A study of the minimum number of doses needed to confer durable protection could provide seminal evidence to justify changing the current vaccine recommendation from two to one dose for adolescents. Therefore, 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. More specifically, we will conduct a four-arm trial of 20,000 12-to-16-year-old girls randomized, in two stages, to receive one or two doses of the Merck nonavalent (Gardasil-9) or GlaxoSmithKline Biologicals bivalent (Cervarix) HPV vaccines and to be followed initially for four years, to formally evaluate the non-inferiority of one versus two doses of each of these two vaccines. This trial will be complemented by an epidemiological HPV survey (followed by vaccination) to estimate the public health benefit of reduced-dosage vaccination versus none. As a primary endpoint, 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 trial participants.