A 12-Year Follow-up on the Long-Term Effectiveness of the Quadrivalent Human Papillomavirus Vaccine in 4 Nordic Countries
Dani Odenthal, Pharm.D, Walgreens/Bethesda Family Medicine Clinic
Background: The quadrivalent human papillomavirus vaccine (qHPV), GARDASIL®, was approved in the United States in 2006 for administration to females aged 9-26 years and was subsequently approved for administration to males aged 9-26 years. This 3-dose series vaccine is indicated for the prevention of human papillomavirus (HPV) types 6, 11, 16, and 18 related cervical cancer and precancerous lesions of the vulvar, vaginal, and anal areas, and genital warts.
Purpose/Objective: The primary objective of this study was to assess the long-term effectiveness of qHPV vaccine in Nordic women vaccinated at age 16-23 years and followed for up to 14 years post-vaccination. This assessment was done by monitoring the combined incidence of cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and cervical cancer related to HPV type 16 or 18. A secondary objective included assessing the long-term effectiveness of the qHPV vaccine against vulvar and vaginal cancer.
Study Design: Base Study: The base study, FUTURE II, was a randomized, double blind, placebo-controlled clinical trial that enrolled 12,167 women from 13 countries covering four continents. Participants who were not pregnant, had no abnormal Pap tests, and had a lifetime number of no more than four sexual partners were eligible for enrollment in the base study. These participants were followed for four years.
Long-Term Follow-up (LTFU) Study: This study is an ongoing 10-year extension of the 4-year base study. Only women who received the 3-dose series qHPV vaccine in the base study (n=2,650) were included in the LTFU. Vaccine effectiveness was estimated by comparing the observed incidence with the expected incidence of HPV type 16/18-related CIN2 or worse (CIN2+) via an unvaccinated cohort using historical registry data from the same region. From this historical data, it was found that the incidence of HPV type 16/18-related CIN2+ was estimated to be 0.287 per 100 person-years in unvaccinated women. An adapted 1-sided c chart was used to monitor the incidence rate of HPV 16/18-related CIN2+ in the LTFU study participants over a 12-year period. Based on the estimated historical rate of HPV 16/18-related CIN2+, the vaccine was assumed to have 90% effectiveness. This chart was used to detect any decrease in vaccine effectiveness below 90%.
Results: There were 2,084 evaluated participants, contributing 13,794.9 person-years of follow-up since day 1 of the base study. There were no observed cases of HPV 16/18-related CIN2+. If vaccine efficacy was maintained at 90%, three cases were expected based on the 13,794.9 person-years of follow-up time accrued. Based on the current available data, the qHPV vaccine has continued to be effective at least 10 years post-vaccination. The same pattern was seen in the interval up to 12 years; however, there is insufficient follow-up time in the 10-12 year interval to make a conclusive claim of effectiveness beyond 10 years at this time.
Conclusion: In this LTFU study, the qHPV vaccine is effective against HPV16/18 CIN2+ through at least 10 years after vaccination of women aged 16-23 years with a trend toward 12 years of protection. The results of this study are important because they suggest that the current 3-dose regimen in young women is sufficient to achieve long-term effectiveness; therefore, there is no need for an additional dose of the qHPV vaccine. Future reports will assess effectiveness of up to 14 years or more.
Key Points: The 3-dose series qHPV vaccine shows at least 10 years of protection in women, with a trend for continued protection through 12 years of follow-up. Even though the guidelines regarding the HPV vaccination schedule have been updated, and a new HPV vaccine has been created with more strain coverage since this study was started, it is still important to see the long lasting protection that the quadrivalent vaccine has provided.
Kjaer SK, Nygård M, Dillner J, et al. A 12-year follow-up on the long-term effectiveness of the quadrivalent human papillomavirus vaccine in 4 nordic countries. Clin Infect Dis. 2018;66(3):339-345. doi:10.1093/cid/cix797.