharyngitis, gastroenteritis, urinary tract infections, cervicovaginal yeast infections, menstrual cycle abnormalities, injury, visits for routine physical examination or visits for vaccination.

Time frame: Throughout the study period, from Month 0 to Month 60.

Number of Subjects With New Onset of Autoimmune Diseases (NOADs)

NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: From Month 0 to Month 7.

Number of Subjects With New Onset of Autoimune Diseases (NOADs)

NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: From Month 0 to Month 48.

Number of Subjects With New Onset of Autoimmune Diseases (NOADs)

NOADs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: Throughout the study period, from Month 0 to Month 60.

Number of Subjects With New Onset of Chronic Diseases (NOCDs)

NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: From Month 0 to Month 7.

Number of Subjects With New Onset of Chronic Diseases (NOCDs)

NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: From Month 0 to Month 48.

Number of Subjects With New Onset of Chronic Diseases (NOCDs)

NOCDs include conditions such as autoimmune disorders, asthma, type I diabetes, or allergies.

Time frame: Throughout the study period, from Month 0 to Month 60.

Number of Subjects With 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.

Time frame: From Month 0 to Month 7.

Number of Subjects With 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.

Time frame: From Month 0 to Month 48.

Number of Subjects With 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.

Time frame: Throughout the study period, from Month 0 to Month 60.

Locations

GSK Investigational Site, Edmonton, Canada

GSK Investigational Site, Langley, Canada

GSK Investigational Site, St. John's, Canada

GSK Investigational Site, Truro, Canada

GSK Investigational Site, Québec, Canada

GSK Investigational Site, Karlsruhe, Germany

GSK Investigational Site, Kehl, Germany

GSK Investigational Site, Rheinstetten, Germany

GSK Investigational Site, Tauberbischofsheim, Germany

GSK Investigational Site, Munich, Germany

GSK Investigational Site, Weilheim, Germany

GSK Investigational Site, Würzburg, Germany

GSK Investigational Site, Frankfurt am Main, Germany

GSK Investigational Site, Hanover, Germany

GSK Investigational Site, Hanover, Germany

GSK Investigational Site, Wolfenbüttel, Germany

GSK Investigational Site, Trier, Germany

GSK Investigational Site, Leipzig, Germany

GSK Investigational Site, Flensburg, Germany

GSK Investigational Site, Nordhausen, Germany

GSK Investigational Site, Berlin, Germany

GSK Investigational Site, Berlin, Germany

GSK Investigational Site, Hamburg, Germany

GSK Investigational Site, Hamburg, Germany

GSK Investigational Site, Hamburg, Germany

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.

Linked Investigators

Hanna Bergman