Prospects for phase III-IVHPV vaccination trials in the Nordic countries and in Estonia

Background: oncogenic, i.e. high risk human papillomavirus (hrHPV) types ar e the major cause of invasive cervical cancer (ICC). Putatively licensable vaccines against the hrHPVs have been developed and are approaching clinica l phase III trials that use persistent HPV infection as end point. Direct e xtension of the phase III trials towards long-term end points (ICC and its immediate precursors: carcinoma in situ and severe dysplasia, i.e. cervical intraepithelial neoplasia grade III, CINIII) is important, to avoid early contamination of the target population by opportunistic use of licensed HPV vaccines. Country-wide registration on population and health events in a s table population of 25 million make Estonia and the Nordic countries a uniq ue venue for long-term evaluation of cervical cancer control measures. Mass -screening programmes exist in all Nordic countries, but not in Estonia. Ai m: design of phase III-IV trials for evaluation of protection against ICC a nd CINIII by preventive HPV vaccines based on cancer registry follow-up. Re sults: in the Nordic countries, population based randomisation of all 15-ye ar-old women to the vaccination (vaccine and placebo) and reference cohorts entering conventional Pap-smear screening after a clinical phase III trial would assure comparability of the cohorts. Enrollment of 10 094 vaccinees + 10 094 placebo vaccinees + 30 282 other hrHPV negative women without vacc ination at the age of 16 would give 80% power for the demonstration of 70% vaccine efficacy (VE) against ICC in 20 years by cancer registry follow-up. On the other hand, vaccination of 8303 Estonian hrHPV negative women among the entire 15-year-old female birth cohort (about 10 000 women) with an al ready licensed HPV vaccine would enable demonstration of 70% VE against ICC by 20 years of registry follow-up of these and comparable 16 606 women ide ntified among the 16-19-year-old birth cohorts. Conclusions: evaluation of the protective effect of an HPV vaccine against ICC is possible both in cou ntries with or without mass-screening. The effects of vaccination on spread of different HPVs in the population would need to be monitored, especially in Estonia. Ethical aspects, cost-benefit evaluation and comparisons with other new means of cervical cancer control warrant further investigation. ( C) 2000 Elsevier Science B.V. All rights reserved.