title: Inconclusive evidence for non-inferior immunogenicity of two- compared with three-dose HPV immunization schedules in preadolescent girls: A systematic review and meta-analysis.
abstract: BACKGROUND
  The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9-14 years to three-dose schedules in young women 15-26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination.
  
  
  METHODS
  A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls.
  
  
  RESULTS
  For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within girls.
  
  
  CONCLUSIONS
  Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two- compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely.
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), P.O Box 1, 3720 BA, Bilthoven, The Netherlands; Department of Pathology, VU University Medical Centre (VUmc), P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands. Electronic address: robine.donken@rivm.nl.
authors.forename: Robine
authors.initials: R
authors.lastname: Donken
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), P.O Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Mirjam J
authors.initials: MJ
authors.lastname: Knol
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), P.O Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Bogaards
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), P.O Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Fiona R M
authors.initials: FR
authors.lastname: van der Klis
authors.affiliation: Department of Pathology, VU University Medical Centre (VUmc), P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
authors.affiliation: Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), P.O Box 1, 3720 BA, Bilthoven, The Netherlands.
authors.forename: Hester E
authors.initials: HE
authors.lastname: de Melker
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D002648:Child; D005260:Female; D006801:Humans; D007115:Immunization Schedule; D030361:Papillomavirus Infections / Q000150:complications / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D053918:Papillomavirus Vaccines
keywords: Antibodies; Human papillomavirus 16; Human papillomavirus 18; Human papillomavirus vaccine L1, type 16,18; Human papillomavirus vaccine L1, type 6,11,16,18; Immunization schedule; Non-inferiority; Vaccination