Immunogenicity and safety of a mixed vaccination schedule with one dose of nonavalent and one dose of bivalent HPV vaccine versus two doses of nonavalent vaccine - A randomized clinical trial

Vaccine. 2018 Nov 12;36(46):7017-7024. doi: 10.1016/j.vaccine.2018.09.057. Epub 2018 Oct 9.


Background: Limited data is available on the use of different HPV vaccines in the same subjects. We evaluated the immunogenicity and safety of a mixed vaccination schedule with one dose of nonavalent (9vHPV) and one dose of bivalent vaccine (2vHPV) administered in different order versus two doses of 9vHPV vaccine.

Methods: 371 girls and boys aged 9-10 years were randomized (1:1) to receive (I) two doses of 9vHPV or (II) a mixed schedule of 2vHPV + 9vHPV or 9vHPV + 2vHPV with a 6 month interval. Antibodies to HPV were tested by ELISA in blood samples collected one or six months post-first dose and one month post-second dose.

Results: Post-first dose of 9vHPV 99.4-100% of subjects were seropositive to 9 HPV types included in the vaccine. GMTs varied from 5.0 to 73.6 IU(AU)/ml depending on HPV type. Post-first dose of 2vHPV all subjects were seropositive to HPV16 and 18 (GMTs 16.7 and 11.7 IU/ml, respectively) and 50.0-76.7% were seropositive to 7 types not included in 2vHPV (GMTs varied from 0.3 to 17.5 AU/ml depending on type). Post-second dose all subjects, regardless of the study group, were seropositive to 9 HPV types included in 9vHPV. Anti-HPV16 and 18 GMTs were higher in subjects with the mixed schedule and for the other 7 HPV types higher in subjects who received two doses of 9vHPV vaccine. A higher proportion of subjects who received 2vHPV reported local or systemic adverse events than those who received 9vHPV as the first dose. Post-second dose there were no differences in reported adverse events between the two vaccines.

Conclusions: The results show the mixed HPV vaccination schedules used in this study are immunogenic and have an acceptable safety profile. Although the seroprotective threshold of antibodies remains unknown the 100% seropositivity to all 9 HPV types included in 9vHPV and the increase of GMTs observed in all study groups post-second dose administration are reassuring and suggest protection might be achieved regardless of the schedule used.

Clinical trials registration: NCT02567955.

Keywords: Bivalent vaccine; Human papillomavirus (HPV); Mixed schedule; Nonavalent vaccine.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Viral / blood
  • Child
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Drug-Related Side Effects and Adverse Reactions / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Humans
  • Immunization Schedule*
  • Male
  • Papillomavirus Infections / prevention & control*
  • Papillomavirus Vaccines / administration & dosage
  • Papillomavirus Vaccines / adverse effects*
  • Papillomavirus Vaccines / immunology*
  • Prospective Studies
  • Treatment Outcome


  • Antibodies, Viral
  • Papillomavirus Vaccines

Associated data