{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:13:56Z","timestamp":1772172836145,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008729","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NSF-NIFA Ecology and Evolution of Infectious Disease","award":["R01 AI149779"],"award-info":[{"award-number":["R01 AI149779"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    In malaria and several other important infectious diseases, high prevalence occurs concomitantly with incomplete immunity. This apparent paradox poses major challenges to malaria elimination in highly endemic regions, where asymptomatic\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    infections are present across all age classes creating a large reservoir that maintains transmission. This reservoir is in turn enabled by extreme antigenic diversity of the parasite and turnover of new variants. We present here the concept of a threshold in local pathogen diversification that defines a sharp transition in transmission intensity below which new antigen-encoding genes generated by either recombination or migration cannot establish. Transmission still occurs below this threshold, but diversity of these genes can neither accumulate nor recover from interventions that further reduce it. An analytical expectation for this threshold is derived and compared to numerical results from a stochastic individual-based model of malaria transmission that incorporates the major antigen-encoding multigene family known as\n                    <jats:italic>var<\/jats:italic>\n                    . This threshold corresponds to an \u201cinnovation\u201d number we call\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>div<\/jats:italic>\n                    <\/jats:sub>\n                    ; it is different from, and complementary to, the one defined by the classic basic reproductive number of infectious diseases,\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>0<\/jats:sub>\n                    , which does not readily is better apply under large and dynamic strain diversity. This new threshold concept can be exploited for effective malaria control and applied more broadly to other pathogens with large multilocus antigenic diversity.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1008729","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T00:12:00Z","timestamp":1613779920000},"page":"e1008729","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["An antigenic diversification threshold for falciparum malaria transmission at high endemicity"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1696-8203","authenticated-orcid":true,"given":"Qixin","family":"He","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3575-7233","authenticated-orcid":true,"given":"Mercedes","family":"Pascual","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"issue":"3","key":"pcbi.1008729.ref001","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1128\/IAI.40.3.985-994.1983","article-title":"Splenic requirement for antigenic variation and expression of the variant antigen on the erythrocyte membrane in cloned Plasmodium knowlesi malaria","volume":"40","author":"JW Barnwell","year":"1983","journal-title":"Infection and Immunity"},{"issue":"5","key":"pcbi.1008729.ref002","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1084\/jem.165.5.1269","article-title":"Antigenic variation of cloned Plasmodium fragile in its natural host Macaca sinica. 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within the multi-copy variant antigen gene families of Plasmodium falciparum","volume":"38","author":"M Frank","year":"2008","journal-title":"International Journal for Parasitology"},{"issue":"1","key":"pcbi.1008729.ref012","doi-asserted-by":"crossref","first-page":"11810","DOI":"10.1038\/s41598-017-11814-9","article-title":"Population genomics of virulence genes of Plasmodium falciparum in clinical isolates from Uganda","volume":"7","author":"S Ruybal-Pes\u00e1ntez","year":"2017","journal-title":"Scientific Reports"},{"issue":"1","key":"pcbi.1008729.ref013","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1038\/s41467-018-04219-3","article-title":"Networks of genetic similarity reveal non-neutral processes shape strain structure in Plasmodium falciparum","volume":"9","author":"Q He","year":"2018","journal-title":"Nature 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Deitsch","year":"1997","journal-title":"Microbiology and Molecular Biology Reviews"},{"issue":"1","key":"pcbi.1008729.ref017","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/s41577-018-0092-5","article-title":"Models of immune selection for multi-locus antigenic diversity of pathogens","volume":"19","author":"M Georgieva","year":"2019","journal-title":"Nature Reviews Immunology"},{"issue":"4","key":"pcbi.1008729.ref018","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1534\/genetics.104.036947","article-title":"Soft sweeps: molecular population genetics of adaptation from standing genetic variation","volume":"169","author":"J Hermisson","year":"2005","journal-title":"Genetics"},{"issue":"4","key":"pcbi.1008729.ref019","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nm0496-437","article-title":"The maintenance of strain structure in populations of recombining infectious agents","volume":"2","author":"S Gupta","year":"1996","journal-title":"Nature Medicine"},{"key":"pcbi.1008729.ref020","doi-asserted-by":"crossref","unstructured":"Ewens WJ. Mathematical population genetics. I, volume 27 of Interdisciplinary Applied Mathematics; 2004.","DOI":"10.1007\/978-0-387-21822-9"},{"issue":"3","key":"pcbi.1008729.ref021","doi-asserted-by":"crossref","first-page":"e1001306","DOI":"10.1371\/journal.ppat.1001306","article-title":"Antigenic variation in Plasmodium falciparum malaria involves a highly structured switching pattern","volume":"7","author":"M Recker","year":"2011","journal-title":"PLOS Pathogens"},{"key":"pcbi.1008729.ref022","doi-asserted-by":"crossref","first-page":"e00093","DOI":"10.7554\/eLife.00093","article-title":"Population structuring of multi-copy, antigen-encoding genes in Plasmodium falciparum","volume":"1:","author":"Y Artzy-Randrup","year":"2012","journal-title":"Elife"},{"issue":"1","key":"pcbi.1008729.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0025-5564(91)90037-J","article-title":"Mathematical biology of HIV infections: antigenic variation and diversity threshold","volume":"106","author":"MA Nowak","year":"1991","journal-title":"Mathematical Biosciences"},{"issue":"25","key":"pcbi.1008729.ref024","doi-asserted-by":"crossref","first-page":"10030","DOI":"10.1073\/pnas.1200841109","article-title":"Force of infection is key to understanding the epidemiology of Plasmodium falciparum malaria in Papua New Guinean children","volume":"109","author":"I Mueller","year":"2012","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"4","key":"pcbi.1008729.ref025","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3390\/v8040109","article-title":"Constraints on the genetic and antigenic variability of measles virus","volume":"8","author":"SM Beaty","year":"2016","journal-title":"Viruses"},{"key":"pcbi.1008729.ref026","doi-asserted-by":"crossref","first-page":"e35962","DOI":"10.7554\/eLife.35962","article-title":"Stochastic processes constrain the within and between host evolution of influenza virus","volume":"7","author":"JT McCrone","year":"2018","journal-title":"eLife"},{"issue":"6","key":"pcbi.1008729.ref027","doi-asserted-by":"crossref","first-page":"e2006459","DOI":"10.1371\/journal.pbio.2006459","article-title":"A speed\u2013fidelity trade-off determines the mutation rate and virulence of an RNA virus","volume":"16","author":"WJ Fitzsimmons","year":"2018","journal-title":"PLOS Biology"},{"issue":"2","key":"pcbi.1008729.ref028","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/genetics\/98.2.441","article-title":"Genetic variability maintained by mutation and overdominant selection in finite populations","volume":"98","author":"T Maruyama","year":"1981","journal-title":"Genetics"},{"issue":"7","key":"pcbi.1008729.ref029","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1073\/pnas.87.7.2419","article-title":"A simple genealogical structure of strongly balanced allelic lines and trans-species evolution of polymorphism","volume":"87","author":"N Takahata","year":"1990","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"3","key":"pcbi.1008729.ref030","doi-asserted-by":"crossref","first-page":"e1002380","DOI":"10.1371\/journal.pbio.1002380","article-title":"Tools and strategies for malaria control and elimination: what do we need to achieve a grand convergence in malaria?","volume":"14","author":"J Hemingway","year":"2016","journal-title":"PLOS Biology"},{"issue":"39","key":"pcbi.1008729.ref031","doi-asserted-by":"crossref","first-page":"15082","DOI":"10.1073\/pnas.0712019105","article-title":"Role of selection in the emergence of lineages and the evolution of virulence in Neisseria meningitidis","volume":"105","author":"CO Buckee","year":"2008","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"5365","key":"pcbi.1008729.ref032","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1126\/science.280.5365.912","article-title":"Chaos, persistence, and evolution of strain structure in antigenically diverse infectious agents","volume":"280","author":"S Gupta","year":"1998","journal-title":"Science"},{"issue":"6991","key":"pcbi.1008729.ref033","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/nature02486","article-title":"Transient cross-reactive immune responses can orchestrate antigenic variation in malaria","volume":"429","author":"M Recker","year":"2004","journal-title":"Nature"},{"issue":"8","key":"pcbi.1008729.ref034","doi-asserted-by":"crossref","first-page":"e1000324","DOI":"10.1371\/journal.pmed.1000324","article-title":"Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies","volume":"7","author":"JT Griffin","year":"2010","journal-title":"PLOS Medicine"},{"issue":"5","key":"pcbi.1008729.ref035","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.trstmh.2003.12.016","article-title":"Evaluating a malaria intervention strategy using knowledge, practices and coverage surveys in rural Bolifamba, southwest Cameroon","volume":"99","author":"TK Nkuo Akenji","year":"2005","journal-title":"Transactions of The Royal Society of Tropical Medicine and Hygiene"},{"issue":"6","key":"pcbi.1008729.ref036","doi-asserted-by":"crossref","first-page":"E189","DOI":"10.1086\/699535","article-title":"Multiscale immune selection and the transmission-diversity feedback in antigenically diverse pathogen systems","volume":"192","author":"T Holding","year":"2018","journal-title":"The American Naturalist"},{"issue":"37","key":"pcbi.1008729.ref037","doi-asserted-by":"crossref","first-page":"15504","DOI":"10.1073\/pnas.1102445108","article-title":"Role of stochastic processes in maintaining discrete strain structure in antigenically diverse pathogen populations","volume":"108","author":"CO Buckee","year":"2011","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1008729.ref038","doi-asserted-by":"crossref","unstructured":"Ozik J, Collier NT, Wozniak JM, Spagnuolo C. From desktop to large-scale model exploration with Swift\/T. In: 2016 Winter Simulation Conference (WSC); 2016. p. 206\u2013220.","DOI":"10.1109\/WSC.2016.7822090"},{"key":"pcbi.1008729.ref039","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/1471-2148-13-110","article-title":"Hypervariable antigen genes in malaria have ancient roots","volume":"13","author":"MM Zilversmit","year":"2013","journal-title":"BMC Evolutionary Biology"},{"issue":"6","key":"pcbi.1008729.ref040","doi-asserted-by":"crossref","first-page":"e3000336","DOI":"10.1371\/journal.pbio.3000336","article-title":"Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum","volume":"17","author":"S Pilosof","year":"2019","journal-title":"PLOS Biology"},{"issue":"4","key":"pcbi.1008729.ref041","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1007\/s11538-005-9041-0","article-title":"Conflicting immune responses can prolong the length of infection in Plasmodium falciparum 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