Long-term effectiveness of the nine-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up

Abstract

A long-term follow-up (LTFU) of the nine-valent human papillomavirus (9vHPV) vaccine efficacy study in young women aged 16-26 years was initiated to evaluate if vaccine effectiveness for up to 14 years post-vaccination will remain above 90%. Vaccine effectiveness is measured as percent reduction in the incidence of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia in the LTFU cohort relative to expected incidence in a similar unvaccinated cohort. We report an interim analysis 8 years post-vaccination. Overall, 2029 participants from Denmark, Norway, and Sweden who received the 9vHPV vaccine during the clinical efficacy study continued into the LTFU study. National health registries were used to identify screening attendance and cervical pre-cancer/cancer diagnoses. Tissue samples were retrieved for HPV testing by PCR and pathology diagnosis adjudication. A control chart method was used to detect signals indicative of vaccine effectiveness waning below 90%. No new cases of HPV16/18/31/33/45/52/58-related high-grade cervical dysplasia were observed during the LTFU study period over 4084.2 person-years' follow-up (per-protocol effectiveness population; n = 1448). Thus, there were no signals indicative of vaccine effectiveness waning below 90%. These observations show that the 9vHPV vaccine provides continued statistically significant protection through at least 6 years, with indications of continued effectiveness through 8 years.

Trial registration: Clinicaltrials.gov: NCT00543543, NCT02653118.

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 the 9vHPV vaccine or qHPV vaccine (control) 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 in the base study and provided consent continued for effectiveness follow-up in the study extension (LTFU study). Follow-up in the study extension 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 2 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