We are proposing to conduct a trial in Costa Rica to formally evaluate one- and two-dose vaccination, and to estimate the public health benefit of one- and two-dose schedules versus none. As a primary aim, we will focus on the prevention of new, persistent infection by HPV types 16 and 18, because they account for the largest public health burden. The trial will also evaluate protection against the other cancer- and genital wart-causing HPV types, while documenting infection by non-vaccine HPV types to verify continued exposure among women in the trial. In addition to the evaluation of efficacy against HPV infection, we propose to monitor participants’ immunological response to vaccination, to demonstrate robust, stable, and durable antibody responses following one- and two-dose vaccination, and to enable studies to compare immune responses induced by the two vaccines, which contain different adjuvants. This effort will establish the foundation for immunobridging studies that could accelerate future vaccine developments in this area.