title: Prospects for phase III-IV HPV vaccination trials in the Nordic countries and in Estonia.
abstract: BACKGROUND
  oncogenic, i.e. high risk human papillomavirus (hrHPV) types are the major cause of invasive cervical cancer (ICC). Putatively licensable vaccines against the hrHPVs have been developed and are approaching clinical phase III trials that use persistent HPV infection as end point. Direct extension 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 stable population of 25 million make Estonia and the Nordic countries a unique venue for long-term evaluation of cervical cancer control measures. Mass-screening programmes exist in all Nordic countries, but not in Estonia.
  
  
  OBJECTIVE
  design of phase III-IV trials for evaluation of protection against ICC and CINIII by preventive HPV vaccines based on cancer registry follow-up.
  
  
  RESULTS
  in the Nordic countries, population based randomisation of all 15-year-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 10094 vaccinees +10094 placebo vaccinees +30282 other hrHPV negative women without vaccination 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 10000 women) with an already licensed HPV vaccine would enable demonstration of 70% VE against ICC by 20 years of registry follow-up of these and comparable 16606 women identified among the 16-19-year-old birth cohorts.
  
  
  CONCLUSIONS
  evaluation of the protective effect of an HPV vaccine against ICC is possible both in countries 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.
authors.affiliation: National Public Health Institute, Mannerheimintie 166, 00300, Helsinki, Finland. llmale@uta.fi
authors.forename: M
authors.initials: M
authors.lastname: Lehtinen
authors.forename: M
authors.initials: M
authors.lastname: Kibur
authors.forename: T
authors.initials: T
authors.lastname: Luostarinen
authors.forename: A
authors.initials: A
authors.lastname: Anttila
authors.forename: E
authors.initials: E
authors.lastname: Pukkala
mesh_terms: D000293:Adolescent; D000328:Adult; D004957:Estonia / Q000453:epidemiology; D005240:Feasibility Studies; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D015994:Incidence; D008403:Mass Screening; D027383:Papillomaviridae / Q000276:immunology*; D030361:Papillomavirus Infections / Q000517:prevention & control*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000639:trends*; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D014412:Tumor Virus Infections / Q000517:prevention & control*; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D014765:Viral Vaccines
chemical_list: D014765:Viral Vaccines