Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates

Abstract

Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naïve subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies. We applied previously described methods to simulate these HPV-naïve subcohorts within the Costa Rica HPV16/18 Vaccine Trial and assessed how these criteria affect the estimation of VE. We applied 2 enzyme-linked immunosorbent assay (ELISA) thresholds for HPV16 and HPV18 seropositivity (8 and 7 ELISA units/mL, respectively, for PATRICIA; 54 and 65 ELISA units/mL, respectively, for FUTURE I/II (to approximate the competitive Luminex immunoassay)) and 2 criteria for HPV DNA positivity (12 oncogenic HPV types, plus HPV66 and 68/73 for PATRICIA; or plus HPV6 and 11 for FUTURE I/II). VE was computed in the 2 naïve subcohorts. Using the FUTURE I/II and PATRICIA criteria, VE estimates against cervical intraepithelial neoplasia grade 2 or worse, regardless of HPV type, were 69.0% (95% confidence interval: 40.3%, 84.9%) and 80.8% (95% confidence interval: 52.6%, 93.5%), respectively (P = 0.1). Although the application of FUTURE I/II criteria to our cohort resulted in the inclusion of more sexually experienced women, methodological differences did not fully explain the VE differences.

Trial registration: ClinicalTrials.gov NCT00128661.

Keywords: human papillomavirus; methodological differences; naïve population; vaccine efficacy.

Figure 1.

CONSORT diagram for naïve cohort 1 in the Costa Rica HPV16/18 Vaccine Trial, 2004–2005. Women were excluded on the basis of 1) human papillomavirus (HPV) type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, or 68/73 DNA positivity and 2) HPV16 or HPV18 seropositivity defined by standard enzyme-linked immunosorbent assay (ELISA) cutoffs of 8 ELISA units/mL or 7 ELISA units/mL, respectively.

Figure 2.

CONSORT diagram for naïve cohort 2 in the Costa Rica HPV16/18 Vaccine Trial, 2004–2005. Women were excluded on the basis of 1) human papillomavirus (HPV) type 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, or 59 DNA positivity and 2) HPV16 or HPV18 seropositivity, defined by modified enzyme-linked immunosorbent assay (ELISA) cutoffs of 54 ELISA units/mL or 65 ELISA units/mL, respectively.