Abstract
Syphilis remains a major global public health challenge, particularly among men who have sex with men (MSM). Although penicillin is effective for treatment, primary prevention options are limited. Recent trials show that doxycycline post-exposure prophylaxis (doxy-PEP) can substantially reduce syphilis incidence, but its long-term population-level impact, effects on transmission dynamics and effective programme enrolment strategies remain unclear, especially when accounting real-world behavioural factors such as screening frequency, uptake, adherence and discontinuation. Here we develop a behavioural transmission-dynamic model calibrated using Bayesian methods with epidemiological and behavioural data from Singapore and England to characterize transmission dynamics in MSM, quantify the potential long-run public health impact, efficiency and robustness of alternative doxy-PEP programme enrolment strategies across different settings (for example, schools, sexual health clinics and risk groups) under varying behavioural patterns and epidemiological settings. Over 15 years, targeting MSM at high-risk (>5 partners per year) at diagnosis is most efficient (averting 2.50 (95% credible interval 0.68–5.94) and 4.60 (2.12–7.79) cases per enrolment in Singapore and England, respectively). Broader strategies to enrol all MSM attending sexual health clinics into a doxy-PEP programme achieved larger total reductions but with much lower efficiency and can avert as few as 0.02 (0.00–0.23) and 0.04 (0.01–0.46) cases per enrolment, respectively. Findings were robust across different behavioural and future scenarios. In summary, doxy-PEP programmes should prioritize enrolling MSM at high-risk diagnosed with syphilis, while maintaining frequent STI screening every 3–4 months, and monitoring the emergence or amplification of tetracycline-resistant Neisseria gonorrhoeae.
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Data availability
All data used to parameterize the model, run the simulations and generate the findings are included in the Supplementary Information and are available with the model code via GitHub at https://github.com/killingbear999/doxypep_syphilis. Detailed data sources are included in the Methods section. Source data are provided with this paper.
Code availability
Source code to reproduce all our experiments, figures and analysis are available via GitHub at https://github.com/killingbear999/doxypep_syphilis.
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Acknowledgements
Generative AI (ChatGPT) was used to assist in refining text in this paper only. All content and scientific interpretations remain the responsibility of the authors. L.K.W. acknowledges funding from the Wellcome Trust (grant no. 218,669/Z/19/Z). L.K.W. acknowledges funding from the Medical Research Council (MRC) Centre for Global Infectious Disease Analysis (grant no. MR/X020258/1), funded by the UK MRC and carried out within the framework of the Global Health EDCTP3 Joint Undertaking, supported by the EU. This work is also supported by Nanyang Technological University, Singapore—Imperial Research Collaboration Fund (grant no. INCF-2023-007 to J.T.L.). J.T.L. is also supported by the Ministry of Education Startup Grant. The funders have no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Z.W. contributed to writing—original draft, software, methodology, formal analysis and conceptualization. J.T.L. contributed to writing—review and editing, supervision, methodology, formal analysis and conceptualization. D.N., D.N.F. and L.K.W. contributed to methodology and conceptualization. All authors contributed to critical review and editing of the paper and take responsibility for the decision to submit for publication. J.T.L. is the guarantor and accepts full responsibility for the work and/or the conduct of the study and controlled the decision to publish. J.T.L. attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.
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Extended data
Extended Data Fig. 1 Model architecture for syphilis transmission.
Individuals enter the sexually active population as uninfected (\(U_{j}\)). Upon infection, they progress through an incubation phase (\(I_{j}\)) before advancing to the primary (\(P_{j}\)), secondary (\(S_{j}\)), early latent (\(E_{j}\)), late latent (\(L_{j}\)), and tertiary (\(T_{j}\)) stages. The primary, secondary, and tertiary stages are symptomatic, prompting individuals to seek treatment and transition to the recovered state (\(R_{j}\)). In contrast, early latent and late latent stages are asymptomatic, with infections typically detected through screening, leading to treatment and recovery (\(R_{j}\)). Individuals in the tertiary stage face a risk of mortality, permanently exiting the compartments. Notably, only the incubation, primary, secondary, and early latent stages are infectious, while the late latent and tertiary stages are non-infectious. All treated infections are considered cured, with individuals returning to the uninfected state. Individuals may exit the sexually active population due to aging at any stage. The model includes separate compartments for individuals with low and high sexual activity levels (\(j\in L,H\)), represented by the purple and grey layers in the figure. Both groups share an identical compartmental structure, though, for clarity, only the transitions in and out of the high-activity group (upper layer) are depicted.
Extended Data Fig. 2 Model architecture of doxy-PEP for syphilis.
For each doxy-PEP stratum \(i\in \left\{N,X,D,M\right\}\), the population is subdivided into compartments representing different stages of syphilis infection. The model distinguishes between individuals with low and high sexual activity levels (\(j\in \{L,H\}\)), illustrated as the grey (low-activity) and purple (high-activity) layers. Both groups follow the same compartmental structure but may differ in transition rates. For clarity, only the transitions in and out of the high-activity group (upper layer) are shown. Individuals \(\alpha\) enter the sexually active population at age 15. With probability \({p}^{{DbE}}\), they initiate doxy-PEP upon entry and enter stratum \(D\); otherwise, they enter stratum \(N\). Individuals at stratum \(D\) may discontinue doxy-PEP and move to stratum \(N\) at a rate \({\xi }_{n}\); become suboptimally adherent and transition to stratum \(X\) at a rate \({\xi }_{x}\); or develop intolerance and transition to stratum \(M\) at a rate \({\xi }_{m}\). Individuals at stratum \(X\) may also discontinue doxy-PEP and return to stratum \(N\) at a rate \({\xi }_{{xn}}\). Individuals at strata \(N\) and \(X\) may initiate or reinitiate doxy-PEP following a sexual health clinic visit - either through screening or diagnosis - with probabilities \({p}^{{DoS}}\) and \({p}^{{DoD}}\), respectively, and transition into stratum \(D.\)
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Wang, Z., Nikitin, D., Dickens, B.L. et al. Long-term public health impact of doxycycline post-exposure prophylaxis on syphilis transmission. Nat. Health (2026). https://doi.org/10.1038/s44360-026-00092-3
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DOI: https://doi.org/10.1038/s44360-026-00092-3
