GARDASIL does not prevent infection with the HPV types not contained in the vaccine. Cases of disease due to non-vaccine types were observed among recipients of GARDASIL and placebo in Phase II and Phase III efficacy studies.

Among cases of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types in subjects in the general population who received GARDASIL, 79% occurred in subjects who had an abnormal Pap test at Day 1 and/or who were positive (PCR positive and/or seropositive) to HPV 6, 11, 16, and/or 18 at Day 1.

An interim analysis of the general population impact for GARDASIL was performed from studies 007, 013, and 015 that had a median duration of follow-up of 1.9 years. GARDASIL reduced the overall rate of CIN 2/3 or AIS caused by vaccine or non-vaccine HPV types by 12.2% (95% CI: -3.2%, 25.3%), compared with placebo.

An analysis of overall population impact for the HPV 16 L1 VLP vaccine was conducted from study 005 that had a median duration of follow-up of 3.9 years. The HPV 16 L1 VLP vaccine reduced the overall incidence of CIN 2/3 caused by vaccine or non-vaccine HPV types by 32.7% (95% CI: -34.7%, 67.3%) through a median duration of follow-up of 1.9 years (fixed case analysis) and by 45.3% (95% CI: 10.9%, 67.1%), through a median duration of follow-up of 3.9 years (end of study).

GARDASIL reduced the incidence of definitive therapy (e.g., loop electrosurgical excision procedure, laser conization, cold knife conization) by 16.5% (95% CI: 2.9%, 28.2%), and surgery to excise external genital lesions by 26.5% (95% CI: 3.6%, 44.2%), compared with placebo for all HPV-related diseases. These analyses were performed in the general population of women which includes women regardless of baseline HPV PCR status or serostatus. GARDASIL has not been shown to protect against the diseases caused by all HPV types and will not treat existing disease caused by the HPV types contained in the vaccine. The overall efficacy of GARDASIL, described above, will depend on the baseline prevalence of HPV infection related to vaccine types in the population vaccinated and the incidence of HPV infection due to types not included in the vaccine.

Because there were few disease cases in subjects naïve (PCR negative and seronegative) to vaccine HPV types at baseline in the group that received GARDASIL, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical disease caused by HPV 6, 11, 16, and/or 18.

The immunogenicity of GARDASIL was assessed in 8915 women (GARDASIL N = 4666; placebo N = 4249) 18 to 26 years of age and female adolescents 9 to 17 years of age (GARDASIL N = 1471; placebo N = 583).

Type-specific competitive immunoassays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not appropriate.

The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and PCR negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month Postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine.

Overall, 99.8%, 99.8%, 99.8%, and 99.5% of girls and women who received GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive, respectively, by 1 month Postdose 3 across all age groups tested. Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs peaked at Month 7. GMTs declined through Month 24 and then stabilized through Month 36 at levels above baseline (Table 3). The duration of immunity following a complete schedule of immunization with GARDASIL has not been established.

Table 3
Summary of Anti-HPV cLIA Geometric Mean Titers in the PPI* Population

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