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To this aim, germline-targeting immunogens have been developed to activate bNAb precursors and initiate the induction of bNAbs. While most preclinical germline-targeting HIV-1 vaccine candidates only include a single bNAb precursor epitope, an effective HIV-1 vaccine will likely require bNAbs that target multiple epitopes on Env. Here, we report a newly designed germline-targeting Env SOSIP trimer, named 3nv.2, that presents three bNAb epitopes on Env: the CD4bs, V3, and V2 epitopes. 3nv.2 forms a stable trimeric Env and binds to bNAb precursors from each of the desired epitopes. Immunization experiments in rhesus macaques and mice demonstrate 3nv.2 elicits the combined effects of its parent immunogens. Our results provide proof of concept for using a germline-targeting immunogen presenting three or more bNAb epitopes and a framework to develop improved next-generation HIV-1 vaccine candidates.<\/jats:p>","DOI":"10.1084\/jem.20250693","type":"journal-article","created":{"date-parts":[[2025,7,11]],"date-time":"2025-07-11T06:20:48Z","timestamp":1752214848000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Design and characterization of HIV-1 vaccine candidates to elicit antibodies targeting multiple epitopes"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1957-2821","authenticated-orcid":true,"given":"Harry B.","family":"Gristick","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05dxps055","id-type":"ROR","asserted-by":"publisher"}],"name":"California Institute of Technology 1 Division of Biology and Biological Engineering, , Pasadena, 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