{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:12:11Z","timestamp":1788174731392,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"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 and objectives<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      infection remains a major global health burden due to increasing drug resistance and lack of an effective vaccine. Targeting the exoerythrocytic liver stage (LS) of malaria infection offers a promising approach to achieve sterile immunity to malaria infection. Therefore, the present work investigates the immunogenic potential of two key LS malaria antigens: circumsporozoite protein of\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      (\n                      <jats:italic>Pf<\/jats:italic>\n                      CSP) and liver stage-expressed tryptophan-rich protein of\n                      <jats:italic>P. berghei<\/jats:italic>\n                      (\n                      <jats:italic>Pb<\/jats:italic>\n                      SLTRiP) formulated with a dual toll-like receptor (TLR) adjuvant combination, Poly(I:C) and R848, to evaluate the potency and durability of the elicited humoral response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      BALB\/c and C57BL\/6 mice were immunized using a multidose regimen with\n                      <jats:italic>Pf<\/jats:italic>\n                      CSP and\n                      <jats:italic>Pb<\/jats:italic>\n                      SLTRiP, either alone or in combination (Poly(I:C) and R848). Humoral immune responses were quantified 30\u201380 days post-immunization through total IgG kinetics, functional IgG isotypes (IgG1, IgG2c\/IgG2a), and antibody avidity (AI).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Coadministration of Poly(I:C) and R848 was shown to evoke greater antibody responses compared to antigen alone.\n                      <jats:italic>Pf<\/jats:italic>\n                      CSP-specific IgG titers remained detectable up to 80 days post immunization and declined gradually over time.\n                      <jats:italic>Pb<\/jats:italic>\n                      SLTRiP immunization, however, produced progressive increases in total IgG, detectable IgG2c responses, and modest changes in antibody avidity, with little non-significant difference between adjuvant regimens.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Combination of Poly(I:C) and R848 adjuvant induced detectable antibody responses against LS malaria antigens, with magnitudes generally like those obtained with single adjuvants. Limited statistical differences highlight preliminary trends warranting future investigations into predicted multi-epitope engagement and hypothesized B cell-mediated CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell cross-presentation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1705839","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T04:10:32Z","timestamp":1774843832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Poly(I:C) and R848 adjuvants elicit sizeable humoral immunity to liver stage malaria antigens"],"prefix":"10.3389","volume":"17","author":[{"given":"Nikunj","family":"Tandel","sequence":"first","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Thakkar","sequence":"additional","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Ahuja","sequence":"additional","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagrut","family":"Shah","sequence":"additional","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devangkumar D.","family":"Trivedi","sequence":"additional","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylviane","family":"Pied","sequence":"additional","affiliation":[{"name":"Center for Infection and Immunity of Lille-9 CIIL, CNRS UMR 9017-INSERM U1019, University de Lille, Institut Pasteur de Lille","place":["Lille, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agam P.","family":"Singh","sequence":"additional","affiliation":[{"name":"Infectious Disease Laboratory, National Institute of Immunology (NII)","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chirag","family":"Prajapati","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Veer Narmad South Gujarat University (VNSGU)","place":["Surat, Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeev K.","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Division of Cell Biology and Immunology, Biomedical Parasitology and Translational-immunology Lab, CSIR-Institute of Microbial Technology (IMTECH)","place":["Chandigarh, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarat K.","family":"Dalai","sequence":"additional","affiliation":[{"name":"Institute of Science, Nirma University, Ahmedabad","place":["Gujarat, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101073","DOI":"10.1016\/j.lanmic.2025.101073","article-title":"WHO world malaria report 2024","volume":"6","author":"Venkatesan","year":"2025","journal-title":"Lancet Microbe"},{"key":"B2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s41182-023-00516-w","article-title":"Malaria vaccines: the 60-year journey of hope and final success-lessons learned and future prospects","volume":"51","author":"El-Moamly","year":"2023","journal-title":"Trop Med Health"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1013431","article-title":"Emerging challenges for mosquito-borne disease control and the promise of symbiont-based transmission-blocking strategies","volume":"21","author":"Gao","year":"2025","journal-title":"PloS Pathog"},{"key":"B4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.chom.2018.06.008","article-title":"Malaria vaccines: recent advances and new horizons","volume":"24","author":"Draper","year":"2018","journal-title":"Cell Host Microbe"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e105","DOI":"10.1038\/cti.2016.60","article-title":"Protective immunity to liver-stage malaria","volume":"5","author":"Holz","year":"2016","journal-title":"Clin Trans Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nm1628","article-title":"CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes","volume":"13","author":"Chakravarty","year":"2007","journal-title":"Nat Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/j.immuni.2016.08.011","article-title":"Liver-resident memory CD8(+) T cells form a front-line defense against malaria liver-stage infection","volume":"45","author":"Fernandez-Ruiz","year":"2016","journal-title":"Immunity"},{"key":"B8","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cellimm.2017.05.001","article-title":"Frequent inoculations with radiation attenuated sporozoite is essential for inducing sterile protection that correlates with a threshold level of plasmodia liver-stage specific CD8+ T cells","volume":"317","author":"Patel","year":"2017","journal-title":"Cell Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.684116","article-title":"Identification, selection and immune assessment of liver stage CD8 T cell epitopes from plasmodium falciparum","volume":"12","author":"Tucker","year":"2021","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1111\/1348-0421.12948","article-title":"Infectious sporozoite challenge modulates radiation attenuated sporozoite vaccine-induced memory CD8(+) T cells for better survival characteristics","volume":"66","author":"Yadav","year":"2022","journal-title":"Microbiol Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/imr.13202","article-title":"Memory CD8+ T cell-mediated protection against liver-stage malaria","volume":"316","author":"Hassert","year":"2023","journal-title":"Immunol Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202451542","article-title":"Plasmodium berghei radiation-attenuated sporozoite-immunized mice require infectious sporozoite challenge to maintain protective immunity","volume":"55","author":"Patel","year":"2025","journal-title":"Eur J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2147\/RMHP.S219294","article-title":"Towards eradication of malaria: is the WHO\u2019s RTS,S\/AS01 vaccination effective enough","volume":"14","author":"Arora","year":"2021","journal-title":"Risk Manag Healthc Policy"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(23)00816-2","article-title":"The public health impact and cost-effectiveness of the R21\/Matrix-M malaria vaccine: a mathematical modelling study","volume":"24","author":"Schmit","year":"2024","journal-title":"Lancet Infect Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1004515","article-title":"Roll out and prospects of the malaria vaccine R21\/Matrix-M","volume":"22","author":"Seidlein","year":"2025","journal-title":"PloS Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"29","DOI":"10.2147\/CPAA.S513282","article-title":"Current developments in malaria vaccination: A concise review on implementation, challenges, and future directions","volume":"17","author":"Sallam","year":"2025","journal-title":"Clin Pharmacol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/vaccines4020012","article-title":"Recent advances in subunit vaccine carriers","volume":"4","author":"Vartak","year":"2016","journal-title":"Vaccines"},{"key":"B18","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/s41392-023-01557-7","article-title":"Vaccine adjuvants: mechanisms and platforms","volume":"8","author":"Zhao","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2017.09.054","article-title":"Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6months in a nonhuman primate neonate model","volume":"35","author":"Holbrook","year":"2017","journal-title":"Vaccine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002408","article-title":"Intratumoral combination therapy with poly(I:C) and resiquimod synergistically triggers tumor-associated macrophages for effective systemic antitumoral immunity","volume":"9","author":"Anfray","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-021-03109-w","article-title":"Blood DCs activated with R848 and poly(I:C) induce antigen-specific immune responses against viral and tumor-associated antigens","volume":"71","author":"H\u00e4nel","year":"2022","journal-title":"Cancer Immunol Immunother"},{"key":"B22","doi-asserted-by":"publisher","first-page":"109591","DOI":"10.1016\/j.celrep.2021.109591","article-title":"B cells promote CD8 T cell primary and memory responses to subunit vaccines","volume":"36","author":"Klarquist","year":"2021","journal-title":"Cell Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e26887","article-title":"Poly(I:C) and R848 ligands show better adjuvanticity to induce B and T cell responses against the antigen(s)","volume":"10","author":"Tandel","year":"2024","journal-title":"Heliyon"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.954936","article-title":"Role of B cells as antigen presenting cells","volume":"13","author":"Rastogi","year":"2022","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-017-0011-y","article-title":"Robust antibody and CD8(+) T-cell responses induced by P. falciparum CSP adsorbed to cationic liposomal adjuvant CAF09 confer sterilizing immunity against experimental rodent malaria infection","volume":"2","author":"Espinosa","year":"2017","journal-title":"NPJ Vaccines"},{"key":"B26","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1128\/IAI.01108-12","article-title":"Full-length Plasmodium falciparum circumsporozoite protein administered with long-chain poly(I\u00b7C) or the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable emulsion elicits potent antibody and CD4+ T cell immunity and protection in mice","volume":"81","author":"Kastenm\u00fcller","year":"2013","journal-title":"Infect Immun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.588129","article-title":"A sporozoite- and liver stage-expressed tryptophan-rich protein plays an auxiliary role in plasmodium liver stage development and is a potential vaccine candidate","volume":"290","author":"Jaijyan","year":"2015","journal-title":"J Biol Chem"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/pim.12622","article-title":"Parasite load stemming from immunization route determines the duration of liver-stage immunity","volume":"41","author":"Patel","year":"2019","journal-title":"Parasite Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/1475-2875-13-92","article-title":"Phenotypic characterization of Plasmodium berghei responsive CD8+ T cells after immunization with live sporozoites under chloroquine cover","volume":"13","author":"Brando","year":"2014","journal-title":"Malar J"},{"key":"B30","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.imlet.2022.05.002","article-title":"TLR3 and TLR7\/8 agonists improve immunization outcome in nicotine exposed mice through different mechanisms","volume":"246","author":"Nouri-Shirazi","year":"2022","journal-title":"Immunol Lett"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c10709","article-title":"Systemically administered TLR7\/8 agonist and antigen-conjugated nanogels govern immune responses against tumors","volume":"16","author":"Stickdorn","year":"2022","journal-title":"ACS Nano"},{"key":"B32","doi-asserted-by":"publisher","first-page":"W24","DOI":"10.1093\/nar\/gkx346","article-title":"BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes","volume":"45","author":"Jespersen","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"W449","DOI":"10.1093\/nar\/gkaa379","article-title":"NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data","volume":"48","author":"Reynisson","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.153.9.4134","article-title":"Elicitation of specific cytotoxic T cells by immunization with malaria soluble synthetic polypeptides","volume":"153","author":"Blum-Tirouvanziam","year":"1994","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024147","article-title":"Vaccine platforms combining circumsporozoite protein and potent immune modulators, rEA or EAT-2, paradoxically result in opposing immune responses","volume":"6","author":"Schuldt","year":"2011"},{"key":"B36","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1002\/iid3.283","article-title":"Identification and characterization of protective CD8(+) T-epitopes in a malaria vaccine candidate SLTRiP","volume":"8","author":"Quadiri","year":"2020","journal-title":"Immun Inflammation Dis"},{"key":"B37","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":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(98)00015-5","article-title":"The need for IgG2c specific antiserum when isotyping antibodies from C57BL\/6 and NOD mice","volume":"212","author":"Martin","year":"1998","journal-title":"J Immunol Methods"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/01.shk.0000142249.08135.e9","article-title":"Innate immune response in Th1- and Th2-dominant mouse strains","volume":"22","author":"Watanabe","year":"2004","journal-title":"Shock"},{"key":"B40","doi-asserted-by":"publisher","first-page":"107944","DOI":"10.1016\/j.exppara.2020.107944","article-title":"Measuring of IgG2c isotype instead of IgG2a in immunized C57BL\/6 mice with Plasmodium vivax TRAP as a subunit vaccine candidate in order to correct interpretation of Th1 versus Th2 immune response","volume":"216","author":"Nazeri","year":"2020","journal-title":"Exp Parasitol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/science.3107127","article-title":"Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production","volume":"236","author":"Snapper","year":"1987","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.626199","article-title":"CXCR5(+)CD8(+) T cells shape antibody responses in vivo following protein immunisation and peripheral viral infection","volume":"12","author":"Tyllis","year":"2021","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2019.1669415","article-title":"RTS,S\/AS01 vaccine (Mosquirix\u2122): an overview","volume":"16","author":"Laurens","year":"2020","journal-title":"Hum Vaccin Immunother"},{"key":"B44","doi-asserted-by":"publisher","first-page":"2189885","DOI":"10.1080\/21645515.2023.2189885","article-title":"The Matrix-M\u2122 adjuvant: A critical component of vaccines for the 21(st) century","volume":"19","author":"Stertman","year":"2023","journal-title":"Hum Vaccin Immunother"},{"key":"B45","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s40794-024-00222-3","article-title":"A landscape review of malaria vaccine candidates in the pipeline","volume":"10","author":"Tajudeen","year":"2024","journal-title":"Trop Dis Travel Med Vaccines"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adw0415","article-title":"B cells targeting parasites capture spatially linked antigens to secure T cell help","volume":"10","author":"Gao","year":"2025","journal-title":"Sci Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01077","article-title":"Co-delivery of dual toll-like receptor agonists and antigen in poly(Lactic-co-glycolic) acid\/polyethylenimine cationic hybrid nanoparticles promote efficient in vivo immune responses","volume":"8","author":"Ebrahimian","year":"2017","journal-title":"Front Immunol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1186\/1475-2875-13-386","article-title":"Humanized HLA-DR4.RagKO.IL2R\u03b3cKO.NOD (DRAG) mice sustain the complex vertebrate life cycle of Plasmodium falciparum malaria","volume":"13","author":"Wijayalath","year":"2014","journal-title":"Malar J"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92587","article-title":"Assessing drug efficacy against Plasmodium falciparum liver stages in vivo","volume":"3","author":"Flannery","year":"2018","journal-title":"JCI Insight"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3390\/microorganisms11092209","article-title":"Using cryopreserved plasmodium falciparum sporozoites in a humanized mouse model to study early malaria infection processes and test prophylactic treatments","volume":"11","author":"Jim\u00e9nez-D\u00edaz","year":"2023","journal-title":"Microorganisms"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1705839\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T04:10:36Z","timestamp":1774843836000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1705839\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2026.1705839"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1705839","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"article-number":"1705839"}}