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Original Investigation
December 13, 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. 2016;316(22):2411-2421. 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

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