Background <p>Mpox is a zoonotic disease caused by the monkeypox virus (MPXV) that became a global health concern following the 2022 outbreak. It poses a significant threat to immunocompromised individuals, children, and pregnant persons. Disease spread in the Democratic Republic of the Congo (DRC) and propagation to other countries has led to recent declarations of public health emergencies. Smallpox vaccination cessation has further heightened population vulnerability to MPXV. In response, MVA-BN and LC16m8, vaccinia-based vaccines originally developed for smallpox, have been repurposed for mpox, demonstrating promising safety and immunogenicity profiles. Despite these advancements, challenges remain in vaccine distribution and in understanding vaccine efficacy across populations, particularly in key at-risk groups. Available evidence remains fragmented and largely derived from adult populations, with limited data in pregnant persons, children, and adolescents. This living systematic review (LSR) aims to evaluate the safety, efficacy, effectiveness, and immunogenicity of mpox vaccines across populations, with particular focus on pregnant persons, children, and adolescents.</p> Methods <p>We aim to conduct a LSR and meta-analysis based on biweekly searches of medical databases and clinical trial registries from inception to the current date to systematically identify relevant studies of mpox vaccines across populations. Pairs of reviewers will independently select eligible studies, extract data, and assess the risk of bias. We will include randomized clinical trials, quasi-experimental studies, cohort studies, case–control studies, cross-sectional studies, and case reports. Primary outcomes will include safety, efficacy/effectiveness, and immunogenicity of mpox vaccines across populations, including outcomes in pregnant persons (with neonatal outcomes), children, and adolescents. Meta-analyses will be conducted, including prespecified subgroup and sensitivity analyses. We will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence.</p> Discussion <p>This LSR will synthesize evidence on mpox vaccines across populations, with particular focus on pregnant persons, children, and adolescents. As mpox continues to pose a global threat, particularly in endemic and low-resource settings, timely and rigorous assessment of vaccine performance is essential to guide equitable immunization policies and maternal-child health strategies.</p> Systematic review registration <p>International Prospective Register of Systematic Reviews (PROSPERO): CRD42024554330 (pregnant persons) and CRD42024556977 (children and adolescents).</p>