{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:09:07Z","timestamp":1774645747730,"version":"3.50.1"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T00:00:00Z","timestamp":1612310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009053","name":"Bill and Melinda Gates Institute for Population and Reproductive Health","doi-asserted-by":"publisher","award":["OPP1034789"],"award-info":[{"award-number":["OPP1034789"]}],"id":[{"id":"10.13039\/100009053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["092741"],"award-info":[{"award-number":["092741"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107769"],"award-info":[{"award-number":["107769"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107499"],"award-info":[{"award-number":["107499"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Malaria caused by <jats:italic>Plasmodium falciparum<\/jats:italic> remains a serious global public health challenge especially in Africa. Interventions that aim to reduce malaria transmission by targeting the gametocyte reservoir are key to malaria elimination and\/or eradication. However, factors that are associated with gametocyte carriage have not been fully explored. Consequently, identifying predictors of the infectious reservoir is fundamental in the elimination campaign.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We cultured <jats:italic>P. falciparum<\/jats:italic> NF54 gametocytes (to stage V) and prepared crude gametocyte extract. Samples from a total of 687 participants (aged 6 months to 67 years) representing two cross-sectional study cohorts in Kilifi, Kenya were used to assess IgG antibody responses by ELISA. We also analyzed IgG antibody responses to the blood-stage antigen AMA1 as a marker of asexual parasite exposure. Gametocytemia and asexual parasitemia data quantified by microscopy and molecular detection (QT-NASBA) were used to determine the relationship with antibody responses, season, age, and transmission setting. Multivariable logistic regression models were used to study the association between antibody responses and gametocyte carriage. The predictive power of the models was tested using the receiver operating characteristic (ROC) curve.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Multivariable logistic regression analysis showed that IgG antibody response to crude gametocyte extract predicted both microscopic (OR=1.81 95% CI: 1.06\u20133.07, <jats:italic>p<\/jats:italic>=0.028) and molecular (OR=1.91, 95% CI: 1.11\u20133.29, <jats:italic>p<\/jats:italic>=0.019) <jats:italic>P. falciparum<\/jats:italic> gametocyte carriage. Antibody responses to AMA1 were also associated with both microscopic (OR=1.61 95% CI: 1.08\u20132.42, <jats:italic>p<\/jats:italic>=0.020) and molecular (OR=3.73 95% CI: 2.03\u20136.74, <jats:italic>p<\/jats:italic>&amp;lt;0.001) gametocytemia. ROC analysis showed that molecular (AUC=0.897, 95% CI: 0.868\u20130.926) and microscopic (AUC=0.812, 95% CI: 0.758\u20130.865) multivariable models adjusted for gametocyte extract showed very high predictive power. Molecular (AUC=0.917, 95% CI: 0.891\u20130.943) and microscopic (AUC=0.806, 95% CI: 0.755\u20130.858) multivariable models adjusted for AMA1 were equally highly predictive.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In our study, it appears that IgG responses to crude gametocyte extract are not an independent predictor of gametocyte carriage after adjusting for AMA1 responses but may predict gametocyte carriage as a proxy marker of exposure to parasites. Serological responses to AMA1 or to gametocyte extract may facilitate identification of individuals within populations who contribute to malaria transmission and support implementation of transmission-blocking interventions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.609474","type":"journal-article","created":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T06:53:50Z","timestamp":1612335230000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Antibody Responses to Crude Gametocyte Extract Predict Plasmodium falciparum Gametocyte Carriage in Kenya"],"prefix":"10.3389","volume":"11","author":[{"given":"Brian R.","family":"Omondi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle K.","family":"Muthui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William I.","family":"Muasya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedict","family":"Orindi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramadhan S.","family":"Mwakubambanya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teun","family":"Bousema","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Drakeley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Marsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip","family":"Bejon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa C.","family":"Kapulu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,3]]},"reference":[{"key":"B1","volume-title":"World Malaria Report.","year":"2018"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004871","article-title":"Targeting Human Transmission Biology for Malaria Elimination","volume":"11","author":"Nilsson","year":"2015","journal-title":"PLoS Pathog"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e1000398","DOI":"10.1371\/journal.pmed.1000398","article-title":"A research agenda for malaria eradication: vaccines","volume":"8","year":"2011","journal-title":"PLoS Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1645\/0022-3395(2002)088[0097:DHCHAS]2.0.CO;2","article-title":"Decreased hemoglobin concentrations, hyperparasitemia, and severe malaria are associated with increased Plasmodium falciparum gametocyte carriage","volume":"88","author":"Nacher","year":"2002","journal-title":"J Parasitol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/jci98012","article-title":"A controlled human malaria infection model enabling evaluation of transmission-blocking interventions","volume":"128","author":"Collins","year":"2018","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(71)90036-8","article-title":"Evidence for cyclic development and short-lived maturity in the gametocytes of Plasmodium falciparum","volume":"65","author":"Hawking","year":"1971","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-08-520767","article-title":"Molecular evidence for the localization of Plasmodium falciparum immature gametocytes in bone marrow","volume":"123","author":"Aguilar","year":"2014","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aat3775","article-title":"Plasmodium gametocytes display homing and vascular transmigration in the host bone marrow","volume":"4","author":"De Niz","year":"2018","journal-title":"Sci Adv"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00625-18","article-title":"Bone Marrow Is a Major Parasite Reservoir in Plasmodium vivax Infection","volume":"9","author":"Obaldia","year":"2018","journal-title":"mBio"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-4758(97)89810-9","article-title":"Why so few transmission stages? Reproductive restraint by malaria parasites","volume":"13","author":"Taylor","year":"1997","journal-title":"Parasitol Today"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01270-4","article-title":"Examining the human infectious reservoir for Plasmodium falciparum malaria in areas of differing transmission intensity","volume":"8","author":"Gon\u00e7alves","year":"2017","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1128\/CMR.00051-10","article-title":"Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination","volume":"24","author":"Bousema","year":"2011","journal-title":"Clin Microbiol Rev"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2006.01.002","article-title":"(Sub)microscopic Plasmodium falciparum gametocytaemia in Kenyan children after treatment with sulphadoxine-pyrimethamine monotherapy or in combination with artesunate","volume":"36","author":"Schneider","year":"2006","journal-title":"Int J Parasitol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.molbiopara.2004.03.018","article-title":"Quantification of Plasmodium falciparum gametocytes in differential stages of development by quantitative nucleic acid sequence-based amplification","volume":"137","author":"Schneider","year":"2004","journal-title":"Mol Biochem Parasitol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-016-1584-z","article-title":"Comparison of molecular quantification of Plasmodium falciparum gametocytes by Pfs25 qRT-PCR and QT-NASBA in relation to mosquito infectivity","volume":"15","author":"Pett","year":"2016","journal-title":"Malaria J"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008410","article-title":"Substantial contribution of submicroscopical Plasmodium falciparum gametocyte carriage to the infectious reservoir in an area of seasonal transmission","volume":"4","author":"Ou\u00e9draogo","year":"2009","journal-title":"PLoS One"},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","first-page":"66","DOI":"10.12688\/wellcomeopenres.15186.2","article-title":"Gametocyte carriage in an era of changing malaria epidemiology: A 19-year analysis of a malaria longitudinal cohort","volume":"4","author":"Muthui","year":"2019","journal-title":"Wellcome Open Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-13-265","article-title":"Longitudinal study on Plasmodium falciparum gametocyte carriage following artemether-lumefantrine administration in a cohort of children aged 12-47 months living in Western Kenya, a high transmission area","volume":"13","author":"Andagalu","year":"2014","journal-title":"Malaria J"},{"key":"B20","doi-asserted-by":"publisher","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":"B21","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1038\/s41598-017-18840-7","article-title":"Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites","volume":"8","author":"Meerstein-Kessel","year":"2018","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0126747","DOI":"10.1371\/journal.pone.0126747","article-title":"Blood-Stage Parasitaemia and Age Determine Plasmodium falciparum and P. vivax Gametocytaemia in Papua New Guinea","volume":"10","author":"Koepfli","year":"2015","journal-title":"PLoS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0076316","article-title":"Strategies for Detection of Plasmodium species Gametocytes","volume":"8","author":"Wampfler","year":"2013","journal-title":"PLoS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-3-18","article-title":"Plasmodium falciparum gametocyte carriage in asymptomatic children in western Kenya","volume":"3","author":"Bousema","year":"2004","journal-title":"Malaria J"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2018.02.009","article-title":"Plasmodium Gametocytes in Field Studies: Do We Measure Commitment to Transmission or Detectability","volume":"34","author":"Koepfli","year":"2018","journal-title":"Trends Parasitol"},{"key":"B26","volume-title":"Guidelines for the treatment of malaria.","year":"2015"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1086\/430006","article-title":"Case definitions of clinical malaria under different transmission conditions in Kilifi District, Kenya","volume":"191","author":"Mwangi","year":"2005","journal-title":"J Infect Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pctr.0010029","article-title":"A phase 2b randomised trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya","volume":"1","author":"Bejon","year":"2006","journal-title":"PLoS Clin Trials"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0128792","DOI":"10.1371\/journal.pone.0128792","article-title":"Changing Malaria Prevalence on the Kenyan Coast since 1974: Climate, Drugs and Vector Control","volume":"10","author":"Snow","year":"2015","journal-title":"PLoS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-1-62703-026-7_2","article-title":"Production of Plasmodium falciparum gametocytes in vitro","volume":"923","author":"Saliba","year":"2013","journal-title":"Methods Mol Biol (Clifton N.J.)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2004.05.031","article-title":"Human antibodies to recombinant protein constructs of Plasmodium falciparum Apical Membrane Antigen 1 (AMA1) and their associations with protection from malaria","volume":"23","author":"Polley","year":"2004","journal-title":"Vaccine"},{"key":"B32","volume-title":"R: A Language and Environment for Statistical Computing","year":"2019"},{"key":"B33","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1002\/9781118548387.ch5","volume-title":"Assessing the Fit of the Model, in Applied Logistic Regression. 3rd Edition","author":"Hosmer","year":"2013"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s12936-016-1587-9","article-title":"High prevalence of Plasmodium falciparum gametocyte infections in school-age children using molecular detection: patterns and predictors of risk from a cross-sectional study in southern Malawi","volume":"15","author":"Coalson","year":"2016","journal-title":"Malaria J"},{"key":"B35","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1186\/1475-2875-9-281","article-title":"The plasticity of Plasmodium falciparum gametocytaemia in relation to age in Burkina Faso","volume":"9","author":"Ouedraogo","year":"2010","journal-title":"Malar J"},{"key":"B36","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1046\/j.0141-9838.2001.00440.x","article-title":"Naturally acquired immunoglobulin (Ig)G subclass antibodies to crude asexual Plasmodium falciparum lysates: evidence for association with protection for IgG1 and disease for IgG2","volume":"24","author":"Ndungu","year":"2002","journal-title":"Parasite Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2174\/156652406776055140","article-title":"Sexual-stage antibody responses to P. falciparum in endemic populations","volume":"6","author":"Bousema","year":"2006","journal-title":"Curr Mol Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1992.46.711","article-title":"Human antibody responses to epitopes on the Plasmodium falciparum gametocyte antigen PFS 48\/45 and their relationship to infectivity of gametocyte carriers","volume":"46","author":"Graves","year":"1992","journal-title":"Am J Trop Med Hyg"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02174.x","article-title":"The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology","volume":"133","author":"Artavanis-Tsakonas","year":"2003","journal-title":"Clin Exp Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmedaav3963","article-title":"Naturally acquired immunity against immature Plasmodium falciparum gametocytes","volume":"11","author":"Dantzler","year":"2019","journal-title":"Sci Transl Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan4479","article-title":"A saliva-based rapid test to quantify the infectious subclinical malaria parasite\u00a0reservoir","volume":"11","author":"Tao","year":"2019","journal-title":"Sci Transl Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12323","article-title":"Antibody responses to surface antigens of Plasmodium falciparum gametocyte-infected erythrocytes and their relation to gametocytaemia","volume":"38","author":"Dinko","year":"2016","journal-title":"Parasite Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002280","article-title":"Plasmodium falciparum antigens on the surface of the gametocyte-infected erythrocyte","volume":"3","author":"Saeed","year":"2008","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","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":"B45","doi-asserted-by":"publisher","DOI":"10.1128\/iai.05288-11","article-title":"Naturally acquired immune responses to Plasmodium falciparum sexual stage antigens Pfs48\/45 and Pfs230 in an area of seasonal transmission","volume":"79","author":"Ouedraogo","year":"2011","journal-title":"Infect Immun"},{"key":"B46","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0035-9203(90)90369-p","article-title":"Seasonal fluctuation of Plasmodium falciparum gametocytaemia","volume":"84","author":"Rosenberg","year":"1990","journal-title":"Trans R Soc Trop Med Hyg"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.609474\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,3]],"date-time":"2021-02-03T06:53:57Z","timestamp":1612335237000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.609474\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,3]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2020.609474"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.609474","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,3]]},"article-number":"609474"}}