Pierre Van Damme1, Geert Leroux-Roels2, Philippe Simon3, Jean-Michel Foidart4, Gilbert Donders5, Karel Hoppenbrouwers6, Myron Levin7, Fabian Tibaldi8, Sylviane Poncelet9, Philippe Moris10, Francis Dessy11, Sandra L Giannini12, Dominique Descamps13, Gary Dubin14. 1. 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. 2. Center for Vaccinology, Ghent University and Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: geert.lerouxroels@ugent.be. 3. Service de Gynécologie Obstétrique, Hôpital Erasme, Route de Lennik 808, 1070 Bruxelles, Belgium. Electronic address: philippe.simon@erasme.ulb.ac.be. 4. CHR Citadelle, Service de Gynécologie Obstétrique, Boulevard du 12ieme de Ligne 1, 4000 Liège, Belgium. Electronic address: jmfoidart@ulg.ac.be. 5. Gynaecologie, Heilig Hartziekenhuis, Kliniekstraat 45, 3300 Tienen, Belgium. Electronic address: gilbert.donders@femicare.net. 6. KULeuven, Jeugdgezondheidszorg, Kapucijnvoer 35/1, 3000 Leuven, Belgium. Electronic address: karel.hoppenbrouwers@med.kuleuven.be. 7. University of Colorado School of Medicine, Building 401, 1784 Racine St., Aurora, CO 80045, USA. Electronic address: Myron.Levin@ucdenver.edu. 8. GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: fabian.s.tibaldi@gsk.com. 9. GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: sylviane.poncelet@gsk.com. 10. GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: philippe.moris@gsk.com. 11. GlaxoSmithKline Vaccines, Avenue Fleming 20, 1300 Wavre, Belgium. Electronic address: francis.dessy@gsk.com. 12. GlaxoSmithKline Vaccines, Rue de l'Institut 89, 1330 Rixensart, Belgium. Electronic address: sandra.giannini@gsk.com. 13. GlaxoSmithKline Vaccines, Avenue Fleming 20, 1300 Wavre, Belgium. Electronic address: dominique.descamps@gsk.com. 14. GlaxoSmithKline SA, 2301 Renaissance Boulevard, RN0220, King of Prussia, PA 19406, USA. Electronic address: Gary.O.Dubin@gsk.com.
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.
RCT Entities:
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.
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