A review of clinical trials of human papillomavirus prophylactic vaccines

Abstract

End of study analyses of the phase III trials of prophylactic human papillomavirus (HPV) virus-like particle (VLP) vaccines in young women are now largely completed. Two distinct vaccines were evaluated, Gardasil(®) (Merck & Co., Whitehouse Station, NJ USA) a quadrivalent vaccine containing VLPs of types 6, 11, 16 and 18 and Cervarix(®) (GlaxoSmithKline Biologicals, Rixensart, Belgium), a bivalent vaccine containing VLPs of types 16 and 18. Both vaccines exhibited excellent safety and immunogenicity profiles. The vaccines also demonstrated remarkably high and similar efficacy against the vaccine-targeted types for a range of cervical endpoints from persistent infection to cervical intraepithelial neoplasia grade 3 (CIN3) in women naïve to the corresponding type at the time of vaccination. However, protection from incident infection or disease from non-vaccine types was restricted, and the vaccines had no effect on prevalent infection or disease. Gardasil(®) also demonstrated strong protection against genital warts and vulvar/vaginal neoplasia associated with the vaccine types. In other trials, Gardasil(®) protected mid-adult women from incident infection and CIN caused by the vaccine types and protected men for incident infection, genital warts and anal intraepithelial neoplasia by the vaccine types. Cervarix(®) protected against vaccine-targeted anal infections in women in an end of study evaluation. For practical reasons, efficacy studies have not been conducted in the primary target populations of current vaccination programs, adolescent girls and boys. However, immunogenicity bridging studies demonstrating excellent safety and strong immune responses in adolescence, coupled with the documentation of durable antibody responses and protection in young adults, leads to an optimistic projection of the effectiveness of the vaccines in adolescent vaccination programs. Taken together, the excellent clinical trial results strongly support the potential of the vaccines as high value public health interventions and justify their widespread implementation to prevent anogenital HPV infections and their associated neoplasia. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Figure 1

Rate reduction and vaccine efficacy are time dependent variables. Time-to-event curves for acquisition of HPV6/11/16/18-related CIN3/AIS in Gardasil^® (Merck & Co., Whitehouse Station, NJ USA) and placebo recipients in the ITT cohort. AIS: Adenocarcinoma in situ; CIN3: Grade 3 cervical intraepithelial neoplasia; ITT: Intention-to-Treat. Taken with permission from reference [21].

Figure 2

Relationships among VLP-specific antibodies detected in ELISA, cLIA, and neutralization assays. Shown is a schematic representation of the constellation of antibodies detected in VLP antibody assays. Red = all VLP antibodies induced; Orange = ELISA detected; Grey = in vitro neutralizing assay detected; Light grey = cLIA detected. cLIA: Competitive Luminex^® immunoassay; VLP antibodies: Virus-like particle-specific antibodies. Adapted from reference [53].

Figure 3

Durability of antibody responses to Cervarix^® in young women. Orange Bars = GMTs in Cervarix^® (GlaxoSmithKline Biologicals, Rixensart, Belgium) vaccinees. Red bars = GMTs in control vaccinees. Numbers above bars indicate the percent seropositive at the indicated month since vaccination. CI: Confidence interval; cLIA: Competitive Luminex^® immunoassay; ED50: Serum dilution causing a 50% reduction in secreted alkaline phosphatase activity compared with a control without serum; ELU: ELISA units; GMT: Geometric mean titer; VLP: Virus-like particle. Taken with permission from reference [31].

Figure 4

Durability of HPV16 antibody responses to Gardasil^® in young women. cLIA: Competitive Luminex^® immunoassay geometric mean titer; GMT: Geometric mean titer; mMU: milliMerck Units. PCR: Polymerase chain reaction; PPI: Per Protocol Immunogenicity cohort. * Gardasil^® (Merck & Co., Whitehouse Station, NJ USA) vaccination (0, 2, 6, and 60 months). Taken with permission from reference [61].