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J Natl Cancer Inst. 2017 Jan 28;109(7). doi: 10.1093/jnci/djw300. Print 2017 Jan.

Evaluation of Type Replacement Following HPV16/18 Vaccination: Pooled Analysis of Two Randomized Trials.

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Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (JET, ARK, MS, AH); GSK Vaccines, Wavre, Belgium (FS, DB); National Institute for Health and Welfare, Oulu, Finland (MM); Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica (PG); Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, CIBER-ESP, L'Hospitalet de Llobregat, Spain (XC); Department of Gynecology and Obstetrics, Federal University of Paraná, Infectious Diseases in Gynecology and Obstetrics Sector/Clinics Hospital, Curitiba, Brazil (NSdC); Department of Microbiology and Infectious Diseases, Royal Women's Hospital, Parkville, Victoria, Australia (SMG); Murdoch Childrens Research Institute, Parkville, Victoria, Australia (SMG); Department of Obstetrics and Gynaecology, University of Melbourne, Victoria, Parkville, Australia (SMG); Geisel School of Medicine at Dartmouth, Hanover, NH (DMH); GSK Vaccines, Bangalore, India (NK); Berner Heerweg 157, Hamburg, Germany (KP); Department of Gynaecology, University Hospital KU Leuven Gasthuisberg, Leuven, Belgium (WAJP); Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, San José, Costa Rica (CP, ACR, RH); DDL Diagnostic Laboratory, Rijswijk, the Netherlands (WQ); Information Management Systems, Rockville, MD (JS); Vaccines Trials Group, Telethon Institute for Child Health Research, Perth, WA, and Sydney University Discipline of Paediatrics and Child Health, Children's Hospital Westmead, Sydney, NSW, Australia (SRS); Department of Gynecology, Oncology Division-CAISM, State University of Campinas, Campinas, Brazil (JCT); University of Tampere, School of Public Health, Tampere, Finland (ML).



Current HPV vaccines do not protect against all oncogenic HPV types. Following vaccination, type replacement may occur, especially if different HPV types competitively interact during natural infection. Because of their common route of transmission, it is difficult to assess type interactions in observational studies. Our aim was to evaluate type replacement in the setting of HPV vaccine randomized controlled trials (RCTs).


Data were pooled from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT001226810)-two large-scale, double-blind RCTs of the HPV-16/18 AS04-adjuvanted vaccine-to compare cumulative incidence of nonprotected HPV infections across trial arms after four years. Negative rate difference estimates (rate in control minus vaccine arm) were interpreted as evidence of replacement if the associated 95% confidence interval excluded zero. All statistical tests were two-sided.


After applying relevant exclusion criteria, 21 596 women were included in our analysis (HPV arm = 10 750; control arm = 10 846). Incidence rates (per 1000 infection-years) were lower in the HPV arm than in the control arm for grouped nonprotected oncogenic types (rate difference = 1.6, 95% confidence interval [CI] = 0.9 to 2.3) and oncogenic/nononcogenic types (rate difference = 0.2, 95% CI = -0.3 to 0.7). Focusing on individual HPV types separately, no deleterious effect was observed. In contrast, a statistically significant protective effect (positive rate difference and 95% CI excluded zero) was observed against oncogenic HPV types 35, 52, 58, and 68/73, as well as nononcogenic types 6 and 70.


HPV type replacement does not occur among vaccinated individuals within four years and is unlikely to occur in vaccinated populations.

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