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To determine its effects on humoral immunity, we conducted a proteomic analysis of polyclonal IgG antibodies directed against the NANP tetrapeptide of the circumsporozoite protein (CSP), which comprises the vaccine\u2019s core immunogen. In 10 malaria-na\u00efve adult volunteers, R21\/Matrix-M induced polarized IgG anti-NANP repertoires, heavily skewed for IGHV3-30\/3-33 genes bearing minimal somatic mutation, which remained static in composition following a controlled human malaria infection challenge. Notably, these vaccine-generated antibodies cross-reacted with another protective CSP epitope, the N-terminal junction region, despite its absence from the R21 construct. NANP-specific IGHV3-30\/3-33 mAbs mined from polyclonal IgG repertoires blocked sporozoite invasion in vitro and prevented parasitemia in vivo. Overall, R21\/Matrix-M elicits polarized, minimally mutated, polyclonal IgG responses that can target multiple protective CSP epitopes, offering molecular insight into the serological basis for its demonstrated efficacy against P. falciparum malaria.<\/jats:p>","DOI":"10.1084\/jem.20241908","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T02:20:46Z","timestamp":1750731646000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Repertoire, function, and structure of serological antibodies induced by the R21\/Matrix-M malaria vaccine"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8575-3535","authenticated-orcid":true,"given":"Jonathan R.","family":"McDaniel","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-1939","authenticated-orcid":true,"given":"William N.","family":"Voss","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2058-4045","authenticated-orcid":true,"given":"Georgina","family":"Bowyer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"The Jenner Institute, University of Oxford 2 , Oxford,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9601-5068","authenticated-orcid":true,"given":"Scott A.","family":"Rush","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7958-6961","authenticated-orcid":true,"given":"Alexandra J.","family":"Spencer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"The Jenner Institute, University of Oxford 2 , Oxford,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3614-0032","authenticated-orcid":true,"given":"Duncan","family":"Bellamy","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"The Jenner Institute, University of Oxford 2 , Oxford,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4288-2892","authenticated-orcid":true,"given":"Marta","family":"Ulaszewska","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/052gg0110","id-type":"ROR","asserted-by":"publisher"}],"name":"The Jenner Institute, University of Oxford 2 , Oxford,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9989-1337","authenticated-orcid":true,"given":"Jule","family":"Goike","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"The University of Texas at Austin 1 , Austin, TX,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-1224","authenticated-orcid":true,"given":"Scott","family":"Gregory","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ycvrx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Vaccine Innovation and Access, PATH 3 , Washington, DC,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8860-0419","authenticated-orcid":true,"given":"C. 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