Follow up immunogenicity of a mixed vaccination schedule with one dose of nonavalent and one dose of bivalent HPV vaccines 36 months post-vaccination among boys and girls.

BACKGROUND: Following up on previously published short-term findings, we assessed the persistence of the immune response at 36 months following mixed-HPV vaccination schedules using one nonavalent (9vHPV) dose and one bivalent (2vHPV) dose (administered interchangeably) compared to a homologous two-dose 9vHPV schedule. METHODS: Girls and boys aged 9-10 years were randomized (1:1) to receive (I) two doses of 9vHPV (n = 168 according-to-protocol (ATP)) or (II) a mixed schedule (n = 169 ATP) of 2vHPV + 9vHPV (n = 86) or 9vHPV + 2vHPV (n = 83) with a 6-month interval. The proportion of participants with detectable antibodies and geometric mean concentrations (GMCs) for HPV types 6/11/16/18/31/33/45/52/58 were measured using M9ELISA at 7 and 36 months after the first dose. RESULTS: Antibodies to HPV16 and HPV18 persisted in all 337 participants (100%) at 36 months. Antibodies to the other 9vHPV-targeted types were detectable in 94-100% of participants vaccinated with a mixed schedule versus 100% for those vaccinated with a 2-dose 9vHPV schedule. GMCs for HPV16 and HPV18 were significantly higher in those vaccinated with a mixed schedule (9vHPV + 2vHPV and 2vHPV + 9vHPV) compared to the 9vHPV + 9vHPV schedule: 184.6 (145.5-234.3) and 151.7 (121.2-189.8) vs 97.7 (83.6-114.1) for HPV16, and 70.4 (53.5-92.7) and 72.7 (57.0-92.8) vs 40.3 (34.9-46.6) for HPV18. Additionally, the 9vHPV + 2vHPV mixed schedule resulted in higher GMCs when compared to the 2vHPV + 9vHPV schedule. GMC ratios (homologous/mixed schedules) decreased for HPV types not included in the bivalent vaccine, indicating that differences observed at 7 months were reduced at 36 months. Sex-stratified analyses showed no substantial differences between boys and girls. CONCLUSION: Serological responses of mixed-HPV vaccination schedules are sustained for at least 36 months post-vaccination and comparable to a 2-dose 9vHPV schedule, for HPV16/18. These findings provide immunogenicity evidence supporting the feasibility of mixed 2-dose HPV schedules, while further research on clinical effectiveness and implementation is needed to inform policy decisions. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT02567955).