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Smallpox eradication followed by the discontinuation of immunization with vaccinia has led to a decline in the level of population immunity against related poxviruses such as mpox. This decline in immunity results in an increase in both the number of spillovers and the extent of human to human transmission. We find that increases in transmissibility of mpox between humans have a much greater effect on the probability of evolutionary emergence compared with increases in the number of zoonotic spillovers. We suggest that while mpox only needs to have a reproductive number slightly greater than one to become endemic, subsequent adaptation is likely to further increase its transmissibility in the human population. As a consequence a much higher level of vaccination (or other intervention) is needed to control the pathogen after its evolutionary emergence compared with what is needed to prevent it from emerging in the first place.<\/jats:p>","DOI":"10.64898\/2026.03.03.709287","type":"posted-content","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:25:26Z","timestamp":1772670326000},"source":"Crossref","is-referenced-by-count":0,"title":["Preventing Disease Emergence Following Eradication: Application to Mpox"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3078-8729","authenticated-orcid":false,"given":"Cora","family":"Hirst","sequence":"first","affiliation":[{"name":"Department of Biology, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1364-908X","authenticated-orcid":false,"given":"Julia","family":"Deichmann","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"name":"Center for Communicable Disease Dynamics, Harvard T.H. Chan School of Public Health, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8205-0716","authenticated-orcid":false,"given":"Ananya","family":"Saha","sequence":"additional","affiliation":[{"name":"Department of Biology, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2780-9382","authenticated-orcid":false,"given":"Ira","family":"Longini","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Florida, Gainesville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-1146","authenticated-orcid":false,"given":"Andreas","family":"Handel","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-9213","authenticated-orcid":false,"given":"Marc","family":"Lipsitch","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA, USA"},{"name":"Department of Biology, Stanford University, Stanford, CA, USA"},{"name":"Center for International Security and Cooperation, Freeman-Spogli Institute, Stanford University, Stanford, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7799-1573","authenticated-orcid":false,"given":"Daniel","family":"Weissman","sequence":"additional","affiliation":[{"name":"Department of Physics, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7991-614X","authenticated-orcid":false,"given":"Rustom","family":"Antia","sequence":"additional","affiliation":[{"name":"Department of Biology, Emory University, Atlanta, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026030614202088000_2026.03.03.709287v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2006.00392.x"},{"key":"2026030614202088000_2026.03.03.709287v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa066092"},{"key":"2026030614202088000_2026.03.03.709287v1.3","doi-asserted-by":"crossref","unstructured":"R. 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