The long-term epidemiological impacts of doxycycline post-exposure prophylaxis and vaccination against multidrug-resistant Neisseria gonorrhoeae: a mathematical modelling study

Doxycycline post-exposure prophylaxis (doxy-PEP) represents major advancements in sexually transmitted infection prevention for men who have sex with men (MSM), yet the joint long-term population-level impact on Neisseria gonorrhoeae transmission dynamics and antimicrobial resistance (AMR) together with a moderately effective vaccine remains uncertain. Here, we developed a deterministic transmission model calibrated to empirical surveillance data from England to evaluate the 15-year epidemiological interactions of implementing doxy-PEP and vaccination at the population level. The model incorporates the tetracycline- and ceftriaxone-susceptible, tetracycline-resistant (Tet-R), ceftriaxone-resistant (Cef-R), and dual-resistant (Dual-R) strains. Our simulations suggest that the unmitigated deployment of doxy-PEP provides only modest reductions in overall gonorrhoea burden, yielding a net programmatic efficiency of 0.072 (95% CrI: 0.018 - 0.23) averted infections per enrolment over the 15-year horizon. Although doxy-PEP reduces tetracycline- and ceftriaxone-susceptible infections, it consistently selects for Tet-R lineages. Conversely, standalone vaccination yields substantially greater epidemiological benefit, averting 0.73 (95% CrI: 0.17 - 1.63) overall infections per enrolment. When deployed in tandem, the dual intervention strategy achieves the greatest overall effectiveness to 0.83 (95% CrI: 0.22 - 1.71) averted infections per enrolment while mitigating the Tet-R selection pressure observed under standalone doxy-PEP. Long-term strain dynamics were found to be governed by background frontline ceftriaxone treatment failure rates rather than intervention uptake. Under a scenario of compromised ceftriaxone efficacy (20% treatment failure), doxy-PEP is projected to favour expansion of Dual-R strain, yielding 510 (95% CrI: 38 -258600) excess Dual-R infections across the 15-year horizon (146.18% [95% CrI: 31.30 - 920.86%] cumulative increase) and triggering sustained transmission exceeding the no-intervention baseline. Conversely, vaccination standalone or combined strategies consistently suppress overall transmission. By year 15, annual Cef-R and Dual-R infections are restricted to less than or equal to 19 infections under both vaccine-inclusive approaches. These findings suggest that the public health utility of antibiotic prophylaxis is heavily contingent upon the preserved efficacy of frontline therapeutics. Our work demonstrates that single-agent prophylaxis risks localized containment of some pathogens at the cost of driving multidrug-resistant selection in others and underscores the necessity of integrating non-selective tools like vaccines to manage N. gonorrhoeae.