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A matched nondivergent tandem RBD (Delta-Delta; \u0394-\u0394) served as a control. In mice, immunization elicited potent antibody responses and increased the frequency of cross-reactive B cells, recognizing Delta, Omicron, and the 2002 pandemic strain SARS-CoV RBDs. Using multicolor RBD tetramers and single-cell B cell receptor sequencing, we show that breadth arises via two distinct pathways. The divergent vaccine preferentially enriches clonally distinct cross-reactive B cells (not present within non-cross-reactive B cell pools) with low levels of somatic hypermutation, consistent with selection of germline-biased precursors. In contrast, the matched control vaccine yields cross-reactivity primarily within existing clonal lineages (clonal overlap between cross-reactive and non-cross-reactive cells) and at higher mutational burdens, consistent with affinity-maturation-driven acquisition of breadth. This work establishes a simple, modular antigen-design principle in which juxtaposing appropriately divergent antigens on a single scaffold promotes the enrichment of bnAb-prone B cells.<\/jats:p>","DOI":"10.1073\/pnas.2602574123","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T16:33:41Z","timestamp":1787762021000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Engineering antigenic breadth against SARS-CoV-2 by pairing divergent RBDs within a single mRNA immunogen"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8204-0687","authenticated-orcid":false,"given":"Isabelle","family":"Montgomerie","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02487ts63","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology Program, Malaghan Institute of Medical Research","place":["Wellington, New 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