{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:54:38Z","timestamp":1791428078005,"version":"4.3.3"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"780","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,1,8]]},"abstract":"<jats:p>Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.<\/jats:p>","DOI":"10.1126\/scitranslmed.adr2218","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T13:58:20Z","timestamp":1736344700000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-8358","authenticated-orcid":true,"given":"Olivia M.","family":"Swanson","sequence":"first","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0518-6484","authenticated-orcid":true,"given":"Qianyi E.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-7345","authenticated-orcid":true,"given":"Elizabeth","family":"Van Itallie","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4350-3380","authenticated-orcid":true,"given":"Ming","family":"Tian","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alecia R.","family":"Brown","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8793-1662","authenticated-orcid":true,"given":"Caitlin","family":"Harris","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyway Brenda","family":"Kapingidza","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5834-8729","authenticated-orcid":true,"given":"Brianna","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9804-6796","authenticated-orcid":true,"given":"Lena M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8976-6827","authenticated-orcid":true,"given":"Sravani","family":"Venkatayogi","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5984-5978","authenticated-orcid":true,"given":"Kenneth","family":"Cronin","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"McKenzie","family":"Frazier","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6259-7610","authenticated-orcid":true,"given":"Rob","family":"Parks","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Bar","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuancang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua S.","family":"Martin Beem","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwei-Ling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9303-6963","authenticated-orcid":true,"given":"Jillian","family":"Davis","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0778-4499","authenticated-orcid":true,"given":"Kelly","family":"McGovern","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Newman","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5988-6729","authenticated-orcid":true,"given":"Derek","family":"Cain","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0941-0703","authenticated-orcid":true,"given":"S. Munir","family":"Alam","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-9618","authenticated-orcid":true,"given":"Kevin","family":"Wiehe","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7399-7954","authenticated-orcid":true,"given":"Kevin O.","family":"Saunders","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Microbiology and Molecular Genetics, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0089-277X","authenticated-orcid":true,"given":"Priyamvada","family":"Acharya","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Alt","sequence":"additional","affiliation":[{"name":"Boston Children\u2019s Hospital, Harvard Medical School and HHMI, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-9023","authenticated-orcid":true,"given":"Barton F.","family":"Haynes","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Integrative Immunology, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7198-1162","authenticated-orcid":true,"given":"Mihai L.","family":"Azoitei","sequence":"additional","affiliation":[{"name":"Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA."},{"name":"Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1178746"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10373"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05045-11"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1187659"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11544"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12053"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2021.09.015"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00753-w"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0103-6"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2197"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax4380"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.09.003"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101003"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.12.002"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay7199"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.add6502"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-024-00811-5"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.04.033"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12075"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.04.018"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad398"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1217207109"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal2144"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03632-y"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003342"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.06.003"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat0381"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008026"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899243"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.08.016"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.029"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109561"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aai7514"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38108-1"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024109"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011401"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.012"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc0870"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02832-w"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0879-y"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2024.04.006"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005815"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9195"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adj8321"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.030"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.94"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzq002"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4169"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3943"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1107\/S2059798319011471"},{"key":"e_1_3_2_53_2","unstructured":"Schr\u00f6dinger The PyMOL Molecular Graphics System version 3.0."},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.10.4528"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1608649113"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1921996117"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.142.12.4475"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/322843a0"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/2.6.579"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/352532a0"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.4.999"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.2.541"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12505"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00170"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004409"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-170-3_26"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adr2218","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T13:58:34Z","timestamp":1736344714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adr2218"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,8]]},"references-count":65,"journal-issue":{"issue":"780","published-print":{"date-parts":[[2025,1,8]]}},"alternative-id":["10.1126\/scitranslmed.adr2218"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adr2218","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,8]]},"assertion":[{"value":"2024-06-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-24","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr2218"}}