Highlights
- Natural MPXV infection induces robust and durable immunological memory persisting for at least 24 months post-infection.
- MVA-BN vaccination results in significantly lower binding and neutralizing antibody concentrations compared to natural infection at 8 months.
- Long-term clinical sequelae are primarily characterized by persistent scarring (32% at 24 months), while most other symptoms resolve within one year.
- Complete viral clearance in saliva, semen, and anorectal sites is achieved by month 8, suggesting a low risk of long-term viral persistence.
Background
The 2022 global outbreak of the monkeypox virus (MPXV) necessitated rapid public health responses, including the deployment of the modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccine. However, the longevity of vaccine-induced immunity compared to natural infection-induced immunity remained poorly understood. Furthermore, concerns regarding viral persistence in biological reservoirs (saliva, semen, anorectum) and the long-term physical and mental health consequences of mpox infection required rigorous evaluation. This synthesis focuses on the findings from the MPX-COHORT and POQS-FU-PLUS studies, providing a 24-month perspective on the clinical and immunological trajectory of MPXV in Belgium.
Key Content
Study Design and Patient Population
The research utilized a mixed retrospective and prospective cohort approach based at the Institute of Tropical Medicine in Antwerp, Belgium. The MPX-COHORT registry enrolled 237 adults with acute MPXV infection starting in May 2022. Subsequently, the POQS-FU-PLUS study extended follow-up to 24 months and established a parallel cohort of 210 adults vaccinated with MVA-BN. The median age of participants was 40 years, with a vast majority (96%) identifying as men. This demographic reflects the primary population affected during the 2022 multi-country outbreak.
Clinical Outcomes and Viral Persistence
One of the primary objectives was to assess the duration of symptoms and the presence of the virus in various anatomical sites.
Viral Clearance: Rigorous PCR testing of saliva, anorectal swabs, and semen (at month 8) yielded entirely negative results across all follow-up intervals (8, 16, and 24 months). For saliva and anorectal sites, the upper 95% confidence intervals for positivity were 5–7%, while for semen at month 8, it was 15%. These data provide strong evidence against long-term viral shedding or persistence in these reservoirs.
Physical and Mental Health: While most systemic and acute symptoms resolved within 12 months, dermatological sequelae were persistent. Scarring was reported in 46% of patients at 8 months, and while this declined, 32% of patients still exhibited scarring at the 24-month mark. Mental health assessments were integrated into the follow-up, though physical scarring remained the most prominent long-term objective finding.
Immunological Dynamics: Infection vs. Vaccination
The study provides a critical comparison of antibody dynamics between naturally infected individuals and those vaccinated with MVA-BN, with a focus on the 8-month post-exposure/vaccination window.
Antibody Concentrations: Among individuals without childhood smallpox vaccination, natural MPXV infection elicited significantly higher binding antibody concentrations than the MVA-BN vaccine. Specifically, at month 8, MVA-BN vaccinees showed a 0.39 fold-change in vaccinia virus (VACV) antibodies and a 0.60 fold-change in MPXV-E8L binding antibodies compared to the infected cohort.
Neutralizing Activity: The most striking divergence was observed in neutralizing antibody titers. While natural infection induced durable neutralizing responses, MPXV neutralizing antibodies were detected in only 4% of individuals who received the MVA-BN vaccine at the 8-month follow-up.
Route of Administration: The study also noted that the method of vaccine delivery influenced the immune response. Intradermal vaccination was associated with significantly lower binding antibody concentrations (0.26 fold-change for VACV; 0.54 fold-change for MPXV-E8L) compared to subcutaneous administration, a finding relevant for dose-sparing strategies used during vaccine shortages.
Expert Commentary
The findings from the POQS-FU-PLUS study present a significant challenge to current long-term vaccination strategies. The rapid waning of neutralizing antibodies in the MVA-BN cohort (only 4% detectable at 8 months) suggests that the protection afforded by the current two-dose primary series may be short-lived compared to the robust, multi-year immunity granted by natural infection.
From a clinical perspective, the resolution of most symptoms within a year is encouraging, yet the persistence of scarring in nearly a third of patients highlights the need for early intervention to minimize skin damage. The absence of viral persistence in semen and other fluids at 8 months is a crucial finding for public health counseling regarding sexual transmission risks post-recovery.
However, a limitation of the study is the decline in follow-up participation at the 24-month mark (27% for the infected group), which may introduce selection bias. Furthermore, while antibody levels are a standard proxy for immunity, the role of cellular immunity (T-cell responses) in providing long-term protection, despite low circulating antibodies, remains an area requiring further investigation.
Conclusion
Natural MPXV infection provides strong and durable immunological protection that lasts at least 24 months. In contrast, MVA-BN-induced immunity appears less robust and subject to significant waning within the first year. These results suggest that while natural infection may protect against reinfection for several years, vaccinated individuals—particularly those who received intradermal doses—may require booster vaccinations to maintain protective thresholds. Future research should focus on the efficacy of booster doses and the specific role of memory T-cells in maintaining long-term defense against MPXV.
References
- Van Dijck C, 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. 2026 Feb;26(2):190-202. PMID: 41213280.
