ABSTRACT The goal of our STI CRC U19 is to use knowledge acquired over decades of research to develop an effective vaccine for syphilis. Two necessary components for the development of a syphilis vaccine are i) the identification of genetic variants for selected vaccine candidates in the circulating pathogen population to inform vaccine development, and ii) the isolation of modern syphilis strains, that best reflect the genetic background and virulence characteristics of circulating pathogens and that can be used for animal challenge following immunization experiments. These are the goals of the Genomics and Isolation Core. Over the three years of activity of this Core, we will use biological samples recently collected from syphilis- infected patients to extract and enrich for Treponema pallidum DNA, and perform next-generation whole genome sequencing of several hundred genomes of the syphilis agent. Such samples, collected from the geographically diverse locations, will provide a deeper understanding of the antigenic variability resulting from differences in the genes encoding our selected vaccine candidates. Additionally, we will isolate modern treponemal strains from biological samples (primary or secondary lesion exudates) collected from early syphilis patients to provide alternatives to historical syphilis isolates for animal challenge experiments. The work we will conduct in this Genomics and Isolation Core will be a critical component of this outstanding effort to develop a syphilis vaccine.