Articles www.thelancet.com Vol 374 July 25, 2009 301 Efficacy of human papillomavirus (HPV)-16/18 AS04- adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women J Paavonen, P Naud, J Salmerón, C M Wheeler, S-N Chow, D Apter, H Kitchener, X Castellsague, J C Teixeira, S R Skinner, J Hedrick, U Jaisamrarn, G Limson, S Garland, A Szarewski, B Romanowski, F Y Aoki, T F Schwarz, W A J Poppe, F X Bosch, D Jenkins, K Hardt, T Zahaf, D Descamps, F Struyf, M Lehtinen, G Dubin, for the HPV PATRICIA Study Group Summary Background The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. Methods Women (15–25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. Findings Mean follow-up was 34·9 months (SD 6·4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92·9% (96·1% CI 79·9–98·3) in the primary analysis and 98·1% (88·4–100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30·4% (16·4–42·1) in the TVC and 70·2% (54·7–80·9) in the TVC-naive. Corresponding values against CIN3+ were 33·4% (9·1–51·5) in the TVC and 87·0% (54·9–97·7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54·0% (34·0–68·4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. Interpretation The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV- 16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. Funding GlaxoSmithKline Biologicals. Introduction Human papillomavirus (HPV) vaccines are now licensed in more than 100 countries. National and regional immunisation programmes aimed at young adolescent girls have been widely implemented, and include catch- up programmes in some countries up to the age of 18 years or older. 1 The HPV-16/18 vaccine is adjuvanted with AS04 (consisting of aluminium hydroxide and 3-O-desacyl-4‘-monophosphoryl lipid A), shown to enhance the vaccine’s immunogenicity. 2 This adjuvanted vaccine has been shown to be highly immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections and associated precancerous lesions, in an event-triggered interim analysis in our phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA), 3 and other trials. 4–7 Additionally, the vaccine has been shown to protect not only against HPV-16 and HPV-18 but also against other non-vaccine oncogenic HPV types. 3,5,8 We now present the final event-driven analysis, which includes cases accrued over a follow-up of about 3 years. As well as a further assessment of the vaccine efficacy against persistent infection and cervical intraepithelial neoplasia grade 2+ (CIN2+) associated with HPV-16/18 that was already noted in the interim analysis, we also assessed the efficacy of the vaccine against CIN3+ lesions, and infections and lesions caused by non-vaccine Lancet 2009; 374: 301–14 This online publication has been corrected. The corrected version first appeared at TheLancet.com on September 24, 2010 Published Online July 7, 2009 DOI:10.1016/S0140- 6736(09)61248-4 See Comment page 268 Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki, Finland (Prof J Paavonen MD); University Federal of Rio Grande do Sul, Hospital de Clínica de Porto Alegre, Porto Alegre, Brazil (Prof P Naud MD); Unidad de Investigación Epidemiológica y en Servicios de Salud, Instituto Mexicano del Seguro Social, Morelos, Mexico (Prof J Salmerón PhD); Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA (Prof C M Wheeler PhD); Department of Obstetrics and Gynecology, College of Medicine and the Hospital, National Taiwan University, Taipei, Taiwan (Prof S-N Chow MD); Family Federation of Finland, Sexual Health Clinic, Helsinki, Finland (D Apter MD); Manchester Academic Health Science Centre, Central Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital, Manchester, UK (Prof H Kitchener MD); Institut Català d’Oncologia, L’Hospitalet de Llobregat, IDIBELL, CIBER-ESP, Catalonia, Spain (X Castellsague MD, F X Bosch MD); University of Campinas, Campinas, Brazil (J C Teixeira MD); Vaccine Trials Group, Telethon Institute for