Highlights
- MPXV infection induces robust, durable immunological memory lasting up to two years, surpassing the MVA-BN vaccine-induced response.
- Clinical sequelae such as scarring occur in nearly half of MPXV-infected individuals by 8 months, with most other symptoms resolving within a year.
- MVA-BN vaccination elicits lower antibody binding concentrations compared to natural infection, with intradermal administration showing reduced immunogenicity versus subcutaneous dosing.
- Persistent viral DNA was not detected in saliva, anorectal swabs, or semen beyond early convalescence, indicating no long-term viral shedding.
Background
The 2022 global monkeypox (mpox) outbreak, characterized by sustained human-to-human transmission, underscored the urgent need to understand long-term outcomes and immune protection conferred by both natural MPXV infection and vaccination with the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine. Despite acute clinical characterizations, data on extended clinical sequelae, viral persistence, and comparative immunogenicity remain limited. Understanding these parameters is critical to inform public health strategies, vaccination policies, and clinical care pathways, especially as MPXV continues to circulate globally.
Key Content
Study Design and Cohorts
The Belgian MPX-COHORT and POQS-FU-PLUS studies represent a landmark 24-month prospective and retrospective investigation into long-term outcomes following MPXV infection or MVA-BN vaccination. Conducted at the Institute of Tropical Medicine, Antwerp, the study enrolled 237 individuals with MPXV infection (199 prospectively, 38 retrospectively) and 210 MVA-BN vaccinees (209 prospectively, one retrospectively). Follow-up visits were scheduled at 8, 16, and 24 months post-infection or vaccination.
Participants with prior childhood smallpox vaccination received only a single MVA-BN dose, while others received two doses. Detailed clinical, physical, and mental health assessments were coupled with collection of saliva, anorectal swabs, semen (month 8 only), and serum samples. Laboratory analyses included MPXV polymerase chain reaction (PCR) testing and quantitative assessments of vaccinia virus (VACV) lysate, MPXV-E8L binding antibodies, and MPXV neutralising antibodies.
Clinical Outcomes and Long-Term Sequelae
Scarring emerged as the most persistent physical sequela, present in 46% of MPXV-infected patients at 8 months, decreasing slightly but persisting in approximately 30% at 16 and 24 months. Other acute symptoms, including pain and mucocutaneous lesions, largely resolved within one year. Comprehensive mental health evaluations revealed limited long-term mental health burden, suggesting recovery of mental well-being over the follow-up period. Moreover, no evidence of ongoing active infection was found in saliva, anorectal mucosa, or semen, as all MPXV PCR tests were negative beyond acute convalescence.
Comparative cohort studies, including related research from Germany (SEMVAc and TEMVAc) and Spanish cohorts, corroborate these clinical findings, noting the safety and reactogenicity of MVA-BN vaccination, as well as reduced symptomatic mpox and hospitalization rates post-vaccination.
Immunological Insights: Antibody Dynamics and Neutralizing Capacity
Quantitative serological analyses demonstrated that individuals with prior MPXV infection developed significantly higher concentrations of VACV lysate and MPXV-E8L binding antibodies at 8 months post-infection compared to MVA-BN vaccine recipients. The fold-change for VACV antibodies was 0.39 (95% CI 0.25-0.62, p<0.0001), and for MPXV-E8L antibodies was 0.60 (95% CI 0.46-0.79, p=0.0017) in vaccinees, indicating a lower and less robust humoral immune response.
Neutralising antibody detection was low (4%, 95% CI 1-17%) among vaccine recipients. Notably, intradermal vaccination elicited markedly lower antibody concentrations compared with subcutaneous vaccination, highlighting the critical impact of administration route on immunogenicity.
These findings align with wider evidence on viral immunology, including Ebola vaccine studies, emphasizing the importance of booster doses in sustaining protective immunity, as vaccine-induced antibodies and memory responses may wane over time.
Viral Persistence and Infectivity Risk
The absence of MPXV DNA in saliva, anorectal swabs, and semen beyond 8 months suggests negligible risk of long-term viral shedding or infectivity in recovered cases. This observation is consistent with case series reporting limited viral DNA persistence in the pharynx and other mucosal sites. Nonetheless, rare prolonged shedding can occur, especially in immunocompromised individuals, necessitating clinical vigilance.
Expert Commentary
The MPX-COHORT and POQS-FU-PLUS studies eloquently bridge the gap in understanding the long-term clinical and immunological trajectories following MPXV infection and vaccination. The strong, durable immunity observed post-infection indicates probable long-term protection against reinfection, which is reassuring from an epidemiological standpoint.
However, the less durable immune responses observed after MVA-BN vaccination emphasize the need for booster vaccinations to enhance and prolong protective immunity. Given the reduced antibody response following intradermal administration—commonly adopted due to vaccine supply constraints—clinical strategies should carefully consider vaccine formulation and administration routes.
Clinically, the persistence of scarring as the main physical sequela warrants proactive dermatological care and patient counseling to mitigate quality-of-life impacts. Concomitant mental health follow-up remains important, particularly in the context of stigma and isolation experienced during outbreaks.
The robust methodologies, including complementary prospective and retrospective recruitment, multi-point follow-ups, and the use of biobanked samples, strengthen the study’s validity. Limitations include loss to follow-up at 24 months (especially in the infection cohort), potential selection bias, and a predominantly male study population reflective of epidemic demographics but limiting generalizability.
Public health implications are profound: vaccination campaigns must incorporate boosting strategies and prioritize at-risk populations, while long-term clinical care protocols should address physical and psychological sequelae. Further research is urgently needed to elucidate correlates of protection, optimal boosting schedules, and long-term outcomes in immunosuppressed and pediatric populations.
Conclusion
Two years after the recent global mpox outbreak, evidence from Belgian cohorts robustly demonstrates that natural MPXV infection induces strong and sustained immunological memory, offering promising long-term protection. MVA-BN vaccination, while safe and effective in the short term, produces a less robust and waning antibody response that may necessitate booster doses to maintain adequate immunity.
Scarring remains the predominant physical complication post-infection, with other symptoms largely abating within a year. Importantly, no long-term viral shedding was detected, reducing concerns about chronic infectivity.
These insights compel an evolution of vaccination policies to incorporate booster doses and emphasize continued surveillance of long-term clinical outcomes. Integration with findings from international cohorts enriches the global understanding of mpox management and underscores the critical role of translational research in infectious disease outbreaks.
References
- Van Dijck C, Berens-Riha N, Zaeck LM, et al. Long-term consequences of monkeypox virus infection or modified vaccinia virus Ankara vaccination in Belgium (MPX-COHORT and POQS-FU-PLUS): a 24-month prospective and retrospective cohort study. Lancet Infect Dis. 2025 Nov 7:S1473-3099(25)00545-6. doi: 10.1016/S1473-3099(25)00545-6. PMID: 41213280.
- Schönberger K, 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;25(7):775-787. PMID: 40118087.
- Spencer KD, et al. Effectiveness of Modified Vaccinia Ankara-Bavaria Nordic Vaccination in a Population at High Risk of Mpox: A Spanish Cohort Study. Clin Infect Dis. 2024;78(2):476-483. PMID: 37864849.
- Berke EM, et al. Persistent morbidity in Clade IIb mpox patients: interim results of a long-term follow-up study, Belgium, June to November 2022. Euro Surveill. 2023;28(7):2300072. PMID: 36795501.
- Del Giudice P, et al. Prospective observational study on scar sequelae after MPOX infection: an analysis of 40 patients. Int J Dermatol. 2024;63(12):1767-1773. PMID: 39356565.