Long-term effectiveness of the nine-valent human papillomavirus vaccine: Interim results after 12 years of follow-up in Scandinavian women

Abstract

A pivotal study in women aged 16-26 years demonstrated that the nine-valent human papillomavirus (9vHPV) vaccine was efficacious against high-grade cervical dysplasia related to the HPV types covered by the vaccine. To evaluate whether effectiveness remains above 90% for up to 14 years post-vaccination, a long-term follow-up (LTFU) extension of the study was conducted in Denmark, Norway, and Sweden (N = 2,029). Interim findings at 12 years post-vaccination are reported. Effectiveness of the vaccine was measured by comparing the percentage reduction in incidence of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia in the LTFU cohort with the expected incidence in an unvaccinated cohort. Cervical pre-cancer/cancer diagnoses were identified using national health registries. Tissue samples were obtained from national and regional biobanks for polymerase chain reaction HPV testing, and pathology diagnosis adjudication. Potential waning of vaccine effectiveness and statistical significance were assessed using a control chart method. During LTFU, there were no cases of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia over 10,396.2 person-years' follow-up in the per-protocol effectiveness population (n = 1,628). No signals indicated vaccine effectiveness decreasing below 90%. Statistically significant protection was provided by the 9vHPV vaccine through at least 10 years, with complete, although not statistically significant, effectiveness through 12 years.

Keywords: Cervical intraepithelial neoplasia; effectiveness; human papillomavirus; long-term follow-up; nine-valent human papillomavirus vaccine; vaccine.

Figure 1.

Study design. In the base study, participants received a three-dose series of the 9vHPV or qHPV vaccine at Day 1, Month 2, and Month 6, and were followed for efficacy every 6 months thereafter up to the Month 54 visit. After their last visit in the base study, participants from Scandinavian countries who received 9vHPV vaccine in the base study and provided consent continued for effectiveness follow-up in the study extension (LTFU study). Follow-up in the extension study begins for each participant after their last visit in the base study to ensure continuous follow-up between the base study and the study extension. In the study extension, follow-up for effectiveness is based on a search of national health registries; analyses of data are conducted every two years. The timing of each analysis is shown as a triangle; the timing of the current analysis is shown as an empty triangle. 9vHPV, nine-valent human papillomavirus; LTFU, long-term follow-up; qHPV, quadrivalent human papillomavirus.

Figure 2.

Control chart analysis of the effectiveness of the 9vHPV vaccine against HPV16/18/31/33/45/52/58-related CIN2, CIN3, AIS, and cervical cancer in the PPE population. The incidence of HPV-related disease was evaluated at 2-year intervals during the LTFU period and, if plotted incidences crossed the 1.83- and 2.75-sigma control limits of the control chart, an inference was made that the accumulating data were indicative of waning effectiveness. Shaded intervals indicate intervals with insufficient follow-up time to declare statistical significance. The center line indicates the expected count in each interval. 9vHPV, nine-valent human papillomavirus; AIS, adenocarcinoma in situ; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LTFU, long-term follow-up; PPE, per-protocol effectiveness.