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Figure.
Flow Diagram for Primary Per-Protocol Immunogenicity Population Administered the 9-Valent Human Papillomavirus (HPV) Vaccine
Flow Diagram for Primary Per-Protocol Immunogenicity Population Administered the 9-Valent Human Papillomavirus (HPV) Vaccine

aFour (aged 9-14 years) were sexually active prior to enrollment; 4 unlikely to adhere to study procedures; 3 unable to give consent or assent; 2 had a history or current evidence of medical conditions that might interfere with the results of the study; 1 was judged to be in poor physical health; 1 had a history of abnormal Papanicolaou test results; and 1 had a history of severe allergic reaction.

bOne participant discontinued the study after providing data for the analyses.

cTo be included in the primary per-protocol immunogenicity population, individuals were required to (1) be seronegative at day 1 for the HPV type being analyzed; (2) receive all planned doses within acceptable day ranges; (3) have a serology result after the last dose within an acceptable day range; and (4) have no other protocol violations that could interfere with the evaluation of participant’s immune response to the study vaccine. Individuals included provided data for analysis of 1 or more HPV types.

dThe total number of participants excluded from the primary analysis only counts a participant once. Individuals were counted once in each applicable exclusion subcategory, but a participant may appear in more than 1 subcategory. Additional data and information appear in eTable 1 in Supplement 2.

Table 1.  
Baseline Characteristics of Participants at Enrollment
Baseline Characteristics of Participants at Enrollment
Table 2.  
Noninferiority Analysis of Antibody Geometric Mean Titers (GMTs) at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
Noninferiority Analysis of Antibody Geometric Mean Titers (GMTs) at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
Table 3.  
Noninferiority Analysis of Seropositivity Rates at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
Noninferiority Analysis of Seropositivity Rates at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
Table 4.  
Post Hoc Analysis of Antibody Geometric Mean Titers (GMTs) at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
Post Hoc Analysis of Antibody Geometric Mean Titers (GMTs) at 1 Month After Administration of the Last Dose of the 9-Valent Human Papillomavirus (HPV) Vaccine
1.
Forman  D, de Martel  C, Lacey  CJ,  et al.  Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(suppl 5):F12-F23.
PubMedArticle
2.
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(10):1997-2008.
PubMedArticle
3.
Serrano  B, de Sanjosé  S, Tous  S,  et al.  Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer. 2015;51(13):1732-1741.
PubMedArticle
4.
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(1):98-107.
PubMedArticle
5.
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(8):711-723.
PubMedArticle
6.
Schiller  JT, Castellsagué  X, Garland  SM.  A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30(suppl 5):F123-F138.
PubMedArticle
7.
Lazcano-Ponce  E, Stanley  M, Muñoz  N,  et al.  Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs a three-dose schedule at 21 months. Vaccine. 2014;32(6):725-732.
PubMedArticle
8.
Donken  R, Bogaards  JA, van der Klis  FRM, Meijer  CJ, de Melker  HE.  An exploration of individual- and population-level impact of the 2-dose HPV vaccination schedule in pre-adolescent girls. Hum Vaccin Immunother. 2016;12(6):1381-1393.
PubMedArticle
9.
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(17):1793-1802.
PubMedArticle
10.
Romanowski  B, Schwarz  TF, Ferguson  LM,  et al.  Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7(12):1374-1386.
PubMedArticle
11.
Puthanakit  T, Huang  LM, Chiu  CH,  et al.  Randomized open trial comparing 2-dose regimens of the human papillomavirus 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years vs a 3-dose regimen in women aged 15-25 years. J Infect Dis. 2016;214(4):525-536.
PubMedArticle
12.
Hernández-Ávila  M, Torres-Ibarra  L, Stanley  M,  et al.  Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: an epidemiological surveillance mechanism for alternate vaccination schemes. Hum Vaccin Immunother. 2016;12(1):30-38.
PubMedArticle
13.
World Health Organization.  Human papillomavirus vaccines: WHO position paper, October 2014. Wkly Epidemiol Rec. 2014;89(43):465-491.
PubMed
14.
Moreira  ED  Jr, Block  SL, Ferris  D,  et al.  Safety profile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics. 2016;138(2):e20154387.
PubMedArticle
15.
Roberts  C, Green  T, Hess  E,  et al.  Development of a human papillomavirus competitive luminex immunoassay for nine HPV types. Hum Vaccin Immunother. 2014;10(8):2168-2174.
PubMedArticle
16.
Wang  WWB, Mehrotra  DV, Chan  ISF, Heyse  JF.  Statistical considerations for noninferiority/equivalence trials in vaccine development. J Biopharm Stat. 2006;16(4):429-441.
PubMedArticle
17.
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(8):1153-1162.
PubMedArticle
18.
Vesikari  T, Brodszki  N, van Damme  P,  et al.  A randomized, double-blind, phase III study of the immunogenicity and safety of a 9-valent human papillomavirus L1 virus-like particle vaccine (V503) vs Gardasil in 9-15-year-old girls. Pediatr Infect Dis J. 2015;34(9):992-998.
PubMedArticle
19.
Stanley  M, Pinto  LA, Trimble  C.  Human papillomavirus vaccines—immune responses. Vaccine. 2012;30(suppl 5):F83-F87.
PubMedArticle
20.
Zimmerman  RK, Nowalk  MP, Lin  CJ,  et al.  Randomized trial of an alternate human papillomavirus vaccine administration schedule in college-aged women. J Womens Health (Larchmt). 2010;19(8):1441-1447.
PubMedArticle
21.
Neuzil  KM, Canh  DG, Thiem  VD,  et al.  Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. JAMA. 2011;305(14):1424-1431.
PubMedArticle
22.
Lamontagne  DS, Thiem  VD, Huong  VM, Tang  Y, Neuzil  KM.  Immunogenicity of quadrivalent HPV vaccine among girls 11 to 13 Years of age vaccinated using alternative dosing schedules: results 29 to 32 months after third dose. J Infect Dis. 2013;208(8):1325-1334.
PubMedArticle
23.
Sankaranarayanan  R, Prabhu  PR, Pawlita  M,  et al; Indian HPV Vaccine Study Group.  Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncol. 2016;17(1):67-77.
PubMedArticle
24.
European Medicines Agency. Gardasil 9: EU summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003852/WC500189111.pdf. Accessed on May 30, 2016.
25.
Herweijer  E, Leval  A, Ploner  A,  et al.  Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma. JAMA. 2014;311(6):597-603.
PubMedArticle
26.
Blomberg  M, Dehlendorff  C, Sand  C, Kjaer  SK.  Dose-related differences in effectiveness of human papillomavirus vaccination against genital warts: a nationwide study of 550,000 young girls. Clin Infect Dis. 2015;61(5):676-682.
PubMedArticle
27.
Donken  R, Knol  MJ, Bogaards  JA, van der Klis  FR, Meijer  CJ, de Melker  HE.  Inconclusive evidence for non-inferior immunogenicity of two- compared with three-dose HPV immunization schedules in preadolescent girls: a systematic review and meta-analysis. J Infect. 2015;71(1):61-73.
PubMedArticle
28.
Kavanagh  K, Pollock  KG, Potts  A,  et al.  Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. Br J Cancer. 2014;110(11):2804-2811.
PubMedArticle
29.
Brotherton  JM, Malloy  M, Budd  AC, Saville  AM, Drennan  K, Gertig  DM.  Effectiveness of less than three doses of quadrivalent human papillomavirus vaccine against cervical intraepithelial neoplasia when administered using a standard dose spacing schedule: observational cohort of young women in Australia. Papillomavirus Res. 2015;1:59-73.Article
30.
Dominiak-Felden  G, Gobbo  C, Simondon  F.  Evaluating the early benefit of quadrivalent HPV vaccine on genital warts in Belgium: a cohort study. PLoS One. 2015;10(7):e0132404.
PubMedArticle
31.
Hofstetter  AM, Ompad  DC, Stockwell  MS, Rosenthal  SL, Soren  K.  Human papillomavirus vaccination and cervical cytology outcomes among urban low-income minority females. JAMA Pediatr. 2016;170(5):445-452.
PubMedArticle
32.
Gertig  DM, Brotherton  JML, Budd  AC, Drennan  K, Chappell  G, Saville  AM.  Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. BMC Med. 2013;11:227.
PubMedArticle
33.
Crowe  E, Pandeya  N, Brotherton  JML,  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.
PubMedArticle
34.
Cuschieri  K, Kavanagh  K, Moore  C, Bhatia  R, Love  J, Pollock  KG.  Impact of partial bivalent HPV vaccination on vaccine-type infection: a population-based analysis. Br J Cancer. 2016;114(11):1261-1264.
PubMedArticle
35.
Cloessner  EA, Stokley  S, Yankey  D, Markowitz  LE.  Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule. Hum Vaccin Immunother. 2016;12(6):1375-1380.
PubMedArticle
36.
Herrero  R, González  P, Markowitz  LE.  Present status of human papillomavirus vaccine development and implementation. Lancet Oncol. 2015;16(5):e206-e216.
PubMedArticle
37.
Schilling  A, Parra  MM, Gutierrez  M,  et al.  Coadministration of a 9-valent human papillomavirus vaccine with meningococcal and Tdap vaccines. Pediatrics. 2015;136(3):e563-e572.
PubMedArticle
38.
Kosalaraksa  P, Mehlsen  J, Vesikari  T,  et al.  An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age. Pediatr Infect Dis J. 2015;34(6):627-634.
PubMedArticle
39.
Jit  M, Choi  YH, Laprise  JF, Boily  MC, Drolet  M, Brisson  M.  Two-dose strategies for human papillomavirus vaccination: how well do they need to protect? Vaccine. 2014;32(26):3237-3242.
PubMedArticle
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Original Investigation
November 21, 2016

Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women

Author Affiliations
  • 1Department of Obstetrics and Gynecology, Haukeland University Hospital, University of Bergen, Bergen, Norway
  • 2Instituto Chileno de Medicina Reproductiva, Santiago, Chile
  • 3Centre d’Atèncio Primària, EBA Centelles, Barcelona, Spain
  • 4Medicus, Clinical Trials, Trondheim, Norway
  • 5Perinatal HIV Research Unit, Baragwanath Hospital, Johannesburg, South Africa
  • 6Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • 7Kentucky Pediatric and Adult Research, Bardstown
  • 8G-CENTRUM Olomouc, Olomouc, Czech Republic
  • 9Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
  • 10Sabah Woman’s and Children’s Hospital, Hospital Likas, Sabah, Malaysia
  • 11Centrum Ambulantní, Brno, Czech Republic
  • 12Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Republic of Korea
  • 13Women’s Research Center of Redlands, Terracina Medical Center, Redlands, California
  • 14Assaf-Harofeh Medical Center, Zerifin, Israel
  • 15Hacettepe Üniversitesi Beytepe Kampüsü, Ankara, Turkey
  • 16Merck & Co Inc, Kenilworth, New Jersey
JAMA. Published online November 21, 2016. doi:10.1001/jama.2016.17615
Key Points

Question  Are 2 doses of the 9-valent human papillomavirus (HPV) vaccine in girls and boys aged 9 to 14 years noninferior to 3 doses in adolescent girls and young women aged 16 to 26 years?

Findings  In this international, open-label, noninferiority trial involving 1518 participants, antibody responses measured 4 weeks after the last dose in girls and boys given 2 doses separated by 6 or 12 months were noninferior to responses in adolescent girls and young women given 3 doses.

Meaning  Short-term immune responses after 2 doses of 9-valent HPV vaccine in girls and boys aged 9 to 14 years were noninferior to immune responses after 3 doses in adolescent girls and young women. Persistence of response and clinical outcomes need to be studied.

Abstract

Importance  Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts.

Objective  To determine whether HPV type–specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses.

Design, Setting, and Participants  Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314).

Interventions  Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months.

Main Outcomes and Measures  The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers.

Results  Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart.

Conclusions and Relevance  Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT01984697

Introduction

Diseases related to the human papillomavirus (HPV) impose a substantial health care burden on both the developing and developed world.1 A 9-valent HPV vaccine was developed to prevent infection and disease from the 9 HPV types (HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, HPV-58) responsible for causing approximately 90% of cervical cancers and other HPV-related anogenital cancers and 90% of genital warts,14 thus providing broader coverage than the earlier bivalent (HPV-16, HPV-18) and quadrivalent (HPV-6, HPV-11, HPV-16, HPV-18) vaccines. In the pivotal trial5 in young women, 3 doses of the 9-valent HPV vaccine reduced infection and disease from all 9 vaccine types.

Clinical efficacy cannot be directly tested during early adolescence because of limited exposure to HPV. Efficacy of all HPV vaccines has been demonstrated as a 3-dose series in young women.5,6 In contrast, efficacy in young adolescents has been inferred from the demonstration of noninferior HPV antibody responses compared with young women (immunobridging). With the bivalent and quadrivalent vaccines, antibody responses 1 month after the second dose in girls within the 9- to 14-year age range who received a 2-dose regimen were noninferior to responses in adolescent girls and young women within the 15- to 26-year age range given 3 doses.712 Based on these results, vaccine efficacy previously established in young women receiving 3 doses was inferred for younger age groups receiving 2 doses. In 2014, the World Health Organization changed its recommendation for routine HPV vaccination of girls aged 9 to 14 years from a 3-dose to a 2-dose schedule based on data from clinical trials with the bivalent and quadrivalent vaccines.13

In this study, immunogenicity of a 2-dose regimen of the 9-valent HPV vaccine was assessed using standard immunobridging criteria by comparing antibody responses to vaccine types in girls and boys given 2 doses separated by 6 or 12 months vs antibody responses in adolescent girls and young women given the standard 3-dose regimen.

Methods
Study Design

An international clinical trial was conducted of the immunogenicity and safety of the 9-valent HPV vaccine in girls and boys aged 9 to 14 years given 2 doses 6 or 12 months apart compared with a control group of adolescent girls and young women aged 16 to 26 years given the standard 3-dose schedule. The protocol is available in Supplement 1. This study assessed whether a 2-dose regimen of the 9-valent HPV vaccine in girls and boys would likely be protective by bridging antibody responses to the older group of adolescent girls and young women shown to be protected against HPV infection and disease. Such an approach allows direct comparison with antibody geometric mean titers (GMTs) proven to be effective against clinically meaningful end points.

The trial was initiated on December 16, 2013, at 52 ambulatory care sites in 15 countries and was conducted according to good clinical practice principles. The protocol was approved by the regulatory agencies of all participating countries and by the institutional review boards with jurisdiction over the study sites. All participants or their parents or guardians signed informed consent at entry. Enrollment was concluded on April 18, 2014, but follow-up is ongoing to assess antibody persistence through month 36. The last participant visit contributing to the current report occurred on June 19, 2015.

Eligible girls and boys aged 9 to 14 years had to be generally healthy and not sexually active prior to enrollment. Adolescent girls and young women aged 16 to 26 years had to be generally healthy with 4 or fewer lifetime sexual partners, without a history of abnormal Papanicolaou test results or other cervical abnormalities, and agree to use effective contraception through study month 7. Participants were required to be afebrile (oral temperature <37.8°C) for 24 hours before each vaccine injection.

Exclusion criteria included pregnancy, known allergy to any vaccine component, thrombocytopenia, prior or ongoing immunosuppression, or previous receipt of an HPV vaccine. An interactive voice response system was used to allocate study participants, balance randomization between sites, and assist with vaccine supply management at the study sites.

The 9-valent HPV vaccine (Gardasil 9, Merck & Co) was administered to 5 vaccination cohorts. The first cohort was composed of girls aged 9 to 14 years who were randomized to receive 2 doses of the HPV vaccine 6 months apart (at 0 and 6 months); the second cohort, boys aged 9 to 14 years were randomized to receive 2 doses of the HPV vaccine 6 months apart (at 0 and 6 months); the third cohort, girls and boys aged 9 to 14 years were randomized to receive 2 doses of the HPV vaccine 12 months apart (at 0 and 12 months); the fourth cohort, girls aged 9 to 14 years were randomized to receive 3 doses of the HPV vaccine (at 0, 2, and 6 months); and the fifth cohort, adolescent girls and young women aged 16 to 26 years were allocated to receive 3 doses of the HPV vaccine (at 0, 2, and 6 months) (Figure).

Each vaccination cohort was to enroll approximately 300 participants. Enrollment of girls and boys was stratified into 3 age strata (9-10, 11-12, and 13-14 years) of similar size. Girls were randomized in a 2:1:2 ratio within each age stratum to girls (vaccine administered at 0 and 6 months), girls and boys (vaccine administered at 0 and 12 months), and girls (vaccine administered at 0, 2, and 6 months). Boys were randomized in a 2:1 ratio within each age stratum to boys (vaccine administered at 0 and 6 months) and girls and boys (vaccine administered at 0 and 12 months).

Participants were observed for 30 minutes after each vaccine injection for any immediate reaction. Serious adverse events were to be reported irrespective of causality from day 1 (month 0) through 6 months after the last vaccination. Serious adverse events were predefined as those events that resulted in death, were deemed life-threatening, led to a persistent or significant disability, required hospitalization, or were associated with a congenital anomaly, cancer, or other important medical event. Investigators were instructed to assign causality to adverse events on the basis of exposure, time course, likely cause, and consistency with the vaccine’s known safety profile (extensively described in previous trials).14

Outcomes

The primary end point was prespecified as the antibody response against HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58 assessed just prior to the first dose and 1 month after the last dose (after dose 2 or after dose 3 depending on the assigned vaccine schedule) using a competitive Luminex immunoassay.15 The secondary end point was seropositivity rates assessed just prior to the first dose and 1 month after the last dose of the given regimen. Seroconversion was defined as a changing serostatus from seronegative at baseline to seropositive by 4 weeks after the last vaccine dose. Serostatus cutoffs were defined as the antibody level above the assay’s lower limit of quantification that reliably distinguished samples classified by clinical likelihood of HPV infection and positive or negative status using previous versions of the competitive Luminex immunoassay.

A participant with an antibody titer at or above the predetermined cutoff for a given HPV type was considered seropositive for that type. Antibody titers function as a surrogate marker for vaccine protection in children before sexual debut, although the actual minimum antibody concentration needed for prevention has not been established. Human papillomavirus seropositivity at day 1 was not a reason for exclusion from the study; however, it was a reason for exclusion from the HPV type–specific per-protocol analyses.

In the primary noninferiority analyses using the per-protocol population, antibody GMTs at 1 month after the last dose in girls and boys who received 2 doses (6 or 12 months apart) were compared with antibody GMTs at 1 month after the last dose in adolescent girls and young women who received 3 doses over 6 months. A supportive intention-to-treat analysis was conducted in all randomized participants. The prespecified secondary analyses examined noninferiority of seropositivity rates at 1 month after the last dose in girls and boys who received 2 doses vs adolescent girls and young women who received 3 doses.

Exploratory analyses were planned to summarize antibody GMTs at 1 month after the last dose in girls and boys who received 2 doses by age strata. Four hypothesis-generating post hoc analyses were performed comparing (1) antibody GMTs 6 months after the last dose in girls and boys who received 2 doses 6 months apart vs adolescent girls and young women who received 3 doses; (2) antibody GMTs 1 month after the last dose in girls and boys who received 2 doses vs girls who received 3 doses; (3) antibody GMTs 1 month after the last dose in girls who received 3 doses vs adolescent girls and young women who received 3 doses; and (4) 2-dose regimens separated by 6 or 12 months.

Statistical Analyses

As a noninferiority trial, the primary analysis used the per-protocol population. Participants were required to (1) be seronegative at day 1 for the HPV type being analyzed (for the HPV-6 and HPV-11 immunogenicity analyses, participants had to be seronegative for both HPV-6 and HPV-11); (2) receive all planned doses of the vaccine within predetermined day ranges; (3) have a serology result after the last dose within an acceptable time window; and (4) have no other protocol violations that could interfere with the evaluation of the participant’s immune response to the vaccine.

Noninferiority of antibody GMTs at 1 month after the last dose in girls and boys who received 2 doses vs adolescent girls and young women who received 3 doses (primary immunogenicity hypothesis) was tested by constructing a 2-sided 95% CI for the ratio of antibody GMTs as stipulated by the trial protocol. Although 2-sided 95% CIs were prespecified by the protocol, 1-sided 97.5% CIs are presented for the primary immunogenicity hypotheses in keeping with currently accepted methods of presenting noninferiority results.

Prespecified noninferiority criteria required that the lower bound of the 2-sided 95% CI (equivalent to the lower bound of the 1-sided 97.5% CI) for the ratio of antibody GMTs in girls and boys who received 2 doses relative to antibody GMTs in adolescent girls and young women who received 3 doses to be 0.67 or greater for each of the 9 vaccine HPV types. For an individual HPV type, the 95% CI for the ratio of antibody GMTs was derived from an analysis of variance model with the log of type-specific antibody titers as the response and vaccination group as the fixed effect.

The lower bound of 0.67 represents a more conservative choice than the 0.5 limit used in the earlier bridging noninferiority study of the quadrivalent HPV vaccine.9,16 The specific choice of the noninferiority margin was based on protective antibody levels in the pivotal efficacy trials of the quadrivalent HPV vaccine, which informed benchmarks set by Merck in conjunction with regulatory agencies for bridging studies leading to licensure.

Noninferiority of seroconversion rates at 1 month after the last dose in girls and boys given 2 doses vs adolescent girls and young women given 3 doses (secondary immunogenicity hypothesis) was tested by constructing a 2-sided 95% CI for the difference in seroconversion rates (girls, boys, or girls and boys minus adolescent girls and young women). Although 2-sided 95% CIs were again prespecified, 1-sided 97.5% CIs are presented for the secondary immunogenicity hypotheses to be consistent with currently accepted methods of presenting noninferiority results. Prespecified noninferiority criteria required that the lower bound of the 2-sided 95% CI (equivalent to the lower bound of the 1-sided 97.5% CI) for the difference in seroconversion rates exceed −5 percentage points for each HPV type. All data analyses were conducted using SAS version 9.3 (SAS Institute Inc).

To satisfy the 3 primary immunogenicity hypotheses, noninferiority criteria had to be met for all 9 HPV types; thus, no multiplicity adjustment was made to account for the multiple HPV types within each hypothesis. A closed stepwise procedure was used to control for multiplicity resulting from 3 primary hypotheses and to ensure an overall 1-sided type I error rate at the 0.025 level. Noninferiority in girls vaccinated at 0 and 6 months had to be established vs adolescent girls and young women vaccinated at 0, 2, and 6 months before noninferiority in boys vaccinated at 0 and 6 months vs adolescent girls and young women vaccinated at 0, 2, and 6 months was tested. Similarly, noninferiority in boys vaccinated at 0 and 6 months vs adolescent girls and young women vaccinated at 0, 2, and 6 months had to be established before noninferiority in girls and boys vaccinated at 0 and 12 months vs adolescent girls and young women vaccinated at 0, 2, and 6 months was tested.

With the planned sample size of approximately 300 participants per cohort, the study had greater than 99% power to establish the primary immunogenicity hypothesis at a 1-sided significance level of 0.025, assuming a true ratio of antibody GMTs of 1.2 for all 9 vaccine HPV types, an exclusion rate from the per-protocol analyses of 20% for girls and boys and 30% for adolescent girls and young women, an SD of 1.2 for the natural log-transformed titers, and a noninferiority margin with a 1.5-fold difference for the ratio of antibody GMTs.

Every participant who received at least 1 study vaccination and had follow-up data was included in the safety analysis. Because the safety profile of the 9-valent HPV vaccine has already been characterized in phase 3 clinical studies,14 the protocol did not use vaccination report cards. Nonserious injection site and systemic events were not actively solicited (although investigators could report such events at their discretion). Consequently, the frequencies of nonserious adverse events reported in this study cannot be quantitatively compared with other HPV vaccine studies that used vaccination report cards.

Results
Baseline Characteristics

A total of 1536 potential participants were screened for inclusion in the study and 1518 (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]) were enrolled, including 1516 who received at least 1 vaccine dose (Figure). Overall, 1474 completed the study and data from 1377 (274 girls aged 9-14 years randomized to receive 2 vaccine doses 6 months apart; 273 boys aged 9-14 years randomized to receive 2 doses 6 months apart; 269 girls and boys aged 9-14 years randomized to receive 2 doses 12 months apart; 275 girls aged 9-14 years randomized to receive 3 doses over 6 months; and 286 adolescent girls and young women aged 16 to 26 years allocated to receive 3 doses over 6 months) were included in the per-protocol analyses.

Baseline characteristics of randomized participants appear in Table 1. The most common reasons for exclusion from the per-protocol immunogenicity analyses were seropositivity for a HPV type included in the vaccine on day 1 or a missing result for the primary end point collected 4 weeks after the last vaccination (eTable 1 in Supplement 2).

Immunogenicity

Antibody GMTs against the 9 HPV types assayed 1 month after the last dose were consistently higher in girls (vaccine doses at 0 and 6 months), boys (vaccine doses at 0 and 6 months), and girls and boys (vaccine doses at 0 and 12 months) than for adolescent girls and young women (vaccine doses at 0, 2, and 6 months) in the per-protocol population (Table 2). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of antibody GMTs at 1 month after the last dose across the 9 HPV vaccine subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received vaccine doses at 0 and 6 months; from 1.37 to ∞ to 2.55 to ∞ for boys who received doses at 0 and 6 months; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received doses at 0 and 12 months. Accordingly, noninferiority criteria of antibody GMTs were met for all 9 HPV types for the 27 primary comparisons (all P < .001). Similar results were found in supportive analyses of the intention-to-treat population (eTable 2 in Supplement 2).

More than 98% of participants in each cohort seroconverted by 1 month after the last vaccine dose to each individual HPV type in the vaccine. The lower bounds of 1-sided 97.5% CIs for the differences in seroconversion rates between girls (vaccine doses at 0 and 6 months), boys (doses at 0 and 6 months), and girls and boys (doses at 0 and 12 months) compared with adolescent girls and young women (vaccine doses at 0, 2, and 6 months) were less than −5 percentage points for all comparisons (Table 3). Thus, the noninferiority criteria for seroconversion rates were met for all 9 HPV types for the 27 secondary comparisons (all P < .001).

In a planned exploratory, hypothesis-generating analysis of antibody GMTs by age strata among girls and boys receiving a 2-dose regimen (eTable 3 in Supplement 2), antibody GMTs for each age stratum of girls and boys receiving 2 doses on a 6- or 12-month schedule were higher than in adolescent girls and young women given 3 doses over 6 months.

Post hoc hypothesis-generating analyses at 1 month after the last dose showed that the 2-dose regimen given at 0 and 6 months in girls aged 9 to 14 years resulted in higher antibody GMTs against 5 HPV types (HPV-6, HPV-11, HPV-16, HPV-33, HPV-58) and lower antibody GMTs against 4 HPV types (HPV-18, HPV-31, HPV-45, HPV-52) than the 3-dose regimen given at 0, 2, and 6 months in girls aged 9 to 14 years. The 2-dose regimen given at 0 and 12 months to girls aged 9 to 14 years resulted in higher antibody GMTs against 8 HPV types (HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-52, HPV-58) and lower antibody GMTs against 1 HPV type (HPV-45) than the 3-dose regimen given at 0, 2, and 6 months in girls (Table 4). Similar relative results for antibody GMTs also were seen for boys after 2 doses compared with girls after 3 doses (eTable 4 in Supplement 2).

A post hoc analysis was performed to assess the persistence of antibody responses at 6 months after the last dose in the vaccine groups receiving 2 or 3 doses on a 6-month schedule. Although antibody GMTs declined in all 4 cohorts (girls, vaccine doses at 0 and 6 months; boys, doses at 0 and 6 months; girls and boys, doses at 0 and 12 months; adolescent girls and young women, doses at 0, 2, and 6 months) over the 5-month period from study month 7 to study month 12, the ratio of antibody GMTs for responses after 2 doses in girls and boys relative to 3 doses in adolescent girls and young women were maintained above the noninferiority threshold (eTable 5 in Supplement 2). Another post hoc analysis of girls aged 9 to 14 years receiving doses at 0, 2, and 6 months showed that antibody GMTs against HPV types in the vaccine were higher in girls than in adolescent girls and young women aged 16 to 26 years (eTable 6 in Supplement 2).

In a hypothesis-generating analysis contrasting 2 doses separated by 6 or 12 months, antibody GMTs were higher in the cohort of girls and boys given doses at 0 and 12 months than in either the cohort of girls or cohort of boys given doses at 0 and 6 months with nonoverlapping 2-sided 95% CIs for all HPV types except HPV-45 (Table 2).

Safety and Tolerability

Twenty-two participants experienced serious adverse events (eTable 7 in Supplement 2), none of which were considered related to the vaccine. One participant (a 9-year-old girl) discontinued the study because of a vaccine-related adverse event of transient urticaria 1 day after the first dose of vaccine, which fully resolved. There were no deaths during the course of the study.

Discussion

In an international immunogenicity trial of the 9-valent HPV vaccine, HPV type–specific antibody responses in girls and boys aged 9 to 14 years after 2 doses separated by 6 or 12 months were noninferior to responses in adolescent girls and young women aged 16 to 26 years after the standard 3-dose series. Quantitative antibody responses to HPV vaccines tend to be higher in children than in adults, as previously shown in studies assessing a 3-dose schedule.17,18 In this study, an exploratory analysis found that antibody GMTs at 1 month after the last dose were higher in each subgroup of girls and boys vaccinated with 2 doses when categorized by age strata (9-10 years, 11-12 years, and 13-14 years) than in adolescent girls and young women after 3 doses for all 9 HPV types. These observations suggest that the overall results of the primary immunogenicity analyses may be applicable across the entire studied age range of girls and boys.

In exploratory analyses, antibody GMTs at 1 month after the last dose were lower for some HPV types in girls who received a 2-dose series compared with girls who received a 3-dose series. Previous studies of 2-dose regimens of the bivalent or quadrivalent vaccines had also reported lower antibody responses with 2 doses for some HPV vaccine types (HPV-16 for the bivalent vaccine and HPV-18 for the quadrivalent vaccine).9,10 Vaccine-mediated protection against HPV infection is thought to be primarily mediated through neutralizing antibodies.19 High seroconversion rates have consistently occurred after HPV vaccination but the minimum protective titer has not been established.

The relevant objective of this study was to demonstrate that 2 doses given to boys and girls aged 9 to 14 years led to protective antibody levels as operationally quantified by efficacy trials, and was not to show which age group and dosing regimen achieved the highest antibody levels. The 2-dose regimens were limited to girls and boys in this study to take advantage of the recognized higher immunogenicity in the younger age cohort. Without direct evidence of vaccine efficacy in girls, the clinical significance of these differences in immunogenicity is unknown.

Dosing interval appears to be an important determinant of immunogenicity. In studies of 3-dose regimens of the quadrivalent HPV vaccine, a longer interval preceding the third dose (ie, third dose at month 12 instead of at month 6) resulted in higher antibody responses after the third dose.20 Likewise, a longer interval between the first 2 doses (ie, 12 months vs 3 or 6 months) resulted in higher antibody responses after the second dose.2123

Vaccination with a 2-dose regimen separated by short intervals is likely to be less immunogenic than separation by longer intervals. In the current study, HPV antibody responses were generally higher in girls and boys who received 2 doses at a 12-month interval than in girls and boys who received 2 doses 6 months apart. These results allow for some flexibility in the spacing of the second dose.

The European Medicines Agency approved the 2-dose regimen of the 9-valent HPV vaccine in April 2016 for young adolescents aged 9 to 14 years,24 recommending that the second dose be administered 5 to 13 months after the first dose. Similarly, the World Health Organization recommended administration of 2 doses separated by 6 months or longer, without specifying a maximum interval.13 In this regard, postlicensure observational data indicate that administering the second dose earlier than 5 months after the initial dose may be associated with reduced effectiveness.25,26

This study provides a broad evaluation of the immunogenicity of 2-dose schedules of the 9-valent HPV vaccine (including a direct comparison of 2 alternative schedules in both girls and boys); however, there are several limitations. First, because children are typically not exposed to HPV prior to adolescence, efficacy of prophylactic HPV vaccines cannot be directly assessed in this population. Thus, the primary objective was to demonstrate noninferior immunogenicity compared with a group in whom efficacy had been established. Second, although this approach has been widely adopted by regulators, there are no universally accepted noninferiority criteria. Nonetheless, it is reassuring that antibody responses in girls and boys who received 2 doses were consistently and substantially greater than the protective responses seen in adolescent girls and young women who received 3 doses.

Third, effectiveness and antibody responses over time were not evaluated. The ratio of antibody GMTs comparing 2-dose with 3-dose regimens for the bivalent and quadrivalent vaccines can vary over time.9,27 Observational studies suggest that administration of less than 3 doses may be associated with reduced effectiveness, although prevalent HPV infection and noncompletion of the vaccination schedule may itself be associated with higher-risk behavior and compliant participants may therefore be at lower risk of HPV exposure.25,26,2834 Duration of protection is important both from clinical and public health standpoints.35 Evaluation of antibody persistence is ongoing and assessment of the duration of protection is planned. The 2-dose schedule has not been tested in persons aged 15 years or older.

In many countries, HPV vaccination rates remain suboptimal.36 Using an effective 2-dose regimen entailing fewer visits could improve adherence to HPV vaccination programs.35 Coadministration of the 9-valent HPV vaccine with diphtheria, tetanus, pertussis, polio, and meningococcal vaccines could also be completed at the same visit, which has been demonstrated in clinical studies.37,38 Based on health economics modeling, use of a 2-dose vaccination schedule could potentially reduce the total costs of HPV vaccination.13,39

Conclusions

Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes.

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Article Information

Corresponding Author: Ole-Erik Iversen, MD, PhD, Department of Obstetrics and Gynecology, Haukeland University Hospital, University of Bergen, Jonas Lies vei 68, Bergen 5021, Norway (ole-erik.iversen@uib.no).

Published Online: November 21, 2016. doi:10.1001/jama.2016.17615

Author Contributions: Dr Iversen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Ellison, Ritter, Yuan, Saah, Luxembourg.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Iversen, Ellison, DiNubile, Saah, Luxembourg.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ellison, Yuan.

Administrative, technical, or material support: Ritter, DiNubile.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. All the academic coauthors have been investigators for Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. Dr Iversen reported being an investigator for HPV vaccine studies sponsored by Merck Sharp & Dohme and GlaxoSmithKline; receiving lecture fees from Merck, Sanofi Pasteur Merck Sharp & Dohme, and GlaxoSmithKline; and receiving personal fees from Sanofi Pasteur Merck Sharp & Dohme. Dr Ulied reported receiving institutional payments from GlaxoSmithKline to conduct clinical trials; and lecture honoraria from Pfizer. Dr Soerdal reported receiving an institutional payment from Merck for participating in this clinical trial. Dr Block reported receiving grant support and speaker fees from Merck; and institutional research support from GlaxoSmithKline. Dr Skrivanek reported receiving personal fees from Merck Sharp & Dohme; serving on advisory boards for Merck Sharp & Dohme, Bayer Healthcare, Richter Gedeon, and Exeltis; and receiving research support for clinical trials from AbbVie, Preglem, Bayer Healthcare, Mithra Pharmaceutical, and Astellas. Dr Fong reported receiving grants from Merck, Sanofi Pasteur, and GlaxoSmithKline. Dr Kim reported receiving lecture fees from Merck and travel grants from GlaxoSmithKline. Dr Cestero reported reported receiving an institutional payment from Merck for participating in this clinical trial. Drs Ellison, Yuan, DiNubile, Saah, and Luxembourg and Mr Ritter are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, and own stock and/or stock options in the company. No other disclosures were reported.

Funding/Support: The study was sponsored and funded by Merck & Co, which manufactures the quadrivalent and nonavalent HPV vaccines.

Role of the Funder/Sponsor: The study was designed, managed, and analyzed by Merck in conjunction with external investigators. Merck, as the study sponsor, was directly involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript. The presentation also underwent formal review by Merck. However, Merck could not prevent submission of the manuscript.

The V503 Protocol 010 Principal Investigators are (alphabetically by country): Canada: Simon Dobson, MD (Department of Pediatrics, University of British Columbia, Vancouver), Murdo Ferguson, MD (Colchester Research Group, Truro, Nova Scotia), Shelly McNeil, MD (Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia), Richard Tytus, MD (McMaster University, Hamilton, Ontario). Chile: Maria Jose Miranda, MD (Instituto Chileno de Medicina Reproductiva, Santiago), Andrea Schilling, MD (Universidad del Desarrollo, Santiago). Colombia: Nestor Balcazar, MD (MedPlus Medicina Prepagada, Bogotá), Ana Maria Guevara, MD (Pablo Tobon Uribe Hospital, Medellín, Antioquia), Jaime Alberto Restrepo, MD (Fundación Centro de Investigación Clinica CIC, Medellín), Humberto Reynales, MD (Centro de Atención e Investigación Médica–CAIMED S. A. S, Bogotá). Czech Republic: Vladimir Dvorak, MD (Centrum Ambulantní, Brno), Ales Skrivanek, MD (G-CENTRUM Olomouc, Olomouc), Alexandra Stara, MD (MediStar, sro Praha 2), Jiri Stepan, MD (First Private Surgical Center Ltd–SANUS, Hradec Králové). Denmark: Jesper Mehlsen, MD (Koordinerende Forskningsenhed/INNOVAcenter, Bispebjerg/Frederiksberg Hospital, Frederiksberg), Ole Mogensen, MD, and Gudrun Neumann, MD (Klinisk forskningscenter, Gynækologisk Obstetrisk afd D, Odense Universitets Hospital, Odense), Lone Kjeld Petersen, MD (Gynækologisk Forskning Aarhus University Hospital, Aarhus). Israel: Mati Berkovitch, MD (Assaf-Harofeh Medical Center, Zerifin), Jacob Bornstein, MD (Western Galilee Medical Center, Nahariya), Avner Herman Cohen, MD (Clalit-Child Health Center, Petah Tikva). Malaysia: Hany Ariffin, MD (University Malaya Medical Centre, Kuala Lumpur), Siew Moy Fong, MD (Sabah Woman’s and Children’s Hospital, Hospital Likas, Sabah), Nur Azurah Abdul Ghani, MD (Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur). Norway: Ole-Erik Iversen, MD (Department of Obstetrics and Gynecology, Haukeland University Hospital, University of Bergen, Bergen); Terje Soerdal, MD (Medicus, Clinical Trials, Trondheim). South Korea: Kyung-Hyo Kim, MD (Department of Pediatrics, Ewha Womans University School of Medicine, Seoul), Yae-Jean Kim, MD (Samsung Medical Center, Seoul), Young Tae Kim, MD (Yonsei University Severance Hospital, Seoul). South Africa: Surita Roux, MBChB (Emavundleni Research Centre, Desmond Tutu HIV Foundation, Cape Town), Erica Lazarus, MBChB (Perinatal HIV Research Unit, Baragwanath Hospital, Johannesburg). Spain: Xavier Castellsague Pique, MD (Institut Català d’Oncologia, Barcelona), Javier Diez Domingo, MD (Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, Valencia), Angels Ulied, MD (Centre d’Atèncio Primària, EBA Centelles, Barcelona). Taiwan: Li-Min Huang, MD (National Taiwan University Hospital, Taipei City). Thailand: Kulkanya Chokephaibulkit, MD (Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok), Punee Pitisuttihum, MD (Vaccine Trial Centre, Bangkok). Turkey: Mehmet Ceyhan, MD (Hacettepe Üniversitesi Beytepe Kampüsü, Ankara), Ener Cagri Dinleyici, MD (Eskisehir Osmangazi Universitesi Tip Fakultesi Hastanesi Cocuk Sagligi ve Hastaliklari Anabilim Dali, Eskisehir), Zafer Kurugol, MD (Ege Üniversitesi Tıp Fakültesi Çocuk Sağlığı ve Hastalıkları Anabilim Dalı, Bornova Izmir). United States: Stanley Block, MD (Kentucky Pediatric and Adult Research, Bardstown), Ramon Cestero, MD (Women’s Research Center of Redlands, Terracina Medical Center, Redlands, California), Eli Engel, MD (Bayview Research Group, Valley Village, Virginia), Daron Gale Ferris, MD (Georgia Regents University, Augusta), Chester Fisher, MD (Health Research of Hampton Roads Inc, Newport News, Virginia), Katie Ann Julien, MD (J. Lewis Research, Inc/Jordan River Family Medicine, South Jordan, Utah), Joseph Leader, MD (Woburn Pediatric Associates, Woburn, Massachusetts), Robert Lipetz, DO (Encompass Clinical Research, Spring Valley, California), Richard Earl Rupp, MD (University of Texas Medical Branch, Galveston), Shelly David Senders, MD (Senders Pediatrics, South Euclid, Ohio), Helen Lee Stacey, MD (Diablo Clinical Research Inc, Walnut Creek, California), Meera Varman, MD (Creighton University Department of Pediatrics, Omaha, Nebraska).

Disclaimer: The views expressed in this article represent the collective views of the authors and do not necessarily reflect the official position of Merck.

Additional Contributions: We are indebted to the participants and their caregivers involved with this study. We appreciate the expert assistance of Amita Joshi, PhD, Karyn Davis, BA, Carol Zecca, BA, and Michele McColgan, BA (all with Merck & Co), in preparing the manuscript. No compensation beyond salary was provided for their contributions.

References
1.
Forman  D, de Martel  C, Lacey  CJ,  et al.  Global burden of human papillomavirus and related diseases. Vaccine. 2012;30(suppl 5):F12-F23.
PubMedArticle
2.
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(10):1997-2008.
PubMedArticle
3.
Serrano  B, de Sanjosé  S, Tous  S,  et al.  Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions. Eur J Cancer. 2015;51(13):1732-1741.
PubMedArticle
4.
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(1):98-107.
PubMedArticle
5.
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(8):711-723.
PubMedArticle
6.
Schiller  JT, Castellsagué  X, Garland  SM.  A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30(suppl 5):F123-F138.
PubMedArticle
7.
Lazcano-Ponce  E, Stanley  M, Muñoz  N,  et al.  Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs a three-dose schedule at 21 months. Vaccine. 2014;32(6):725-732.
PubMedArticle
8.
Donken  R, Bogaards  JA, van der Klis  FRM, Meijer  CJ, de Melker  HE.  An exploration of individual- and population-level impact of the 2-dose HPV vaccination schedule in pre-adolescent girls. Hum Vaccin Immunother. 2016;12(6):1381-1393.
PubMedArticle
9.
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(17):1793-1802.
PubMedArticle
10.
Romanowski  B, Schwarz  TF, Ferguson  LM,  et al.  Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7(12):1374-1386.
PubMedArticle
11.
Puthanakit  T, Huang  LM, Chiu  CH,  et al.  Randomized open trial comparing 2-dose regimens of the human papillomavirus 16/18 AS04-adjuvanted vaccine in girls aged 9-14 years vs a 3-dose regimen in women aged 15-25 years. J Infect Dis. 2016;214(4):525-536.
PubMedArticle
12.
Hernández-Ávila  M, Torres-Ibarra  L, Stanley  M,  et al.  Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: an epidemiological surveillance mechanism for alternate vaccination schemes. Hum Vaccin Immunother. 2016;12(1):30-38.
PubMedArticle
13.
World Health Organization.  Human papillomavirus vaccines: WHO position paper, October 2014. Wkly Epidemiol Rec. 2014;89(43):465-491.
PubMed
14.
Moreira  ED  Jr, Block  SL, Ferris  D,  et al.  Safety profile of the 9-valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics. 2016;138(2):e20154387.
PubMedArticle
15.
Roberts  C, Green  T, Hess  E,  et al.  Development of a human papillomavirus competitive luminex immunoassay for nine HPV types. Hum Vaccin Immunother. 2014;10(8):2168-2174.
PubMedArticle
16.
Wang  WWB, Mehrotra  DV, Chan  ISF, Heyse  JF.  Statistical considerations for noninferiority/equivalence trials in vaccine development. J Biopharm Stat. 2006;16(4):429-441.
PubMedArticle
17.
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(8):1153-1162.
PubMedArticle
18.
Vesikari  T, Brodszki  N, van Damme  P,  et al.  A randomized, double-blind, phase III study of the immunogenicity and safety of a 9-valent human papillomavirus L1 virus-like particle vaccine (V503) vs Gardasil in 9-15-year-old girls. Pediatr Infect Dis J. 2015;34(9):992-998.
PubMedArticle
19.
Stanley  M, Pinto  LA, Trimble  C.  Human papillomavirus vaccines—immune responses. Vaccine. 2012;30(suppl 5):F83-F87.
PubMedArticle
20.
Zimmerman  RK, Nowalk  MP, Lin  CJ,  et al.  Randomized trial of an alternate human papillomavirus vaccine administration schedule in college-aged women. J Womens Health (Larchmt). 2010;19(8):1441-1447.
PubMedArticle
21.
Neuzil  KM, Canh  DG, Thiem  VD,  et al.  Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. JAMA. 2011;305(14):1424-1431.
PubMedArticle
22.
Lamontagne  DS, Thiem  VD, Huong  VM, Tang  Y, Neuzil  KM.  Immunogenicity of quadrivalent HPV vaccine among girls 11 to 13 Years of age vaccinated using alternative dosing schedules: results 29 to 32 months after third dose. J Infect Dis. 2013;208(8):1325-1334.
PubMedArticle
23.
Sankaranarayanan  R, Prabhu  PR, Pawlita  M,  et al; Indian HPV Vaccine Study Group.  Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncol. 2016;17(1):67-77.
PubMedArticle
24.
European Medicines Agency. Gardasil 9: EU summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003852/WC500189111.pdf. Accessed on May 30, 2016.
25.
Herweijer  E, Leval  A, Ploner  A,  et al.  Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma. JAMA. 2014;311(6):597-603.
PubMedArticle
26.
Blomberg  M, Dehlendorff  C, Sand  C, Kjaer  SK.  Dose-related differences in effectiveness of human papillomavirus vaccination against genital warts: a nationwide study of 550,000 young girls. Clin Infect Dis. 2015;61(5):676-682.
PubMedArticle
27.
Donken  R, Knol  MJ, Bogaards  JA, van der Klis  FR, Meijer  CJ, de Melker  HE.  Inconclusive evidence for non-inferior immunogenicity of two- compared with three-dose HPV immunization schedules in preadolescent girls: a systematic review and meta-analysis. J Infect. 2015;71(1):61-73.
PubMedArticle
28.
Kavanagh  K, Pollock  KG, Potts  A,  et al.  Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. Br J Cancer. 2014;110(11):2804-2811.
PubMedArticle
29.
Brotherton  JM, Malloy  M, Budd  AC, Saville  AM, Drennan  K, Gertig  DM.  Effectiveness of less than three doses of quadrivalent human papillomavirus vaccine against cervical intraepithelial neoplasia when administered using a standard dose spacing schedule: observational cohort of young women in Australia. Papillomavirus Res. 2015;1:59-73.Article
30.
Dominiak-Felden  G, Gobbo  C, Simondon  F.  Evaluating the early benefit of quadrivalent HPV vaccine on genital warts in Belgium: a cohort study. PLoS One. 2015;10(7):e0132404.
PubMedArticle
31.
Hofstetter  AM, Ompad  DC, Stockwell  MS, Rosenthal  SL, Soren  K.  Human papillomavirus vaccination and cervical cytology outcomes among urban low-income minority females. JAMA Pediatr. 2016;170(5):445-452.
PubMedArticle
32.
Gertig  DM, Brotherton  JML, Budd  AC, Drennan  K, Chappell  G, Saville  AM.  Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. BMC Med. 2013;11:227.
PubMedArticle
33.
Crowe  E, Pandeya  N, Brotherton  JML,  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.
PubMedArticle
34.
Cuschieri  K, Kavanagh  K, Moore  C, Bhatia  R, Love  J, Pollock  KG.  Impact of partial bivalent HPV vaccination on vaccine-type infection: a population-based analysis. Br J Cancer. 2016;114(11):1261-1264.
PubMedArticle
35.
Cloessner  EA, Stokley  S, Yankey  D, Markowitz  LE.  Timing of HPV vaccine intervals among United States teens with consideration to the current ACIP schedule and the WHO 2-dose schedule. Hum Vaccin Immunother. 2016;12(6):1375-1380.
PubMedArticle
36.
Herrero  R, González  P, Markowitz  LE.  Present status of human papillomavirus vaccine development and implementation. Lancet Oncol. 2015;16(5):e206-e216.
PubMedArticle
37.
Schilling  A, Parra  MM, Gutierrez  M,  et al.  Coadministration of a 9-valent human papillomavirus vaccine with meningococcal and Tdap vaccines. Pediatrics. 2015;136(3):e563-e572.
PubMedArticle
38.
Kosalaraksa  P, Mehlsen  J, Vesikari  T,  et al.  An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age. Pediatr Infect Dis J. 2015;34(6):627-634.
PubMedArticle
39.
Jit  M, Choi  YH, Laprise  JF, Boily  MC, Drolet  M, Brisson  M.  Two-dose strategies for human papillomavirus vaccination: how well do they need to protect? Vaccine. 2014;32(26):3237-3242.
PubMedArticle
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