{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T20:28:51Z","timestamp":1770841731043,"version":"3.50.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1060785, 637406, 1166753, 1173046, 1196068, 1134989"],"award-info":[{"award-number":["1060785, 637406, 1166753, 1173046, 1196068, 1134989"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009860","name":"Ramaciotti Foundations","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009860","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001047","name":"Ian Potter Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004752","name":"State Government of Victoria","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004752","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000278","name":"Department for International Development, UK Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000278","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Understanding the human immune response to <jats:italic>Plasmodium falciparum<\/jats:italic> gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking vaccine candidates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant <jats:italic>P. falciparum<\/jats:italic> gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates <jats:italic>Pf<\/jats:italic>s230 (<jats:italic>Pf<\/jats:italic>s230c and <jats:italic>Pf<\/jats:italic>s230D1M) and <jats:italic>Pf<\/jats:italic>s48\/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Microscopy detectable gametocytemia was observed in 11% (127\/1,114) of participants at enrolment, and an additional 9% (95\/1,114) over the follow-up period (up to day 42) (total 20% of participants [222\/1,114]). IgG levels in response to <jats:italic>Pf<\/jats:italic>s230c, <jats:italic>Pf<\/jats:italic>s48\/45 and <jats:italic>Pf<\/jats:italic>s230D1M varied across study sites at enrolment (<jats:italic>p &amp;lt; 0.001<\/jats:italic>), as did IgG seroprevalence for anti-<jats:italic>Pf<\/jats:italic>s230c and D1M IgG (<jats:italic>p &amp;lt; 0.001<\/jats:italic>), but not for anti-<jats:italic>Pf<\/jats:italic>s48\/45 IgG (<jats:italic>p = 0.159<\/jats:italic>). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (<jats:italic>Pf<\/jats:italic>s230c OR [95% CI], <jats:italic>p<\/jats:italic>: 1.70 [1.10, 2.62], <jats:italic>0.017<\/jats:italic>; <jats:italic>Pf<\/jats:italic>s48\/45: 1.45 [0.85, 2.46], <jats:italic>0.174<\/jats:italic>; <jats:italic>Pf<\/jats:italic>s230D1M: 1.70 [1.03, 2.80], <jats:italic>0.037<\/jats:italic>), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density <jats:italic>Pf<\/jats:italic>s230c OR [95% CI], <jats:italic>p<\/jats:italic>: 1.09 [1.02, 1.17], <jats:italic>0.008<\/jats:italic>; <jats:italic>Pf<\/jats:italic>s48\/45: 1.05 [0.98, 1.13], <jats:italic>0.185<\/jats:italic>; <jats:italic>Pf<\/jats:italic>s230D1M: 1.07 [0.99, 1.14], <jats:italic>0.071<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Pf<\/jats:italic>s230 and <jats:italic>Pf<\/jats:italic>s48\/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant <jats:italic>P. falciparum<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.804470","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T11:00:16Z","timestamp":1649329216000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Anti-Gametocyte Antigen Humoral Immunity and Gametocytemia During Treatment of Uncomplicated Falciparum Malaria: A Multi-National Study"],"prefix":"10.3389","volume":"12","author":[{"given":"Katherine","family":"O\u2019Flaherty","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo-Anne","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia C.","family":"Cutts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie G.","family":"Zaloumis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth A.","family":"Ashley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aung Pyae","family":"Phyo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damien R.","family":"Drew","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjen M.","family":"Dondorp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas P.","family":"Day","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehul","family":"Dhorda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rick M.","family":"Fairhurst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pharath","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chanaki","family":"Amaratunga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sasithon","family":"Pukrittayakamee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tran Tinh","family":"Hien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ye","family":"Htut","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayfong","family":"Mayxay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Abul","family":"Faiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olugbenga A.","family":"Mokuolu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie A.","family":"Onyamboko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Fanello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eizo","family":"Takashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Tsuboi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Theisen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Nosten","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James G.","family":"Beeson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie A.","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas J.","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freya J. I.","family":"Fowkes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of Artemisinin Resistance in Plasmodium Falciparum Malaria","volume":"371","author":"Ashley","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1615875114","article-title":"Host Immunity to Plasmodium Falciparum and the Assessment of Emerging Artemisinin Resistance in a Multinational Cohort","author":"Ataide","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau1458","article-title":"Challenges and Strategies for Developing Efficacious and Long-Lasting Malaria Vaccines","volume":"11","author":"Beeson","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1093\/infdis\/jit431","article-title":"Residual Plasmodium Falciparum Parasitemia in Kenyan Children After Artemisinin-Combination Therapy Is Associated With Increased Transmission to Mosquitoes and Parasite Recurrence","volume":"208","author":"Beshir","year":"2013","journal-title":"J. Infect. Dis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1111\/j.1365-3024.2007.00948.x","article-title":"A Longitudinal Study of Immune Responses to Plasmodium Falciparum Sexual Stage Antigens in Tanzanian Adults","volume":"29","author":"Bousema","year":"2007","journal-title":"Parasite Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e14114","DOI":"10.1371\/journal.pone.0014114","article-title":"The Dynamics of Naturally Acquired Immune Responses to Plasmodium Falciparum Sexual Stage Antigens Pfs230 & Pfs48\/45 in a Low Endemic Area in Tanzania","volume":"5","author":"Bousema","year":"2010","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"425","DOI":"10.4269\/ajtmh.2006.74.425","article-title":"Rapid Onset of Transmission-Reducing Antibodies in Javanese Migrants Exposed to Malaria in Papua, Indonesia","volume":"74","author":"Bousema","year":"2006","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03126","article-title":"Low Levels of Human Antibodies to Gametocyte-Infected Erythrocytes Contrasts the PfEMP1-Dominant Response to Asexual Stages in P. Falciparum Malaria","volume":"9","author":"Chan","year":"2018","journal-title":"Front. Immunol."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav3963","article-title":"Naturally Acquired Immunity Against Immature Plasmodium Falciparum Gametocytes","volume":"11","author":"Dantzler","year":"2019","journal-title":"Sci.\u00a0Transl. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1111\/j.1365-3024.2005.00818.x","article-title":"Transmission-Reducing Immunity Is Inversely Related to Age in Plasmodium Falciparum Gametocyte Carriers","volume":"28","author":"Drakeley","year":"2006","journal-title":"Parasite Immunol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1111\/j.0141-9838.2004.00696.x","article-title":"Parasite Infectivity and Immunity to Plasmodium Falciparum Gametocytes in Gambian Children","volume":"26","author":"Drakeley","year":"2004","journal-title":"Parasite Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1111\/j.1365-2958.2006.05284.x","article-title":"Malaria Transmission-Blocking Antigen, Pfs230, Mediates Human Red Blood Cell Binding to Exflagellating Male Parasites and Oocyst Production","volume":"61","author":"Eksi","year":"2006","journal-title":"Mol. Microbiol."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-339","article-title":"Standardizing the Measurement of Parasite Clearance in Falciparum Malaria: The Parasite Clearance Estimator","volume":"10","author":"Flegg","year":"2011","journal-title":"Malar. J."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/jci146221","article-title":"Pfs230 Yields Higher Malaria Transmission-Blocking Vaccine Activity Than Pfs25 in Humans But Not Mice","volume":"131","author":"Healy","year":"2021","journal-title":"J. Clin. Invest."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1016\/s1473-3099(20)30228-0","article-title":"Molecular Epidemiology of Resistance to Antimalarial Drugs in the Greater Mekong Subregion: An Observational Study","volume":"20","author":"Imwong","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.jinf.2015.03.007","article-title":"Naturally Acquired Antibody Responses to Recombinant Pfs230 and Pfs48\/45 Transmission Blocking Vaccine Candidates","volume":"71","author":"Jones","year":"2015","journal-title":"J. Infect."},{"key":"B17","doi-asserted-by":"publisher","first-page":"19913","DOI":"10.1074\/jbc.M116.732305","article-title":"Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium Falciparum Sexual Stage Protein Pfs230","volume":"291","author":"MacDonald","year":"2016","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"4377","DOI":"10.1128\/iai.01056-13","article-title":"Functional Comparison of Plasmodium Falciparum Transmission-Blocking Vaccine Candidates by the Standard Membrane-Feeding Assay","volume":"81","author":"Miura","year":"2013","journal-title":"Infect. Immun."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.4269\/ajtmh.1999.60.1019","article-title":"Risk Factors for Gametocyte Carriage in Uncomplicated Falciparum Malaria","volume":"60","author":"Price","year":"1999","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B20","doi-asserted-by":"publisher","first-page":"470","DOI":"10.4269\/ajtmh.2007.76.470","article-title":"Submicroscopic Plasmodium Falciparum Gametocyte Densities Frequently Result in Mosquito Infection","volume":"76","author":"Schneider","year":"2007","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B21","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1111\/j.1365-3156.2007.01821.x","article-title":"Submicroscopic Plasmodium Falciparum Gametocyte Carriage Is Common in an Area of Low and Seasonal Transmission in Tanzania","volume":"12","author":"Shekalaghe","year":"2007","journal-title":"Trop. Med. Int. Health"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1016\/j.vaccine.2015.02.040","article-title":"A Plasmodium Falciparum 48\/45 Single Epitope R0.6C Subunit Protein Elicits High Levels of Transmission Blocking Antibodies","volume":"33","author":"Singh","year":"2015","journal-title":"Vaccine"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4229","DOI":"10.1128\/iai.00644-15","article-title":"Plasmodium Falciparum Gametocyte-Specific Antibody Profiling Reveals Boosting Through Natural Infection and Identifies Potential Markers of Gametocyte Exposure","volume":"83","author":"Skinner","year":"2015","journal-title":"Infect. Immun."},{"key":"B24","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/s41467-017-02646-2","article-title":"Unravelling the Immune Signature of Plasmodium Falciparum Transmission-Reducing Immunity","volume":"9","author":"Stone","year":"2018","journal-title":"Nat. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1017\/s0031182015001341","article-title":"Naturally Acquired Immunity to Sexual Stage P. Falciparum Parasites","volume":"143","author":"Stone","year":"2016","journal-title":"Parasitology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1016\/s1473-3099(21)00142-0","article-title":"Association of Plasmodium Falciparum Kelch13 R561H Genotypes With Delayed Parasite Clearance in Rwanda: An Open-Label, Single-Arm, Multicentre, Therapeutic Efficacy Study","volume":"21","author":"Uwimana","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/j.ijpara.2006.05.004","article-title":"Reduction and Enhancement of Plasmodium Falciparum Transmission by Endemic Human Sera","volume":"36","author":"van der Kolk","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s0092-8674(01)00199-4","article-title":"A Central Role for P48\/45 in Malaria Parasite Male Gamete Fertility","volume":"104","author":"van Dijk","year":"2001","journal-title":"Cell"},{"key":"B29","volume-title":"Eliminating Malaria in the Greater Mekong Subregion","year":"2016"},{"key":"B30","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s12916-016-0621-7","article-title":"Gametocyte Carriage in Uncomplicated Plasmodium Falciparum Malaria Following Treatment With Artemisinin Combination Therapy: A Systematic Review and Meta-Analysis of Individual Patient Data","volume":"14","year":"2016","journal-title":"BMC Med."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.804470\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T11:00:21Z","timestamp":1649329221000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.804470\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,7]]},"references-count":30,"alternative-id":["10.3389\/fcimb.2022.804470"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.804470","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,7]]},"article-number":"804470"}}