{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T18:05:40Z","timestamp":1781028340970,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014243","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000}}],"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gates Foundation","award":["INV-004923, INV-056202"],"award-info":[{"award-number":["INV-004923, INV-056202"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Monoclonal antibodies (mAbs) targeting the\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    circumsporozoite protein (PfCSP) have demonstrated substantial promise in preventing malaria infection and disease. PfCSP is characterized by a central region composed of repetitive NANP motifs, which serve as major targets for protective antibodies. Several potent mAbs targeting this region exhibit homotypic Fab-Fab interactions, which enhance antigen binding and contribute to their neutralization potency. Among these, mAb 399, encoded by the\n                    <jats:italic>IGHV3-49\/IGKV2D-29<\/jats:italic>\n                    (V\n                    <jats:sub>H<\/jats:sub>\n                    3-49\/V\n                    <jats:sub>K<\/jats:sub>\n                    2D-29\n                    <jats:italic>)<\/jats:italic>\n                    germline lineages, forms head-to-head inter-Fab contacts mediated primarily by germline-encoded residues. Here, we determined X-ray and cryo-EM structures of two additional Fabs, derived from the same germline lineages, 7160 and 7118, in their unliganded forms and with PfCSP-derived peptides or recombinant shortened CSP. Both Fabs bound NANP\n                    <jats:sub>6<\/jats:sub>\n                    repeats with high affinity (K\n                    <jats:sub>D<\/jats:sub>\n                    6\u201310 nM). Fab 7160 formed germline-encoded inter-Fab homotypic interactions resembling Fab 399, indicating a conserved and preconfigured mode of antigen recognition. In contrast, Fab 7118 does not form homotypic contacts and adopts a distinct binding mode, which precludes inter-Fab interactions. These findings highlight the structural versatility of V\n                    <jats:sub>H<\/jats:sub>\n                    3-49\/V\n                    <jats:sub>K<\/jats:sub>\n                    2D-29-derived antibodies and demonstrate that their CDR loop variations can modulate antibody conformation, homotypic Fab-Fab interactions, and epitope engagement. Our study further defines this class of germline-encoded anti-CSP antibodies and provides mechanistic insights into how they achieve high-avidity binding and protective immunity either through or independent of pre-configured Fab-Fab interactions with important implications for germline-targeting malaria vaccine design.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014243","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:46:46Z","timestamp":1780508806000},"page":"e1014243","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural basis for conserved and distinct antigen recognition by a lineage of malaria-protective 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E.","family":"Gonz\u00e1lez-P\u00e1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Re\u2019em","family":"Moskovitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6469-2419","authenticated-orcid":true,"given":"Ian A.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"ppat.1014243.ref001","first-page":"104366","article-title":"Increasing challenges of malaria control in sub-Saharan Africa: Priorities for public health research and policymakers","volume":"81","author":"HJ Oladipo","year":"2022","journal-title":"Ann Med Surg 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Flores-Garcia","year":"2021","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1014243.ref018","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1056\/NEJMoa2034031","article-title":"A monoclonal antibody for malaria prevention","volume":"385","author":"MR Gaudinski","year":"2021","journal-title":"N Engl J Med"},{"issue":"10","key":"ppat.1014243.ref019","doi-asserted-by":"crossref","first-page":"100786","DOI":"10.1016\/j.xcrm.2022.100786","article-title":"Accelerated development of malaria monoclonal antibodies","volume":"3","author":"N Nekkab","year":"2022","journal-title":"Cell Rep Med"},{"issue":"1","key":"ppat.1014243.ref020","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/s41591-023-02659-z","article-title":"A candidate antibody drug for prevention of malaria","volume":"30","author":"KL Williams","year":"2024","journal-title":"Nat 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