Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study

Cosette M. Wheeler, S. Rachel Skinner, M. Rowena Del Rosario-Raymundo, Suzanne M. Garland, Archana Chatterjee, Eduardo Lazcano-Ponce, Jorge Salmerón, Shelly McNeil, Jack T. Stapleton, Céline Bouchard, Mark G. Martens, Deborah M. Money, Swee Chong Quek, Barbara Romanowski, Carlos S. Vallejos, Bram ter Harmsel, Vera Prilepskaya, Kah Leng Fong, Henry Kitchener, Galina MinkinaYong Kuei Timothy Lim, Tanya Stoney, Nahida Chakhtoura, Margaret E. Cruickshank, Alevtina Savicheva, Daniel Pereira da Silva, Murdo Ferguson, Anco C. Molijn, Wim G V Quint, Karin Hardt, Dominique Descamps, Pemmaraju V. Suryakiran, Naveen Karkada, Brecht Geeraerts, Gary Dubin, Frank Struyf

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalThe Lancet Infectious Diseases
DOIs
StateAccepted/In press - 2016

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Human papillomavirus 18
Human papillomavirus 16
Vaccines
Safety
Papillomavirus Infections
Human papillomavirus 31
Infection
Aluminum Hydroxide
Cervical Intraepithelial Neoplasia
Internet
Vaccination
Randomized Controlled Trials
Age Groups

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years : 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. / Wheeler, Cosette M.; Skinner, S. Rachel; Del Rosario-Raymundo, M. Rowena; Garland, Suzanne M.; Chatterjee, Archana; Lazcano-Ponce, Eduardo; Salmerón, Jorge; McNeil, Shelly; Stapleton, Jack T.; Bouchard, Céline; Martens, Mark G.; Money, Deborah M.; Quek, Swee Chong; Romanowski, Barbara; Vallejos, Carlos S.; ter Harmsel, Bram; Prilepskaya, Vera; Fong, Kah Leng; Kitchener, Henry; Minkina, Galina; Lim, Yong Kuei Timothy; Stoney, Tanya; Chakhtoura, Nahida; Cruickshank, Margaret E.; Savicheva, Alevtina; da Silva, Daniel Pereira; Ferguson, Murdo; Molijn, Anco C.; Quint, Wim G V; Hardt, Karin; Descamps, Dominique; Suryakiran, Pemmaraju V.; Karkada, Naveen; Geeraerts, Brecht; Dubin, Gary; Struyf, Frank.

In: The Lancet Infectious Diseases, 2016.

Research output: Contribution to journalArticle

Wheeler, CM, Skinner, SR, Del Rosario-Raymundo, MR, Garland, SM, Chatterjee, A, Lazcano-Ponce, E, Salmerón, J, McNeil, S, Stapleton, JT, Bouchard, C, Martens, MG, Money, DM, Quek, SC, Romanowski, B, Vallejos, CS, ter Harmsel, B, Prilepskaya, V, Fong, KL, Kitchener, H, Minkina, G, Lim, YKT, Stoney, T, Chakhtoura, N, Cruickshank, ME, Savicheva, A, da Silva, DP, Ferguson, M, Molijn, AC, Quint, WGV, Hardt, K, Descamps, D, Suryakiran, PV, Karkada, N, Geeraerts, B, Dubin, G & Struyf, F 2016, 'Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study', The Lancet Infectious Diseases. https://doi.org/10.1016/S1473-3099(16)30120-7
Wheeler, Cosette M. ; Skinner, S. Rachel ; Del Rosario-Raymundo, M. Rowena ; Garland, Suzanne M. ; Chatterjee, Archana ; Lazcano-Ponce, Eduardo ; Salmerón, Jorge ; McNeil, Shelly ; Stapleton, Jack T. ; Bouchard, Céline ; Martens, Mark G. ; Money, Deborah M. ; Quek, Swee Chong ; Romanowski, Barbara ; Vallejos, Carlos S. ; ter Harmsel, Bram ; Prilepskaya, Vera ; Fong, Kah Leng ; Kitchener, Henry ; Minkina, Galina ; Lim, Yong Kuei Timothy ; Stoney, Tanya ; Chakhtoura, Nahida ; Cruickshank, Margaret E. ; Savicheva, Alevtina ; da Silva, Daniel Pereira ; Ferguson, Murdo ; Molijn, Anco C. ; Quint, Wim G V ; Hardt, Karin ; Descamps, Dominique ; Suryakiran, Pemmaraju V. ; Karkada, Naveen ; Geeraerts, Brecht ; Dubin, Gary ; Struyf, Frank. / Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years : 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. In: The Lancet Infectious Diseases. 2016.
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title = "Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study",
abstract = "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.",
author = "Wheeler, {Cosette M.} and Skinner, {S. Rachel} and {Del Rosario-Raymundo}, {M. Rowena} and Garland, {Suzanne M.} and Archana Chatterjee and Eduardo Lazcano-Ponce and Jorge Salmer{\'o}n and Shelly McNeil and Stapleton, {Jack T.} and C{\'e}line Bouchard and Martens, {Mark G.} and Money, {Deborah M.} and Quek, {Swee Chong} and Barbara Romanowski and Vallejos, {Carlos S.} and {ter Harmsel}, Bram and Vera Prilepskaya and Fong, {Kah Leng} and Henry Kitchener and Galina Minkina and Lim, {Yong Kuei Timothy} and Tanya Stoney and Nahida Chakhtoura and Cruickshank, {Margaret E.} and Alevtina Savicheva and {da Silva}, {Daniel Pereira} and Murdo Ferguson and Molijn, {Anco C.} and Quint, {Wim G V} and Karin Hardt and Dominique Descamps and Suryakiran, {Pemmaraju V.} and Naveen Karkada and Brecht Geeraerts and Gary Dubin and Frank Struyf",
year = "2016",
doi = "10.1016/S1473-3099(16)30120-7",
language = "English (US)",
journal = "The Lancet Infectious Diseases",
issn = "1473-3099",
publisher = "Lancet Publishing Group",

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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

PY - 2016

Y1 - 2016

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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