{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:08:39Z","timestamp":1775538519067,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Advancing the development of highly efficacious and long-lasting malaria vaccines is hampered by incomplete knowledge of protective immune mechanisms and an absence of established correlates of immunity. Antibody avidity is frequently evaluated as an indicator of a high-quality or protective antibody response to vaccination. However, the importance of avidity in vaccine-induced immunity to malaria remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods\/approach<\/jats:title>\n                    <jats:p>\n                      We investigated the association between antibody avidity, Fc-mediated functional activities, and antibody longevity in two different\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      vaccine trials; a phase 1 trial of merozoite surface protein 2 in malaria-na\u00efve adults, and a phase 2b trial of the RTS,S vaccine in African children.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In both trials, we found that the magnitude of IgG induced by vaccination correlated strongly with antibody avidity indicating the two vaccine immunogenicity outcomes are related. Antibody avidity was not a major determinant of Fc-mediated functional activity, including complement fixation, binding of Fc\u03b3-receptors, or opsonic phagocytosis. In analysis models, IgG magnitude was a stronger determinant of function than IgG avidity. Although avidity positively correlated with antibody functional activities, this was largely due to the confounding effect of the correlation between IgG magnitude and Fc functional activity. Additionally, we found that antibody avidity showed only a weak and antigen-specific association with antibody longevity. Similar findings in the two vaccine trials, which differed by vaccine antigen, adjuvant, and age group, suggests that these observations are likely to be generalisable and not specific to a vaccine type.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Antibody avidity was not a better predictor of Fc-mediated functional activity than antibody magnitude and avidity was not a strong correlate of antibody longevity. These findings suggest that vaccine approaches that focus on increasing antibody avidity\n                      <jats:italic>per se<\/jats:italic>\n                      may not be sufficient to achieve more efficacious or long-lasting vaccines.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1808822","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T04:26:03Z","timestamp":1775535963000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Relationship between antibody avidity, Fc-mediated functional activity and longevity of malaria vaccine responses in clinical trials"],"prefix":"10.3389","volume":"17","author":[{"given":"Jessica L","family":"Horton","sequence":"first","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine and Department of Infectious Diseases University of Melbourne","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo-Anne","family":"Chan","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine and Department of Infectious Diseases University of Melbourne","place":["Melbourne, VIC, Australia"]},{"name":"School of Translational Medicine, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liriye","family":"Kurtovic","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine and Department of Infectious Diseases University of Melbourne","place":["Melbourne, VIC, Australia"]},{"name":"School of Translational Medicine, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Reiling","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"School of Translational Medicine, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaoqian","family":"Feng","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"National Vaccine Innovation Platform, NHC Key Laboratory of Antibody Technique, Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology, Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina E M","family":"Persson","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Lund University","place":["Lund, Sweden"]},{"name":"Clinical Chemistry and Pharmacology, Laboratory Medicine, Sk\u00e5ne University Hospital","place":["Lund, Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jahit","family":"Sacarlal","sequence":"additional","affiliation":[{"name":"Centro de Investigaco em Saude de Manhica","place":["Maputo, Mozambique"]},{"name":"Faculdade de Medicina, Universidade Eduardo Mondlane (UEM)","place":["Maputo, Mozambique"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin F","family":"Anders","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Genetics, La Trobe University","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James S","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Services, Doherty Institute, University of Melbourne","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlota","family":"Doba\u00f1o","sequence":"additional","affiliation":[{"name":"ISGlobal, Hospital Cl\u0131nic Universitat de Barcelona","place":["Barcelona, Catalonia, Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle J","family":"Boyle","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine and Department of Infectious Diseases University of Melbourne","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James G","family":"Beeson","sequence":"additional","affiliation":[{"name":"Burnet Institute","place":["Melbourne, VIC, Australia"]},{"name":"Department of Medicine and Department of Infectious Diseases University of Melbourne","place":["Melbourne, VIC, Australia"]},{"name":"School of Translational Medicine, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"B1","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":"B2","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(15)60721-8","article-title":"Efficacy and safety of RTS,S\/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial","volume":"386","year":"2015","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00239-X","article-title":"Immunogenicity of the RTS,S\/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial","volume":"15","author":"White","year":"2015","journal-title":"Lancet Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)02511-4","article-title":"Safety and efficacy of malaria vaccine candidate R21\/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial","volume":"403","author":"Datoo","year":"2024","journal-title":"Lancet"},{"key":"B5","unstructured":"World malaria report 2025\n          \n          \n          \n          2025"},{"key":"B6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s43856-021-00030-2","article-title":"Recent clinical trials inform the future for malaria vaccines","volume":"1","author":"Kurtovic","year":"2021","journal-title":"Commun Med (Lond)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(24)00752-7","article-title":"Safety and efficacy of the blood-stage malaria vaccine RH5.1\/Matrix-M in Burkina Faso: interim results of a double-blind, randomised, controlled, phase 2b trial in children","volume":"25","author":"Natama","year":"2024","journal-title":"Lancet Infect Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/14760584.2021.1981864","article-title":"Multi-functional antibody profiling for malaria vaccine development and evaluation","volume":"20","author":"Opi","year":"2021","journal-title":"Expert Rev Vaccines"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/s2666-5247(24)00130-7","article-title":"Antibody mechanisms of protection against malaria in RTS, S-vaccinated children: a post-hoc serological analysis of phase 2 trial","volume":"5","author":"Kurtovic","year":"2024","journal-title":"Lancet Microbe"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2011.07.007","article-title":"Important parameters for evaluation of antibody avidity by immunosorbent assay","volume":"418","author":"Dimitrov","year":"2011","journal-title":"Anal Biochem"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1038\/s41467-019-10195-z","article-title":"Concentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S\/AS01E malaria vaccine efficacy","volume":"10","author":"Doba\u00f1o","year":"2019","journal-title":"Nat Commun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s12936-015-0605-7","article-title":"The effect of immunization schedule with the malaria vaccine candidate RTS,S\/AS01E on protective efficacy and anti-circumsporozoite protein antibody avidity in African infants","volume":"14","author":"Ajua","year":"2015","journal-title":"Malar J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.012","article-title":"Human Antibodies Fix Complement to Inhibit Plasmodium falciparum Invasion of Erythrocytes and Are Associated with Protection against Malaria","volume":"42","author":"Boyle","year":"2015","journal-title":"Immunity"},{"key":"B14","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s12916-018-1054-2","article-title":"Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children","volume":"16","author":"Kurtovic","year":"2018","journal-title":"BMC Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1038\/s41467-021-21998-4","article-title":"Mechanisms and targets of Fc\u03b3-receptor mediated immunity to malaria sporozoites","volume":"12","author":"Feng","year":"2021","journal-title":"Nat Commun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-12-108","article-title":"Opsonic phagocytosis of Plasmodium falciparum merozoites: mechanism in human immunity and a correlate of protection against malaria","volume":"12","author":"Osier","year":"2014","journal-title":"BMC Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051692","article-title":"Opsonising antibodies to P. falciparum merozoites associated with immunity to clinical malaria","volume":"8","author":"Hill","year":"2013","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abn5993","article-title":"Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria","volume":"15","author":"Odera","year":"2023","journal-title":"Sci Transl Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa144","article-title":"Multifunctional antibodies are induced by the RTS, S malaria vaccine and associated with protection in a phase 1\/2a trial","volume":"224","author":"Kurtovic","year":"2021","journal-title":"J Infect Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb4757","article-title":"Mapping functional humoral correlates of protection against malaria challenge following RTS,S\/AS01 vaccination","volume":"12","author":"Suscovich","year":"2020","journal-title":"Sci Transl Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.coi.2017.03.006","article-title":"Plasma cell and memory B cell differentiation from the germinal center","volume":"45","author":"Suan","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02138","article-title":"Factors affecting early antibody secreting cell maturation into long-lived plasma cells","volume":"10","author":"Nguyen","year":"2019","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo6646","article-title":"The RTS,S malaria vaccine: Current impact and foundation for the future","volume":"14","author":"Beeson","year":"2022","journal-title":"Sci Transl Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)17223-1","article-title":"Efficacy of the RTS,S\/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial","volume":"364","author":"Alonso","year":"2004","journal-title":"Lancet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024413","article-title":"A phase 1 trial of MSP2-C1, a blood-stage malaria vaccine containing 2 isoforms of MSP2 formulated with montanide\u00ae ISA 720","volume":"6","author":"McCarthy","year":"2011","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","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":"Genton","year":"2002","journal-title":"J Infect Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiv224","article-title":"Plasmodium falciparum protein microarray antibody profiles correlate with protection from symptomatic malaria in Kenya","volume":"212","author":"Dent","year":"2015","journal-title":"J Infect Dis"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit556","article-title":"Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria","volume":"57","author":"Rono","year":"2013","journal-title":"Clin Infect Dis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1186\/s12916-022-02466-2","article-title":"Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children","volume":"20","author":"Feng","year":"2022","journal-title":"BMC Med"},{"key":"B30","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/s41467-019-08528-z","article-title":"Targets of complement-fixing antibodies in protective immunity against malaria in children","volume":"10","author":"Reiling","year":"2019","journal-title":"Nat Commun"},{"key":"B31","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s43856-024-00686-6","article-title":"Induction of Fc-dependent functional antibodies against different variants of SARS-CoV-2 varies by vaccine type and prior infection","volume":"4","author":"Harris","year":"2024","journal-title":"Commun Med (Lond)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/infdis\/jiy170","article-title":"Human immunization with a polymorphic malaria vaccine candidate induced antibodies to conserved epitopes that promote functional antibodies to multiple parasite strains","volume":"218","author":"Feng","year":"2018","journal-title":"J Infect Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae259","article-title":"Declining antibody affinity over time after human vaccination with a Plasmodium falciparum merozoite vaccine candidate","volume":"230","author":"Persson","year":"2024","journal-title":"J Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0032242","article-title":"High affinity antibodies to Plasmodium falciparum merozoite antigens are associated with protection from malaria","volume":"7","author":"Reddy","year":"2012","journal-title":"PLoS One"},{"key":"B35","volume-title":"RStudio: integrated development for R","year":"2020"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800323","article-title":"Qualified biolayer interferometry avidity measurements distinguish the heterogeneity of antibody interactions with plasmodium falciparum circumsporozoite protein antigens","volume":"201","author":"Dennison","year":"2018","journal-title":"J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1248943","article-title":"Complement is activated by IgG hexamers assembled at the cell surface","volume":"343","author":"Diebolder","year":"2014","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00520","article-title":"IgG subclasses and allotypes: from structure to effector functions","volume":"5","author":"Vidarsson","year":"2014","journal-title":"Front Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"9026","DOI":"10.1038\/s41598-018-27361-w","article-title":"Factors influencing the induction of high affinity antibodies to Plasmodium falciparum merozoite antigens and how affinity changes over time","volume":"8","author":"Tijani","year":"2018","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1111\/j.1365-3024.2009.01193.x","article-title":"Boosting antibody responses to Plasmodium falciparum merozoite antigens in children with highly seasonal exposure to infection","volume":"32","author":"Akpogheneta","year":"2010","journal-title":"J Parasite Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1056\/NEJMoa2203067","article-title":"Low-dose subcutaneous or intravenous monoclonal antibody to prevent malaria","volume":"387","author":"Wu","year":"2022","journal-title":"N Engl J Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02659-z","article-title":"A candidate antibody drug for prevention of malaria","volume":"30","author":"Williams","year":"2024","journal-title":"Nat Med"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/femsre\/fuw001","article-title":"Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria","volume":"40","author":"Beeson","year":"2016","journal-title":"FEMS Microbiol Rev"},{"key":"B44","unstructured":"Investigating protective mechanisms of anti-sporozoite vaccines\n          \n          \n            \n              Bellamy\n              DG\n            \n          \n          United Kingdom\n          Oxford University\n          \n          2023"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01787","article-title":"Remembrance of things past: long-term B cell memory after infection and vaccination","volume":"10","author":"Palm","year":"2019","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00665-12","article-title":"Antigenic characterization of an intrinsically unstructured protein, Plasmodium falciparum merozoite surface protein 2","volume":"80","author":"Adda","year":"2012","journal-title":"Infect Immun"},{"key":"B47","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/s12866-015-0461-1","article-title":"Differences in affinity of monoclonal and naturally acquired polyclonal antibodies against Plasmodium falciparum merozoite antigens","volume":"15","author":"Reddy","year":"2015","journal-title":"BMC Microbiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1808822\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T04:26:06Z","timestamp":1775535966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1808822\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,7]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2026.1808822"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1808822","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,7]]},"article-number":"1808822"}}