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A Randomized, Double-Blind, Phase III Study of the Immunogenicity and Safety of a 9-Valent Human Papillomavirus L1 Virus-Like Particle Vaccine (V503) Versus Gardasil® in 9–15-Year-Old Girls

Vesikari, Timo MD, PhD*; Brodszki, Nicholas MD; van Damme, Pierre MD, PhD; Diez-Domingo, Javier MD, PhD§; Icardi, Giancarlo MD; Petersen, Lone Kjeld DMSc; Tran, Clément MSc**; Thomas, Stéphane MSc**; Luxembourg, Alain MD, PhD††; Baudin, Martine MD**

The Pediatric Infectious Disease Journal: September 2015 - Volume 34 - Issue 9 - p 992–998
doi: 10.1097/INF.0000000000000773
Vaccine Reports

Background: A 9-valent human papillomavirus (9vHPV) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 [as per the licensed quadrivalent HPV (qHPV) vaccine], as well as 5 additional oncogenic HPV types (HPV 31/33/45/52/58). Compared with the qHPV vaccine, the 9vHPV vaccine potentially increases the coverage of protection from 70% to 90% of cervical cancers. We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 9–15-year-old girls.

Methods: Participants (n = 600) were randomized to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titers (anti-HPV 6/11/16/18/31/33/45/52/58) were determined by competitive Luminex immunoassay and expressed as geometric mean titers and seroconversion rates. Vaccine safety was also assessed.

Results: The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine. All participants (except 1 for HPV 45) receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles, although the incidence of injection-site swelling was higher in the 9vHPV vaccine group.

Conclusions: In addition to immune responses to HPV 31/33/45/52/58, a 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years. The safety profile was also similar for the 2 vaccines.

From the *Vaccine Research Centre, University of Tampere, Tampere, Finland; Children’s Hospital, Lund University, Lund, Sweden; Centre for the Evaluation of Vaccination, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium; §Vaccine Research Department, FISABIO-Public Health, Valencia, Spain; Department of Health Sciences, University of Genoa, IRCSS AOU San Martino-IST, Genoa, Italy; Department of Gynaecology and Obstetrics, Aarhus University Hospital, Skejby, Denmark; **Sanofi Pasteur MSD, Lyon, France; and ††Merck & Co., Inc., Whitehouse Station, NJ.

Accepted for publication April 14, 2015.

This study was funded by Sanofi Pasteur MSD. T.V. has received payments in respect of Board membership (Sanofi Pasteur MSD) and Consultancy (GSK, Merck & Co., Novartis); N.B. has received payments in respect of Speaker Bureaux services (MEDA Sweden); P.V.D. acts as investigator for Merck vaccine trials conducted on behalf of the University of Antwerp, for which the University obtains research grants; J.D-.D. has received payments in respect of Consultancy (GSK) and Speaker Bureaux services (Pfizer); G.I. has received payments in respect of Board membership (Sanofi Pasteur MSD and GSK), meeting expenses (Sanofi Pasteur MSD and Pfizer) and research grants from (Sanofi Pasteur MSD, GSK, Pfizer and Novartis); The institution of L.K.P. (Aarhus University Hospital, Skejby, Denmark) has received research grants from Merck; A.L. is an employee of Merck & Co., Inc; C.T., S.T. and M.B. are employees of Sanofi Pasteur MSD.

Address for correspondence: Martine Baudin, MD, Sanofi Pasteur MSD, 162 avenue Jean Jaurès, CS 50712, 69367 Lyon Cedex 07, France. E-mail:

Infection with human papillomavirus (HPV) can cause precancerous and cancerous lesions of the cervix, vagina, vulva, anus and penis, and oropharyngeal cancers, as well as genital warts.1–10 The most clinically relevant HPV types are HPV 6/11/16/18, with approximately 70% of all cervical cancers being caused by HPV 16/18 and approximately 90% of all genital warts being caused by HPV 6/11.11–14

The quadrivalent HPV (qHPV) virus-like particle (VLP) prophylactic vaccine [4-valent HPV L1 VLP vaccine (recombinant, adsorbed; Gardasil, Sanofi Pasteur MSD, Lyon, France, manufactured by Merck & Co., NJ)] against HPV types 6/11/16/18 was licensed in 2006,15,16 and more than 183 million doses have been administered (data on file). Clinical trials have shown the qHPV vaccine to be effective in preventing infection by HPV 6/11/16/18 and protecting against cervical/vaginal/vulvar/anal dysplasia and genital warts caused by HPV 6/11/16/18,17–21 with a favorable safety and tolerability profile.22–28 Similarly, the bivalent HPV (16/18) VLP vaccine was highly efficacious against HPV 16/18-related infection and cervical dysplasia29 and was well tolerated. Furthermore, in countries with established vaccination programs, HPV vaccination has reduced, at a population level, the burden of HPV-related diseases. Such programs have resulted in decreases in the incidence of high-grade cervical abnormalities,30–33 the prevalence of vaccine HPV types34–36 and the incidence of genital warts, as early as 3 years after program implementation.37–41

An investigational 9-valent HPV VLP (9vHPV) vaccine has been developed by Merck & Co., NJ to protect against 5 additional oncogenic HPV types (31/33/45/52/58), as well as HPV 6/11/16/18. Current HPV vaccines address approximately 70% of cervical cancers via protection from HPV 16/18. Partial cross-protection against nonvaccine HPV types has been reported for both licensed vaccines, although its significance remains unproved over time.42 The added value of the 9vHPV vaccine versus the qHPV vaccine primarily concerns the prevention of cervical lesions, with the 9vHPV vaccine offering the potential to protect against an additional 20% of cervical cancers and an additional 30% of high-grade cervical intraepithelial neoplasias.2,43,44 Furthermore, the 9vHPV vaccine may also protect against an extra 10% of vaginal/vulvar cancers and high-grade vaginal/vulvar intraepithelial neoplasias1,45 and an extra 5% of anal cancers and high-grade anal intraepithelial neoplasias.46

In developing a second-generation HPV vaccine, it must be ensured that the adjusted composition of the existing HPV VLPs, addition of new HPV VLPs and adjuvant do not compromise the immunogenicity and efficacy against the HPV 16/18 VLPs contained in the first-generation vaccine, which has been shown to be challenging in another HPV vaccine development program.47 However, results from a phase IIb/III efficacy and immunogenicity study in young women aged 16–26 years have shown that the 9vHPV vaccine elicits noninferior anti-HPV 6/11/16/18 responses compared with the qHPV vaccine and is highly efficacious in preventing disease associated with the 9 vaccine HPV types.48

Efficacy studies of HPV vaccines are not conducted in children aged ≤15 years because of low exposure to HPV in this age group and the social, cultural and legal constraints regarding gynecological examination in children. As a consequence, efficacy findings in adults are extended to preadolescents/adolescents based on similar vaccine immunogenicity profiles observed in adults and preadolescents/adolescents.49 Results from a phase III study demonstrated that the 9vHPV vaccine induces anti-HPV antibody responses in girls and boys 9–15 years of age that are noninferior to responses in young women 16–26 years of age for all 9 vaccine HPV types.50

This article reports the results from a study that was designed to directly compare the immunogenicity for HPV 6/11/16/18 and safety of the investigational 9vHPV vaccine versus the licensed qHPV vaccine in 9–15-year-old girls.

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This was a multicenter, double-blind, randomized (1:1), controlled (with qHPV vaccine) study of the immunogenicity and tolerability of the 9vHPV vaccine in girls aged 9–15 years, conducted in 24 centers across Belgium, Denmark, Finland, Italy, Spain and Sweden (NCT01304498). Participating centers included hospitals, pediatric and gynecological departments and vaccination clinics. Participants were equally enrolled within 2 age strata (9–12 and 13–15 years) to allow immune responses to be assessed separately in young girls and adolescents.

The study was conducted in accordance with national and local requirements regarding ethical committee review, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice standards, the Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association, Declaration of Helsinki and local/national guidelines. Parents/legal guardians provided written, informed consent, and assent was obtained from participants before any study procedure.

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Study Population

Eligible participants were girls aged ≥9 to <16 years at enrolment, in good physical health, who were virgins and who were not planning to become sexually active through month 7 of the study.

Individuals with a known allergy to any vaccine component, a history of severe allergic reaction, thrombocytopenia, coagulation disorder, positive urine pregnancy test or a previous positive HPV test were excluded. Others who were ineligible for the study included those who were immunocompromised (including anyone who had had a splenectomy), had received immunosuppressive therapy in the previous year, had received immunoglobulin or a blood-derived product within the previous 6 months, had enrolled in any other clinical study of an investigational medicinal product, had received a marketed HPV vaccine or participated in a previous HPV vaccine clinical trial (active agent or placebo) or had a history of any other condition that could confound study results or interfere with participation in the study.

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A central randomization system, which used an interactive web response system, assigned participants to a vaccine group (blinded) and an allocation number according to the randomized allocation schedules. The randomized allocation schedule was age-stratified (9–12 years and 13–15 years), with a capping at 300 participants per stratum, and was based on balanced randomization blocks of size 6 (ie, 50 blocks of size 6 per stratum). Participants were randomized in a 1:1 ratio within each age stratum to receive the investigational 9vHPV vaccine or the licensed qHPV vaccine.

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Study Vaccination

The vaccines were administered as a 0.5-mL injection in the deltoid muscle of the nondominant arm on day 1, and in month 2 and month 6. Participants were required to be afebrile (oral temperature <37.8°C) for 24 hours before vaccination.

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Vaccine Immunogenicity

Immunogenicity Objectives

The primary immunogenicity objective was to demonstrate that the 9vHPV vaccine induces noninferior geometric mean titers (GMTs) for anti-HPV 16/18 versus the qHPV vaccine, at 4 weeks postdose 3. Secondary immunogenicity objectives were to summarize the humoral immune response in terms of anti-HPV 6/11/16/18 GMTs and seroconversion rates at 4 weeks postdose 3. The humoral immune response after vaccination with the 9vHPV vaccine (anti-HPV 31/33/45/52/58 GMTs and seroconversion rates at 4 weeks postdose 3) was investigated as exploratory immunogenicity objectives.

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Serum samples were obtained at day 1 and month 7 for anti-HPV antibody testing. The serum samples were assessed for antibodies to HPV VLP types 6/11/16/18/31/33/45/52/58 by competitive Luminex immunoassay (HPV-9 cLIA Version 2.0; performed by PPD Vaccines and Biologics Lab, Wayne, PA), as described previously.51 Antibody titers for each individual HPV type were determined using type-specific monoclonal antibodies, so it is not possible to directly compare assay results across HPV types.

The serum samples from day 1 were analyzed to identify participants who were seropositive for each vaccine HPV type before enrolment, and these participants were subsequently excluded from the per-protocol immunogenicity analysis for the corresponding HPV type.

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Vaccine Safety and Tolerability

Participants were observed for 30 minutes after each vaccination for any immediate reaction. All subjects received a vaccination report card at the day 1, month 2 and month 6 study vaccination visits. Oral temperature was reported from day 1 to day 5 after any vaccination, and injection-site reactions and systemic adverse events (AEs) were recorded on the vaccination report card from day 1 to day 15 after any vaccination. An elevated temperature (fever) was defined as maximum temperature ≥37.8°C during the follow-up period. Investigators assigned causality to AEs based on exposure, time course, likely cause and consistency with the vaccine’s known profile. Vaccine-related AEs were determined by the investigator to be possibly, probably or definitely vaccine-related. For each AE, participants rated the symptom as mild (awareness of symptom but easily tolerated), moderate (discomfort enough to cause interference with usual activities) or severe (incapacitating with inability to work or do usual activity); injection-site AEs of swelling and erythema were rated by size. Serious AEs were predefined as any AE that resulted in death, were deemed by the investigator to be life-threatening, resulted in a persistent or significant disability or incapacity, resulted in or prolonged an existing in-patient hospitalization or was a congenital anomaly, a cancer or an “other important medical event.” Serious AEs (SAEs) were monitored throughout the study regardless of cause.

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Statistical Methods

Sample Size and Power

The per-protocol set was to comprise participants who received all 3 vaccinations, had a month 7 serology result, were seronegative for the corresponding HPV type at day 1 and had no protocol violations that could interfere with immune responses. It was estimated that there would be approximately a 20% exclusion rate from the per-protocol set, leaving 240 of 300 evaluable participants per vaccine group for the primary analysis.

The noninferiority margin was set at 0.67; the true GMT ratio was estimated to be 1.0, and the standard deviation (natural log scale) was estimated at 1.2 (for both HPV 16 and HPV 18 postvaccination titers). Based on these parameters, the study has over 90% power to demonstrate the noninferiority of the HPV 16/18 GMTs after vaccination with the 9vHPV vaccine versus the qHPV vaccine.

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Immunogenicity and Safety Analyses

Immunogenicity results are presented for the per-protocol set. Noninferiority of anti-HPV 16 and anti-HPV 18 GMTs was demonstrated by two 1-sided tests (1 for each HPV type) conducted at α = 0.025 level (1-sided). Noninferiority was achieved if the lower bound of the 2-sided 95% confidence intervals (CI) for the GMT ratio (postdose 3 9vHPV vaccine GMT/postdose 3 qHPV vaccine GMT) was greater than 0.67. Each test was conducted using an analysis of variance model with a response of log individual titers and a fixed effect for group and age strata (as per randomization). Descriptive statistics were used for all other immunogenicity analyses.

Safety analyses are described for the safety set (all participants who received at least 1 study vaccine dose and for whom safety follow-up data were available).

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Study Population

A total of 603 individuals were screened between February 23, 2011 and May 11, 2011, of whom 600 were randomly allocated to receive either the 9vHPV or qHPV vaccine (Fig. 1). Forty-nine participants (9vHPV vaccine: n = 17, 5.7%; qHPV vaccine: n = 32, 10.7%) were seropositive for at least 1 vaccine HPV type at baseline and were excluded from the per-protocol set for the corresponding HPV type. The per-protocol set included 547 (91.2%) participants (9vHPV vaccine: n = 276; qHPV vaccine: n = 271), and the safety set included 599 participants (1 participant was lost to follow-up before providing any safety data). Mean age at first dose was 12.6 years. Baseline characteristics were comparable between vaccine groups (Table 1).

Table 1

Table 1



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Vaccine Immunogenicity

Anti-HPV 6/11/16/18 Antibody Responses

Anti-HPV 16 and anti-HPV 18 GMTs postdose 3 (Table 2) were similar between vaccines (anti-HPV 16 GMTs: 6739.5 vs. 6887.4 mMU/mL for 9vHPV and qHPV vaccines, respectively; anti-HPV 18 GMTs: 1956.6 vs. 1795.6 mMU/mL for 9vHPV and qHPV vaccines, respectively). Anti-HPV 16 and anti-HPV 18 GMTs elicited by the 9vHPV vaccine were noninferior to those elicited by the qHPV vaccine [the lower bound of the 2-sided 95% CI for the GMT ratio (9vHPV vaccine/qHPV vaccine) was >0.67, and the 95% CI included 1.0 for both HPV types; P <0.001; Table 2].

Table 2

Table 2

Anti-HPV 6 and anti-HPV 11 GMTs postdose 3 were numerically similar between vaccines (anti-HPV 6: 1679.4 vs. 1565.9 mMU/mL for 9vHPV vs. qHPV vaccines, respectively; anti-HPV 11: 1315.6 vs. 1417.3 mMU/mL for 9vHPV vs. qHPV vaccines, respectively). The 95% CI for the GMT ratio (9vHPV vaccine/qHPV vaccine) included 1.0 for both HPV types.

When stratified by age (9–12 and 13–15 years), anti-HPV 16 and anti-HPV 18 GMTs were numerically higher for the younger age group and comparable for both vaccines (Table 2). A similar profile was observed for anti-HPV 6 and anti-HPV 11 GMTs (Table 2).

All participants seroconverted for HPV 6/11/16/18 after receiving 3 doses of the 9vHPV vaccine or qHPV vaccine.

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Anti-HPV 31/33/45/52/58 Antibody Responses

As shown in Table 2, robust anti-HPV 31/33/45/52/58 GMTs postdose 3 were elicited by the 9vHPV vaccine. Anti-HPV 31/33/45/52/58 GMTs postdose 3 were numerically greater by 1–2 orders of magnitude in the 9vHPV vaccine group compared with the qHPV vaccine group. Anti-HPV 31/33/45/52/58 GMTs were numerically higher in 9–12 year olds than in 13–15 year olds. All participants seroconverted for HPV 31/33/45/52/58 after receiving 3 doses of the 9vHPV vaccine, except 1 participant who did not seroconvert for HPV 45. This participant, who was 9 years of age at the time of the first injection, had no relevant medical history reported at baseline and was seronegative for all 9 HPV types before vaccination. This participant also had low immune responses to the other 8 HPV types with antibody titers generally 6- fold to 17-fold lower than the GMTs. Although the GMTs were low, the qHPV vaccine also induced some level of postdose 3 immune responses to the HPV types not included in the vaccine (GMTs are shown in Table 2), including a seroconversion rate as high as 73.5% for HPV 31 and 54.8% for HPV 58.

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Vaccine Tolerability

Most participants experienced at least 1 AE during the study. Vaccine-related AEs were reported for 93.3% of participants receiving the 9vHPV vaccine and 90.3% of participants receiving the qHPV vaccine from day 1 to month 7 (Table 3).

Table 3

Table 3

A comparable percentage of participants reported at least 1 injection-site reaction from day 1 to day 5 after vaccination (9vHPV vaccine: 91.6%; qHPV vaccine: 88.3%). Although more participants reported swelling after receiving the 9vHPV vaccine (47.8%) compared with the qHPV vaccine (36.0%; P = 0.003), severe injection-site swelling (>5 cm) was reported in a similar proportion of participants in each vaccine group (9vHPV vaccine: 6.0%; qHPV vaccine: 6.3%).

Vaccine-related systemic AEs were reported for 20.7% and 24.3% of participants receiving the 9vHPV and qHPV vaccines, respectively. The most common vaccine-related systemic AEs in the 9vHPV vaccine group were headache (11.4%), pyrexia (5.0%), nausea (3.0%), oropharyngeal pain (2.7%) and upper abdominal pain (1.7%). Among participants receiving the qHPV vaccine, the most frequent vaccine-related systemic AEs were headache (11.3%), nausea (3.7%), pyrexia (2.7%), fatigue (2.7%) and upper abdominal pain (1.3%).

Three participants experienced SAEs, which led to the withdrawal of 2 participants from the study. None of these SAEs were considered by the investigators as vaccine related. (1) A 13-year-old girl with no prior medical history experienced anemia and pulmonary vasculitis with positive antinuclear antibodies, diagnosed approximately 2 months after the second dose of 9vHPV vaccine. She was treated with cyclophosphamide and prednisone and fully recovered. Further testing demonstrated positive antinuclear antibodies in a prevaccination serum sample. Within 33 months after the resolution of the SAE, the participant reported no major medical problems, and systemic autoimmune conditions, such as Wegener’s granulomatosis, microscopic polyangiitis or lupus pneumonia, were ruled out. (2) A 12-year-old girl with no prior medical history experienced Henoch–Schönlein purpura 46 days after receiving the second dose of qHPV vaccine. She fully recovered and did not receive the third dose of qHPV vaccine; it was noted that the participant had otitis media, treated with amoxicillin, 2 days before the onset of purpura. (3) A 14-year-old girl with no prior medical history experienced complex partial seizures 36 days after receiving the first dose of the qHPV vaccine. She was treated with oxcarbazepine, which ended the seizures, and she received doses 2 and 3 without experiencing any further AEs.

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In this study comparing the 9vHPV vaccine and the qHPV vaccine in girls aged 9–15 years, we observed a similar antibody response for HPV types 6/11/16/18 after a 3-dose regimen of the 9vHPV or qHPV vaccines. As the antibody responses to the oncogenic HPV types 16 and 18 elicited by the 9vHPV vaccine were noninferior to those elicited by the qHPV vaccine, the primary objective of the study was met. As the HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were demonstrated to be similar to those elicited by the qHPV vaccine, the efficacy of the 9vHPV vaccine against HPV 6/11/16/18 can be inferred to be comparable with that of the qHPV vaccine.

The safety and tolerability profile was similar for the 2 vaccines and comparable with that observed previously in 16–26-year-old women.48 The higher incidence of swelling reported with the 9vHPV vaccine versus the qHPV vaccine could be because of the higher dose of VLPs and adjuvant contained in the 9vHPV vaccine. However, HBVaxPro 10 µg (Sanofi Pasteur MSD, manufactured by Merck & Co.), which has been widely administered to children and young adults and has a proven favorable safety profile,52 contains the same quantity of the same adjuvant as the 9vHPV vaccine. Moreover, there were no withdrawals from the study because of injection-site reactions, so we do not anticipate injection-site swelling to have a significant impact on vaccine uptake.

A relationship was observed between antibody response and the age of the vaccine recipients, with higher GMTs obtained in younger participants. Similar findings have also been reported in the qHPV vaccine clinical development program.53 As it is anticipated that long-term immunogenicity, safety and effectiveness data for the 9vHPV vaccine will be comparable with that for the qHPV vaccine, this age-effect supports vaccination of children at the younger end of the 9–15-year-old cohort.

Seroconversion rates for the nonvaccine HPV types after vaccination with the qHPV vaccine indicate the induction of cross-reactive antibodies, especially for HPV 31/58. Some degree of cross-protection for HPV 31/58 has been previously reported after vaccination with the qHPV vaccine.54 However, in the current study, the GMTs induced by the qHPV vaccine against HPV 31/33/45/52/58 were much lower than those obtained after vaccination with the 9vHPV vaccine. This correlates with a previous observation that protection against nonvaccine HPV types was not reported to be of the same magnitude over time as protection against vaccine HPV types.55

A recent study demonstrated that administration of a 2-dose regimen of qHPV vaccine in girls aged 9–13 years induced anti-HPV GMTs that were noninferior to those elicited by administration of a 3-dose regimen in young women aged 16–26 years,56 thereby supporting that a 2-dose regimen may be an acceptable alternative to a 3-dose regimen. Because the 9vHPV vaccine and qHPV vaccine have similar immunogenicity profiles, it is anticipated that similar results may be verified with the 9vHPV vaccine.

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A 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years. The safety and tolerability profile was also similar for the 2 vaccines, although more injection-site reactions were seen with the 9vHPV vaccine. We would expect the efficacy of the 9vHPV vaccine against HPV 6/11/16/18 to be comparable with that of the qHPV vaccine based on the immunogenicity of both vaccines in the primary vaccination cohort (9–15-year-old girls). Furthermore, as recently reported, the 9vHPV vaccine offers additional clinical benefit because of the protection it offers against HPV types 31/33/45/52/58.48

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The authors take full responsibility for the content of this contribution and thank Communigen Ltd, Oxford, United Kingdom (supported by Sanofi Pasteur MSD) for preparing the manuscript drafts.

The authors thank the study participants, as well as the investigators and their study-site personnel for their contribution to the study: Belgium: Karel Hoppenbrouwers and Etienne Sokal; Denmark: Ole Mogensen, Danny Svane and Kim Toftager-Larsen; Finland: Anitta Ahonen, Tiina Karppa, Aino Karvonen (Forsten), Pia-Maria Lagerström-Tirri and Samuli Rounioja; Italy: Maria Desole, Giancarlo Tisi, Alberto Tozzi and Massimo Zuliani; Spain: María Garces Sanchez, Federico Martinon Torres, Miguel Tortajada, Isabel Úbeda and Ángels Ulied; Sweden: Kristiina Kask, Lennart Nilsson, Sven-Eric Olsson and Jan Wall.

The authors also thank Xavier Cornen, Armelle Marais and Catherine Lambermont (Sanofi Pasteur MSD, Lyon, France) and Leena Kämäri (TFS Develop, Espoo, Finland) for their contribution to the conduct of the study; Sandrine Samson (Sanofi Pasteur MSD, Lyon, France) for her critical review of the manuscript and Rhonda Heffelfinger-Wenner (PPD Vaccine and Biologics, LLC, Wayne, PA) for overseeing the immune tests.

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1. de Sanjosé S, Alemany L, Ordi J, et al.HPV VVAP Study Group. Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Eur J Cancer. 2013;49:3450–3461
2. de Sanjose S, Quint WG, Alemany L, et al.Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–1056
3. Garland SM, Steben M, Sings HL, et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis. 2009;199:805–814
4. Hatch KD. A3. Vaginal intraepithelial neoplasia (VAIN). Int J Gynaecol Obstet. 2006;94(Suppl 1):S40–S43
5. Kjaer SK, Tran TN, Sparen P, et al. The burden of genital warts: a study of nearly 70,000 women from the general female population in the 4 Nordic countries. J Infect Dis. 2007;196:1447–1454
6. Palefsky JM. Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection. J Acquir Immune Defic Syndr. 1999;21(Suppl 1):S42–S48
7. Picconi MA, Eiján AM, Distéfano AL, et al. Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: analysis of primary tumors and lymph nodes. J Med Virol. 2000;61:65–69
8. Srodon M, Stoler MH, Baber GB, et al. The distribution of low and high-risk HPV types in vulvar and vaginal intraepithelial neoplasia (VIN and VaIN). Am J Surg Pathol. 2006;30:1513–1518
9. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19
10. Kreimer AR, Clifford GM, Boyle P, et al. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467–475
11. Acay R, Rezende N, Fontes A, et al. Human papillomavirus as a risk factor in oral carcinogenesis: a study using in situ hybridization with signal amplification. Oral Microbiol Immunol. 2008;23:271–274
12. Kirrander P, Kolaric A, Helenius G, et al. Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma. BJU Int. 2011;108:355–359
13. Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007;121:621–632
14. Yanofsky VR, Patel RV, Goldenberg G. Genital warts: a comprehensive review. J Clin Aesthet Dermatol. 2012;5:25–36
15. Baylor NW. June 8, 2006 Approval Letter─Human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant [US Food and Drug Administration Website]; 2006 Available at: Accessed April 1, 2014
16. European Medicines Agency. . Gardasil® human papillomavirus vaccine [types 6,11,16,18] (recombinant, adsorbed) [European Public Assessment Report; European Medicines Agency website]; 2014 Available at: Accessed April 1, 2014
17. Garland SM, Hernandez-Avila M, Wheeler CM, et al.Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928–1943
18. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. 2011;364:401–411
19. Future II Study Group. . Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915–1927
20. Joura EA, Leodolter S, Hernandez-Avila M, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007;369:1693–1702
21. Palefsky JM, Giuliano AR, Goldstone S, et al. HPV vaccine against anal HPV infection and anal intraepithelial neoplasia. N Engl J Med. 2011;365:1576–1585
22. Arnheim-Dahlström L, Pasternak B, Svanström H, et al. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906
23. Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine. Pediatr Infect Dis J. 2010;29:95–101
24. Chao C, Klein NP, Velicer CM, et al. Surveillance of autoimmune conditions following routine use of quadrivalent human papillomavirus vaccine. J Intern Med. 2012;271:193–203
25. Gee J, Naleway A, Shui I, et al. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine. 2011;29:8279–8284
26. Grimaldi-Bensouda L, Guillemot D, Godeau B, et al.PGRx-AID Study Group. Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects. J Intern Med. 2014;275:398–408
27. Klein NP, Hansen J, Chao C, et al. Safety of quadrivalent human papillomavirus vaccine administered routinely to females. Arch Pediatr Adolesc Med. 2012;166:1140–1148
28. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302:750–757
29. Paavonen J, Jenkins D, Bosch FX, et al.HPV PATRICIA Study Group. 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. Lancet. 2007;369:2161–2170
30. Baldur-Felskov B, Dehlendorff C, Munk C, et al. Early impact of human papillomavirus vaccination on cervical neoplasia–nationwide follow-up of young Danish women. J Natl Cancer Inst. 2014;106:djt460
31. Brotherton JM, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011;377:2085–2092
32. Crowe E, Pandeya N, Brotherton JM, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia. BMJ. 2014;348:g1458
33. Powell SE, Hariri S, Steinau M, et al. Impact of human papillomavirus (HPV) vaccination on HPV 16/18-related prevalence in precancerous cervical lesions. Vaccine. 2012;31:109–113
34. Kahn JA, Brown DR, Ding L, et al. Vaccine-type human papillomavirus and evidence of herd protection after vaccine introduction. Pediatrics. 2012;130:e249–e256
35. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis. 2013;208:385–393
36. Tabrizi SN, Brotherton JM, Kaldor JM, et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis. 2012;206:1645–1651
37. Baandrup L, Blomberg M, Dehlendorff C, et al. Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program. Sex Transm Dis. 2013;40:130–135
38. Bauer HM, Wright G, Chow J. Evidence of human papillomavirus vaccine effectiveness in reducing genital warts: an analysis of California public family planning administrative claims data, 2007–2010. Am J Public Health. 2012;102:833–835
39. Leval A, Herweijer E, Arnheim-Dahlström L, et al. Incidence of genital warts in Sweden before and after quadrivalent human papillomavirus vaccine availability. J Infect Dis. 2012;206:860–866
40. Nsouli-Maktabi H, Ludwig SL, Yerubandi UD, et al. Incidence of genital warts among U.S. service members before and after the introduction of the quadrivalent human papillomavirus vaccine. MSMR. 2013;20:17–20
41. Read TR, Hocking JS, Chen MY, et al. The near disappearance of genital warts in young women 4 years after commencing a national human papillomavirus (HPV) vaccination programme. Sex Transm Infect. 2011;87:544–547
42. Schiller JT, Castellsagué X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30(Suppl 5):F123–F138
43. Serrano B, Alemany L, Tous S, et al. Potential impact of a nine-valent vaccine in human papillomavirus related cervical disease. Infect Agent Cancer. 2012;7:38
44. Joura EA, Ault KA, Bosch FX, et al. Attribution of 12 high-risk human papillomavirus genotypes to infection and cervical disease. Cancer Epidemiol Biomarkers Prev. 2014;23:1997–2008
45. Alemany L, Saunier M, Tinoco L, et al.HPV VVAP study group. Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples. Eur J Cancer. 2014;50:2846–2854
46. Alemany L, Saunier M, Alvarado-Cabrero I, et al.HPV VVAP Study Group. Human papillomavirus DNA prevalence and type distribution in anal carcinomas worldwide. Int J Cancer. 2015;136:98–107
47. Van Damme P, Leroux-Roels G, Simon P, et al. Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials. Vaccine. 2014;32:3694–3705
48. Joura EA, Giuliano AR, Iversen OE, et al.Broad Spectrum HPV Vaccine Study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711–723
49. World Health Organization. Guidelines to Assure the Quality, Safety and Efficacy of Recombinant Human Papillomavirus Virus-like Particle Vaccines. 2006 Geneva, Switzerland: World Health Organization
50. Van Damme P, Olsson SE, Block S, et al. Immunogenicity and safety of a 9-valent HPV vaccine. Pediatrics. 2015;136:e28–e39
51. Roberts C, Green T, Hess E, et al. Development of a human papillomavirus competitive immunoassay for nine HPV types. Hum Vaccin Immunother. 2014;10:2174–2103
52. Sanofi Pasteur MSD. . Summary of product characteristics—HBVaxPro 10 mcg [electronic Medicines Compendium website]. 2011 Available at: Accessed April 1, 2014
53. Giuliano AR, Lazcano-Ponce E, Villa L, et al. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis. 2007;196:1153–1162
54. Sanofi Pasteur MSD. . Summary of product characteristics─Gardasil [electronic medicines compendium website]; 2013 Available at: Accessed April 1, 2014
55. Romanowski B, de Borba PC, Naud PS, et al.GlaxoSmithKline Vaccine HPV Study Group. GlaxoSmithKline Vaccine HPV Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009;374:1975–1985
56. Dobson SR, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309:1793–1802

human papillomavirus; cervical cancer; genital warts; vaccine; immunogenicity

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