Multiple Introductions of Mpox virus to Ireland during the 2022 International Outbreak

Background mpox (formerly Monkeypox) virus (MPXV) was considered a rare zoonotic disease prior to May 2022, when a global epidemic of cases in non-endemic countries led to the declaration of a Public Health Emergency of International Concern. Previously, mpox infection was associated with symptoms similar to smallpox, although substantially less severe, including fever, an extensive characteristic rash and swollen lymph nodes. Aim Elucidating the origin and molecular characteristics of the virus circulating in the Republic of Ireland in the period between May and November 2022. Methods Whole-genome sequencing of all MPXV cases (80%; n=178/219) analysed against sequences from public databases (n=2695). Bayesian approaches were used to infer the divergence time between sequences from different subclades and transmission events involving different countries. Results The circulating virus belonged to the clade IIb B.1 lineage and, notably, the presence of twelve separable and highly-supported subclades consistent with multiple introductions into the country. Such a hypothesis of multiple importation events was supported further by the estimation of the time to the divergence of subclades. Additionally, inferred MPXV transmissions involving different countries and continents were indicative of an extended international spread. The analysis of the mutations in the Irish sequences revealed 93% of the mutations were from cytosine to thymine (or from guanine to adenine), leading to a high number of non-synonymous mutations across the subclades. Conclusion In the context of extremely high national sequencing coverage, we provide new insights into the international origin and transmission dynamics supporting multiple introductions into the Republic of Ireland. Conflict of Interests None to declare. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Irish Health Service Executive. Also, this study was partially supported by AMED under the grant number JP223fa627005. ### 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: The analysis of the data was approved by the University College Dublin Human Research Committee - Sciences analysed data with the Research Ethics Reference Number: LS-LRSD-23-197-Gonzalez-Hare. 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 All data produced are available online at GenBank ([www.ncbi.nlm.nih.gov/genbank/][1]) and GISAID ([gisaid.org][2]). Accession numbers are provided in the manuscript. [1]: http://www.ncbi.nlm.nih.gov/genbank/ [2]: http://gisaid.org