Age-patterns of severity of clade I mpox in historically endemic countries

Background The last two years have seen mpox emerge as a notable pandemic threat. The global 2022-23 outbreak of clade II mpox caused over 93,000 cases worldwide, while the 2023-24 epidemic of the more severe clade I virus in the Democratic Republic of Congo (DRC) has caused over 14,000 cases and over 650 deaths thus far. Of particular concern is that both case incidence and mortality in the DRC outbreak are concentrated in children. However, quantification of age variation in severity for clade I infections has been lacking to date. Methods Using Bayesian binomial regression models, we analysed data from systematically reviewed clade I outbreaks to estimate case fatality ratios (CFR) by age, smallpox vaccination status and over time. We compared model predictive performance using leave-one-out cross-validation and compared our findings to the ongoing DRC outbreak. Findings The CFR had a near-reciprocal relationship with age, declining from 9.7% (95% credible interval: 6.9%-13.0%) among 5-year-olds to 1.2% (95%CrI: 0.3%-3.7%) by age 30. Accounting for vaccination status in addition to age did not improve model fit, but posterior parameter estimates suggest substantial vaccine-protection against death. Reanalysis incorporating cases from the ongoing DRC outbreak suggested less steep declines in severity with age and a protective effect of vaccination against death of 64% (95%CrI: - 3.4%-95.6%) and reduction in severity over time. Interpretation We provide estimates of the mpox clade I CFR in historically endemic settings by vaccine status, and find the highest risk of death in the youngest children. Funding Wellcome, NIHR, MRC, Community Jameel ### Competing Interest Statement LKW reports personal fees from WHO-EURO for consulting on the 2022-23 Mpox clade II outbreak. LKW reports grants from the Wellcome Trust and NIHR, personal fees from Pacific Life Re, honoraria from the Luxembourg National Research Fund and Lancet Infectious Diseases for rapid peer review, and participating on a DSMB for the Wellcome Trust, all outside the submitted work. NMF reports grants from the Wellcome Trust, NIHR, the Bill and Melinda Gates Foundation, Gavi, a philanthropic donation from Community Jameel and fees for journal editing from eLife. ### Funding Statement LKW acknowledges funding from the Wellcome Trust (grant number 218669/Z/19/Z). LKW and NMF acknowledge funding from the MRC Centre for Global Infectious Disease Analysis (reference MR/R015600/1), jointly funded by the UK Medical Research Council (MRC) and the UK Foreign, Commonwealth & Development Office (FCDO), under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. NMF acknowledges funding provided by the NIHR Health Protection Unit in Modelling and Health Economics (reference NIHR200908) and the Jameel Institute (supported by a philanthropic donation from Community Jameel). The views expressed are those of the authors and not necessarily those of the funders. ### 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 study used only openly available human data that were originally located at the publications cited in the manuscript. 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 and code to reproduce the analysis are available at [https://github.com/mrc-ide/mpox\_clade\_i_severity][1] [https://github.com/mrc-ide/mpox\_clade\_i_severity][1] [1]: https://github.com/mrc-ide/mpox_clade_i_severity