After years of steady decline during the 1990s, syphilis, a sexually transmitted infection caused by the uncultivatable spirochete Treponema pallidum subsp. pallidum (TPA), has undergone a dramatic resurgence in the United States, particularly among men who have sex with men. Syphilis also poses a major threat globally with an estimated 5.6 million new cases annually and 350,000 adverse pregnancy outcomes due to mother-to-child transmission. The inability of epidemiological approaches to curtail the spread of syphilis underscores the need for a safe and effective vaccine. Our CRC proposal is based on the premise that our success identifying and topologically characterizing TPA outer membrane proteins (OMPs) translates to a roadmap for a vaccine against geographically widespread TPA strains.