Highlights
- MVA-BN (modified vaccinia Ankara-Bavarian Nordic) vaccination is safe and well tolerated among at-risk adults, with low rates of severe adverse reactions.
- Vaccine effectiveness (VE) for one dose is moderate (58–76%) but improves with two doses (82%). Effectiveness is notably reduced in people living with HIV.
- Breakthrough mpox infections after vaccination are milder compared to those in unvaccinated individuals.
- Host baseline immunological states may influence vaccine response and need to be considered in vaccination strategies, especially with constrained vaccine supply.
Study Background and Disease Burden
Since 2022, mpox (monkeypox) has become a global public health concern, with over 115,000 confirmed cases across continents. This outbreak, driven primarily by clade II monkeypox virus (MPXV) but complicated by spread of more virulent clade I, has disproportionately affected men who have sex with men (MSM) and certain transgender populations—many of whom have multiple or changing sexual partners. The rapid expansion and morbidity of mpox, alongside its impact on sexual health and broader public health systems, prompted the World Health Organization to declare a Public Health Emergency of International Concern. In response, the third-generation smallpox vaccine MVA-BN was recommended for at-risk groups, including MSM and transgender individuals, despite limited real-world evidence for its safety and effectiveness in preventing mpox. Understanding the true impact and optimal use of MVA-BN in diverse, high-risk populations remains a pressing clinical and public health need.
Study Design
The German SEMVAc and TEMVAc studies provide robust, real-world data, employing a hybrid design:
- SEMVAc (prospective safety cohort): 6,459 MSM and transgender adults (≥18 years, with changing sexual partners) were enrolled across German centers between July 2022 and December 2023 to assess the safety and reactogenicity of one and two doses of subcutaneous MVA-BN.
- TEMVAc (retrospective effectiveness cohort): An emulated target trial matched 3,027 vaccinated individuals to 3,027 unvaccinated controls from the same population, estimating vaccine effectiveness using a Kaplan-Meier risk ratio approach. Median follow-up was 55 days (IQR 23–89 days).
This approach provides both prospective safety surveillance and an emulated trial framework to estimate real-world effectiveness, particularly valuable when randomized controlled trials are logistically challenging during an outbreak.
To contextualize these findings, a systematic review and meta-analysis of third-generation mpox vaccines (mostly MVA-BN) synthesized data from 33 studies, while an Oxford-based immunogenicity cohort examined the biological predictors of vaccine response.
Key Findings
Safety and Reactogenicity (SEMVAc)
The MVA-BN vaccine exhibited a favorable safety profile:
- Adverse reactions were uncommon: 0.35% (95% CI 0.20–0.60) after the first dose and 0.14% (0.06–0.33) after the second.
- Local reactions (e.g., injection site pain, erythema) were more common after the first dose (70.2%) than the second (56.8%). Systemic reactions (e.g., fever, malaise) were also more frequent after the first dose (22.3%) than the second (17.6%).
- No serious vaccine-related safety signals emerged during the study period.
Vaccine Effectiveness (TEMVAc, Meta-Analysis)
- In the TEMVAc cohort, 16 cases of confirmed mpox occurred among vaccinated individuals versus 32 in unvaccinated matched controls. Effectiveness ≥14 days after one dose was 57.8% (95% CI 11.8–83.0).
- Subgroup analysis revealed much higher VE in people without HIV (84.1%, 95% CI 42.0–100) but substantially reduced VE in people living with HIV (34.9%, 95% CI –72.8 to 79.0).
- Breakthrough cases in vaccinated recipients exhibited milder disease courses compared to unvaccinated cases.
- The systematic review/meta-analysis corroborated these findings across diverse settings: pooled VE for one dose was 76% (95% CI 64–88%), and for two doses 82% (95% CI 72–92%). However, VE for post-exposure prophylaxis (PEP) was only 20% (95% CI –24 to 65%), reflecting likely biases and suboptimal real-world vaccine timing.
- Meta-analytic quality was variable, but studies included in pooled VE estimates were mostly rated as good quality.
Immunogenicity and Host Factors
The Oxford immunogenicity cohort provided mechanistic insights:
- Among vaccinees without prior smallpox vaccination, only 47% seroconverted by day 28 after the first dose, but 89% seroconverted 90 days after the second dose, supporting the two-dose schedule.
- Individuals seronegative at day 28 had persistently lower antibody responses and cellular immunity.
- Early upregulation of type I and II interferon signatures post-vaccination was linked to better serological response, while higher baseline inflammation was associated with poorer vaccine-induced immunity.
- These findings suggest host immunological state at vaccination could inform timing and strategy, particularly in immunocompromised or high-inflammation individuals.
Expert Commentary and Clinical Implications
The combined German SEMVAc/TEMVAc data, meta-analytic synthesis, and immunogenicity findings converge on several clinically meaningful points:
- Safety: MVA-BN is safe and well tolerated in real-world, high-exposure populations. Its reactogenicity profile is consistent with prior smallpox vaccine experience.
- Efficacy: One dose confers moderate short-term protection, substantially improved with a second dose, aligning with international guidance for a two-dose schedule. However, PEP effectiveness is limited—emphasizing pre-exposure vaccination for at-risk groups.
- Equity and Risk Groups: Reduced protection in people living with HIV highlights a critical gap. Tailored strategies—including additional booster doses, close post-vaccination follow-up, or immunological monitoring—may be warranted for immunocompromised patients. The immunogenicity study’s results reinforce the importance of considering host factors and inflammation at the time of vaccination.
- Translational Value: The hybrid study design (prospective and emulated target trial) offers a valuable template for rapid public health evidence generation during infectious disease emergencies.
- Dose-Sparing Potential: Fractionated dosing and optimization of timing, especially in resource-limited or surge settings, require further research but are promising for maximizing population-level benefit.
Conclusion
MVA-BN vaccination is a critical tool for mpox outbreak control among at-risk populations, delivering strong safety and effectiveness signals in real-world settings. Nevertheless, protection is suboptimal in people living with HIV and may depend on baseline immunological state. A full two-dose course is preferable, and tailored strategies for immunocompromised individuals are needed. Future studies should refine optimal dosing, address host variability, and further evaluate vaccine performance in diverse populations. The hybrid study model employed here provides a roadmap for rapid, robust vaccine evaluation during dynamic public health crises.
References
- Hillus D, Le NH, Tober-Lau P, et al. 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. Lancet Infect Dis. 2025 Jul;25(7):775-787. doi: 10.1016/S1473-3099(25)00018-0 IF: 31.0 Q1 . PMID: 40118087 IF: 31.0 Q1 .
- Pischel L, Martini BA, Yu N, et al. Vaccine effectiveness of 3rd generation mpox vaccines against mpox and disease severity: A systematic review and meta-analysis. Vaccine. 2024 Nov 14;42(25):126053. doi: 10.1016/j.vaccine.2024.06.021 IF: 3.5 Q2 . PMID: 38906763 IF: 3.5 Q2 .
- Drennan PG, Provine NM, Harris SA, et al. Immunogenicity of MVA-BN vaccine deployed as mpox prophylaxis: a prospective, single-centre, cohort study and analysis of transcriptomic predictors of response. Lancet Microbe. 2025 Jun;6(6):101045. doi: 10.1016/j.lanmic.2024.101045 IF: 20.4 Q1 . PMID: 40286799 IF: 20.4 Q1 .
