Long-Term Follow-up Observation of the Safety, Immunogenicity, and Effectiveness of Gardasil™ in Adult Women

and Effectiveness of GardasilTM in Adult Women. PLoS ONE 8(12): e83431. doi:10.1371/journal.pone.0083431 Long-Term Follow-up Observation of the Safety, TM Immunogenicity, and Effectiveness of Gardasil in Adult Women Joaquin Luna 0 Manuel Plata 0 Mauricio Gonzalez 0 Alfonso Correa 0 Ivete Maldonado 0 Claudia Nossa 0 David Radley 0 Scott Vuocolo 0 Richard M. Haupt 0 Alfred Saah 0 Sarah Pett, University of New South Wales, Australia 0 1 Instituto Nacional de Cancerologia , Bogota , Colombia, 2 Fundacion Cardioinfantil, Bogota , Colombia, 3 Clinica del Country, Bogota , Colombia, 4 Fundacion Santa Fe de Bogota , Bogota , Colombia, 5 Cafam, Bogota , Colombia , 6 Merck Sharp & Dohme Corp., Whitehouse Station , New Jersey , United States of America Background: Previous analyses from a randomized trial in women aged 24-45 have shown the quadrivalent HPV vaccine to be efficacious in the prevention of infection, cervical intraepithelial neoplasia (CIN) and external genital lesions (EGL) related to HPV 6/11/16/18 through 4 years. In this report we present long term follow-up data on the efficacy, safety and immunogenicity of the quadrivalent HPV vaccine in adult women. Methods: Follow-up data are from a study being conducted in 5 sites in Colombia designed to evaluate the long-term immunogenicity, effectiveness, and safety of the qHPV vaccine in women who were vaccinated at 24 to 45 years of age (in the original vaccine group during the base study [n = 684]) or 29 to 50 years of age (in the original placebo group during the base study [n = 651]). This analysis summarizes data collected as of the year 6 post-vaccination visit relative to day 1 of the base study (median follow-up of 6.26 years) from both the original base study and the Colombian follow-up. Results: There were no cases of HPV 6/11/16/18-related CIN or EGL during the extended follow-up phase in the per-protocol population. Immunogenicity persists against vaccine-related HPV types, and no evidence of HPV type replacement has been observed. No new serious adverse experiences have been reported. Conclusions: Vaccination with qHPV vaccine provides generally safe and effective protection from HPV 6-, 11-, 16-, and 18related genital warts and cervical dysplasia through 6 years following administration to 24-45 year-old women. Trial Registration: Clinicaltrials.gov NCT00090220 Funding: The study was designed and funded by the sponsor (Merck & Co, Inc.) in collaboration with external investigators and an external data and safety monitoring board. The sponsor collated the data, monitored the conduct of the study, performed the statistical analysis and coordinated the writing of the manuscript with all authors. The authors were actively involved in the collection, analysis or interpretation of the data, the revising of the manuscript for intellectual content, and approved the final manuscript. All authors had access to data and took part in the decision on where to submit the paper for publication. - Introduction Persistent infection of the uterine cervix by 15 to 20 carcinogenic human papillomavirus (HPV) genotypes leads to the vast majority of cervical cancers [1,2] and related precursor lesions [3]. While all sexually active women are at risk of HPV infection, the incidence of HPV infection peaks soon after the onset of sexual activity in most populations [46]. Incidence rates tend to decline thereafter, however some women older than age 25 are likely to remain at significant risk for acquisition of new HPV infections [7,8]. The quadrivalent HPV (qHPV) (types 6, 11, 16, 18) L1 viruslike particle (VLP) vaccine is highly effective in preventing HPV 6, 11, 16, or 18-related high-grade intraepithelial neoplasia and condyloma in men and women aged 16 to 26 nave to the respective vaccine HPV types at enrollment [9,10] In the pivotal FUTURE II trial (1095) 12,167 women between the ages of 15 and 26 received three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of HPV 16/18 disease was 98% (95% CI: 86100) in the perprotocol susceptible population. In addition, the efficacy of the qHPV vaccine has previously been demonstrated in women 24 to 45 years of age participating in an international double blind clinical trial (FUTURE III) [11]. End of study data (mean followup time of 3.8 years) from FUTURE III demonstrated qHPV vaccine efficacy of 88.7% (95% CI: 78.1, 94.8) against the combined incidence of persistent infection, cervical intraepithelial neoplasia (CIN) or external genital lesions (EGL) related to vaccine HPV types in the per-protocol population on women aged 2445 [12]. Through the end of study follow-up, 91.5%, 92.0%, 97.4% and 47.9% of vaccinated women were still considered seropositive to HPV 6, 11, 16 and 18, respectively. In this report we elaborate on previous FUTURE III results by presenting the findings of a long-term follow-up of that study evaluating the effectiveness, immunogenicity and safety of the qHPV vaccine in women originally enrolled into the trial from Colombian study sites. Analyses are cumulative incidence since vaccination, and therefore include base study data from all subjects as well as follow-up data from subjects in Colombia only. Base study design Between June 18, 2004 and April 30, 2005, 3,819 women between the ages of 24 and 45 years were enrolled at 38 international study sites into a randomized, placebo-controlled, double-blind safety, immunogenicity, and efficacy study (NCT00090220). Subjects were enrolled from community health centers, academic health centers, and primary health care providers in Colombia, France, Germany, Philippines, Spain, Thailand, and the United States. Descriptions of treatments, endpoints, hypotheses and case definitions have been published [11,12]. The institutional review board (IRB) at each participating center approved the protocol and written informed consent was obtained from all subjects. Studies were conducted in conformance with applicable country or local requirements regarding ethical committee review, informed consent and other statutes or regulations regarding the protection of the rights and welfare of human subjects participating in biomedical research. The names of each participating IRB can be seen in the supplementary file IRB. The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1. Follow-up study V501-Protocol 019-21 is a study being conducted in 5 sites in Colombia and is designed to evaluate the long-term immunogenicity, effectiveness, and safety of V501, the quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) recombinant vaccine (qHPV vaccine) in women who were vaccinated at 24 to 45 years of age (for those enrolled in the original vaccine group during the protocol (...truncated)