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Objectives:

We have previously shown in a primary efficacy study [580299/001] and its extended follow-up phase (EFU) [580299/007] that the HPV-16/18 L1 VLP AS04 candidate vaccine is immunogenic and provides protection up to 4.5 years against HPV-16/18 incident and persistent infections and associated cytohistological outcomes (1;2). Furthermore, we have shown preliminary evidence of cross-protection against incident infections with oncogenic HPV types 31 and 45, which are not included in the vaccine (1). We report a second interim analysis of the EFU now up to 5.5 years evaluating long-term immunogenicity, vaccine efficacy, and safety.

Methods:

In the primary efficacy study 1113 women 15-25 years of age in North America and Brazil were randomized to receive 3 doses of HPV vaccine or control (Al[OH]3) on a 0, 1, 6 month schedule and evaluated for up to 27 months. During the EFU phase, 776 original participants who were seronegative for HPV-16 and HPV-18, and DNA negative for 14 high risk HPV types at entry into the primary study, were followed. HPV-16/18 antibody titers were assessed by ELISA. Cervical samples were collected at 6-month intervals and tested for HPV using PCR methods. Cytology was performed annually with colposcopy and biopsy performed according to a management algorithm.

Results:

During the EFU phase (following the primary efficacy study), ≥98% HPV-16 and HPV-18 seropositivity was maintained and substantial vaccine efficacy (VE, 95% CI) was observed against HPV-16 and/or HPV-18 end points: incident infection (98%, 89-100), 6-month persistent infection (100%, 81-100), 12-month persistent infection (100%, 54-100), and ASCUS or worse cytology (100%, 85-100). In a pooled analysis of the primary study and the EFU phase (a total of 5.5 years of follow-up), VE was 100% (62-100) against HPV-16/18 associated CIN1+ (0 vs 11 cases) and 100% (33-100) against CIN2+ (0 vs 7 cases). VE was 68% (7-91) against CIN2+ lesions independent of HPV status (5 vs 15 cases). Furthermore, we continue to observe substantial cross-protection against incident infection with non-vaccine oncogenic types HPV-45 and HPV-31. Safety data were comparable in both vaccine and placebo groups.

Conclusions:

Effective cervical cancer prevention through prophylactic HPV vaccination will be dependent on long-term and broad protection against cancer-causing HPV types. Our findings provide evidence that the HPV-16/18 L1 VLP AS04 vaccine candidate is highly efficacious against HPV-16/18 up to 5.5 years, prevents most CIN2+ lesions irrespective of HPV status, and also shows continued cross-protection against HPV-45 and HPV-31 incident infections.

(1) Harper et al. Lancet. 2006;367:1247-55.

(2) Harper et al. Lancet. 2004;364:1757-65.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA