Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18

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1 Vaccine 24 (2006) Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18 Luisa L. Villa a,, Kevin A. Ault b,1, Anna R. Giuliano c,2, Ronaldo L.R. Costa d, Carlos A. Petta e, Rosires P. Andrade f, Darron R. Brown g, Alex Ferenczy h, Diane M. Harper i, Laura A. Koutsky j, Robert J. Kurman k, Matti Lehtinen l, Christian Malm l, Sven-Eric Olsson m, Brigitte M. Ronnett k, Finn Egil Skjeldestad n, Margareta Steinwall o, Mark H. Stoler p, Cosette M. Wheeler q, Frank J. Taddeo r, Jimmy Yu s, Lisa Lupinacci s, Radha Railkar s, Rocio Marchese r, Mark T. Esser r, Janine Bryan r, Kathrin U. Jansen r, Heather L. Sings t, Gretchen M. Tamms u, Alfred J. Saah u, Eliav Barr u a Department of Virology, Ludwig Institute for Cancer Research, R. Prof. Antonio Prudente 109, 4th floor, Sao Paulo, SP, Brazil b Department of Obstetrics, Gynecology and Epidemiology, University of Iowa, Iowa City, IA, USA c University of Arizona Cancer Center, Tucson, AZ, USA d Gynecology Department, Instituto Brasileiro de Controle do Cancer, and Hospital do Cancer, Sao Paulo, Brazil e Department of Obstetrics and Gynecology, Universidade Estadual de Campinas, Campinas Brazil f CERHFAC-Center of Human Reproduction Studies and Clinical Trials, Curitiba, Brazil g Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA h Department of Pathology, McGill University and the SMBD-Jewish General Hospital, Montreal, Que., Canada i Norris Cotton Cancer Center, Departments of Obstetrics & Gynecology and Community & Family Medicine, Dartmouth Medical School, Hanover, NH, USA j Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA k Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA l Department of Infectious Disease Epidemiology, National Public Health Institute, Helsinki, Finland m Karolinska Institute at Danderyd Hospital, Stockholm, Sweden n Department of Epidemiology, SINTEF Health Research, Trondheim, Norway o University Hospital, Lund, Sweden p Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA q Departments of Molecular Genetics and Microbiology and Obstetrics and Gynecology, University of New Mexico, Albuquerque, NM, USA r Departments of Vaccine and Biologics Research, Merck Research Laboratories, West Point, PA, USA s Department of Biostatistics, Merck Research Laboratories, West Point, PA, USA t Department of Medical Communications, Merck Research Laboratories, West Point, PA, USA u Department of Biologics Clinical Research, Merck Research Laboratories, West Point, PA, USA Received 26 November 2005; received in revised form 13 April 2006; accepted 20 April 2006 Available online 15 May 2006 Abstract Human papillomavirus (HPV) infection causes cervical cancer and genital warts. Young women (1106) were randomized to receive one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 virus-like particle (VLP) vaccine or one of two placebo formulations. The goal was to assess vaccine safety and immunogenicity in baseline HPV 6/11/16 or 18-naïve and previously infected subjects. All three Corresponding author. Tel.: ; fax: address: llvilla@ludwig.org.br (L.L. Villa). 1 Now at Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA. 2 Now at Moffitt Cancer Center, Tampa, FL, USA X/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi: /j.vaccine

2 5572 L.L. Villa et al. / Vaccine 24 (2006) formulations were highly immunogenic. At Month 2 (postdose 1), among women with vaccine-type antibodies at baseline, vaccine-induced anti-hpv responses were 12- to 26-fold higher than those observed in baseline-naïve women, suggesting an anamnestic response. Following an initial, similar sized decline, anti-hpv responses plateaued and remained stable through end-of-study (3.0 years). No vaccine-related serious adverse experiences were reported Elsevier Ltd. All rights reserved. Keywords: Human papillomavirus; Vaccine; Immunogenicity 1. Introduction Human papillomavirus (HPV) infection is a cause of cervical cancer and genital warts [1 6]. HPV infection is also associated with the development of anal, vulvar, vaginal, and penile cancers. The oncogenicity of HPV is mediated by the HPV E6 and E7 proteins, which induce accelerated and disordered cellular proliferation resulting in pre-cancerous epithelial lesions. Such lesions can progress to invasive cancer. HPV infection is one of the most common sexually transmitted diseases worldwide [5 7]. The lifetime risk of HPV infection for sexually active males and females is approximately 50% [7]. An estimation of worldwide cancer incidence and mortality for 2002 showed that persistent HPV infection had caused about 500,000 cases of cervical cancer [8]. Despite organized screening programs using the Papanicolaou (Pap) test, approximately 35,000 women died from this disease in the USA and Europe [8]. While Pap testing reduces mortality from cervical neoplasia, it does not prevent HPV infection or development of pre-cancerous lesions such as high-grade cervical intraepithelial neoplasia 2/3 (CIN 2/3) and persistent low-grade lesions (CIN 1), all of which require treatment. A recent study has estimated that in the United States alone, cervical HPV-related disease accounts for a total health care cost of $3.4 billion (in 2002 dollars) [9]. Another non-negligible complication of genital HPV infection is anogenital warts, which affect approximately 1% of sexually active individuals between the ages of 15 and 50 years old [10]. Of the approximately 40 distinct HPV types that are known to infect the anogenital epithelium, only a small number cause the majority of disease. HPV Types 16 and 18 cause approximately 70% of all cervical cancer cases worldwide [3]. HPV 6 and 11 cause a majority of genital warts (men and women) [11]. HPV 6, 11, 16 or 18 are found in approximately a third of low-grade cervical lesions [12]. Thus, an effective HPV (Types 6/11/16/18) vaccine would target HPV types that cause about 70% of cervical cancers and high-grade pre-cancerous lesions, about a third of low-grade dysplastic lesions, and a majority of genital wart cases. Such a vaccine has the potential to substantially reduce the burden of clinical HPV disease in both men and women. HPV is a small, non-enveloped, double-stranded DNA virus. The HPV L1 capsid protein, when expressed in yeast cells, forms non-infectious virus-like particles (VLPs) that resemble native virions [13]. Recent Phase I and II clinical trials have demonstrated that HPV vaccines based on the HPV L1 capsid protein are generally well-tolerated and induce neutralizing anti-hpv responses [14 22]. These trials served as the basis for evaluating a quadrivalent HPV vaccine targeting HPV 6/11/16/18. Recently, we described results from a Phase II study designed to select one of three formulations of quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine for use in Phase III studies. This 3-year, randomized, placebo-controlled trial showed that the formulation comprising the lowest dose of HPV 6, 11, 16 and 18 L1 VLPs was generally well-tolerated and reduced the combined incidence of persistent HPV 6, 11, 16 or 18 infection or related genital disease by 90%, compared to placebo [20]. In this study, subjects with vaccine-type antibodies or DNA at baseline were eligible for vaccination. This design feature allowed for an assessment of the tolerability, immunogenicity, and efficacy of the quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine in women who had presumably already been infected with vaccine HPV types prior to enrollment. This report extends previous findings by presenting immunogenicity and tolerability results for all three doses of quadrivalent vaccine. These data provide the rationale for selecting the quadrivalent HPV vaccine dose used in Phase III studies. In addition, an exploratory analysis of the immunogenicity of this Phase III formulation in HPV 6, 11, 16, or 18-naïve and previously infected women, is presented. 2. Methods 2.1. Vaccine The active quadrivalent vaccine consists of a mixture of four recombinant HPV type-specific VLPs (Merck Research Laboratories, West Point, PA) composed of the L1 major capsid proteins of HPV 6, 11, 16 and 18 synthesized in Saccharomyces cerevisiae [20]. The four VLP types were purified and adsorbed onto a proprietary amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHS), also referred to as Merck Aluminum Adjuvant (MAA). The two placebo formulations contained the same adjuvant and were visually indistinguishable from vaccine Study design Protocol 007 was a Phase II, randomized, multi-center, double-blind, placebo-controlled study. The protocol was designed to select one of three formulations of quadrivalent

3 L.L. Villa et al. / Vaccine 24 (2006) Fig. 1. Trial profile. HPV (Types 6/11/16/18) L1 VLP vaccine for use in Phase III studies and to preliminarily evaluate the safety, immunogenicity, and efficacy of the selected formulation [20]. The HPV 6, 11, 16 or 18 L1 VLP doses present in each formulation were based on Phase I HPV 11, 16, and 18 L1 VLP vaccine safety and immunogenicity studies [16,17,21]. This study was conducted in two parts (Fig. 1). Part A was a sequential dose-escalating evaluation. Both the subject and the investigator and his/her staff were blinded to who received vaccine and who received placebo, but not to the dose of the active group. Part B was a fully blinded dose-ranging evaluation of safety, efficacy and immunogenicity. Study procedures for all subjects in Part A and B were identical. Data presented here are from Part B, as Part A was not fully blinded. For Part B, a total of 1106 women with nearly all aged years (one subject was 13, other was 15) were recruited in Brazil, Europe, and the USA. Subjects were randomized in a 2:2:2:1:1 ratio to receive 20/40/40/20 g of HPV 6, 11, 16 and 18 L1 VLP (including 225 g AAHS), 40/40/40/40 gof HPV 6, 11, 16 and 18 L1 VLP (including 225 g AAHS), or 80/80/40/80 g of HPV 6, 11, 16 and 18 L1 VLP (including 395 g AAHS), placebo with 225 g of AAHS, or placebo with 450 g of AAHS. To enrich the study population for HPV-naïve women, only non-pregnant, healthy women who reported no prior abnormal Pap smears of low-grade squamous intraepithelial lesion (LSIL) or worse, and reported a lifetime history of four or fewer male sex partners were enrolled. Among virgins, enrollment was limited to those women who were 18 years of age and seeking contraception. This study did not exclude subjects with prior or ongoing HPV infection of any type. Thus, women who were anti- HPV seropositive (i.e., had developed immune responses to an HPV infection) and women who were HPV DNA positive (i.e., had evidence of ongoing HPV infection) were enrolled. The study was 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. All subjects and/or parents/legal guardians signed informed consents following review of the protocol procedures. Vaccine or placebo was administered at day 1, Month 2, and Month 6, given as a 0.5 ml intramuscular injection. All subjects were observed for at least 30 min after each vaccination for any immediate reaction. Temperatures were recorded orally for 5 days following each injection. All adverse experiences were collected daily by the participant on a Vaccination Report Card (VRC) for 14 days following each vaccination. Participants agreed to use effective contraception during the vaccination phase.

4 5574 L.L. Villa et al. / Vaccine 24 (2006) A complete gynecological history and a gynecological physical examination were conducted at day 1, and at Months 7, 12, 24, and 36 [20]. Genital specimens were obtained from all subjects at day 1 and at Months 7, 12, 18, 24, 30, and 36 for HPV DNA detection as described [20]. An interim analysis was planned for the time when approximately 50% of the postdose 3 (Month 7) responses from Part B were available. The purpose of this interim analysis was to select a dose of quadrivalent vaccine for Phase III studies HPV Serologic assays Serum antibodies to HPV 6, 11, 16 and 18 were measured using a competitive radioimmunoassay (cria) or a competitive Luminex immunoassay (clia) in both vaccine and placebo groups [23 25]. Serum samples were obtained from all subjects at day 1 and at Months 2, 3, 6, 7, 12, 18, 24, 30, and 36. Under a Protocol Amendment, the assay method was changed from cria to clia. The optimization and validation of the assay and cria-to-clia concordance is published elsewhere [23,25]. Prior to the Protocol Amendment, all day 1 and Months 2, 3, 6 and 7 samples were tested by cria. After the Protocol Amendment, the clia assay was used consistently for the analysis of only one dose formulation of vaccine (i.e., 20/40/40/20 g dose) over 36 months of follow-up and included testing of samples from day 1 and Months 2, 3, 6, 7, 12, 18, 24, 30, and HPV competitive radioimmunoassays (crias) Four separate HPV crias (one assay per HPV type), developed by Merck Research Laboratories, were used to quantitate serum HPV 6, 11, 16 and 18 specific antibodies as described [24]. Briefly, polystyrene beads were coated with a limiting amount of HPV 6, 11, 16 or 18 L1 VLP antigen, incubated with the corresponding HPV 6, 11, 16 or 18 specific mouse MAbs (H6.B10.5 [26], H11.B2 [27], H16.V5 [28] and H18.J4 [28], respectively) and a serum sample. Goat anti-mouse antibodies tagged with 125 I were used to detect the amount of mouse MAb bound to the VLPs. Standard curves were constructed using dilutions of serum from an HPV 6, 11 or 18 L1 VLP immunized African Green Monkey or an HPV 16 L1 VLP immunized Chimpanzee. As a competitive assay, the measure of VLP bound MAb is an indirect measurement of the presence of serum antibody to a neutralizing epitope of the VLP. Sample titers were interpolated from the four-parameter logistic regression fit to the standard curve, corrected for dilution, and reported in arbitrary units (milli- Merck Units per milliliter [mmu/ml]). The lower limits of quantitation were 4.0, 6.5, 1.3, and 6.5 mmu/ml and the serostatus cutoffs were 8.0, 13.0, 6.0 and 13.0 mmu/ml for antibodies to HPV 6, 11, 16 and 18, respectively HPV competitive luminex immunoassay (HPV clia) The HPV clia is a competitive assay that measures in a single serum sample HPV 6, 11, 16 and 18 type-specific antibodies to conformationally sensitive, neutralizing epitopes on HPV L1 VLPs [25]. The assay uses yeast-derived HPV L1 6, 11, 16 and 18 VLPs that have been covalently conjugated to Luminex microspheres 6, 11, 16 and 18, respectively. The type-specific HPV-VLP antibody responses are associated with specific Luminex microspheres that are identified by their distinct red and infrared fluorescent dye spectral properties on a Luminex 100 BioPlex instrument. Antibody titers are determined in a competitive format, where known, typespecific phycoerythrin (PE)-labeled, neutralizing antibodies H6.M48 [26] for HPV 6, K11.B2 [25] for HPV 11, H16.V5 [28] for HPV 16 and H18.J4 [28] for HPV 18, compete with patient serum antibodies for binding to conformationally sensitive, neutralizing epitopes on the VLPs. For each HPV type, relative inhibition of mab-pe binding is compared to a pooled standard reference serum using a four-parameter logistic curve fit [29], corrected for dilution and reported in mmu/ml. The lower limits of quantitation were 8.0, 8.0, 12.0 and 8.0 mmu/ml and the serostatus cutoffs were 20, 16, 20 and 24 mmu/ml for HPV 6, 11, 16 and 18, respectively Statistical analysis The immunogenicity objectives of this report were: (1) to report the results of the pre-specified interim summary of immune responses for dose selection of quadrivalent vaccine for use in Phase III studies; (2) to report the results of an exploratory evaluation of immune responses over time for the dose selected for Phase III development; and (3) to report the results of an exploratory comparison of immune responses between subjects that were naïve to a given vaccine HPV type at day 1 and subjects with serologic evidence of having cleared a prior infection with the same vaccine HPV type. All of these evaluations were exploratory in nature and therefore no statistical tests were performed. When approximately 50% of the postdose 3 (Month 7) responses as measured by cria were available from subjects enrolled in Part B (June 2001), an interim summary of immunogenicity and safety was conducted in subjects who were seronegative (by cria) and PCR negative to the relative vaccine HPV type at day 1. Subjects in the placebo arms were pooled for this analysis. For the interim summary of immunogenicity, anti-hpv levels in seronegative subjects were set to 4.0, 6.5, 3.0 and 6.5 mmu/ml, respectively. For consistency of analysis, the cria assay was used for the interim summary through Month 7. Geometric mean titers (GMTs) and their associated 95% confidence intervals, and longitudinal plots were used in evaluating the immunogenicity of the quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine 20/40/40/20 g dose. For consistency of analysis, the clia assay was used for the analysis of this one, low-dose of vaccine over the entire 36 months of follow-up. GMTs were measured in three cohorts: (1) the per-protocol immunogenicity (PPI) cohort which consisted of subjects who were naïve to the relevant HPV type at enrollment, remained free of infection with the same vaccine

5 L.L. Villa et al. / Vaccine 24 (2006) HPV type through the completion of the vaccination regimen, received all 3 doses of vaccine or placebo within the protocol specified time frames (vaccination 2 = days relative to vaccination 1; vaccination 3 = days relative to vaccination 1; Month 7 serum sample collected within days following the third vaccination) and did not violate the protocol; (2) a cohort consisting of subjects who were seropositive, but PCR negative to the relevant HPV type at enrollment; and (3) a cohort of subjects who were seronegative, but PCR positive to the relevant HPV type at enrollment. For the PPI population, percentages of subjects who seroconverted at Month 7 and subsequently were seropositive at Months 18 and 36 were calculated. In addition, the percentages of subjects who remained seropositive at Months 18 and 36 were determined among quadrivalent vaccine recipients who were seropositive and PCR negative to the relevant vaccine HPV type at enrollment, who received all three vaccinations, and had a Month 7 serum sample collected. In addition, the Month 7 antibody responses in the PPI population were compared by region (USA, Brazil, and Europe). With the exception of a designated unblinded statistician, in-house blinding was maintained until the completion of the study. The designated unblinded statistician was appointed to perform the safety and immunogenicity interim analysis on data through the Month 7 time point. Subjects, investigators (and their staff), HPV vaccine clinical, data management, statistics, regulatory, and quality assurance personnel at the Sponsor, Pathology Panel members, and laboratory personnel conducting the PCR and serology assays were not informed of individual vaccination allocations until the end of the study. Dose selection for future studies was not disclosed to investigators until the initiation of the Phase III program (December 2001). The primary safety hypothesis for Part B of the study stated that quadrivalent HPV L1 VLP vaccine is generally welltolerated. If no serious vaccine-related adverse experiences were observed among the 250 subjects in each quadrivalent vaccine dose group, there was a 97.5% probability that the true rate is <1.5%. The proportion of subjects with serious adverse experiences and all adverse experiences were summarized by vaccination group and type of adverse experience. Per-protocol, p-values were computed for those prompted adverse experiences on the VRC, including injection-site pain, erythema and redness. Due to differing concentrations of AAHS in the various vaccine and placebo treatment groups, subjects who received the low- and intermediatedoses of quadrivalent vaccine (containing 225 g AAHS) were compared to the low-dose placebo formulation (225 g AAHS), while subjects who received the high-dose formulation of vaccine (containing 395 g AAHS) were compared to the high-dose placebo formulation (450 g AAHS). The method of Miettinen and Nurminen [30] was used for all comparisons of safety profiles among the vaccination groups. The safety profiles were also summarized in two subpopulations: (1) subjects who were seronegative at day 1 and PCR negative from day 1 through Month 7 to all vaccine HPV types; and (2) subjects who were seropositive at day 1 or PCR positive to any of the vaccine HPV types at any time from day 1 through Month 7, to evaluate the impact of baseline HPV 6, 11, 16 or 18 status on the tolerability of the quadrivalent HPV vaccine. 3. Results 3.1. Baseline demographics The baseline demographic characteristics were generally well-balanced among the five vaccination groups (Table 1). These year-old women were predominantly Caucasians and approximately 25% (277/1106) were current smokers. The mean age at first sexual intercourse was between 16 and 17 for each vaccination group. Over 60% (707/1106) of subjects reported fewer than 3 lifetime sexual partners at enrollment. The percentages of subjects who used barrier, behavior, hormonal, and other contraceptive methods were comparable among the five vaccination groups. The most common contraceptive methods were hormonal contraceptives (640/1106; 57.9%) and male condom (271/1106; 24.5%). The percentages of subjects who were seropositive or PCR positive to at least one of the vaccine HPV types at baseline were generally comparable among the vaccination groups (Table 2). For the overall study cohort, approximately 18.2% (201/1103) and 12.1% (133/1100) of these women were anti- HPV 6, 11, 16 or 18 seropositive and HPV 6, 11, 16 or 18 DNA positive at baseline, respectively. Similarly, within each HPV type, seropositivity was more prevalent than PCR positivity. At baseline, more subjects were seropositive or PCR positive to HPV 16 than to the other three vaccine HPV types. In general, the percentages of subjects that had abnormal Pap test diagnoses (8.9% to 12.1%) were comparable among the five vaccination groups (Table 1) Primary Dose Selection The primary immunogenicity objective was to select one of three formulations of a quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine for use in Phase III studies [20]. Based on the interim summary of immune responses, for each of the four components, the postdose 3 (Month 7) anti-hpv GMTs were 27- to 145-fold higher than those observed in placebo recipients who were vaccine-type HPV seropositive at day 1 (Fig. 2). For each of the four components, anti-hpv GMTs at Month 7 appeared to be comparable among the three formulations of quadrivalent vaccine (Fig. 2). For all three formulations, 100% of subjects seroconverted (i.e., showed evidence of vaccine-induced immune responses) by Month 7. The formulation comprising the lowest dose (20/40/40/20 g) of HPV 6, 11, 16 and 18 L1 VLPs was therefore chosen for evaluation in Phase III studies.

6 5576 L.L. Villa et al. / Vaccine 24 (2006) Table 1 Summary of subject characteristics by vaccination group at enrollment Placebo (aluminum adjuvant) Quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine Total N = 1106, Placebo (225 g), N = 135, n (%) a Placebo (450 g), N = 140, n (%) a 20/40/40/20 g, N = 277, n (%) a 40/40/40/40 g, N = 274, n (%) a 80/80/40/80 g, N = 280, n (%) a Age (years) Mean ± S.D ± ± ± ± ± ± 1.7 Range Ethnicity Asian 6 (4.4) 5 (3.6) 7 (2.5) 11 (4.0) 4 (1.4) 33 (3.0) Black 11 (8.1) 7 (5.0) 25 (9.0) 32 (11.7) 26 (9.3) 101 (9.1) Hispanic American 10 (7.4) 10 (7.1) 14 (5.1) 14 (5.1) 10 (3.6) 58 (5.2) Native American 0 (0.0) 1 (0.7) 2 (0.7) 4 (1.5) 2 (0.7) 9 (0.8) White 101 (74.8) 113 (80.7) 216 (78.0) 204 (74.5) 230 (82.1) 864 (78.1) Other 7 (5.2) 4 (2.9) 13 (4.7) 9 (3.3) 8 (2.9) 41 (3.7) Smoking status Never smoked 92 (68.1) 79 (56.4) 183 (66.1) 169 (61.7) 170 (60.7) 693 (62.7) Ex-smoker 15 (11.1) 18 (12.9) 29 (10.5) 31 (11.3) 38 (13.6) 131 (11.8) Current smoker 27 (20.0) 42 (30.0) 64 (23.1) 72 (26.3) 72 (25.7) 277 (25.0) Unknown 1 (0.7) 1 (0.7) 1 (0.4) 2 (0.7) 0 (0) 5 (0.5) National origin USA 63 (46.7) 63 (45.0) 125 (45.1) 123 (44.9) 127 (45.4) 501 (45.3) Brazil 46 (34.0) 47 (33.6) 94 (33.9) 91 (33.2) 94 (33.6) 372 (33.6) Europe 26 (19.3) 30 (21.4) 58 (20.9) 60 (21.9) 59 (21.1) 233 (21.1) Age at first sexual intercourse (years) Mean ± S.D ± ± ± ± ± ± 1.8 Median (range) 17 (13 23) 17 (12 23) 16 (12 22) 17 (13 23) 17 (11 22) 17 (11 23) Lifetime number of sexual partners at enrollment 0 6 (4.4) 10 (7.1) 17 (6.1) 25 (9.1) 18 (6.4) 76 (6.9) 1 47 (34.8) 41 (29.3) 80 (28.9) 74 (27.0) 88 (31.4) 330 (29.8) 2 41 (30.4) 34 (24.3) 73 (26.4) 83 (30.3) 70 (25.0) 301 (27.2) 3 19 (14.1) 31 (22.1) 67 (24.2) 51 (18.6) 62 (22.1) 230 (20.8) 4 22 (16.3) 24 (17.1) 40 (14.4) 41 (15.0) 41 (14.6) 168 (15.2) Median (range) 2 (0 4) 2 (0 4) 2 (0 4) 2 (0 4) 2 (0 4) 2 (0 4) Pap test Without Pap test at day 1 3 (2.2) 3 (2.1) 10 (3.6) 10 (3.6) 8 (2.9) 34 (3.1) Unsatisfactory 1 (0.7) 1 (0.7) 3 (1.1) 4 (1.5) 3 (1.1) 12 (1.1) Normal 119 (88.1) 119 (85.0) 231 (83.4) 229 (83.6) 239 (85.4) 937 (84.7) Abnormal 12 (8.9) 17 (12.1) 33 (11.9) 31 (11.3) 30 (10.7) 123 (11.1) ASCUS 6 (4.4) 11 (7.9) 16 (5.8) 11 (4.0) 14 (5.0) 58 (5.2) LSIL 5 (3.7) 5 (3.6) 15 (5.4) 18 (6.6) 14 (5.0) 57 (5.2) HSIL 1 (0.7) 1 (0.7) 1 (0.4) 2 (0.7) 2 (0.7) 7 (0.6) AGC 0 (0.0) 0 (0.0) 1 (0.4) 0 (0.0) 0 (0.0) 1 (0.1) Contraception method b Male condom 40 (29.6) 36 (25.7) 63 (22.8) 58 (21.3) 74 (26.4) 271 (24.5) Behavioral 23 (17.0) 25 (17.9) 48 (17.4) 51 (18.8) 50 (17.9) 1497 (17.8) Hormonal 76 (56.3) 81 (57.9) 161 (58.3) 163 (59.9) 159 (56.8) 640 (57.9) Other 8 (5.9) 9 (6.4) 21 (7.6) 14 (5.1) 17 (6.1) 69 (6.2) SIL, squamous intraepithelial lesion; ASCUS, atypical squamous cells of undetermined significance; LSIL, low-grade SIL; HSIL, high-grade SIL; AGC, atypical glandular cells; N, number of subjects randomized to the respective vaccination group; n, number of subjects with the indicated characteristic. a Percentage was computed as 100 (n/n). b The same subject may appear in more than one category. n (%) a 3.3. Immunogenicity of the Phase III formulation Of the 552 participants randomized to the Phase III formulation and pooled placebo arms, 551 received at least one injection of vaccine or placebo. Among these subjects, 406, 379, and 428 were included in the PPI analyses for Types 6/11, 16, and 18, respectively [20]. The primary reason for exclusion from the PPI analysis was detection of vaccinetype HPV antibodies at day 1 and/or detection of vaccine-type HPV DNA at day 1 through Month 7, followed by general protocol violations (57 subjects). The most common protocol violation was an incomplete vaccination series (30 subjects)

7 L.L. Villa et al. / Vaccine 24 (2006) Table 2 Summary of anti-hpv serostatus and HPV PCR status at day 1 by vaccination group and HPV type Pooled placebo (250 g g), N = 275, m/n (%) 20/40/40/20 g, N = 277, m/n (%) 40/40/40/40 g, N = 274, m/n (%) 80/80/40/80 g, N = 280, m/n (%) Total N = 1106, m/n (%) Day 1 status HPV 6 Seropositive 21/275 (7.6) 16/276 (5.8) 21/272 (7.7) 15/280 (5.4) 73/1103 (6.6) DNA positive 5/275 (1.8) 8/275 (2.9) 14/271 (5.2) 3/279 (1.1) 30/1100 (2.7) HPV 11 Seropositive 6/275 (2.2) 6/276 (2.2) 8/272 (2.9) 5/280 (1.8) 25/1103 (2.3) DNA positive 3/275 (1.1) 2/275 (0.7) 5/271 (1.8) 2/279 (0.7) 12/1100 (1.1) HPV 16 Seropositive 29/275 (10.5) 32/276 (11.6) 31/272 (11.4) 24/280 (8.6) 116/1103 (10.5) DNA positive 25/275 (9.1) 24/275 (8.7) 24/271 (8.9) 17/279 (6.1) 90/1100 (8.2) HPV 18 Seropositive 12/275 (4.4) 10/276 (3.6) 12/272 (4.4) 12/280 (4.3) 46/1103 (4.2) DNA positive 4/275 (1.5) 4/275 (1.5) 6/271 (2.2) 6/279 (2.2) 20/1100 (1.8) HPV 6, 11, 16 or 18 Seropositive 51/275 (18.5) 50/276 (18.1) 57/272 (21.0) 43/280 (15.4) 201/1103 (18.2) DNA positive 32/275 (11.6) 32/275 (11.6) 43/271 (15.9) 26/279 (9.3) 133/1100 (12.1) N, number of subjects randomized to the respective vaccination group; m, number of subjects contributing to the analysis; n, number of subjects with a valid or non-missing day 1 immunoassay or PCR result. Fig. 2. Interim analysis of immunogenicity of three formulations of quadrivalent vaccine. Postdose 3 (Month 7) anti-hpv cria GMTs (mmu/ml with 95% confidence intervals on a logarithmic scale) are shown for: (a) HPV 6; (b) HPV 11; (c) HPV 16; and (d) HPV 18. Because the titers of the reference sera are not identical, one cannot draw conclusions from the absolute titers with regard to the relative immunogenicity of the four VLP components in the vaccine; n is the number of subjects contributing to the analysis.

8 5578 L.L. Villa et al. / Vaccine 24 (2006) Fig. 3. Anti-HPV clia GMTs (mmu/ml with 95% confidence intervals) for quadrivalent vaccine (Phase III formulation) and placebo recipients (pooled placebo arms). Longitudinal plots are shown by HPV type for the PPI population and for subjects who were baseline seropositive and PCR negative: (A) HPV 6; (B) HPV 11; (C) HPV 16; and (D) HPV 18. Because the titers of the reference sera are not identical, one cannot draw conclusions from the absolute titers with regard to the relative immunogenicity of the four VLP components in the vaccine. n = number of subjects contributing to the Month 36 time point. or vaccination 2 or 3 out of the protocol-specified time window (26 subjects). Baseline vaccine-type HPV naïve subjects who received the 20/40/40/20 g formulation of quadrivalent vaccine mounted a robust immune response (Fig. 3, Table 3). For comparison, antibody titers for baseline seropositive and DNA negative subjects who received placebo are also plotted in Fig. 3. This population is enriched for subjects who had presumably been infected with the relevant vaccine HPV type, mounted an immune response to the infection, and then cleared that infection prior to enrollment. The GMTs observed in these subjects provide a reference against which to evaluate vaccine-induced anti-hpv responses. Although the total number of women in these subpopulations was small, the HPV 6, 11, 16 and 18 antibody titers in these baseline seropositive and PCR negative subjects who received placebo remained constant throughout the 3-year period of the study. One month after the primary dose (Month 2) vaccineinduced antibody levels were above those seen in the baseline seropositive and DNA negative placebo subjects for the HPV 16 component only. However, upon completion of a 3-dose regimen, anti-hpv 6, 11, 16 and 18 antibody levels were 10- to 104-fold higher than those observed in these placebo recipients who were vaccine-type HPV seropositive at enrollment. Furthermore, 100% of vaccine recipients with a valid Month 7 serum result had detectable HPV 6, 11, 16 and 18 antibodies. As shown in Fig. 3, the vaccine-induced immune response appears highest for HPV 16, however direct comparisons of the relative immunogenicity of the four VLP components cannot be made from the absolute titers, as the titers for each of the reference sera for the individual assays were not identical. Following an initial, similar sized decline, vaccineinduced HPV 6, 11, 16 and 18 antibody levels plateaued and remained stable for at least 2.5 years postdose 3 for all four types. In the PPI population, anti-hpv 6, 11, 16 or 18 GMTs at Month 24 (93.7, 99.8, and 59.9 mmu/ml, respectively) were comparable to those observed at Month 36 (93.4, 94.0, and 59.7 mmu/ml, respectively). At Month 36, vaccine-induced antibody titers reached that of natural infection for HPV 6, 11, and 18, while HPV 16 antibody titers remained 17-fold higher than that of natural infection (Fig. 3C). As shown in Fig. 3, average serum HPV antibody levels remained below the limits of quantitation in baseline vaccine-type HPV-naïve placebo recipients. Administration of quadrivalent vaccine to women with detectable HPV antibodies at enrollment resulted in higher anti-hpv responses than those observed among quadrivalent vaccine recipients who were naïve to the relevant HPV type at baseline, although the 95% confidence intervals overlapped at most time points (Fig. 3, Table 3). The difference was particularly evident after the first vaccine injection: At Month 2, among women with detectable anti-hpv 6, 11, 16 or 18 antibodies at baseline, vaccine-induced anti-hpv responses were 12- to 26-fold higher than those observed in the baseline-naïve vaccine recipients (i.e., the PPI population). Taken together, these results suggest that women who were baseline anti-hpv positive had developed a booster response to the vaccination. To further investigate the long-term immunogenicity of the Phase III formulation, percentages of per-protocol subjects who seroconverted at Month 7 and subsequently were seropositive at Months 18 and 36 were calculated. At Month 7, for each vaccine HPV type, 100% of subjects who received the vaccine in the PPI population became seropositive for

9 L.L. Villa et al. / Vaccine 24 (2006) Table 3 Summary of anti-hpv clia titers among the PPI population, and subjects who were HPV seropositive/pcr negative to the corresponding HPV vaccine-type at day 1 Cohort n Phase III formulation (N = 276) n Pooled placebo arms (N = 275) Day 1 serology status Day 1 DNA status GMT (mmu/ml) 95% CI GMT (mmu/ml) 95% CI HPV 6 Month 2 Negative Negative (27 37) ( ) Month 2 Positive Negative ( ) (32 99) Month 7 Negative Negative ( ) ( ) Month 7 Positive Negative ( ) (28 108) Month 36 Negative Negative (81 108) ( ) Month 36 Positive Negative (97 582) (33 139) HPV 11 Month 2 Negative Negative (32 43) ( ) Month 2 Positive Negative ( ) 4 95 ( ) Month 7 Negative Negative ( ) ( ) Month 7 Positive Negative ( ) 4 94 ( ) Month 36 Negative Negative (81 110) ( ) Month 36 Positive Negative ( ) 4 96 (19 498) HPV 16 Month 2 Negative Negative ( ) ( ) Month 2 Positive Negative ( ) (12 63) Month 7 Negative Negative ( ) ( ) Month 7 Positive Negative ( ) (17 85) Month 36 Negative Negative ( ) ( ) Month 36 Positive Negative ( ) (12 69) HPV 18 Month 2 Negative Negative (12 16) ( ) Month 2 Positive Negative ( ) (22 79) Month 7 Negative Negative ( ) ( ) Month 7 Positive Negative ( ) (23 75) Month 36 Negative Negative (49 74) ( ) Month 36 Positive Negative 9 94 (41 214) (15 59) N, number of subjects randomized to the respective vaccination group who received at least one injection; n, number of subjects contributing to the analysis. the relevant vaccine HPV type. Among subjects who had valid immunoassay results, 98%, 98% 100% and 86% were seropositive for HPV Types 6, 11, 16 and 18 at Month 18; and 94%, 96%, 100% and 76% were seropositive for HPV Types 6, 11, 16 and 18 at Month 36, respectively. In comparison to the PPI population, among quadrivalent vaccine recipients who were seropositive and PCR negative to the relevant vaccine HPV type at enrollment 85% (11/13), 100% (6/6), 100% (15/15), and 100% (9/9) were seropositive for HPV Types 6, 11, 16 and 18 at Month 18; and 92% (12/13), 100% (6/6), 100% (13/13) and 88% (8/9) were seropositive for HPV Types 6, 11, 16 and 18 at Month 36, respectively. The anti-hpv serum clia responses among subjects who were baseline PCR positive and seronegative to the relevant HPV type(s) were also measured. These subjects had vaccine-type HPV DNA detected at day 1 but did not have measurable antibodies to the same type. Anti-HPV 6, 11, 16, and 18 GMTs in these subjects appeared to be comparable to those observed in the PPI population (data not shown). However, the small sample size in this study limited the capacity to detect potential differences in vaccine-induced immune responses between the groups. The Month 7 antibody responses in the PPI population were compared by geographic region. There was no apparent difference in vaccine immunogenicity among women from the United States, Europe, and Brazil (data not shown) Safety Safety data for the low-dose Phase III formulation has been described [20]. A detailed comparison of safety data for all three formulation of quadrivalent vaccine is provided in Table 4. As shown in Table 4, the proportion of subjects who reported any adverse experience (day 1 through day 15 following any vaccination visit) was slightly increased among the quadrivalent HPV vaccine groups compared with the placebo groups. The incidences of systemic clinical adverse experiences were generally comparable among the five vaccination groups. The most commonly reported systemic clinical adverse experiences judged by the site investigator to be vaccine-related were headache and pyrexia. The most commonly reported injection-site adverse experiences across the 5 vaccination groups were injection-site pain, erythema, and swelling. A total of six serious adverse experiences were reported. None was judged to be vaccine-related. Within

10 5580 L.L. Villa et al. / Vaccine 24 (2006) Table 4 Clinical adverse experience summary (days 1 15 following any vaccination visit) Placebo (aluminum adjuvant) Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP vaccine Placebo (225 g), N = 135, n (%) a Placebo (450 g), N = 140, n (%) a 20/40/40/20 g, N = 275, n (%) a 40/40/40/40 g, N = 272, n (%) a 80/80/40/80 g, N = 280, n (%) a Subjects with follow-up With one or more AE 116 (86.6) 126 (90.0) 250 (91.9) 251 (93.3) 265 (95.7) With one or more systemic AE 95 (70.9) 95 (67.9) 187 (68.8) 186 (69.1) 192 (69.3) Gastrointestinal disorders 29 (21.6) 30 (21.4) 67 (24.6) 69 (25.7) 66 (23.8) Fatigue 9 (6.7) 8 (5.7) 15 (5.5) 8 (3.0) 11 (4.0) Dizziness 1 (0.7) 5 (3.6) 13 (4.8) 9 (3.3) 9 (3.2) Headache 48 (35.8) 54 (38.6) 110 (40.4) 98 (36.4) 112 (40.4) Rash 1 (0.7) 2 (1.4) 3 (1.1) 5 (1.9) 0 (0.0) Pyrexia 13 (9.7) 16 (11.4) 30 (11.0) 37 (13.8) 41 (14.8) With one or more injection-site AE 100 (74.6) 112 (80.0) 234 (86.0) 240 (89.2) 255 (92.1) Injection site bruising 6 (4.5) 3 (2.1) 13 (4.8) 7 (2.6) 9 (3.2) Injection site erythema 26 (19.4) 30 (21.4) 73 (26.8) 58 (21.6) 75 (27.1) Injection site pain b 98 (73.1) 111 (79.3) 232 (85.3) 238 (88.5) 251 (90.6) Injection site pruritus 1 (0.7) 3 (2.1) 8 (2.9) 11 (4.1) 9 (3.2) Injection site reaction 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 5 (1.8) Injection site swelling c 20 (14.9) 29 (20.7) 76 (27.9) 72 (26.8) 89 (32.1) With serious AE 0 (0.0) 2 (1.4) 2 (0.7) 0 (0.0) 2 (0.7) With serious vaccine-related AE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)) 0 (0.0) N, number of subjects randomized to the respective vaccination group who received at least one injection; n, number of subjects within category. a Percentage was computed as 100 (n/number of subjects with follow-up). b p = 0.003, <0.001, and for the low-, intermediate-, and high-dose, respectively. c p = 0.004, 0.008, and for the low-, intermediate-, and high-dose, respectively. each vaccination group, the majority (approximately 95%, 5430/5797) of the reported adverse experiences were mild or moderate in intensity. When compared with the corresponding placebo group, the percentages of subjects who had injection-site pain and injection-site swelling were statistically higher among the recipients of active quadrivalent vaccine (Table 4). It should be noted that no multiplicity adjustment was made to control the overall type I error rate for these comparisons. Among the active vaccine recipients, the rates of clinical adverse experiences, injection-site adverse experiences, or systemic adverse experiences tended to be lower among subjects who were seropositive at day 1 or PCR positive from day 1 through Month 7 to any vaccine HPV type, as compared to subjects who were seronegative at day 1 and PCR negative from day 1 through Month 7 to all vaccine HPV types (data not shown). 4. Discussion The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions. Some vaccines induce long-term immunity. Others require the administration of booster doses. Experience with hepatitis B vaccine may provide some guidance on long-term immunity raised by HPV vaccination since these two vaccines are similar in design. Vaccine-induced antibody against hepatitis B wanes over the course of several years, but re-exposure to antigen results in a rapid anamnestic response, or memory immune response [31]. In field studies, good long-term protection in absence of any booster has been seen against both infection and, moreover, chronic carriage [32,33]. In the current study we included a cohort of women that was sexually active, at risk for acquisition of HPV 6, 11, 16, and 18 infections and was broadly comparable to the general population of young women in developed and developing countries [34,35]. Unlike other vaccine studies [19] we had the opportunity to examine immune responses among HPV seropositive women at baseline, as women were not prescreened for HPV DNA or seropositivity prior to enrollment. In this study, as well as in a previous study focusing on a monovalent HPV 16 L1 VLP vaccine [21], women with detectable vaccine-type anti-hpv levels prior to vaccination were shown to respond with faster rises, higher peaks, and higher persistence levels following administration of HPV vaccine compared to baseline HPV naïve women. The results for the monovalent HPV 16 vaccine, in addition to the results presented here for a quadrivalent vaccine, suggest that HPV L1 VLP vaccines formulated on aluminum adjuvant can induce anamnestic responses. Such responses may allow for long-term vaccine-induced protection, either following a primary series, or with booster vaccinations. To our knowledge this is the first report demonstrating that administration of a quadrivalent HPV (6/11/16/18) L1 VLP vaccine to women with detectable HPV antibodies prior to vaccination results in an anamnestic response. In addition, the vaccine was generally well-tolerated in women who were infected with vaccine-hpv types prior to vaccination. However, a limitation of the present study is the small number of sub-

11 L.L. Villa et al. / Vaccine 24 (2006) jects who were seropositive at day 1 or PCR positive to any of the vaccine HPV types. Therefore, these data should be considered preliminary. The serology assays used in these studies measured HPV antibody titers in a competitive format whereby the serum antibodies compete with HPV type-specific mouse MAbs to neutralizing epitopes present on each VLP. In the dose selection phase of the study, serum antibodies to HPV 6, 11, 16 and 18 were measured using a competitive radioimmunoassay. Following dose selection, under a Protocol Amendment, the assay method was changed from the cria to a competitive Luminex immunoassay. The switch from the crias to the clias following dose selection occurred for several reasons. First and foremost, the radio-immunoassay kits were being discontinued by the manufacturer. Second, the crias used radioactive 125 I-labeled secondary antibodies whereas fluorescent-based technologies represented a safer alternative. Third, the crias were labor intensive whereas the Luminex assay was amenable to high-throughput screening. Lastly, the microsphere-based fluorescence technology is considerably more precise than the historical RIAs. Although the serostatus cutoffs are slightly different between the cria and clia assays, due to differences in the platform technologies, VLPs and MAbs used in the individual assays, these differences do not impact the findings of this study, as the cria data was used consistently for dose selection whereas the clia was used consistently for comparing long-term immunogenicity data for the low-dose phase III formulation. Regardless of the type of assay used (clia or cria), the antibody titers of the four HPV types in the reference sera are not identical between the cria and clia. In addition, the four mabs used in the four assays recognize unique epitopes, therefore one can not draw conclusions with regard to the relative immunogenicity of the four VLP components in the vaccine. In addition, antibody titer levels should not be compared across vaccine studies in which different HPV antibody assays are conducted [19]. Antibodies are generated against a number of epitopes on the VLPs. The mabs used in the competitive assays each recognize typespecific epitopes. Overall, some epitopes appear to be more immunogenic than others, however the immunogencity of entire VLPs appears to be about the same. The four mabs used in the four-plex clia assay each recognize epitopes having a unique binding affinity and a unique ranking in the total immunogloblulin immunodominance spectra for their respective HPV VLP type. Therefore, the scale of the competitive immune response is dependent upon the particular attributes of the mabs and the epitope that they recognize. It is fairly uncommon that a vaccine will produce an immune response greater than that achieved by natural infection. The fact that a persistent and measurable immune response equal to or greater than that observed during natural infection is encouraging with regard to the utility and longevity of the vaccine response. Again, the scale of persistent titers achieved for the four types should not be compared with one another. The immunodominance of the epitope being monitored and the mab binding affinities are independent type-specific factors affecting the scale of the titer noted. Vaccine studies in rhesus macaques suggest that the four VLPs are equally immunogenic and that the differences in titers measured by cria or clia are due to differences in the assigned potencies of the reference sera [36]. The fact that the relative changes in the GMTs for all the vaccine HPV types are remarkably similar over time suggests that the immunogenicity of the four HPV VLPs is probably comparable. A measurement of the total IgG response demonstrates immunogenicity, but does not assess the utility of the antibodies generated. The advantage of using a competitive assay, rather than measuring the total IgG response to vaccine VLPs by any variety of assays such as ELISA or Luminex, is that it allows one to monitor the antibody response to known neutralizing epitopes [25,26], thus providing a specific measure of immunogenicity that is clinically related to protection against HPV infection. In developed countries, the greatest risk for acquisition of HPV infections is correlated to the period subsequent to sexual debut. Women remain at risk for HPV infection as long as they continue to have genital skin contact with other HPV infected skin. Based on the immunogenicity and efficacy findings [20] of this study, it is clear that administration of quadrivalent HPV (Types 6/11/16/18) L1 VLP vaccine confers protective efficacy for at least 2.5 years post-vaccination. Among placebo recipients who were anti-hpv 6, 11, 16 or 18 seropositive, antibody levels remained stable during this 3-year study. In the PPI-population there was a decline in seropositivity over time. The decline in seropositivey was highest for HPV 18, however there were no breakthrough cases of HPV 18-related cervical intraepithelial neoplasia in quadrivalent vaccine recipients [20]. The stability of both vaccine-induced and infection-induced anti-hpv levels over time suggests that vaccine-induced protective efficacy will be long-lasting. Long-term follow-up of HPV vaccine studies will provide information on the duration of efficacy. Ongoing phase III efficacy studies have the potential to detect breakthrough HPV disease in a large population of vaccinated women and to confirm the long-term duration of the immune response and the potential correlation between anti- HPV levels and vaccine efficacy. Results from this dose-ranging, quadrivalent HPV 6/11/16/18 vaccine trial showed that all three vaccine doses were highly immunogenic and generally safe and welltolerated. Thus, the lowest dose was selected for licensure evaluation in Phase III clinical trials. This dose of vaccine also appeared to stimulate an anamnestic response among the subcohorts of immunized women who had serological evidence of prior infection with a vaccine HPV type at baseline. Worldwide Phase III studies of this quadrivalent vaccine (GARDASIL ) in more than 25,000 subjects are underway. These studies will provide a definitive evaluation of the vaccine s impact on HPV-related clinical disease in adolescents and in young adult women. A primary focus on this age group

12 5582 L.L. Villa et al. / Vaccine 24 (2006) for vaccination is supported by a peak of infection in the early twenties, expected higher effectiveness of the vaccine prior to exposure and easier access to public health interventions in early teens rather than in adult age. However, including older women and young men in a universal immunization policy against cervical cancer and genital warts, as a complement to cervical screening, also warrants investigation. Acknowledgements We would like to thank Sheri Kelly, Derek Puchalski, Jeff Van Doren, Patricia Boerckel, Joanne Erick, Dan Sylvester, DeeMarie Skulsky, Christine Roberts, Amha Tadesse, Timothy Hamilton, Robert Wittrock, Michael Sharer, Elizabeth Orlow Else, Liesje Germ, Mary Biersack, and Weli Li for their expert technical assistance in performing the HPV serology and PCR assays. We also thank Darcy Hille for assistance in the preparation of this manuscript. Source of funding: Merck Research Laboratories, a Division of Merck & Company Inc., funded this study. Principal and main co-investigators: Brazil C Goes, G Andreoni, R Carneiro, E Fukazawa, J Mesquita, F Coelho, M Perrotti; Finland R Heikkila, R Zilliacus; Norway JP Hoye, O-E Iversen, G Riis-Johannessen; Sweden A Andersson-Ellstrom, K Elfgren, G von Krogh; USA JT Comerci, RP Edwards, SA Gall, CM Peterson, YC Wade. References [1] Melbye M, Frisch M. The role of human papillomaviruses in anogenital cancers. Semin Cancer Biol 1998;8: [2] zur Hausen H. Oncogenic DNA viruses. Oncogene 2001;20: [3] Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003;348(6): [4] Bosch FX, Manos MM, Muñoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 1995;87(11): [5] Maw RD. Treatment of anogenital warts. 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