Integrating vaccination with short-term behavioral guidance enables mpox outbreak control

Background. Despite the decline of the 2022 global outbreak, mpox remains an ongoing public health concern, with persistent transmission and emerging viral clades sustaining resurgence risk. Improving preparedness and response is a priority, yet it remains unclear how best pre-exposure vaccination and community response can effectively limit transmission under realistic conditions and whether behavioral adaptation is critical. Methods. We used a data-driven network model of mpox transmission among men who have sex with men in the Paris region, parameterized with sexual behavioral data and calibrated to surveillance data from the 2022 outbreak. We evaluated counterfactual scenarios by varying vaccination timing, rollout speed, prioritization, and behavioral responses. Results. Here we show that, with respect to the 2022 epidemic in the Paris region, vaccination alone delivered at the observed rollout speed would not have reproduced the observed epidemic decline, even if initiated the day of the first European alert, corresponding to 12 days before the first case was reported in France. Achieving comparable control through vaccination alone would have required more than a fourfold increase in rollout speed. Large-scale and long-term reductions in sexual contacts remain instrumental to limit the epidemic size, although earlier vaccination reduces the proportion of MSM needing to change behavior. In contrast, short-term behavioral measures adopted by the vaccinees, such as sexual abstinence during the 14-day immunity-building period, combined with moderately faster vaccine rollout, (+68% for 50% compliance; +34% for 75% compliance) could achieve comparable epidemic control. Targeting individuals with higher sexual activity further improved intervention efficiency. Conclusions. Under realistic reactive vaccination scenarios, mpox control still requires strong behavioral responses. Combining timely vaccination with short-term behavioral change guidance at vaccine administration offers a feasible path to limit transmission and strengthen outbreak preparedness and response.