Target Trial Emulation to Assess the Efficacy of the MVA-BN Vaccine as a Pre-Exposure Strategy in Individuals with Risk Factors for Mpox

Background: The MVA-BN vaccine is considered effective for preventing mpox in key populations, based on observational studies, though its effectiveness remains unconfirmed by randomized trials. Observational studies published to date rely on retrospective analyses of routine data, often missing information on relevant risk factors for mpox. Methods: Multi-country target trial emulation study with prospective data collection. Between September 1, 2022, and June 15, 2023, we recruited individuals eligible for mpox vaccination based on clinical history and exposure behaviors via healthcare centers and social venues in Spain, Peru, Panama, and Chile. Vaccinated individuals were paired with unvaccinated counterparts matched by mpox risk factors, country, recruitment date, and age. Follow-up continued via periodic surveys until March 31, 2024. The primary endpoint was symptomatic mpox occurrence ≥14 days post-vaccination. Results: The primary analysis included 1,028 individuals (514 vaccinated, 514 unvaccinated) with a median follow-up time of 9.3 months (IQR 4.7–13.7). Mpox occurred in 8 participants (0.8%): 3 vaccinated and 5 unvaccinated (HR 0.6; 95% CI 0.21–1.70). Adverse reactions were reported by 731 (49.6%) participants, predominantly skin reactions (703/1,475; 47.7%), while systemic reactions occurred in 107 (7.3%). Long-lasting erythema at the injection site was reported in 1,058 (71.7%) participants, persisting >6 months in 17% (107/1,058). Conclusions: Although not statistically significant, our findings—accounting for key confounders such as exposure behaviors—support the use of MVA-BN as pre-exposure prevention for mpox. The MVA-BN was generally safe, though long-lasting erythema at the injection site, previously unreported, was noted in a substantial proportion of participants.