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Here we identify specific requirements for a new class of models simulating pandemics across three scales: (1) pathogen evolution, often punctuated by the rapid emergence of new variants, (2) human interactions within a heterogeneous population, and (3) public health responses which constrain individual actions to control the disease transmission. We then present a pandemic modelling framework satisfying these requirements and capable of simulating feedback loops between dynamics unfolding at these different scales. The developed framework comprises a stochastic agent-based model of pandemic spread, coupled with a phylodynamic model that incorporates within-host pathogen evolution. It is validated with a case study, modelling the punctuated evolution of SARS-CoV-2, based on global and contemporary genomic surveillance data, which captures a large heterogeneous population. We demonstrate that the model replicates the essential features of the COVID-19 pandemic and virus evolution, while retaining computational tractability and scalability.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013295","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T17:33:03Z","timestamp":1752514383000},"page":"e1013295","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-scale phylodynamic modelling of rapid punctuated pathogen evolution"],"prefix":"10.1371","volume":"21","author":[{"given":"Quang Dang","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6119-828X","authenticated-orcid":true,"given":"Sheryl L.","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7021-9380","authenticated-orcid":true,"given":"Carl J. 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