Design of a long-term follow-up effectiveness, immunogenicity and safety study of women who received the 9-valent human papillomavirus vaccine.

The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets four HPV types (6/11/16/18) also covered by the quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). Vaccine efficacy to prevent HPV infection and disease was established in a Phase III clinical study in women 16-26years of age. A long-term follow-up (LTFU) study has been initiated as an extension of the Phase III clinical study to assess effectiveness of the 9vHPV vaccine up to at least 14years after the start of vaccination. It includes participants from Denmark, Norway and Sweden and uses national health registries from these countries to assess incidence of cervical pre-cancers and cancers due to the 7 oncogenic types in the vaccine (HPV 16/18/31/33/45/52/58). Incidences will be compared to the estimated incidence rate in an unvaccinated cohort of similar age and risk level. This LTFU study uses a unique design: it is an extension of a Phase III clinical study and also has elements of an epidemiological study (i.e., endpoints based on standard clinical practice; surveillance using searches from health registries); it uses a control chart method to determine whether vaccine effectiveness may be waning. Control chart methods which were developed in industrial and manufacturing settings for process and production monitoring, can be used to monitor disease incidence in real-time and promptly detect a decrease in vaccine effectiveness. Experience from this innovative study design may be applicable to other medicinal products when long-term outcomes need to be assessed, there is no control group, or outcomes are rare.

Luxembourg A ，Kjaer SK ，Nygard M ，Ellison MC ，Group T ，Marshall JB ，Radley D ，Saah A ... -  《-》

Long-term effectiveness of the nine-valent human papillomavirus vaccine: Interim results after 12 years of follow-up in Scandinavian women.

Kjaer SK ，Falkenthal TEH ，Sundström K ，Munk C ，Sture T ，Bautista O ，Thomas Group ，Rawat S ，Luxembourg A ... -  《-》

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial.

Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. Merck & Co, Inc.

Huh WK ，Joura EA ，Giuliano AR ，Iversen OE ，de Andrade RP ，Ault KA ，Bartholomew D ，Cestero RM ，Fedrizzi EN ，Hirschberg AL ，Mayrand MH ，Ruiz-Sternberg AM ，Stapleton JT ，Wiley DJ ，Ferenczy A ，Kurman R ，Ronnett BM ，Stoler MH ，Cuzick J ，Garland SM ，Kjaer SK ，Bautista OM ，Haupt R ，Moeller E ，Ritter M ，Roberts CC ，Shields C ，Luxembourg A ... -  《-》

Targeting human papillomavirus to reduce the burden of cervical, vulvar and vaginal cancer and pre-invasive neoplasia: establishing the baseline for surveillance.

Nygård M ，Hansen BT ，Dillner J ，Munk C ，Oddsson K ，Tryggvadottir L ，Hortlund M ，Liaw KL ，Dasbach EJ ，Kjær SK ... -  《PLoS One》

A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women.

Joura EA ，Giuliano AR ，Iversen OE ，Bouchard C ，Mao C ，Mehlsen J ，Moreira ED Jr ，Ngan Y ，Petersen LK ，Lazcano-Ponce E ，Pitisuttithum P ，Restrepo JA ，Stuart G ，Woelber L ，Yang YC ，Cuzick J ，Garland SM ，Huh W ，Kjaer SK ，Bautista OM ，Chan IS ，Chen J ，Gesser R ，Moeller E ，Ritter M ，Vuocolo S ，Luxembourg A ，Broad Spectrum HPV Vaccine Study ... -  《-》