There are approximately 7.5 million Americans infected with a documented new human papillomavirus (HPV) every year. Rates of persistent HPV, cervical intraepithelial neoplasia, and cervical cancer are especially high in Bronx, NY. The early success of the HPV L1-based vaccines is encouraging, but when used alone, and with limited early adoption, will not eliminate HPV infections, abnormal Pap tests, or prevent all cervical cancers. Several vaginal microbicides have been tested for efficacy against HIV. However, there are no clinical trials to date that have been conducted to primarily determine efficacy against other sexually transmitted infections (STI). This project builds on in vitro and animal model studies demonstrating that carageenans provide protection against human papillomavirus (HPV) infection at concentrations that are 1000-fold less than those required to inhibit HIV. A recently completed Phase III efficacy trial testing the ability of Carraguard to prevent HIV infection in women revealed that Carraguard is safe and that the frequency of HIV infection was lower in the Carraguard arm than in the placebo group. These findings provide the framework for proposing a trial to test Carraguard efficacy against HPV. Two hundred Bronx women will be enrolled in an expanded Phase II randomized double-blind placebo controlled study to evaluate the efficacy of Carraguard gel in preventing incident HPV infections over a one year period. This trial will provide the opportunity to build on translational laboratory studies designed to enhance our knowledge of efficacy and mechanism of activity against HPV as well as mucosal safety. Female genital tract secretions will be collected by cervicovaginal lavage (CVL) at different times post-application and spiked with HPV pseudovirions in the absence and presence of seminal plasma to evaluate the antiviral activity of Carraguard ex vivo. We will also further explore the safety of Carraguard by collecting CVL and vaginal swabs following repeated application to determine if Carraguard induces changes in the genital tract mucosal environment or alters vaginal flora. This proposed project will be based at the Albert Einstein College of Medicine (AECOM) and will include its primary affiliated University Hospital, Montefiore Medical Center, and Jacobi Medical Center, a New York public hospital and long-time affiliate of AECOM. The project will also include the Population Council, a nonprofit, non-governmental research organization located in Manhattan. This partnership with Population Council reflects a common vision to aggressively pursue cutting edge STI prevention strategies that include microbicides for HPV prevention. If Carraguard proves active against HPV, this would support further development of Carraguard as a promising formulation vehicle, to which potent anti-HIV agents could also be potentially added to provide an effective combination microbicide.