Highlights
- Natural MPXV infection provides significantly stronger and more durable immunological memory (up to 24 months) compared to the two-dose MVA-BN vaccination series.
- Clinical symptoms of mpox, including systemic and localized manifestations, typically resolve within 12 months, though cutaneous scarring persists in approximately 30-46% of patients at two years.
- Viral clearance in saliva, semen, and anorectal mucosa is achieved in almost all cases by month 8, suggesting a low risk of long-term viral persistence or subacute transmission.
- MVA-BN vaccine-induced immunity wanes rapidly; at 8 months post-vaccination, only 4% of individuals without childhood smallpox vaccination retained detectable neutralizing antibodies.
- The route of vaccine administration matters: intradermal MVA-BN vaccination elicited lower binding antibody concentrations than the subcutaneous route.
Background
The 2022 global outbreak of mpox (formerly monkeypox), caused by the Monkeypox virus (MPXV) Clade IIb, marked a significant shift in the epidemiology of orthopoxviruses. Unlike previous sporadic zoonotic transmissions, this outbreak was characterized by sustained human-to-human transmission, primarily within networks of men who have sex with men (MSM). As the acute phase of the public health emergency subsided, the clinical and scientific focus shifted toward understanding the long-term sequelae of infection and the durability of vaccine-induced protection.
Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN) was rapidly deployed as a primary preventive measure. However, much of the initial data regarding its efficacy were derived from early-phase trials or real-world effectiveness studies with short follow-up periods. Crucial questions remained regarding the long-term persistence of MPXV in bodily fluids, the duration of physical and mental health consequences post-infection, and the comparative strength of the immune response between those who recovered from the disease and those who were vaccinated. The MPX-COHORT and POQS-FU-PLUS studies in Belgium were designed to provide these definitive long-term insights through a rigorous 24-month follow-up period.
Key Content
Chronological Resolution of Clinical Symptoms
The clinical trajectory of mpox infection in the Belgian cohort showed a distinct pattern of acute morbidity followed by gradual resolution. In the acute phase, patients presented with characteristic pleomorphic lesions, proctitis, and systemic symptoms. By the 8-month follow-up, the majority of these symptoms had resolved. However, scarring emerged as the most significant persistent physical consequence. At 8 months, 46% of patients reported visible scarring. While this proportion decreased to 30% by month 16, it remained stable at 32% at the 24-month mark, indicating that for a significant minority, the dermatological impact of MPXV is permanent. Other complications, such as chronic proctalgia or functional impairment, largely dissipated within the first year, providing reassurance regarding the low incidence of severe, permanent systemic disability in immunocompetent hosts.
Viral Persistence and Transmission Risk
A critical concern for public health officials was whether MPXV could establish a reservoir in immunologically privileged sites, such as the testes or the anorectal mucosa, potentially leading to delayed transmission. The POQS-FU-PLUS study rigorously tested saliva and anorectal swabs at 8, 16, and 24 months, and semen at 8 months. All samples tested negative by MPXV PCR. Specifically, the negative results for the 23 semen samples at month 8 (with an upper 95% CI of 15%) provide strong evidence against the prolonged shedding of infectious virus in the genital tract beyond the acute and early convalescent phases. This finding is instrumental in refining isolation and safe-sex guidelines for convalescent patients.
Comparative Immunodynamics: Infection vs. Vaccination
The most striking findings of the study involve the divergence between infection-acquired and vaccine-induced immunity. The study measured antibodies against vaccinia virus (VACV) lysate and the MPXV-specific E8L protein, as well as MPXV neutralizing antibodies.
At 8 months post-exposure, individuals who had recovered from MPXV infection exhibited robust antibody titers. In contrast, among those who received the MVA-BN vaccine and had no history of childhood smallpox vaccination, binding antibody concentrations were significantly lower (0.39 fold-change for VACV antibodies; 0.60 fold-change for MPXV-E8L antibodies). Even more concerning was the status of neutralizing antibodies—the gold standard for functional immunity. Only 4% of the MVA-BN vaccinated group had detectable neutralizing antibodies at month 8, compared to much higher and more sustained levels in the infection cohort. This suggests that while MVA-BN is effective in preventing severe disease in the short term, its ability to maintain a neutralizing barrier against infection wanes rapidly within a year.
Impact of Vaccination Strategy and Prior Immunity
The study also addressed the impact of the administration route. Due to vaccine shortages in 2022, many jurisdictions adopted intradermal (ID) administration to conserve doses. The Belgian data indicate that ID vaccination elicited significantly lower binding antibody concentrations compared to the standard subcutaneous (SC) route (0.26 fold-change for VACV; 0.54 for MPXV-E8L). This quantitative difference suggests that dose-sparing strategies, while necessary during emergencies, may come at the cost of immunological durability.
Furthermore, the data highlighted the ‘prime-boost’ effect of historical smallpox vaccination. Participants who had received childhood smallpox vaccines showed a more robust response to a single MVA-BN dose than younger, vaccine-naive individuals did to a full two-dose series. This reinforces the concept of long-lived B-cell memory from older-generation orthopoxvirus vaccines that can be successfully cross-boosted by MVA-BN.
Expert Commentary
The results of the MPX-COHORT and POQS-FU-PLUS trials necessitate a re-evaluation of current mpox vaccination strategies. The rapid decline in neutralizing antibodies among vaccinees—dropping to near undetectable levels in 96% of the cohort by month 8—is a stark contrast to the durable immunity seen after natural infection. This suggests that the current two-dose MVA-BN regimen may not provide long-term population-level ‘herd immunity,’ particularly as the virus continues to circulate globally.
From a mechanistic perspective, the superiority of natural infection likely stems from exposure to the full array of MPXV antigens and the localized immune response at the sites of mucosal entry, which MVA-BN, a highly attenuated and non-replicating virus, cannot fully replicate. The clinical applicability of these findings is clear: clinicians should advise vaccinated patients that their protection may wane over time, and health policy experts must begin planning for potential booster campaigns, especially for high-risk populations. Moreover, the persistence of scarring underscores the need for early antiviral intervention (e.g., tecovirimat) in the acute phase to limit tissue damage, rather than relying solely on symptomatic management.
Conclusion
In summary, the 24-month data from Belgium provide a definitive look at the long-term landscape of mpox. While the clinical resolution of symptoms is generally favorable, the immunological data reveal a significant ‘protection gap’ between natural infection and vaccination. MPXV infection confers strong, durable immunity lasting at least two years, whereas MVA-BN-induced immunity, particularly when administered intradermally, wanes significantly within months. Future research must focus on the efficacy of booster doses and the development of next-generation vaccines that can better mimic the robust protection offered by natural exposure. Until then, targeted revaccination and continued clinical vigilance remain the cornerstones of preventing future mpox resurgences.
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. doi: 10.1016/S1473-3099(25)00545-6. PMID: 41213280.
- Thornhill JP, et al. Monkeypox Virus Infection in Humans across 16 Countries — April–June 2022. N Engl J Med. 2022;387:679-691. PMID: 35866258.
- Titanji BK, et al. Monkeypox: A Contemporary Review for Healthcare Professionals. Open Forum Infect Dis. 2022;9(7):ofac310. PMID: 35891689.
