Safety and effectiveness of MVA-BN vaccination against mpox in at-risk individuals in Germany (SEMVAc and TEMVAc): a combined prospective and retrospective cohort study.

Background: More than 115 000 cases of mpox have been confirmed since the onset of a global outbreak in 2022. In addition to global transmission of clade II monkeypox virus (MPXV), the recent spread of clade I has caused a Public Health Emergency of International Concern. The third-generation smallpox vaccine modified vaccinia Ankara-Bavarian Nordic (MVA-BN) was recommended for at-risk populations in 2022, despite a scarcity of data on safety and effectiveness against mpox.

Methods: We did a prospective, multicentre, observational study, enrolling men who have sex with men and transgender people aged 18 years or older with changing sexual partners in Germany (Safety and Effectiveness of MVA-BN Vaccination Against MPXV Infection [SEMVAc]) between July 7, 2022, and Dec 31, 2023, evaluating safety and reactogenicity of one and two doses of subcutaneous MVA-BN. Vaccine effectiveness was estimated using risk ratios from the Kaplan-Meier estimator in an emulated retrospective target trial (Emulated Target Trial for Effectiveness of MVA-BN Vaccination Against mpox Infection in At-risk Individuals [TEMVAc]) from 3027 vaccinated individuals matched (1:1) to 3027 unvaccinated controls. SEMVAc and TEMVAc were registered in the HMA-EMA Catalogue, EUPAS50093, and the German Clinical Trials Register, DRKS00029638, and are complete.

Findings: 6459 individuals were prospectively enrolled in SEMVAc. Adverse reactions were infrequent (first dose: 0·35% [95% CI 0·20-0·60] and second dose: 0·14% [0·06-0·33]). Local reactions were more frequent after the first dose (70·2% [95% CI 68·5-71·8]) compared with the second dose (56·8% [54·6-59]), as were systemic reactions (first dose, 22·3% [95% CI 20·9-23·9]; second dose, 17·6% [15·9-19·4]). In TEMVAc, 16 mpox cases were reported in vaccinated individuals versus 32 cases in matched unvaccinated individuals (median follow-up 55 days [IQR 23-89]). Effectiveness by 14 days or later after one dose was 57·8% (95% CI 11·8 to 83·0) overall, 84·1% (42·0 to 100) in people without HIV, but 34·9% (-72·8 to 79·0) in people living with HIV. Breakthrough infections were associated with reduced symptoms, compared with infections in unvaccinated individuals.

Interpretation: MVA-BN vaccination was safe and well tolerated. One dose of MVA-BN offered protection against mpox but effectiveness was reduced in people living with HIV. Although randomised controlled trials remain the preferred approach for assessing vaccine efficacy, combining prospective and retrospective study designs can be valuable during dynamic public health emergencies.

Funding: European Medicines Agency.

Translation: For the German translation of the abstract see Supplementary Materials section.