Given the continued global circulation of monkeypox virus (MPXV), we aimed to assess the long-term clinical consequences of MPXV infection and the continued presence of the virus in saliva, semen, and the anorectum. We also aimed to compare long-term antibody dynamics after MPXV infection with modified vaccinia Ankara–Bavarian Nordic (MVA-BN) vaccination.

In this mixed retrospective and prospective cohort study, adults with acute MPXV infection at the Institute of Tropical Medicine (Antwerp, Belgium) were enrolled in a clinical registry (MPX-COHORT) from May 13, 2022, with follow-up at 1 month after infection. On Oct 3, 2022, we initiated a long-term follow-up study (POQS-FU-PLUS) to extend follow-up of people with mpox and to establish a parallel cohort of adults who received MVA-BN vaccination between Aug 3, 2022, and Jan 4, 2023. Participants were eligible for the second cohort if they received two doses of MVA-BN, unless they had previous smallpox vaccination, in which case one dose of MVA-BN sufficed. POQS-FU-PLUS visits were prospectively scheduled 8, 16, and 24 months after infection or vaccination. During these visits, participants with mpox underwent physical and mental health assessments and provided saliva, anorectal swabs, and serum and optionally semen (at month 8 only); people vaccinated with MVA-BN provided serum only. Missing serum samples were supplemented by biobanked serum samples collected during routine clinic visits within the same timeframe, as were serum samples predating MPXV infection and MVA-BN vaccination. Saliva, anorectal swabs, and semen were tested by MPXV PCR, and serum samples were tested for vaccinia virus (VACV) lysate, MPXV-E8L binding, and MPXV neutralising antibodies. Results were compared between people with MPXV infections and MVA-BN vaccination, taking into account childhood smallpox vaccination. The main outcomes were the in-depth clinical description of people with mpox, including complications, the long-term physical and mental health consequences of mpox, and antibody concentrations 8 months after MPXV infection and MVA-BN vaccination.

Of 250 individuals with MPXV infection, 237 were enrolled (199 prospectively and 38 retrospectively). Of 1728 people with MVA-BN vaccines, 210 were enrolled (209 prospectively and one retrospectively). Of people with MPXV infection, 112 (47%) of 237 attended follow-up at 8 months, 134 (57%) at 16 months, and 63 (27%) at 24 months. For people vaccinated with MVA-BN, 205 (98%) of 210 attended follow-up at 8 months, 161 (77%) at 16 months, and 144 (69%) at 24 months. The median age of all participants was 40 years (IQR 33–48). The majority (425 [96%] of 443) identified as men. Scarring occurred in 33 (46%) of 71 patients with mpox at month 8, 17 (30%) of 57 at month 16, and 20 (32%) of 63 at month 24. Other symptoms largely resolved within a year. All saliva and anorectal MPXV PCR were negative at follow-up (69 swabs were collected at 8 months, 51 at 16 months, and 63 at 24 months; upper 95% CI 5%, 7%, and 6% respectively); semen MPXV PCR at month 8 was negative for all 23 swabs (upper 95% CI 15%). At month 8, among participants not vaccinated against smallpox during childhood, MVA-BN induced lower binding antibody concentrations than MPXV infection (0·39 fold-change, 95% CI 0·25–0·62, p<0·0001 for VACV antibodies; 0·60 fold-change, 95% CI 0·46–0·79, p=0·0017 for MPXV-E8L antibodies); MPXV neutralising antibodies were detected in only 4% (95% CI 1–17%) of people with MVA-BN vaccines; and intradermal vaccination elicited lower binding antibody concentrations than subcutaneous vaccination (0·26 fold-change, 95% CI 0·17–0·39, p<0·0001 for VACV antibodies; 0·54 fold-change, 95% CI 0·37–0·77, p=0·0009 for MPXV-E8L antibodies).

Individuals previously infected with MPXV show strong and durable immunological memory lasting up to 2 years after infection, in contrast to the less robust and shorter-lived response observed after MVA-BN vaccination. These findings suggest that MPXV infection confers long-term protection against reinfection, whereas vaccine-induced immunity can wane over time and requires boosting. Further studies are needed to determine whether booster doses can enhance the durability of immunological memory in previously vaccinated individuals. Should booster vaccination prove beneficial, targeted revaccination campaigns will be necessary to maintain population-level protection.

Research Foundation–Flanders; Department of Economy, Science and Innovation Flanders; and Netherlands Organization for Health Research and Development.