Effects of varying antigens and adjuvant systems on the immunogenicity and safety of investigational tetravalent human oncogenic papillomavirus vaccines: results from two randomized trials

Vaccine. 2014 Jun 17;32(29):3694-705. doi: 10.1016/j.vaccine.2014.03.040. Epub 2014 Mar 25.

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.

Keywords: Bivalent vaccine; Human papillomavirus vaccine; Immune interference; Immunogenicity; Safety; Tetravalent vaccine.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage*
  • Adolescent
  • Adult
  • Antibodies, Viral / blood
  • Antibody Formation*
  • Antigens, Viral / immunology
  • B-Lymphocytes / immunology
  • Belgium
  • Dose-Response Relationship, Immunologic
  • Double-Blind Method
  • Drugs, Investigational / therapeutic use
  • Female
  • Human papillomavirus 16
  • Human papillomavirus 18
  • Humans
  • Immunologic Memory
  • Papillomavirus Infections / prevention & control*
  • Papillomavirus Vaccines / immunology
  • Papillomavirus Vaccines / therapeutic use*
  • United States
  • Uterine Cervical Neoplasms / prevention & control
  • Uterine Cervical Neoplasms / virology
  • Vaccines, Virus-Like Particle / immunology
  • Vaccines, Virus-Like Particle / therapeutic use
  • Young Adult

Substances

  • Adjuvants, Immunologic
  • Antibodies, Viral
  • Antigens, Viral
  • Drugs, Investigational
  • Papillomavirus Vaccines
  • Vaccines, Virus-Like Particle
  • human papillomavirus vaccine, L1 type 16, 18

Associated data

  • ClinicalTrials.gov/NCT00231413
  • ClinicalTrials.gov/NCT00478621