A retrospective review of patients requiring outreach for syphilis results after emergency department (ED) screening showed that adding a chart flag to address results at return ED visits for patients otherwise unable to be contacted resulted in a 76.6% contact rate and 93.6% linkage to care among those needing treatment.

Although long-term in vitro cultivation of the syphilis agent, Treponema pallidum subspecies pallidum, was introduced less than a decade ago, it has revolutionized and accelerated research with this difficult pathogen. Moreover, it is allowing for the exploration of topics that could not easily be pursued when propagation in the rabbit model was the only possible method for the expansion of treponemes. This report, based on talks presented at the Shanghai International Syphilis Symposium 2025, provides an overview of how in vitro cultivation is currently being applied to syphilis research.

In the last decade, we have witnessed outstanding scientific advances towards the development of a globally efficacious syphilis vaccine. This manuscript summarizes information presented at the Shanghai International Syphilis Symposium (October 20-22, 2025, Shanghai, China) during the Vaccine Development session. Dr. Lorenzo Giacani (University of Washington) moderated the session. Dr. Justin Radolf (UConn Health) summarized key historical research findings that inform modern vaccine development, emphasizing how protective immunity was demonstrated in the early days of syphilis vaccine research and attributed to antibodies. Drs. Caroline Cameron (University of Victoria), Melissa Caimano (UConn Health), and Feijun Zhao (University of South China) discussed their research relating to antigen selection, identification of potentially protective B cell epitopes, results of immunization/challenge experiments, vaccine delivery platforms, and manufacturing requirements, with particular emphasis on the development of chimeric vaccine candidates. While challenges remain, the application of high-throughput immunological, proteomic, and genomic techniques discussed here has revealed surface-exposed epitopes of TPA outer membrane proteins with promising, but as yet unproven, vaccine potential. Multiple vaccine designs have emerged as options to efficiently and effectively package these epitopes in chimeric structures and platforms that can meet manufacturing standards and requirements. Efforts are also ongoing to identify and procure clinically approved adjuvants to be delivered alongside vaccine candidates.

Ethical abuses related to syphilis research have led to significant barriers to implementation of syphilis clinical trials. Insights from an expert meeting included ways to actively involve participants in clinical research, considerations for community engagement, and strategies to enhance clinical syphilis research.

Syphilis rates among men who have sex with men have risen sharply worldwide, reflecting evolving sexual networks, persistent gaps in screening and care, and behavioral changes that have accompanied the broader uptake of HIV preexposure prophylaxis. At the same time, a new generation of biomedical tools, such as doxycycline postexposure prophylaxis and rapid point-of-care diagnostics, are reshaping prevention. However, implementation has been inconsistent across programs and jurisdictions, and important challenges remain in access, effectiveness, and sustainability. This narrative review synthesizes current evidence on innovative syphilis screening and prevention strategies among men who have sex with men, highlighting both promising interventions and critical limitations. We emphasize doxycycline postexposure prophylaxis, point-of-care testing, self-testing, and digital health innovations for their potential to extend reach to underserved populations and address structural barriers to care and argue that durable control of the epidemic will require equity-focused, multidisciplinary strategies integrating clinical, public health, and community-based efforts.

For more than 70 years, penicillin has remained the cornerstone of treatment for syphilis. While penicillin remains highly effective, there is a pressing need to develop new therapeutic options driven both by ongoing challenges in the supply of benzathine-benzylpenicillin G (BPG) and the need for therapeutics that are more suitable for use in key populations such as pregnant women and infants. Our understanding of syphilis treatment was traditionally based on studies in the rabbit model, with an absence of robust human randomized control trial data. In the last decade, the emergence of the culture model has allowed a comprehensive assessment of a wide range of alternative antibiotics, and there are now a number of phase 2 and phase 3 trials of new therapeutics planned or in progress. Despite this, trials of novel agents for syphilis continue to face a number of major challenges. Progress remains limited by our reliance on indirect diagnostic methods, the need for agents to achieve adequate concentrations in the central nervous system, and for drugs to be suitable for use in pregnancy and infants. Overcoming these challenges requires multidisciplinary research incorporating basic science, pharmacokinetics, clinical trialists, and affected populations to drive forward the therapeutic agenda.