Project Abstract - A Global Syphilis Vaccine Targeting Outer Membrane Proteins of Treponema pallidum The scientific premise of this CRC proposal rests upon our three decades of work defining the molecular architecture of the outer membrane (OM) of Treponema pallidum subsp. pallidum (TPA), coupled with our successes combining bioinformatics, biophysical techniques, and localization methods with live TPA to topologically characterize TPA outer membrane proteins (OMPs) and define the syphilis spirochete’s ‘OMPeome’--its repertoire of OMPs. The central hypothesis is that the principal targets for a syphilis vaccine reside within TPA’s repertoire of rare OMPs. The current application builds upon the work of the current CRC U19 grant awarded to the two mPIs of this proposal (Moody and Radolf). This proposal brings together the expertise in spirochetology (Univ. of Connecticut) and vaccine development (Duke Human Vaccine Institute) to develop vaccines targeting TPA OMPs. The overarching hypothesis is that vaccines targeting TPA OMPs will elicit antibodies that can recognize intact treponemes, provide protection in animal models, and be producible using Good Manufacturing Practices (GMP) at the scale needed to perform a phase 1 clinical trial. This CRC proposal will focus on two main aims: Aim 1) Selection of an ECL vaccinogen panel and production of ECL mAbs with functional activity, with subaim 1.1 of finalizing the ECL vaccinogen panel through robust preclinical animal studies (Univ. of Connecticut) and subaim 1.2 of producing ECL mAbs with functional activity (Duke Human Vaccine Institute), and Aim 2) Selection and optimization of an ECL vaccine platform, with subaim 2.1 of generating functional ECL-specific Abs using mRNA-LNP immunogens (Univ. of Pennsylvania), and subaim 2.2 of generating functional ECL-specific Abs using SpyVLPs (Univ. of Connecticut), to be compared in animal protection studies in subaim2.3. Successful completion of the aims of this CRC U01 proposal will provide the preclinical data needed for an IND submission to the FDA, complete the process development for GMP production, and will result in the full design of a GMP campaign strategy and a plan for toxicology testing.