Design of a large outcome trial for a multivalent human papillomavirus L1 virus-like particle vaccine.

Background: The 9-valent human papillomavirus (HPV) (9vHPV) vaccine targets the four HPV types (6/11/16/18) covered by the licensed quadrivalent HPV (qHPV) vaccine and five additional types (31/33/45/52/58). A large outcome trial of 9vHPV vaccine was conducted.

Methods: An active control (qHPV vaccine) was used because a placebo is not ethically acceptable. Since qHPV vaccine is (and 9vHPV vaccine was anticipated to be) highly efficacious against HPV 6/11/16/18, low incidence of HPV 6/11/16/18-associated disease was expected. Consequently, an efficacy comparison of 9vHPV versus qHPV vaccine for HPV 6/11/16/18 would have been prohibitively large in size. Moreover, no minimum antibody level predicting protection against infection or disease is defined for HPV vaccination. As an alternative approach, the two vaccines were compared using immunogenicity bridging for HPV 6/11/16/18 and clinical efficacy for HPV 31/33/45/52/58.

Results: The two co-primary objectives were to demonstrate: (1) non-inferior anti-HPV 6/11/16/18 antibody response; and (2) superior efficacy in HPV 31/33/45/52/58-related clinical outcome, for 9vHPV vaccine versus qHPV vaccine. For HPV 6/11/16/18, supportive analyses included a non-inferiority assessment of the percent risk reduction (compared to historical placebo) for 9vHPV versus qHPV vaccine.

Conclusions: A Phase III study of 9vHPV vaccine was successfully implemented. Experience from this study design may be applicable when developing a multivalent vaccine covering the same serotypes as an existing vaccine plus additional serotypes and there is no immune correlate of protection. Also, this study established that efficacy of a new HPV vaccine may be demonstrated using immunogenicity endpoints, which may open new options in HPV vaccine development.