{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:04:41Z","timestamp":1775606681993,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009801","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,14]],"date-time":"2022-02-14T00:00:00Z","timestamp":1644796800000}}],"reference-count":108,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T00:00:00Z","timestamp":1643760000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"national health and medical research council","doi-asserted-by":"publisher","award":["GNT1161066"],"award-info":[{"award-number":["GNT1161066"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U19AI129392"],"award-info":[{"award-number":["U19AI129392"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"national health and medical research council","doi-asserted-by":"publisher","award":["GNT1102971"],"award-info":[{"award-number":["GNT1102971"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"national health and medical research council","doi-asserted-by":"publisher","award":["GNT1155075"],"award-info":[{"award-number":["GNT1155075"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite,\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    , have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene \u2018haplotypes\u2019 from the global dataset and a new R-package named\n                    <jats:italic>VaxPack<\/jats:italic>\n                    was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including\n                    <jats:italic>csp<\/jats:italic>\n                    ,\n                    <jats:italic>trap<\/jats:italic>\n                    ,\n                    <jats:italic>eba175<\/jats:italic>\n                    ,\n                    <jats:italic>ama1<\/jats:italic>\n                    ,\n                    <jats:italic>rh5<\/jats:italic>\n                    , and\n                    <jats:italic>CelTOS<\/jats:italic>\n                    . Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of\n                    <jats:italic>P<\/jats:italic>\n                    .\n                    <jats:italic>falciparum<\/jats:italic>\n                    antigens to be considered in the design of the next generation of malaria vaccines.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009801","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T13:42:48Z","timestamp":1643809368000},"page":"e1009801","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens"],"prefix":"10.1371","volume":"18","author":[{"given":"Myo T.","family":"Naung","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7961-2795","authenticated-orcid":true,"given":"Elijah","family":"Martin","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2751-0989","authenticated-orcid":true,"given":"Jacob","family":"Munro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0507-3204","authenticated-orcid":true,"given":"Somya","family":"Mehra","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0376-2329","authenticated-orcid":true,"given":"Andrew J.","family":"Guy","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0964-805X","authenticated-orcid":true,"given":"Moses","family":"Laman","sequence":"additional","affiliation":[]},{"given":"G. 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Abby","family":"Harrison","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7962-4320","authenticated-orcid":true,"given":"Livingstone","family":"Tavul","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5285-3254","authenticated-orcid":true,"given":"Manuel","family":"Hetzel","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5023-0176","authenticated-orcid":true,"given":"Dominic","family":"Kwiatkowski","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6554-6889","authenticated-orcid":true,"given":"Ivo","family":"Mueller","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5132-0774","authenticated-orcid":true,"given":"Melanie","family":"Bahlo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1189-2310","authenticated-orcid":true,"given":"Alyssa E.","family":"Barry","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,2,2]]},"reference":[{"key":"pcbi.1009801.ref001","doi-asserted-by":"crossref","first-page":"e1001283","DOI":"10.1371\/journal.ppat.1001283","article-title":"A Fresh Look at the Origin of Plasmodium falciparum, the Most Malignant Malaria Agent","volume":"7","author":"F Prugnolle","year":"2011","journal-title":"PLOS Pathog"},{"key":"pcbi.1009801.ref002","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1093\/molbev\/msu106","article-title":"Genome-Wide Analysis of Selection on the Malaria Parasite Plasmodium falciparum in West African Populations of Differing Infection Endemicity","volume":"31","author":"VA Mobegi","year":"2014","journal-title":"Mol Biol Evol"},{"key":"pcbi.1009801.ref003","first-page":"356","article-title":"Resistance to malaria through structural variation of red blood cell invasion receptors","author":"EM Leffler","year":"2017","journal-title":"Science"},{"key":"pcbi.1009801.ref004","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.immuni.2010.10.005","article-title":"Malaria vaccine design: immunological considerations","volume":"33","author":"MF Good","year":"2010","journal-title":"Immunity"},{"key":"pcbi.1009801.ref005","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/femsre\/fuv046","article-title":"The immunological balance between host and parasite in malaria","volume":"40","author":"K Deroost","year":"2016","journal-title":"FEMS Microbiol Rev"},{"key":"pcbi.1009801.ref006","doi-asserted-by":"crossref","first-page":"eaau1458","DOI":"10.1126\/scitranslmed.aau1458","article-title":"Challenges and strategies for developing efficacious and long-lasting malaria vaccines","volume":"11","author":"JG Beeson","year":"2019","journal-title":"Sci Transl Med."},{"key":"pcbi.1009801.ref007","doi-asserted-by":"crossref","first-page":"6622","DOI":"10.1038\/s41598-018-24585-8","article-title":"RTS,S\/AS01 malaria vaccine mismatch observed among Plasmodium falciparum isolates from southern and central Africa and globally","volume":"8","author":"JC Pringle","year":"2018","journal-title":"Sci Rep"},{"key":"pcbi.1009801.ref008","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1086\/339342","article-title":"A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea","volume":"185","author":"B Genton","year":"2002","journal-title":"J Infect Dis"},{"key":"pcbi.1009801.ref009","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41591-020-1118-7","article-title":"A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial","volume":"27","author":"R Nachbagauer","year":"2021","journal-title":"Nature Medicine"},{"key":"pcbi.1009801.ref010","unstructured":"Pf3k pilot data release 5 | MalariaGEN. 2020. 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