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Here, we use electron microscopy\u2013based polyclonal epitope mapping (EMPEM) to elucidate how repeated immunization with HIV Env SOSIP immunogens results in the generation of Ab2\u03b1 anti-idiotypic antibodies in rabbits and rhesus macaques. We present the structures of six anti\u2013immune complex antibodies and find that they target idiotopes composed of framework regions of antibodies bound to Env. Examination of cryo\u2013electron microscopy density enabled prediction of sequences for an anti\u2013immune complex antibody, the paratope of which is enriched with aromatic amino acids. This work sheds light on current vaccine development efforts for HIV, as well as for other pathogens in which repeated exposure to antigen is required.<\/jats:p>","DOI":"10.1126\/sciimmunol.adp5218","type":"journal-article","created":{"date-parts":[[2025,1,17]],"date-time":"2025-01-17T13:59:06Z","timestamp":1737122346000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["Anti\u2013immune complex antibodies are elicited during repeated immunization with HIV Env immunogens"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3166-6548","authenticated-orcid":true,"given":"Sharidan","family":"Brown","sequence":"first","affiliation":[{"name":"Department of Integrative, Structural and Computational Biology, Scripps Research, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandar","family":"Antanasijevic","sequence":"additional","affiliation":[{"name":"Global Health Institute, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, Lausanne, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2020-2991","authenticated-orcid":true,"given":"Leigh M.","family":"Sewall","sequence":"additional","affiliation":[{"name":"Department of Integrative, Structural and Computational Biology, Scripps Research, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5915-7016","authenticated-orcid":true,"given":"Daniel Montiel","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Integrative, Structural and Computational Biology, Scripps Research, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-0850","authenticated-orcid":true,"given":"James","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Integrative, Structural and Computational Biology, Scripps Research, La Jolla, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-7739","authenticated-orcid":true,"given":"Philip J. 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