{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T02:53:05Z","timestamp":1784947985888,"version":"3.55.0"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Pregnant women infected with <jats:italic>Plasmodium falciparum<\/jats:italic> often produce antibodies (<jats:bold>Abs<\/jats:bold>) to VAR2CSA, a ligand that binds to placental chondroitin sulfate A causing placental malaria (<jats:bold>PM<\/jats:bold>). Antibodies to VAR2CSA are associated with improved pregnancy outcomes. Antibody avidity is a surrogate marker for the extent of maturation of the humoral immune response. Little is known about high avidity Abs to VAR2CSA for women living in urban African cities. Therefore, this study sought to determine: i) if high avidity Abs to full-length VAR2CSA (<jats:bold>FV2<\/jats:bold>) increase with gravidity in women in Yaound\u00e9, Cameroon exposed to ~ 0.3-1.1 infectious mosquito bites per month, ii) if high avidity Abs to FV2 are directed against a specific region of VAR2CSA, and iii) if having high avidity Abs to FV2 improve pregnancy outcomes. Plasma samples collected at delivery from 695 women who had Abs to FV2 were evaluated. Ab levels and the Avidity Index (<jats:bold>AI<\/jats:bold>), defined as the percent Abs remaining bound to FV2 after incubation with 3M NH<jats:sub>4<\/jats:sub>SCN, were determined. Similar Ab levels to FV2 were present in women of all gravidities (G1 through 6+; <jats:italic>p<\/jats:italic>=0.80), except significantly lower levels were detected in PM\u2212negative (PM\u2212) primigravidae (<jats:italic>p &amp;lt;<\/jats:italic>0.001). Median Ab avidities increased between gravidity 1 and 2 (<jats:italic>p<\/jats:italic>&amp;lt;0.001) and remained stable thereafter (G3-G6+: <jats:italic>p<\/jats:italic>=0.51). These results suggest that B cell clonal expansion began during the first pregnancy, with clonal selection primarily occurring during the second. However, the majority of women (84%) had AI &amp;lt;35, a level of high avidity Abs previously reported to be associated with improved pregnancy outcomes. When plasma from 107 Cameroonian women was tested against 8 different regions of FV2, high avidity Abs were predominately restricted to DBL5 with median AI of 50 compared to AI &amp;lt;25 for the other domains. The only significance influence of high avidity Abs on pregnancy outcome was that babies born to mothers with AI above the median were 104\u00a0g heavier than babies born to women with AI below the median (<jats:italic>p<\/jats:italic>=0.045). These results suggest that a vaccine that boosts maturation of the immune response to VAR2CSA may be beneficial for women residing in urban areas.<\/jats:p>","DOI":"10.3389\/fimmu.2021.610108","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T07:28:52Z","timestamp":1614324532000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The Development, Fine Specificity, and Importance of High-Avidity Antibodies to VAR2CSA in Pregnant Cameroonian Women Living in Yaound\u00e9, an Urban City"],"prefix":"10.3389","volume":"12","author":[{"given":"Koko","family":"Vanda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naveen","family":"Bobbili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masako","family":"Matsunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Salanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rose F. G.","family":"Leke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane Wallace","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/S1473-3099(07)70021-X","article-title":"Epidemiology and burden of malaria in pregnancy","volume":"7","author":"Desai","year":"2007","journal-title":"Lancet Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2003.10.019","article-title":"The sick placenta - The role of malaria","volume":"25","author":"Brabin","year":"2004","journal-title":"Placenta"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(17)30340-6","article-title":"Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis","volume":"5","author":"Moore","year":"2017","journal-title":"Lancet Glob Heal"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(07)70022-1","article-title":"Malaria in pregnancy: pathogenesis and immunity","volume":"7","author":"Rogerson","year":"2007","journal-title":"Lancet Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5267.1502","article-title":"Adherence of Plasmodium falciparum to chondroitin sulfate A in the human placenta","volume":"272","author":"Fried","year":"1996","journal-title":"Science"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041579","article-title":"Evidence for the involvement of VAR2CSA in pregnancy-associated malaria","volume":"200","author":"Salanti","year":"2004","journal-title":"J Exp Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.11.6620-6623.2003","article-title":"Antibodies that inhibit Plasmodium falciparum adhesion to chondroitin sulfate A are asociated with increased birth weight and gestational age of newborns","volume":"71","author":"Duffy","year":"2003","journal-title":"Infect Immun"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00166-18","article-title":"Association of antibodies to VAR2CSA and merozoite antigens with pregnancy outcomes in women living in Yaound\u00e9, Cameroon","volume":"86","author":"Lloyd","year":"2018","journal-title":"Infect Immun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)15386-XTitle","article-title":"Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria","volume":"363","author":"Staalsoe","year":"2004","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3201\/eid2105.141626","article-title":"Protective antibodies against placental malaria and poor outcomes during pregnancy, Benin","volume":"21","author":"Tuikue Ndam","year":"2015","journal-title":"Emerg Infect Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12916-019-1467-6","article-title":"Pregnancy-specific malarial immunity and risk of malaria in pregnancy and adverse birth outcomes: A systematic review","volume":"18","author":"Cutts","year":"2020","journal-title":"BMC Med BMC Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/00013542-199307000-00001","article-title":"Avidity of IgG in serodiagnosis of infectious diseases","volume":"4","author":"Hedman","year":"1993","journal-title":"Rev Med Microbiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040049","article-title":"High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria","volume":"7","author":"Tutterrow","year":"2012","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-015-1023-6","article-title":"Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: A retrospective case-control study","volume":"14","author":"Babakhanyan","year":"2015","journal-title":"Malar J BioMed Cent"},{"key":"B15","article-title":"Le pludisme urbain a Yaound\u00e9, Cameroun. 1. Etude entomologique dans deux quartiers centraux","volume":"35","author":"Manga","year":"1992","journal-title":"Mem Soc r belge Ent"},{"key":"B16","first-page":"57","article-title":"Le paludisme urbain a Yaound\u00e9 (Cameroun) 2. Etude entomologique dans deux quartiers per urbanises","volume":"85","author":"Fondjo","year":"1992","journal-title":"Bull La Soc Pathol Exot"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00071-12","article-title":"High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission","volume":"80","author":"Tutterrow","year":"2012","journal-title":"Infect Immun"},{"key":"B18","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1186\/s12936-017-2041-3","article-title":"Statistical prediction of immunity to placental malaria based on multi-assay antibody data for malarial antigens","volume":"16","author":"Siriwardhana","year":"2017","journal-title":"Malar J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.2005.72.236","article-title":"Risk factors for placental malaria and its effect on pregnancy outcome in Yaound\u00e9, Cameroon","volume":"72","author":"Tako","year":"2005","journal-title":"Am J Trop Med Hyg"},{"key":"B20","volume-title":"Cameroon: epidemiological fact sheets on HIV\/AIDS and sexually transmitted infections \u2013 2004 update","year":"2004"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.01.040","article-title":"Full-length recombinant Plasmodium falciparum VAR2CSA binds specifically to CSPG and induces potent parasite adhesion-blocking antibodies","volume":"397","author":"Khunrae","year":"2010","journal-title":"J Mol Biol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1186\/s12936-020-03243-3","article-title":"Measuring antibody avidity to Plasmodium falciparum merozoite antigens using a multiplex immunoassay approach","volume":"19","author":"Taylor","year":"2020","journal-title":"Malar J"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00159-09","article-title":"Induction of adhesion-inhibitory antibodies against placental Plasmodium falciparum parasites by using single domains of VAR2CSA","volume":"77","author":"Nielsen","year":"2009","journal-title":"Infect Immun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.348839","article-title":"Structural and functional insight into how the Plasmodium falciparum VAR2CSA protein mediates binding to chondroitin sulfate A in placental malaria","volume":"287","author":"Clausen","year":"2012","journal-title":"J Biol Chem"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e42","DOI":"10.1371\/journal.ppat.0040042","article-title":"Structural insight into epitopes in the pregnancy-associated malaria protein VAR2CSA","author":"Andersen","year":"2008","journal-title":"PloS Pathog"},{"key":"B26","doi-asserted-by":"publisher","first-page":"996","DOI":"10.4269\/ajtmh.2010.10-0249","article-title":"Longitudinal studies of Plasmodium falciparum malaria in pregnant women living in a rural Cameroonian village with high perennial transmission","volume":"83","author":"Leke","year":"2010","journal-title":"Am J Trop Med Hyg"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00410-09","article-title":"Immunization with VAR2CSA-DBL5 recombinant protein elicits broadly cross-reactive antibodies to placental Plasmodium falciparum-infected erythrocytes","volume":"78","author":"Avril","year":"2010","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e10807","DOI":"10.1371\/journal.pone.0010807","article-title":"Using an improved phagocytosis assay to evaluate the effect of HIV on specific antibodies to pregnancy- associated malaria","volume":"5","author":"Ata\u00edde","year":"2010","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0022491","article-title":"Antibodies that induce phagocytosis of malaria infected erythrocytes: Effect of HIV infection and correlation with clinical outcomes","volume":"6","author":"Ata\u00edde","year":"2011","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1086\/599841","article-title":"Antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes are associated with protection from treatment failure and the development of anemia in pregnancy","volume":"200","author":"Feng","year":"2009","journal-title":"J Infect Dis"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13071-018-2653-7","article-title":"Evaluating antibody functional activity and strain-specificity of vaccine candidates for malaria in pregnancy using in vitro phagocytosis assays","volume":"11","author":"Hommel","year":"2018","journal-title":"Parasites Vectors Parasites Vectors"},{"key":"B32","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1475-2875-3-21","article-title":"Analysis of IgG with specificity for variant surface antigens expressed by placental Plasmodium falciparum isolates","volume":"3","author":"Khattab","year":"2004","journal-title":"Mala J"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01000-10","article-title":"Parity and placental infection affect antibody responses against Plasmodium falciparum during pregnancy","volume":"79","author":"Mayor","year":"2011","journal-title":"Infect Immun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit083","article-title":"Improved pregnancy outcomes in women exposed to malaria with high antibody levels against Plasmodium falciparum","volume":"207","author":"Mayor","year":"2013","journal-title":"J Infect Dis"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1086\/648595","article-title":"The effect of intermittent preventive treatment during pregnancy on malarial antibodies depends on HIV status and is not associated with poor delivery outcomes","volume":"201","author":"Serra-Casas","year":"2010","journal-title":"J Infect Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01365-09","article-title":"Evaluation of the antigenic diversity of placenta-binding Plasmodium falciparum variants and the antibody repertoire among pregnant women","volume":"78","author":"Hommel","year":"2010","journal-title":"Infect Immun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1086\/381186","article-title":"Antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes and adhesion inhibitory antibodies are associated with placental malaria and have overlapping and distinct targets","volume":"189","author":"Beeson","year":"2004","journal-title":"J Infect Dis"},{"key":"B38","article-title":"ISBN: 978-92-4-156572-1","year":"2019"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.610108\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T07:28:57Z","timestamp":1614324537000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.610108\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,26]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2021.610108"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.610108","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,26]]},"article-number":"610108"}}