{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:09:59Z","timestamp":1768550999382,"version":"3.49.0"},"posted":{"date-parts":[[2020,11,24]]},"group-title":"Epidemiology","reference-count":40,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2020,11,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>While pathogens often evolve towards reduced virulence, many counterexamples are evident. When faced with a new pathogen, such as SARS-CoV-2, it is highly desirable to be able to forecast the case fatality rate (CFR) into the future. Considerable effort has been invested towards the development of a mathematical framework for predicting virulence evolution. Although these approaches accurately recapitulate some complex outcomes, most rely on an assumed trade-off between mortality and infectivity. It is often impractical to empirically validate this constraint for human pathogens.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Using a compartment model with parameters tuning the degree to which symptomatic individuals are isolated and the duration of immunity, we reveal kinetic constraints where the variation of multiple parameters in concert leads to decreased virulence and increased pathogen fitness, whereas independent variation of the parameters decreases pathogen fitness. Smallpox, SARS-CoV-2, and Influenza are analyzed as diverse representatives of human respiratory viruses. We show that highly virulent viruses, such as Smallpox, are likely often constrained by host behavior, whereas moderately virulent viruses, such as SARS-CoV-2, appear to be typically constrained by the relationship between the duration of immunity and CFR.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The evolution of human respiratory epidemics appears to be often kinetically constrained and a reduction in virulence should not be assumed. Our findings imply that, without continued public health intervention, SARS-CoV-2 is likely to continue presenting a substantial disease burden. The existence of a parameter regime admitting endemic equilibrium suggests that herd immunity is unachievable. However, we demonstrate that even partial isolation of symptomatic individuals can have a major effect not only by reducing the number of fatalities in the short term but also by potentially changing the evolutionary trajectory of the virus towards reduced virulence.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2020.11.23.20237503","type":"posted-content","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T21:57:14Z","timestamp":1606255034000},"source":"Crossref","is-referenced-by-count":6,"title":["Evolution of Human Respiratory Virus Epidemics"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7991-8505","authenticated-orcid":false,"given":"Nash D.","family":"Rochman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-8708","authenticated-orcid":false,"given":"Yuri I.","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3943-8299","authenticated-orcid":false,"given":"Eugene V.","family":"Koonin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"16","key":"2020112711500735000_2020.11.23.20237503v1.1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1098\/rsif.2006.0207","article-title":"The evolutionary epidemiology of vaccination","volume":"4","year":"2007","journal-title":"Journal of the Royal Society Interface"},{"key":"2020112711500735000_2020.11.23.20237503v1.2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2016.1170"},{"key":"2020112711500735000_2020.11.23.20237503v1.3","doi-asserted-by":"publisher","DOI":"10.1086\/419267"},{"key":"2020112711500735000_2020.11.23.20237503v1.4","doi-asserted-by":"publisher","DOI":"10.1086\/382548"},{"key":"2020112711500735000_2020.11.23.20237503v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/ele.12076"},{"key":"2020112711500735000_2020.11.23.20237503v1.6","doi-asserted-by":"publisher","DOI":"10.1017\/S003118201500092X"},{"key":"2020112711500735000_2020.11.23.20237503v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0055-5"},{"key":"2020112711500735000_2020.11.23.20237503v1.8","doi-asserted-by":"publisher","DOI":"10.1111\/j.1420-9101.2008.01658.x"},{"key":"2020112711500735000_2020.11.23.20237503v1.9","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182000055360"},{"key":"2020112711500735000_2020.11.23.20237503v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/414751a"},{"key":"2020112711500735000_2020.11.23.20237503v1.11","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2003.1414"},{"key":"2020112711500735000_2020.11.23.20237503v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/417609a"},{"issue":"6889","key":"2020112711500735000_2020.11.23.20237503v1.13","first-page":"610","article-title":"Antitoxin vaccines and pathogen virulence","volume":"417","year":"2002","journal-title":"Nature"},{"issue":"10","key":"2020112711500735000_2020.11.23.20237503v1.14","first-page":"15091516","article-title":"Viral shedding and clinical illness in naturally acquired influenza virus infections","volume":"201","year":"2010","journal-title":"The Journal of infectious diseases"},{"key":"2020112711500735000_2020.11.23.20237503v1.15","doi-asserted-by":"crossref","unstructured":"Bi Q et al. Epidemiology and transmission of covid-19 in 391 cases and 1286 of their close contacts in shenzhen, china: a retrospective cohort study. The Lancet Infectious Diseases, 2020.","DOI":"10.1016\/S1473-3099(20)30287-5"},{"key":"2020112711500735000_2020.11.23.20237503v1.16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-10-1"},{"key":"2020112711500735000_2020.11.23.20237503v1.17","doi-asserted-by":"publisher","DOI":"10.1017\/dmp.2015.38"},{"key":"2020112711500735000_2020.11.23.20237503v1.18","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00077-12"},{"key":"2020112711500735000_2020.11.23.20237503v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv263"},{"key":"2020112711500735000_2020.11.23.20237503v1.20","unstructured":"CDC. https:\/\/www.cdc.gov\/."},{"key":"2020112711500735000_2020.11.23.20237503v1.21","unstructured":"UpToDate. https:\/\/www.uptodate.com\/."},{"key":"2020112711500735000_2020.11.23.20237503v1.22","doi-asserted-by":"crossref","unstructured":"Song Y et al. Asymptomatic middle east respiratory syndrome coronavirus infection using a serologic survey in korea. Epidemiology and health, 2018;40..","DOI":"10.4178\/epih.e2018014"},{"issue":"8","key":"2020112711500735000_2020.11.23.20237503v1.23","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1098\/rsif.2006.0112","article-title":"Simple models for containment of a pandemic","volume":"3","year":"2006","journal-title":"Journal of the Royal Society Interface"},{"issue":"1","key":"2020112711500735000_2020.11.23.20237503v1.24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3934\/mbe.2006.3.1","article-title":"Some simple epidemic models","volume":"3","year":"2006","journal-title":"Mathematical Biosciences & Engineering"},{"issue":"5627","key":"2020112711500735000_2020.11.23.20237503v1.25","first-page":"19661970","article-title":"Transmission dynamics and control of severe acute respiratory syndrome","volume":"300","year":"2003","journal-title":"Science"},{"issue":"47","key":"2020112711500735000_2020.11.23.20237503v1.26","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1098\/rsif.2009.0386","article-title":"The construction of next-generation matrices for compartmental epidemic models","volume":"7","year":"2010","journal-title":"Journal of the Royal Society Interface"},{"issue":"3","key":"2020112711500735000_2020.11.23.20237503v1.27","first-page":"259","article-title":"Global stability of the endemic equilibrium of multigroup sir epidemic models","volume":"14","year":"2006","journal-title":"Canadian applied mathematics quarterly"},{"issue":"8","key":"2020112711500735000_2020.11.23.20237503v1.28","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1016\/j.camwa.2010.08.020","article-title":"Global stability of the endemic equilibrium of multigroup sir models with nonlinear incidence","volume":"60","year":"2010","journal-title":"Computers & Mathematics with Applications"},{"key":"2020112711500735000_2020.11.23.20237503v1.29","unstructured":"Inc. The MathWorks. Symbolic Math Toolbox. Natick, Massachusetts, United State, 2019."},{"key":"2020112711500735000_2020.11.23.20237503v1.30","doi-asserted-by":"crossref","unstructured":"M\u00fchlemann B et al. Diverse variola virus (smallpox) strains were widespread in northern europe in the viking age. Science, 2020;369(6502).","DOI":"10.1126\/science.aaw8977"},{"key":"2020112711500735000_2020.11.23.20237503v1.31","doi-asserted-by":"publisher","DOI":"10.3390\/v2091933"},{"key":"2020112711500735000_2020.11.23.20237503v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/417609a"},{"key":"2020112711500735000_2020.11.23.20237503v1.33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001769"},{"issue":"1","key":"2020112711500735000_2020.11.23.20237503v1.34","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/1745-6150-1-34","article-title":"Long intervals of stasis punctuated by bursts of positive selection in the seasonal evolution of influenza a virus","volume":"1","year":"2006","journal-title":"Biology direct"},{"key":"2020112711500735000_2020.11.23.20237503v1.35","doi-asserted-by":"crossref","unstructured":"Gong LI , Suchard MA , Bloom JD . Stability-mediated epistasis constrains the evolution of an influenza protein. Elife 2, 2013;e00631.","DOI":"10.7554\/eLife.00631"},{"key":"2020112711500735000_2020.11.23.20237503v1.36","first-page":"e1001301","article-title":"Prevalence of epistasis in the evolution of influenza A surface proteins","volume":"7.2","year":"2011","journal-title":"PLoS Genet"},{"key":"2020112711500735000_2020.11.23.20237503v1.37","doi-asserted-by":"crossref","unstructured":"Rochman ND et al. Ongoing Global and Regional Adaptive Evolution of SARS3 CoV-2. bioRxiv. 2020.","DOI":"10.1101\/2020.10.12.336644"},{"key":"2020112711500735000_2020.11.23.20237503v1.38","doi-asserted-by":"crossref","unstructured":"Y. Zhang et al. The ORF8 Protein of SARS-CoV-2 Mediates Immune Evasion through Potently Downregulating MHC-I. bioRxiv. 2020.","DOI":"10.1101\/2020.05.24.111823"},{"key":"2020112711500735000_2020.11.23.20237503v1.39","first-page":"812","article-title":"Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus","volume":"182.4","year":"2020","journal-title":"Cell"},{"key":"2020112711500735000_2020.11.23.20237503v1.40","doi-asserted-by":"crossref","unstructured":"Tan Y , Schneider T , Leong M , Aravind L , Zhang D. Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis of SARS-CoV-2-Related Viruses. Mbio. 2020;30;11(3).","DOI":"10.1128\/mBio.00760-20"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2020.11.23.20237503","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T13:59:39Z","timestamp":1768485579000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2020.11.23.20237503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":40,"URL":"https:\/\/doi.org\/10.1101\/2020.11.23.20237503","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.12688\/f1000research.53392.1","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2020,11,24]]},"subtype":"preprint"}}