The risk of future mpox outbreaks among men who have sex with men: a modelling study based on cross-sectional seroprevalence data

Background In the wake of the 2022-2023 mpox outbreak, crucial knowledge gaps exist regarding orthopoxvirus-specific immunity in risk groups and its impact on future outbreaks. Here, we combined cross-sectional seroprevalence studies in two cities in the Netherlands with mathematical modelling to evaluate the risk of future mpox outbreaks among men who have sex with men (MSM). Methods Serum samples were obtained from 1,065 MSM visiting the Centres for Sexual Health (CSH) in Rotterdam or Amsterdam after the introduction of vaccination and the peak of the Dutch mpox outbreak. For MSM visiting the CSH in Rotterdam, sera were linked to epidemiological and vaccination data. An in-house developed ELISA was used to detect vaccinia virus (VACV)- specific IgG; plaque reduction neutralization tests (PRNT) were performed on a selection of samples. These observations were combined with literature data on infection dynamics and vaccine effectiveness to inform a stochastic transmission model to estimate the risk on future mpox outbreaks. Findings The seroprevalence of VACV-specific IgG was 45.4% and 47.1% in Rotterdam and Amsterdam, respectively. Based on the correlation between serological parameters, we identified confirmed MPXV infections and inferred nine undiagnosed infections in individuals without childhood smallpox vaccination in the Rotterdam cohort (5.1%). Transmission modelling showed that the overall number of mpox cases in new outbreaks would be low, but that the current level of immunity alone may not prevent future outbreaks. Maintaining a short time-to-diagnosis will be a key component of any strategy to prevent new outbreaks. Interpretation Our findings indicate a reduced likelihood of future mpox outbreaks among MSM in the Netherlands under the current conditions, but emphasise the importance of maintaining population immunity, diagnostic capacities, and disease awareness. Funding National Institute for Public Health and the Environment (RIVM), HORIZON-HLTH-2022-MPX-14 (101115188). Evidence before this study We searched PubMed from database inception to July 24th, 2023, using the search terms (“monkeypox” OR “mpox” OR “orthopoxvirus”) AND (“immunity” OR “antibodies” OR vaccin*) OR (model*) OR (“epidemiology” OR “outbreak”) OR (“seroprevalence” OR “serosurveillance”), with no date or language restrictions. We included the cited references of retrieved publications in our search. We found that there are crucial knowledge gaps with respect to monkeypox virus (MPXV)-specific immunity and the impact of risk group vaccination with third-generation smallpox vaccines on the prevention of future outbreaks. No seroprevalence studies following the 2022-2023 mpox outbreak have been published yet. Recent observational studies from Israel, the United Kingdom, and the United States reported adjusted vaccine effectiveness levels between 36% - 86% following one or two doses of MVA. After the massive 2022-2023 outbreak, the number of new cases is now at a very low level, although there are continouing reports of small clusters of infections, including breakthrough infections and re-infections. This long tail to the epi curve, raises concerns about the potential of future outbreaks. We found no studies that predicted the risk of future mpox outbreaks after risk group vaccination based on measured seroprevalence data. Added value of this study The primary goal of this study was to estimate the risk of future mpox outbreaks among men who have sex with men (MSM) in the Netherlands using mathematical modelling based on real-world data. To this end, we used a combination of serological assays to determine the presence and abundance of (functional) poxvirus-specific antibodies in a Dutch MSM cohort. Next, we demonstrate the impact of rapid diagnosis (followed by isolation) of mpox cases on the size and duration of future outbreaks employing a mathematical model. Implications of all the available evidence A seroprevalence level of approximately 45% among MSM in the Netherlands visiting the Centres for Sexual Health was found. Modelling showed that this seroprevalence level alone may not be sufficient to prevent future outbreaks, which emphasises the importance of continued disease awareness, and maintaining population immunity and diagnostic capacities. These insights have important implications for public health policy making and fill critical knowledge gaps to help inform surveillance activities and guide vaccination strategies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the National Institute for Public Health and the Environment (RIVM), and HORIZON-HLTH-2022-MPX-14 (101115188). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Prior to the study, we obtained approval from the Erasmus MC Medical Ethics Review Committee (MEC-2022-0675) granting permission to conduct research using residual materials. The AmsterdamUMC Medical Ethics Review committee granted permission for samples from Amsterdam (W22_428#22.506). A privacy impact assessment was made for combining data from the CSH Rotterdam clients, including vaccination indication and infection status, with their vaccination data. No additional data or samples were collected specifically for this study and all samples were pseudonymised, ensuring that no identifiable data from participants were collected, transferred, or analysed. This study did not involve any direct interaction with participants or any potential harm. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Deidentified individual participant data, the analytics code, and other supporting documents will be made available when the study is complete, upon requests made to the corresponding author.