pediatrics
September 2015, VOLUME136 /ISSUE 3

Coadministration of a 9-Valent Human Papillomavirus Vaccine With Meningococcal and Tdap Vaccines

  1. Andrea Schilling, MDa,
  2. Mercedes Macias Parra, MDb,
  3. Maricruz Gutierrez, MDc,
  4. Jaime Restrepo, MDd,
  5. Santiago Ucros, MDe,
  6. Teobaldo Herrera, MDf,
  7. Eli Engel, MDg,
  8. Luis Huicho, MDh,
  9. Marcia Shew, MDi,
  10. Roger Maansson, MSj,
  11. Nicole Caldwell, BSj,
  12. Alain Luxembourg, MD, PhDj, and
  13. Ajoke Sobanjo ter Meulen, MDj
  1. aFacultad de Medicina Clinica Alemana-Universidad del Desarrollo, Santiago, Chile;
  2. bInstituto Nacional de Pediatría, Mexico City, Mexico;
  3. cHospital del Niño Poblano, Puebla, Mexico;
  4. dFundacion Centro de Investigacion Clinica CIC, Medellín, Colombia;
  5. eCentro de Investigaciones en Salud, Fundacion Santa Fe de Bogotá, Bogotá, Colombia;
  6. fInsituto de Investigación Nutricional anexo Huáscar, Lima, Perú;
  7. gBayview Research Group, Valley Village, California;
  8. hInstituto Nacional de Salud del Niño, Lima, Perú;
  9. iIndiana University School of Medicine/Department of Pediatrics, Indianapolis, Indiana; and
  10. jMerck & Co., Inc., Kenilworth, New Jersey

Abstract

BACKGROUND: This study in 11- to 15-year-old boys and girls compared the immunogenicity and safety of GARDASIL 9 (9-valent human papillomavirus [9vHPV] vaccine) administered either concomitantly or nonconcomitantly with 2 vaccines routinely administered in this age group (Menactra [MCV4; Neisseria meningitidis serotypes A/C/Y/W-135] or Adacel [Tdap; diphtheria/tetanus/acellular pertussis]).

METHODS: Participants received 9vHPV vaccine at day 1 and months 2 and 6; the concomitant group (n = 621) received MCV4/Tdap concomitantly with 9vHPV vaccine at day 1; the nonconcomitant group (n = 620) received MCV4/Tdap at month 1. Antibodies to HPV-, MCV4-, and Tdap-relevant antigens were determined. Injection-site and systemic adverse events (AEs) were monitored for 15 days after any vaccination; serious AEs were monitored throughout the study.

RESULTS: The geometric mean titers for all HPV types in 9vHPV vaccine 4 weeks after dose 3, proportion of subjects with a fourfold rise or greater in titers for 4 N meningitidis serotypes 4 weeks after injection with MCV4, proportion of subjects with antibody titers to diphtheria and tetanus ≥0.1 IU/mL, and geometric mean titers for pertussis antigens 4 weeks after injection with Tdap were all noninferior in the concomitant group compared with the nonconcomitant group. Injection-site swelling occurred more frequently in the concomitant group. There were no vaccine-related serious AEs.

CONCLUSIONS: Concomitant administration of 9vHPV vaccine with MCV4/Tdap was generally well tolerated and did not interfere with the antibody response to any of these vaccines. This strategy would minimize the number of visits required to deliver each vaccine individually.

  • Abbreviations:
    9vHPV
    9-valent HPV (6/11/16/18/31/33/45/52/58) L1 virus-like particle vaccine
    AEs
    adverse events
    ELISA
    enzyme-linked immunosorbent assay
    FHA
    filamentous hemagglutinin
    FIM
    fimbriae 2/3
    GMT
    geometric mean titers
    HPV
    human papillomavirus
    PRN
    pertactin
    PT
    pertussis toxin
    VRC
    vaccination report card
  • What’s Known on This Subject:

    Previous studies have shown that concomitant administration of the quadrivalent human papillomavirus vaccine with MCV4 and Tdap was generally well tolerated and did not interfere with the immune responses to the respective vaccines.

    What This Study Adds:

    Concomitant administration of the novel 9-valent human papillomavirus vaccine with MCV4 and Tdap, 2 vaccines that are currently recommended for routine vaccination of adolescents, did not compromise the safety, tolerability, and immunogenicity of the individual vaccines.

    A 9-valent (6/11/16/18/31/33/45/52/58) human papillomavirus (HPV; 9vHPV) vaccine was developed to cover 7 cancer-causing HPV types (HPV 16, 18, 31, 33, 45, 52, 58) that are together responsible for ∼90% of cervical cancers and HPV-related vulvar, vaginal, and anal cancers, and 2 HPV types (HPV 6 and 11) that are responsible for 90% of genital warts.15 In clinical studies, the 9vHPV vaccine prevented persistent infection and disease due to the HPV vaccine types in females 16 to 26 years of age6; efficacy findings were extended to girls and boys 9 to 15 years of age based on noninferior immunogenicity.7 The 9vHPV vaccine was licensed in the United States in December 2014 under the name GARDASIL9 (Merck & Co., Inc., Kenilworth, NJ).8 In February 2015, the Advisory Committee on Immunization Practices included GARDASIL9 in its recommendations for routine HPV vaccination of boys and girls at age 11 or 12 years and catchup vaccination in females 13 to 26 years and males 13 to 21 years not vaccinated previously.9 Epidemiologic studies have demonstrated the acquisition of HPV soon after sexual initiation.10 The median age of sexual debut is in the late teens (15–19 years) in most countries.11 Thus, preadolescent boys and girls ≤15 years of age represent the ideal HPV vaccination population.

    Most vaccine schedules worldwide rely on the concomitant administration of vaccines to improve the adherence to vaccination and to lower the cost of the programs, both in childhood and in adolescent vaccination. Because adolescents and adults need to maintain the protection given by several childhood vaccines, such as diphtheria, tetanus, and whooping cough, and need to be protected against Neisseria meningitidis before exposure to new populations such as those in high schools, college, or military service, etc, a booster dose of the diphtheria, tetanus, and acellular pertussis vaccines and routine vaccination for meningococcal serogroups A/C/Y/W-135 are recommended for adolescents in several countries.1214 A logical step was to include the 9vHPV vaccine in those already-established programs.

    This study in boys and girls 11 to 15 years of age was designed to evaluate the immunogenicity and safety of the concomitant administration of a first dose of the 9vHPV vaccine with MCV4 (Menactra [meningococcal polysaccharide conjugate serogroups A/C/Y/W-135, Sanofi-Pasteur Inc, Lyon France]) and Tdap (Adacel [tetanus, diphtheria, acellular pertussis, Sanofi-Pasteur Inc]), 2 vaccines that are also recommended by the Advisory Committee on Immunization Practices for routine vaccination of preadolescents and adolescents and thereby help inform decisions by those who would be administering these vaccines together (Merck Protocol V503-005; NCT00988884).

    Methods

    Study Population

    Between October 22, 2009, and February 22, 2011, 1241 healthy boys and girls aged 11 to 15 who denied any sexual activity (and who were not planning on becoming sexually active through the course of the study) from 41 sites located in Chile (n = 100), Colombia (n = 140), Mexico (n = 200), Peru (n = 100), and the United States (n = 701) participated in the study. Reasons for exclusion from the study included pregnancy (determined by urine or serum β-human chorionic gonadotropin testing), known allergy to any vaccine component, thrombocytopenia, and immunosuppression/prior immunosuppressive therapy or previous receipt of an HPV vaccine. Subjects must not have been immunized against diphtheria, tetanus, and pertussis in the past 5 years or received a meningococcal vaccine. The study was conducted in conformity with applicable national or local requirements regarding ethical committee review, informed consent, and the protection of the rights and welfare of human subjects participating in biomedical research. An external data monitoring committee assessed safety findings throughout the study.

    Study Design

    This was an open-label, randomized, multicenter, comparative study. Subjects were stratified by gender (1:1 ratio) and randomly assigned to 1 of 2 vaccination groups (concomitant group [Group A] or nonconcomitant group [Group B]) in a 1:1 ratio. At day 1, subjects in Group A received the first dose of 9vHPV vaccine in the deltoid muscle of the nondominant arm and MCV4 and Tdap in the deltoid muscle of the opposite arm. Subjects in Group B received the first dose of the 9vHPV vaccine on day 1 in the nondominant arm and MCV4 and Tdap 1 month later (month 1) in the dominant arm. All subjects received the second dose of the 9vHPV vaccine at month 2 and the third dose at month 6. The compositions of the 3 vaccines have been described previously.6,15,16

    Blood samples were drawn immediately before vaccination at day 1, month 1, month 2 (Group B only), and month 7. Serum collected from all subjects at day 1 and month 7 underwent analysis of anti-HPV responses with a competitive Luminex Immunoassay, performed by PPD Vaccines and Biologics (Wayne, PA).17 Serum collected at day 1 and month 1 for Group A and month 1 and month 2 for Group B underwent antibody testing for N meningitidis serogroups A/C/Y/W-135, diphtheria, tetanus, and pertussis. N meningitidis serogroups A/C/Y/W-135 serum bactericidal antibody assay was performed by the Health Protection Agency, Manchester Medical Microbiology Partnership (Manchester, United Kingdom). Diphtheria antibodies were measured by a diphtheria antitoxin cell culture assay performed by CSL Limited (Parkville, Australia) and calibrated against the First International Standard for Diphtheria Antitoxin. Tetanus antibodies were measured by a tetanus antitoxin enzyme immunoassay performed by CSL Limited and calibrated against the First International Standard for Tetanus Immunoglobulin. Pertussis antibodies were measured by an anti–pertussis toxin (PT) enzyme-linked immunosorbent assay (ELISA), anti–filamentous hemagglutinin (FHA) ELISA, anti-pertactin (PRN) ELISA, and anti–fimbriae 2/3 (FIM) ELISA performed by Michael E. Pichichero Laboratory, Rochester General Hospital Research Institute (Rochester, NY). The anti-PT ELISA, anti-FHA ELISA, and anti-FIM ELISA were calibrated against the US Food and Drug Administration Pertussis reference lot 3, and the anti-PRN ELISA was calibrated against the US Food and Drug Administration Pertussis reference lot 4.

    Safety Measurements

    All subjects received a vaccination report card (VRC) at the day 1 and months 1, 2, and 6 visits. VRCs for all the subjects were to be completed after the month-1 visit to provide a common period of follow-up even though subjects in the Group A were not vaccinated at month 1. On the VRC, the parent/guardian was asked to record (1) the subject’s oral temperature in the evening of the day of each study vaccination and daily for a total of 5 days and (2) injection-site and systemic adverse events (AEs) for a total of 15 days including the day of vaccination after each study vaccination. Serious AEs were collected for the whole duration of the study regardless of causality and were followed for outcome. For all injection-site AEs, except erythema and swelling, subjects were instructed by the VRC to estimate the severity of AEs 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). For erythema and swelling, subjects were instructed by the VRC to measure an injection-site reaction at its greatest width (“maximum size”) from edge to edge in maximum units ranging from 0 to >7 inches (17.5 cm) on the VRC, rounding up to the next unit if in between 2 units (each unit on the VRC measured ∼1 inch [2.5 cm]).

    Statistical Analysis

    Primary immunogenicity analyses were done “per-protocol”. Subjects in per-protocol analyses for the 9vHPV vaccine analyses had to receive all 3 doses of 9vHPV vaccine within acceptable day ranges and 1 dose of MCV4 and Tdap. In addition, for per-protocol analysis for 9vHPV vaccine, subjects had to (1) have at least 1 postdose 3 serology result within acceptable day ranges; (2) in analyses for the HPV6 and HPV11 components, be seronegative to both HPV6 and 11 at day 1; (3) in analyses for the other vaccine HPV types, be seronegative at day 1 only for the HPV type being analyzed; and (4) have no protocol violations that were considered to affect the immune responses. For per-protocol analysis for MCV4 and Tdap, subjects had to (1) have received MCV4 and Tdap within acceptable day ranges; (2) have at least 1 serology result after administration of MCV4 and Tdap within acceptable day ranges; and (3) have no protocol violations that were considered to affect the immune responses.

    The primary and secondary end points for evaluating antibody responses to the 9vHPV vaccine were geometric mean titers (GMTs) to HPV6/11/16/18/31/33/45/52/58 and the percentages of subjects who seroconverted for each HPV type by 4 weeks after the third dose of 9vHPV vaccine. Anti-HPV cutoffs for determining serostatus were 30, 16, 20, 24, 10, 8, 8, 8, and 8 milli-Merck units/mL for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, respectively. The primary end points for evaluating antibody response to MCV4 and Tdap were the proportions of subjects who achieved acceptable serological responses to N meningitidis serogroups A/C/Y/W-135, diphtheria, and tetanus and GMTs for pertussis (anti-PT, anti-FHA, anti-PRN, and anti-FIM) 4 weeks postvaccination with MCV4 and Tdap.

    Noninferiority criteria for each immunogenicity hypothesis are shown in Table 1. Noninferiority of anti-HPV GMTs 4 weeks postdose 3 and pertussis GMTs 4 weeks postvaccination with MCV4 and Tdap was based on 1-sided tests of noninferiority (conducted at the 0.025 significance level) comparing GMTs between Group A and Group B for each component. An analysis of variance model (1 for each component) was used with a response of loge individual titers and fixed effects for vaccination group and gender. Noninferiority of anti-HPV seroconversion rates and of serologic responses to N meningitidis serogroups A/C/Y/W-135, diphtheria, and tetanus was tested by 1-sided tests of noninferiority comparing proportions between Group A and Group B for each component. These tests were conducted based on methods developed by Miettinen and Nurminen.18 All tests were conducted at the 0.025 significance level. Success in this study was declared if the primary hypotheses of noninferiority were demonstrated for all components of 9vHPV vaccine and at least 1 of MCV4 and Tdap. With 620 subjects per group (1240 total), this study had an overall power >99% for the primary immunogenicity hypotheses (Table 1).

    TABLE 1

    Noninferiority Criteria Corresponding to the Primary Hypotheses Related to Immunogenicity

    All subjects who received at least 1 study vaccination and had follow-up data were included in safety analyses. AEs were summarized descriptively as frequencies and percentages by participant groups.

    Results

    A total of 1254 subjects residing in Latin America and North America were screened for inclusion in this study and 1241 were randomized (621 to Group A and 620 to Group B). The numbers of subjects who were randomized, vaccinated, and completed or discontinued the study are shown in Supplemental Figure 1. Both vaccination groups were comparable with respect to baseline demographics (Table 2). Approximately 6.4% (79 of 1241) of patients were African American, and 1.1% (14/1241) were Asian.

    TABLE 2

    Summary of Subject Characteristics by Vaccination Group at Enrollment

    The most common reason for exclusion from the per-protocol analyses was having a serum sample or result missing at 4 weeks postinjection (Table 3). Few subjects (0.3%–4.7%) were excluded from the per-protocol analyses for 9vHPV vaccine because of testing positive for HPV on Day 1.

    TABLE 3

    Summary of Exclusionsa From the Per-Protocol Immunogenicity Populations for 9vHPV Vaccine and MCV4 and Tdap

    Month 7 anti-HPV GMTs against all HPV types were comparable in Group A and Group B, with fold differences (ie, Group A/Group B) ranging from 0.97 for HPV6 and HPV11 to 1.10 for HPV45 (Table 4). The noninferiority criteria for the anti-HPV GMT responses in Group A relative to Group B were achieved. Seroconversion rates were 100% for all HPV types in both groups and were noninferior in Group A compared with Group B (Table 5).

    TABLE 4

    Anti-HPV GMTs and Estimated Fold Difference at 4 Weeks After Dose 3 in the HPV Per-Protocol Populations

    TABLE 5

    Seroconversion Rates and Estimated Percent Difference at 4 Weeks After Dose 3 in the HPV Per-Protocol Populations

    At least 75% of subjects achieved a fourfold or higher rise in titers to N meningitidis serogroup A in both Group A and Group B, and at least 89% of subjects achieved a fourfold or higher rise in titers to N meningitidis serogroups C, Y, and W-135 in both Group A and Group B (Table 6). The noninferiority criterion was met for all 4 N meningitidis serogroups. More than 99.8% of subjects in both Group A and Group B achieved a diphtheria and tetanus titer ≥0.1 IU/mL at 4 weeks postvaccination with Tdap. There was a 0 to 0.2 percentage point difference (Group A – Group B) in the percentage of subjects who achieved titers ≥0.1 IU/mL, and the noninferiority criteria for both antigens were met (Table 7). With respect to pertussis antigens the per-protocol immunogenicity analysis also showed that anti-PT, anti-FHA, anti-PRN, and anti-FIM GMTs were noninferior in Group A compared with Group B (Table 8).

    TABLE 6

    Estimated Percentage Point Difference in the Per-Protocol Population for MCV4 for Percent of Subjects With Fourfold or Greater Rise in Titers for N meningitidis Serogroups at 4 Weeks Postvaccination

    TABLE 7

    Estimated Percentage Point Difference in the Per-Protocol Population for Tdap for Percent of Subjects With Diphtheria and Tetanus Titers ≥0.1 IU/mL at 4 Weeks Postvaccination

    TABLE 8

    Antipertussis GMTs and Estimated Fold Difference at 4 Weeks Postvaccination in the Per-Protocol Population for Tdap

    Few subjects (∼0.2%) discontinued because of an AE, and no deaths were reported (Table 9). Throughout the study period, 5 subjects (0.8%) in Group A and 5 subjects (0.8%) in Group B reported nonfatal serious AEs; none were vaccine related. Regarding injection-site AEs, a higher proportion of subjects in Group A reported swelling (14.4%) at the 9vHPV vaccination site compared with Group B (9.4%), and the difference between the groups was statistically significant (P = .007; Table 10). Comparable proportions of subjects reported swelling at MCV4 and Tdap vaccination site in Group A and Group B (P = .526; Table 10). Most of the swelling was mild to moderate in intensity (ie, with a maximum size <5 cm) both at the 9vHPV vaccine injection site and the MCV4 and Tdap injection site. Most subjects in each group (Group A: 92.3%; Group B: 91.9%) reported a maximum temperature <37.8°C (<100°F) within 5 days of the first vaccination. The proportions with elevated temperatures (≥37.8°C) within 5 days of the first vaccination were similar between the 2 groups (risk difference: –0.4; 95% confidence interval: –3.5 to 2.7). No subject became pregnant during the study.

    TABLE 9

    AEs Reported Day 1 Through 15 After the Respective Vaccination Visit

    TABLE 10

    Injection-Site AEs Prompted for on the VRC

    Discussion

    This study demonstrated that when the first dose of 9vHPV vaccine is administered concomitantly with MCV4 and Tdap at a separate injection site, the immune response to all vaccine components is noninferior to the immune response achieved when the 3 vaccines are administered nonconcomitantly. Specifically, GMTs to all 9 vaccine HPV types were noninferior in Group A compared with Group B, and all subjects in both vaccination groups seroconverted after the third dose of 9vHPV vaccine. Also, antibody responses to N meningitidis serogroups A/C/Y/W-135, diphtheria, tetanus, and pertussis at 4 weeks after administration of MCV4 and Tdap were noninferior in Group A compared with Group B.

    Concomitant administration of the first dose of 9vHPV vaccine with MCV4 and Tdap was generally well tolerated. The proportion of subjects reporting injection site AEs postvaccination 1 was similar in the concomitant vaccination group (85.3%) and the nonconcomitant vaccination group (85.1%). Significantly more subjects reported swelling at the 9vHPV vaccine injection site after the first vaccination in the concomitant group. Injection-site swelling at the 9vHPV vaccine injection site was mostly mild to moderate in intensity. Moreover, there were few discontinuations due to an AE. Thus, the finding of increased rates of injection-site swelling is likely to be of minor clinical significance. In another study that investigated concomitant administration of 9vHPV vaccine with a diphtheria/tetanus/pertussis/polio vaccine, more subjects also reported swelling at the 9vHPV vaccine injection site in the concomitant vaccination group.19 This suggests that the increase in injection-site swelling may be due to the concomitant administration of diphtheria/tetanus/pertussis antigens (rather than meningococcal antigens) with 9vHPV vaccine.

    The results of this study are similar to those of a previous study of concomitant administration of the quadrivalent HPV (types 6/11/16/18) vaccine and MCV4 and Tdap, which showed that concomitant administration of dose 1 of quadrivalent HPV vaccine and MCV4 and Tdap was generally well tolerated and did not interfere with the antibody response to any of the vaccine antigens; similar to this study, increased rates in injection-site swelling were also noted in the concomitant vaccination group.20

    The primary limitation of this study was its unblinded nature. As such, safety assessment could have been biased toward an overestimation of AEs being reported in the concomitant vaccination group because subjects who are receiving 2 injections on the same day may more likely report injection-site or systemic AEs compared with subjects who receive only 1 injection. Another limitation of this study is that the coadministration of Tdap and MCV4 was assessed only with the first dose of HPV vaccine and not with subsequent doses.

    Even though only 1 Tdap vaccine was assessed in this study, one can reasonably assume that the results may be generalizable to other Tdap vaccines. Differences in antigen and aluminum dose between diphtheria/tetanus/pertussis vaccines such as Adacel, Boostrix-IPV, or Repevax are relatively modest and therefore expected to have limited impact on 9vHPV vaccine immunogenicity. A limited impact on 9vHPV vaccine immunogenicity is unlikely to have clinical significance: the 9vHPV vaccine efficacy findings in young women were extended to adolescents based on the demonstration of noninferior anti-HPV responses7; anti-HPV responses in adolescents were actually much higher than in young women. Even if concomitant administration of a different diphtheria/tetanus/pertussis vaccine were associated with a small decrease in 9vHPV vaccine immunogenicity, anti-HPV responses would still be substantially higher than in young women, and therefore protection elicited by 9vHPV vaccine would not be compromised.

    When the study was initiated in 2009, other meningococcal serotype A/C/Y/W-135 vaccines (Menveo and Nimenrix) had not yet been licensed. Although Menactra, Menveo, and Nimenrix contain similar amounts of polysaccharide and carrier protein, they use different carrier proteins; thus, it is difficult to speculate whether results obtained in this study can be extrapolated to other meningococcal vaccines. Regulatory guidelines caution against such extrapolation for conjugated polysaccharide vaccines.21

    This study demonstrates that concomitant administration of 9vHPV vaccine and MCV4 and Tdap was generally well tolerated and the immune responses to components of either vaccine were noninferior compared with nonconcomitant administration. Providing vaccinations to adolescents is challenging because they make infrequent health care visits. Concomitant administration would minimize the number of visits required to deliver each vaccine individually and therefore facilitate adherence to recommended vaccination regimens. In the United States, coverage for the first dose of HPV vaccine remains substantially lower (by ∼20–25 percentage points) than coverage for other vaccines recommended by the Advisory Committee on Immunization Practices for children 11 to 12 years of age.22,23 It is estimated that coadministration of HPV vaccine with other vaccines such as diphtheria, tetanus, pertussis, meningococcal conjugate, and influenza vaccines could increase coverage for the first dose of HPV vaccine to >90%.24

    Acknowledgments

    The authors thank Frank Dutko, PhD, Ms Danielle Mancaruso, and Ms Karyn Davis (Merck & Co, Inc, Kenilworth, NJ) for assistance in the preparation of the manuscript.

    Footnotes

      • Accepted June 11, 2015.
    • Address correspondence to Andrea Schilling, MD, Facultad de Medicina Clinica Alemana-Universidad del Desarrollo, Santiago, Chile. E-mail: dra.andrea.schilling{at}gmail.com
    • Dr Schilling was the lead clinical author; substantially contributed to acquisition of the data, interpretation of the results, and drafting of the manuscript; and reviewed and revised the manuscript for important intellectual content; Drs Parra, Gutierrez, Restrepo, Ucros, and Engel substantially contributed to acquisition of the data and reviewed and revised the manuscript for important intellectual content; Dr Herrera substantially contributed to acquisition of the data and drafting of the manuscript and reviewed and revised the manuscript for important intellectual content; Dr Shew substantially contributed to acquisition of the data and interpretation of the results and reviewed and revised the manuscript for important intellectual content; Mr Maansson substantially contributed to analysis of the data and reviewed and revised the manuscript for important intellectual content; Ms Caldwell substantially contributed to conception, design, and planning of the study and acquisition of the data and reviewed and revised the manuscript for important intellectual content; Drs Huicho and Luxembourg substantially contributed to interpretation of the results and drafting of the manuscript and reviewed and revised the manuscript for important intellectual content; Dr Sobanjo-ter Meulen substantially contributed to conception, design and planning of the study and interpretation of the results and reviewed and revised the manuscript for important intellectual content; and all authors approved the final manuscript as submitted.

    • This trial has been registered at www.clinicaltrials.gov (identifier NCT00988884).

    • FINANCIAL DISCLOSURE: Dr Schilling has received research support for this clinical study and other HPV vaccine-related studies from Merck and honoraria outside the submitted work from Merck-Chile, Grunenthal-Chile, and Grunenthal-L.A. Dr Parra has received research support for this clinical study and grant support from Merck. Dr Gutierrez has received research support for this clinical study from Merck. Dr Restrepo has received research support for this clinical study from Merck and has received compensation from Froost Laboratories for Board Membership for GARDASIL. Drs Ucros, Herrera, Engel, and Huicho have received research support for this clinical study from Merck. Dr Shew has received research support for this clinical study and other HPV vaccine-related studies from Merck. Mr Maansson is a former employee of Merck & Co., Inc. Ms Caldwell is a former employee of Merck & Co., Inc., and holds stock and stock options in Merck & Co., Inc. Dr Luxembourg is a current employee receiving salary from Merck & Co., Inc., and holds stock and stock options in Merck & Co., Inc. Ajoke Sobanjo-ter Meulen is a former employee of Merck & Co., Inc. and now works at Novartis.

    • FUNDING: Supported by Merck & Co., Inc, Kenilworth, NJ.

    • POTENTIAL CONFLICT OF INTEREST: Dr Schilling has received research support for this clinical study and other HPV vaccine-related studies from Merck and honoraria outside the submitted work from Merck-Chile, Grunenthal-Chile, and Grunenthal-L.A. Dr Parra has received research support for this clinical study and grant support from Merck. Dr Gutierrez has received research support for this clinical study from Merck. Dr Restrepo has received research support for this clinical study from Merck and has received compensation from Froost Laboratories for Board Membership for GARDASIL. Drs Ucros, Herrera, Engel, and Huicho have received research support for this clinical study from Merck. Dr Shew has received research support for this clinical study and other HPV vaccine-related studies from Merck. Mr Maansson is a former employee of Merck & Co., Inc. Ms Caldwell is a former employee of Merck & Co., Inc., and holds stock and stock options in Merck & Co., Inc. Dr Luxembourg is a current employee receiving salary from Merck & Co., Inc., and holds stock and stock options in Merck & Co., Inc. Ajoke Sobanjo-ter Meulen is a former employee of Merck & Co., Inc. and now works at Novartis.

    References