Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial.
BACKGROUND
The aim of this interim analysis of a large, international phase III study was to assess the efficacy of an AS04 adjuvanted L1 virus-like-particle prophylactic candidate vaccine against infection with human papillomavirus (HPV) types 16 and 18 in young women.


METHODS
18,644 women aged 15-25 years were randomly assigned to receive either HPV16/18 vaccine (n=9319) or hepatitis A vaccine (n=9325) at 0, 1, and 6 months. Of these women, 88 were excluded because of high-grade cytology and 31 for missing cytology results. Thus, 9258 women received the HPV16/18 vaccine and 9267 received the control vaccine in the total vaccinated cohort for efficacy, which included women who had prevalent oncogenic HPV infections, often with several HPV types, as well as low-grade cytological abnormalities at study entry and who received at least one vaccine dose. We assessed cervical cytology and subsequent biopsy for 14 oncogenic HPV types by PCR. The primary endpoint--vaccine efficacy against cervical intraepithelial neoplasia (CIN) 2+ associated with HPV16 or HPV18--was assessed in women who were seronegative and DNA negative for the corresponding vaccine type at baseline (month 0) and allowed inclusion of lesions with several oncogenic HPV types. This interim event-defined analysis was triggered when at least 23 cases of CIN2+ with HPV16 or HPV18 DNA in the lesion were detected in the total vaccinated cohort for efficacy. Analyses were done on a modified intention-to-treat basis. This trial is registered with the US National Institutes of Health clinical trial registry, number NCT00122681.


RESULTS
Mean length of follow-up for women in the primary analysis for efficacy at the time of the interim analysis was 14.8 (SD 4.9) months. Two cases of CIN2+ associated with HPV16 or HPV18 DNA were seen in the HPV16/18 vaccine group; 21 were recorded in the control group. Of the 23 cases, 14 (two in the HPV16/18 vaccine group, 12 in the control group) contained several oncogenic HPV types. Vaccine efficacy against CIN2+ containing HPV16/18 DNA was 90.4% (97.9% CI 53.4-99.3; p<0.0001). No clinically meaningful differences were noted in safety outcomes between the study groups.


CONCLUSIONS
The adjuvanted HPV16/18 vaccine showed prophylactic efficacy against CIN2+ associated with HPV16 or HPV18 and thus could be used for cervical cancer prevention.
Paavonen
Jorma
J
University of Helsinki, Department of Obstetrics and Gynaecology, Helsinki, Finland. Electronic address: Jorma.Paavonen@hus.fi.
Jenkins
David
D
GlaxoSmithKline Biologicals, Rixensart, Belgium.
Bosch
F Xavier
FX
Institut Català d'Oncologia, Epidemiology and Cancer Registration Unit, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Naud
Paulo
P
University Federal of Rio Grande do Sul, Hospital de Clínica de Porto Alegre, Porto Alegre, Brazil.
Salmerón
Jorge
J
Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, México.
Wheeler
Cosette M
CM
University of New Mexico Health Sciences Center, Department of Molecular Genetics and Microbiology, Albuquerque, New Mexico, USA.
Chow
Song-Nan
SN
Department of Obstetrics and Gynecology, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan.
Apter
Dan L
DL
Family Federation of Finland, Sexual Health Clinic, Helsinki, Finland.
Kitchener
Henry C
HC
University of Manchester, Academic Unit of Obstetrics and Gynaecology, Manchester, UK.
Castellsague
Xavier
X
Institut Català d'Oncologia, Epidemiology and Cancer Registration Unit, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
de Carvalho
Newton S
NS
Department of Obstetrics and Gynaecology, University Federal of Parana and Obstetric Gynecological and Infectious Diseases Sector, Clinic Hospital, Curitiba, Parana, Brazil.
Skinner
S Rachel
SR
TVWTelethon Institute for Child Health Research, and School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.
Harper
Diane M
DM
Dartmouth Medical School, Hanover, NH, USA.
Hedrick
James A
JA
Kentucky Pediatric and Adult Research, Bardstown, KY, USA.
Jaisamrarn
Unnop
U
Chulalongkorn University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Bangkok, Thailand.
Limson
Genara Am
GA
University of the Philippines, College of Medicine, Philippine General Hospital, Makati Medical Center, Makati City, Philippines.
Dionne
Marc
M
Centre Hospitalier Universitaire du Québec, Department of Public Health, Beauport, Québec, Canada.
Quint
Wim
W
DDL Diagnostic Laboratory, Voorburg, Netherlands.
Spiessens
Bart
B
GlaxoSmithKline Biologicals, Rixensart, Belgium.
Peeters
Pascal
P
GlaxoSmithKline Biologicals, Rixensart, Belgium.
Struyf
Frank
F
GlaxoSmithKline Biologicals, Rixensart, Belgium.
Wieting
Susan L
SL
GlaxoSmithKline Biologicals, Rixensart, Belgium.
Lehtinen
Matti O
MO
University of Tampere, School of Public Health, Tampere, Finland.
Dubin
Gary
G
GlaxoSmithKline Biologicals, King of Prussia, PA, USA.
D000293:Adolescent; D000328:Adult; D004279:DNA, Viral / Q000187:drug effects / Q000302:isolation & purification; D004311:Double-Blind Method; D005260:Female; D052162:Human papillomavirus 16 / Q000187:drug effects* / Q000472:pathogenicity; D052161:Human papillomavirus 18 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D030361:Papillomavirus Infections / Q000150:complications / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000494:pharmacology* / Q000627:therapeutic use*; D002578:Uterine Cervical Dysplasia / Q000209:etiology / Q000517:prevention & control* / Q000821:virology
D004279:DNA, Viral; D053918:Papillomavirus Vaccines; C510352:human papillomavirus vaccine, L1 type 16, 18