title: Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials.
abstract: BACKGROUND
  A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in addition to HPV-16 and -18 may broaden protection against cervical cancer. Two Phase I/II, randomized, controlled studies were conducted to compare the immunogenicity and safety of investigational tetravalent HPV L1 virus-like particle (VLP) vaccines, containing VLPs from two additional oncogenic genotypes, with the licensed HPV-16/18 AS04-adjuvanted vaccine (control) in healthy 18-25 year-old women.
  
  
  METHODS
  In one trial (NCT00231413), subjects received control or one of 6 tetravalent HPV-16/18/31/45 AS04 vaccine formulations at months (M) 0,1,6. In a second trial (NCT00478621), subjects received control or one of 5 tetravalent HPV-16/18/33/58 vaccines formulated with different adjuvant systems (AS04, AS01 or AS02), administered on different schedules (M0,1,6 or M0,3 or M0,6).
  
  
  RESULTS
  One month after the third injection (Month 7), there was a consistent trend for lower anti-HPV-16 and -18 geometric mean antibody titers (GMTs) for tetravalent AS04-adjuvanted vaccines compared with control. GMTs were statistically significantly lower for an HPV-16/18/31/45 AS04 vaccine containing 20/20/10/10 μg VLPs for both anti-HPV-16 and anti-HPV-18 antibodies, and for an HPV-16/18/33/58 AS04 vaccine containing 20/20/20/20 μg VLPs for anti-HPV-16 antibodies. There was also a trend for lower HPV-16 and -18-specific memory B-cell responses for tetravalent AS04 vaccines versus control. No such trends were observed for CD4(+) T-cell responses. Immune interference could not always be overcome by increasing the dose of HPV-16/18 L1 VLPs or by using a different adjuvant system. All formulations had acceptable reactogenicity and safety profiles. Reactogenicity in the 7-day post-vaccination period tended to increase with the introduction of additional VLPs, especially for formulations containing AS01.
  
  
  CONCLUSIONS
  HPV-16 and -18 antibody responses were lower when additional HPV L1 VLPs were added to the HPV-16/18 AS04-adjuvanted vaccine. Immune interference is a complex phenomenon that cannot always be overcome by changing the antigen dose or adjuvant system.
authors.affiliation: Universiteit Antwerpen, Vaccine & Infectious Disease Institute, Centre for the Evaluation of Vaccination, Building R, 2nd Floor, Universiteitsplein 1, 2610 Antwerpen, Belgium. Electronic address: pierre.vandamme@ua.ac.be.
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Damme
authors.affiliation: Center for Vaccinology, Ghent University and Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: geert.lerouxroels@ugent.be.
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.affiliation: Service de Gynécologie Obstétrique, Hôpital Erasme, Route de Lennik 808, 1070 Bruxelles, Belgium. Electronic address: philippe.simon@erasme.ulb.ac.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Simon
authors.affiliation: CHR Citadelle, Service de Gynécologie Obstétrique, Boulevard du 12ieme de Ligne 1, 4000 Liège, Belgium. Electronic address: jmfoidart@ulg.ac.be.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Gynaecologie, Heilig Hartziekenhuis, Kliniekstraat 45, 3300 Tienen, Belgium. Electronic address: gilbert.donders@femicare.net.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Donders
authors.affiliation: KULeuven, Jeugdgezondheidszorg, Kapucijnvoer 35/1, 3000 Leuven, Belgium. Electronic address: karel.hoppenbrouwers@med.kuleuven.be.
authors.forename: Karel
authors.initials: K
authors.lastname: Hoppenbrouwers
authors.affiliation: University of Colorado School of Medicine, Building 401, 1784 Racine St., Aurora, CO 80045, USA. Electronic address: Myron.Levin@ucdenver.edu.
authors.forename: Myron
authors.initials: M
authors.lastname: Levin
authors.affiliation: GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: fabian.s.tibaldi@gsk.com.
authors.forename: Fabian
authors.initials: F
authors.lastname: Tibaldi
authors.affiliation: GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: sylviane.poncelet@gsk.com.
authors.forename: Sylviane
authors.initials: S
authors.lastname: Poncelet
authors.affiliation: GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: philippe.moris@gsk.com.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moris
authors.affiliation: GlaxoSmithKline Vaccines, Avenue Fleming 20, 1300 Wavre, Belgium. Electronic address: francis.dessy@gsk.com.
authors.forename: Francis
authors.initials: F
authors.lastname: Dessy
authors.affiliation: GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: sandra.giannini@gsk.com.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Giannini
authors.affiliation: GlaxoSmithKline Vaccines, Avenue Fleming 20, 1300 Wavre, Belgium. Electronic address: dominique.descamps@gsk.com.
authors.forename: Dominique
authors.initials: D
authors.lastname: Descamps
authors.affiliation: GlaxoSmithKline SA, 2301 Renaissance Boulevard, RN0220, King of Prussia, PA 19406, USA. Electronic address: Gary.O.Dubin@gsk.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Dubin
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood; D000917:Antibody Formation; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D001530:Belgium; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D015507:Drugs, Investigational / Q000627:therapeutic use; D005260:Female; D052162:Human papillomavirus 16; D052161:Human papillomavirus 18; D006801:Humans; D007156:Immunologic Memory; D030361:Papillomavirus Infections / Q000517:prevention & control*; D053918:Papillomavirus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D014481:United States; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control / Q000821:virology; D058425:Vaccines, Virus-Like Particle / Q000276:immunology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D000956:Antigens, Viral; D015507:Drugs, Investigational; D053918:Papillomavirus Vaccines; D058425:Vaccines, Virus-Like Particle; C510352:human papillomavirus vaccine, L1 type 16, 18
keywords: Bivalent vaccine; Human papillomavirus vaccine; Immune interference; Immunogenicity; Safety; Tetravalent vaccine