TY - JOUR
T1 - Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years
T2 - 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study
AU - Wheeler, Cosette M.
AU - Skinner, S. Rachel
AU - Del Rosario-Raymundo, M. Rowena
AU - Garland, Suzanne M.
AU - Chatterjee, Archana
AU - Lazcano-Ponce, Eduardo
AU - Salmerón, Jorge
AU - McNeil, Shelly
AU - Stapleton, Jack T.
AU - Bouchard, Céline
AU - Martens, Mark G.
AU - Money, Deborah M.
AU - Quek, Swee Chong
AU - Romanowski, Barbara
AU - Vallejos, Carlos S.
AU - ter Harmsel, Bram
AU - Prilepskaya, Vera
AU - Fong, Kah Leng
AU - Kitchener, Henry
AU - Minkina, Galina
AU - Lim, Yong Kuei Timothy
AU - Stoney, Tanya
AU - Chakhtoura, Nahida
AU - Cruickshank, Margaret E.
AU - Savicheva, Alevtina
AU - da Silva, Daniel Pereira
AU - Ferguson, Murdo
AU - Molijn, Anco C.
AU - Quint, Wim G.V.
AU - Hardt, Karin
AU - Descamps, Dominique
AU - Suryakiran, Pemmaraju V.
AU - Karkada, Naveen
AU - Geeraerts, Brecht
AU - Dubin, Gary
AU - Struyf, Frank
N1 - Funding Information:
The institutions of NC, CMW, SRS, JTS, and TS received a contract from the GlaxoSmithKline group of companies for the clinical trial site. CMW's and SRS's institutions received reimbursements for travel related to publication activities and for HPV vaccine studies. CMW's institution also received funding from Merck to do HPV vaccine trials, and from Roche Molecular Systems equipment and reagents for HPV genotyping studies, outside of this study. SRS's institution received honoraria and reimbursement for travel associated with participation on the advisory board, educational symposia, and funds for investigator initiated research from the GlaxoSmithKline group of companies. SRS's institution also received funds for investigator initiated research from bioCSL. AC received reimbursement from the GlaxoSmithKline group of companies for travel related to publications activities, and from Merck as consultant. MEC received reimbursement from the GlaxoSmithKline group of companies for travel related to publications activities. HK received funding from the GlaxoSmithKline group of companies to support conduct of the trial in his hospital. He is also a member of the HPV sub-group of the UK Joint Committee of Vaccination and Immunisation. JTS and MGM received grants from the GlaxoSmithKline group of companies. JTS's institution received a contract from the Merck to act as a clinical trial site for this and other studies. SM received grants as an investigator from the GlaxoSmithKline group of companies and from Pfizer Canada. She also received speaker honoraria from Merck. SCQ received honoraria and travel expenses from the GlaxoSmithKline group of companies for speaking at various symposia. TS received honoraria from the GSK group of companies for study committee membership (Asia Pacific study follow-up committee for Zoster studies), for conference attendance, and travel support. Her institution also received additional funding from a bioCSL grant for a project of which she is an investigator, funded by National Health and Medical Research Council. She also received travel support for participation in study investigator meetings from Novartis Vaccine and Diagnostics, Sanofi Pasteur, Alios bio Pharma, and Pfizer. AS received grants and fees from the GSK group of companies to participate in an epidemiological study (HERACLES). BR received research grants from the GlaxoSmithKline group of companies through her institution in addition to fees for speaking engagements, travel support, and expert testimony. JS received grants from the GlaxoSmithKline group of companies, Qiagen and Merck Inc. MRDR-R received honorarium as a principal investigator, support for travel to meetings for the study, and payment for lectures including service on speakers bureaus from the GlaxoSmithKline group of companies. SMG received grants through her institution for the VIVIANE study from GlaxoSmithKline group of companies, grants from CSL (Cervical Cancer Australia for HPV) through her institution for fare and accommodation to participate to Merck Cervical Cancer Global Advisory Board and Merck Scientific Advisory Board. She received a researcher initiated grant from Merck to perform surveillance RPP in Australia after HPV vaccines and fees for travel, accommodation, meeting expenses unrelated to activities listed, attending international conferences, and work performed in her own time. KLF received a grant from the Singapore General Hospital. CB received grants from the GSK group of companies and Merck as a principal investigator for her research centre. She also received honorarium for lectures and a travel grant for attending an international scientific meeting from Merck. GD was employed by the GlaxoSmithKline group of companies at the time of the study. GD and FS and own stock shares and stock options from the GlaxoSmithKline group of companies. GD has several patents in the HPV and herpes simplex virus vaccine fields. He is currently a full-time employee of Takeda Pharmaceuticals and receives salary and stock shares. BG, FS, PVS, NK, KH, and DD are employees of the GlaxoSmithKline group of companies. BG, KH, and DD own stock options from the GlaxoSmithKline group of companies. ACM and WGVQ received payment for services during the conduct of the study and received funding through their institution to do HPV vaccine studies from the GlaxoSmithKline group of companies. ACM received support for travel to meetings for the study from the GlaxoSmithKline group of companies. CSV, VP, DMM, GM, YKTL, EL-P, DPdS, MF, and BtH declare no competing interests.
Publisher Copyright:
© 2016 Elsevier Ltd
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Background Although the risk of human papillomavirus (HPV) infection is greatest in young women, women older than 25 years remain at risk. We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up. Methods In this phase 3, double-blind, randomised controlled trial, healthy women older than 25 years were enrolled (age stratified: 26–35 years, 36–45 years, and ≥46 years). Up to 15% in each age stratum had a history of HPV infection or disease. Women were randomly assigned (1:1) to receive HPV 16/18 vaccine or aluminium hydroxide control, with an internet-based system. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater (CIN1+) associated with HPV 16/18. We did analyses in the according-to-protocol cohort for efficacy and total vaccinated cohort. Data for the combined primary endpoint in the according-to-protocol cohort for efficacy were considered significant when the lower limit of the 96·2% CI around the point estimate was greater than 30%. For all other endpoints and cohorts, data were considered significant when the lower limit of the 96·2% CI was greater than 0%. This study is registered with ClinicalTrials.gov, number NCT00294047. Findings The first participant was enrolled on Feb 16, 2006, and the last study visit took place on Jan 29, 2014. 4407 women were in the according-to-protocol cohort for efficacy (n=2209 vaccine, n=2198 control) and 5747 women in the total vaccinated cohort (n=2877 vaccine, n=2870 control). At month 84, in women seronegative for the corresponding HPV type in the according-to-protocol cohort for efficacy, vaccine efficacy against 6-month persistent infection or CIN1+ associated with HPV 16/18 was significant in all age groups combined (90·5%, 96·2% CI 78·6–96·5). Vaccine efficacy against HPV 16/18-related cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and CIN1+ was also significant. We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 (65·8%, 96·2% CI 24·9–85·8) and HPV 45 (70·7%, 96·2% CI 34·2–88·4). In the total vaccinated cohort, vaccine efficacy against CIN1+ irrespective of HPV was significant (22·9%, 96·2% CI 4·8–37·7). Serious adverse events related to vaccination occurred in five (0·2%) of 2877 women in the vaccine group and eight (0·3%) of 2870 women in the control group. Interpretation In women older than 25 years, the HPV 16/18 vaccine continues to protect against infections, cytological abnormalities, and lesions associated with HPV 16/18 and CIN1+ irrespective of HPV type, and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up. Funding GlaxoSmithKline Biologicals SA.
AB - Background Although the risk of human papillomavirus (HPV) infection is greatest in young women, women older than 25 years remain at risk. We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up. Methods In this phase 3, double-blind, randomised controlled trial, healthy women older than 25 years were enrolled (age stratified: 26–35 years, 36–45 years, and ≥46 years). Up to 15% in each age stratum had a history of HPV infection or disease. Women were randomly assigned (1:1) to receive HPV 16/18 vaccine or aluminium hydroxide control, with an internet-based system. The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater (CIN1+) associated with HPV 16/18. We did analyses in the according-to-protocol cohort for efficacy and total vaccinated cohort. Data for the combined primary endpoint in the according-to-protocol cohort for efficacy were considered significant when the lower limit of the 96·2% CI around the point estimate was greater than 30%. For all other endpoints and cohorts, data were considered significant when the lower limit of the 96·2% CI was greater than 0%. This study is registered with ClinicalTrials.gov, number NCT00294047. Findings The first participant was enrolled on Feb 16, 2006, and the last study visit took place on Jan 29, 2014. 4407 women were in the according-to-protocol cohort for efficacy (n=2209 vaccine, n=2198 control) and 5747 women in the total vaccinated cohort (n=2877 vaccine, n=2870 control). At month 84, in women seronegative for the corresponding HPV type in the according-to-protocol cohort for efficacy, vaccine efficacy against 6-month persistent infection or CIN1+ associated with HPV 16/18 was significant in all age groups combined (90·5%, 96·2% CI 78·6–96·5). Vaccine efficacy against HPV 16/18-related cytological abnormalities (atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion) and CIN1+ was also significant. We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 (65·8%, 96·2% CI 24·9–85·8) and HPV 45 (70·7%, 96·2% CI 34·2–88·4). In the total vaccinated cohort, vaccine efficacy against CIN1+ irrespective of HPV was significant (22·9%, 96·2% CI 4·8–37·7). Serious adverse events related to vaccination occurred in five (0·2%) of 2877 women in the vaccine group and eight (0·3%) of 2870 women in the control group. Interpretation In women older than 25 years, the HPV 16/18 vaccine continues to protect against infections, cytological abnormalities, and lesions associated with HPV 16/18 and CIN1+ irrespective of HPV type, and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up. Funding GlaxoSmithKline Biologicals SA.
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U2 - 10.1016/S1473-3099(16)30120-7
DO - 10.1016/S1473-3099(16)30120-7
M3 - Article
C2 - 27373900
AN - SCOPUS:84977668330
VL - 16
SP - 1154
EP - 1168
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
SN - 1473-3099
IS - 10
ER -